Systematic reviews of the evidence regarding chronic cerebral spinal venous insufficiency (CCSVI) and multiple sclerosis - Summary of Second Report for CIHR Expert Panel, November 21, 2011

Andreas Laupacis, MD, MSc1,2
Erin Lillie MSc1
Andrew Dueck, MD, MSc2,3
Richard Aviv, MBChB, FRCR1,4
Sharon Straus, MD, MSc1,2
Laure Perrier, Med, MLIS1,5
Jodie Burton, MD, MSc6
Kevin Thorpe, MMath1,7
Thomas Feasby, MD8
Julian Spears1,2

1. Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto
2. Faculty of Medicine, University of Toronto
3. Schulich Heart Centre, Sunnybrook Health Sciences Centre, Toronto
4. Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto
5. Office of Continuing Education and Professional Development, Faculty of Medicine, University of Toronto
6. Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary
7. Dalla Lana School of Public Health, University of Toronto
8. Faculty of Medicine, University of Calgary

Funding for this study was provided by the Canadian Institutes of Health Research.

Address correspondence to Dr. Andreas Laupacis,
Li Ka Shing Knowledge Institute, St. Michael's Hospital,
30 Bond Street, Toronto, Ontario, Canada
laupacisa@smh.ca

Executive Summary
Background
Zamboni has proposed that multiple sclerosis (MS) is caused by abnormalities in the anatomy and flow of the cerebral veins, which he has called chronic cerebrospinal venous insufficiency (CCSVI). This systematic review is an update of a systematic review initially presented to the Canadian Institutes of Health Research in June 2011, which reviewed the evidence regarding the association between venous abnormalities and MS, and the benefits and harms of endovascular treatment for CCSVI in patients with MS.
Original review

Methods
Studies assessing ultrasound and magnetic resonance venography (MRV) were given priority if they compared MS patients with patients without MS [either healthy controls (HC) or patients with other neurological diseases (OND)]. Only randomized trials were thought to provide good evidence about the benefits of endovascular treatment for MS; therefore these studies were given priority. To assess the harms of endovascular treatment, we gave priority to observational studies of >10 patients. An extensive literature search of peer-reviewed publications, with no language restrictions, was undertaken to identify eligible studies. Studies using ultrasound were statistically combined using a random effects model.

Results
Diagnosis of CCSVI with ultrasonography:
Nine studies compared the frequency of CCSVI diagnosed with ultrasound in MS patients with HC, and 5 studies compared MS patients with OND. CCSVI was diagnosed more frequently in patients with MS than in HC [odds ratio (OR) 12.8, 95% CI 2.8-59.1], but there was extensive heterogeneity. There continued to be a statistically significant association in the most conservative analysis, which involved removing Zamboni's initial study and adding a study in which no CCSVI was found in any patient (OR 4.0, 95% CI 1.4-11.0). The 5 studies that compared MS patients and OND patients found a higher frequency of CCSVI in MS patients, but this finding was not statistically significant (OR 32.5, 95% CI 0.6-1776.0); removal of Zamboni's study and adding a study in which no CCSVI was seen in any patient resulted in an OR of 2.4 (95% CI: 0.8-7.9) None of the studies using ultrasound reported the success of blinding of the technicians or radiologists.

A study of 710 MS patients in six centers found a large variation in the frequency with which the individual CCSVI criteria were positive, despite all centers being trained by Zamboni. This suggests the need for further standardization of the technique and/or interpretation of ultrasonography to diagnose CCSVI.

Magnetic Resonance Venography (MRV)
Only 3 small studies evaluated MRV findings in patients with MS and HC, and they found no statistically significant differences.

Contrast venography: One study of CV in 42 patients with MS found that 1/11 (9%) of patients with clinically isolated syndrome had extracranial venous stenosis, compared to 6/18 (33%) of patients with early relapsing remitting MS and 11/13 (85%) of patients with long-standing MS.

Endovascular treatment for CCSVI
One pseudo randomized trial of 15 patients comparing immediate with delayed endovascular treatment has been published – the poor study design and small number of patients means that the impact of this intervention upon the symptoms and signs of MS cannot be reliably assessed. Six studies reported peri-procedure complications of endovascular therapy in a total of 1148 patients. There were no deaths, and serious peri-procedure side-effects occurred in <2% of patients. The most frequent serious adverse effect was cardiac arrhythmia during the procedure, which occurred in between 1-2% of patients. Restenosis 6 to 18 months after endovascular therapy was reported in between 29% and 47% of patients. One study followed 240 patients for 30 days after endovascular therapy and found one patient with stent thrombosis one week later, but no other major complications. However, serious medium to long-term complications after endovascular therapy have been reported, such as stent migration, serious hemorrhage, pulmonary embolism, thrombosis of the internal jugular vein requiring thrombectomy, and death. More studies of long-term follow-up after endovascular therapy are needed.

Conclusion
A meta-analysis of 9 studies found a positive association between CCSVI and MS patients (compared to HC) that was statistically significant, even when a "conservative" analysis was conducted. However, poor reporting of the success of blinding, and the marked heterogeneity of the results do not allow definitive conclusions to be reached. Further high quality studies, using standardized ultrasound techniques and careful measurement of the reproducibility of the technique, are needed to definitively determine whether CCSVI is more frequent in patients with MS then those without MS. Endovascular therapy is associated with serious peri-procedure adverse events in <2% of patients. However, because of the poor methodological quality of published studies evaluating the benefits of endovascular therapy for CCSVI in MS patients, the impact of treatment on radiological and patient-relevant outcomes is not known.

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