Is Chronic Cerebrospinal Venous Insufficiency Implicated in the Pathogenesis of MS?
By Jai S. Perumal, MD, Assistant Professor of Neurology, Weill Cornell Medical College. Dr. Perumal is a consultant for Biogen Idec and Genzyme, and is on the speakers bureau for Teva and Biogen Idec.
Synopsis: In this case-control study, the authors report that there is no difference in the prevalence of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis vs non-multiple sclerosis participants.
Source: Barreto AD, et al. Chronic cerebrospinal venous insufficiency: Case-control neurosonography results. Ann Neurol 2012 Dec 13; DOI: 10.1002/ana.23839 [Epub ahead of print].
Multiple sclerosis (ms) is a chronic inflammatory demyelinating disease of the central nervous system. The exact etiology triggering the disease has not been elucidated. In a study published in 2009, Zamboni et al put forth the hypothesis that chronic cerebrospinal venous outflow impairment was a potential cause for the pathogenesis of MS and they reported that patients benefit from procedures to correct this obstruction.1 They defined criteria for diagnosis of what was termed "chronic cerebrospinal venous insufficiency or CCSVI." In the wake of this report, widespread dissemination through social networks and websites on the Internet triggered tremendous interest among MS patients. Numerous MS patients sought and underwent diagnostic procedures for the detection of CCSVI, and many of them went on to have endovascular corrective procedures. These surgical interventions have not been without harmful effects, including death from intracranial hemorrhage. In light of the interest generated by the hypothesis that CCSVI was the underlying cause of MS, and endovascular procedures to correct CCSVI were touted as a cure for MS, several independent studies were undertaken to investigate this hypothesis. The present study examines this hypothesis.
In this single-center, prospective, case-control study, 276 subjects participated, including 206 MS patients and 70 non-MS participants, including healthy volunteers and patients with other neurologic diseases. A certified neurosonologist who was blinded to the diagnosis performed the sonography tests. Extracranial and intracranial vessels were imaged. They included the internal jugular and vertebral veins and the deep cerebral veins. After acquisition of the images and flow velocity data, it was analyzed in a blinded manner without prior knowledge of the study subjects' diagnosis or any other information that could potentially bias the assessment. The mean age of the MS patients was 48.3 ± 9.9 years, while that of the non-MS participants was 44.3 ± 11.8 years (P < 0.007). Among MS patients, the mean disease duration from onset of symptoms was 13.7 ± 10 years, and the mean Expanded Disability Status Scale was 2.6 ± 2.0.
The participants were assessed to determine if they met the criteria for CCSVI and if there was a specific pattern seen in patients with MS. According to the diagnostic criteria proposed by Zamboni, patients need to meet at least two of five criteria to have a diagnosis of CCSVI. The five diagnostic criteria were based on extracranial reflux, intracranial reflux, B-mode jugular stenosis, detection of flow by Doppler in jugular and vertebral veins, and upright vs supine cross-sectional area in the jugular veins, respectively. In the present study, 82/276 (29.7%) subjects fulfilled at least one of the Zamboni criteria. There was no difference in the proportion of patients who met the criteria in either group, MS patients vs non-MS participants. There was also no statistically significant difference between MS (3.88%) and non-MS (7.14%) subjects who met at least two criteria (P = 0.266). The proportion of subjects with 0, 1, or 2 criteria did not differ significantly across the groups. The authors concluded that there was no difference in the incidence of venous outflow patterns among MS and non-MS subjects, and the study did not demonstrate any association between CCSVI and MS.
CCSVI has received immense attention as a plausible cause for MS, and despite the lack of proven efficacy, numerous patients have undergone endovascular procedures to correct CCSVI. Since the publication of Zamboni's initial reports, multiple centers have investigated a potential association between CCSVI and MS, and some centers have even conducted clinical trials evaluating outcomes after corrective procedures for CCSVI in patients with MS. A tremendous amount of resources have been spent testing this hypothesis. None of these studies have demonstrated a causative association or therapeutic benefit from surgical interventions. The present study adds to the overwhelming evidence that CCSVI is not implicated in the pathogenesis of MS. Our experience with this hypothesis has highlighted the need for the MS community to approach theories, without clear scientific basis, with great caution and deter patients from undergoing often expensive and potentially hazardous procedures without any proven benefit.
1. Zamboni P, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80:392-399.