Efficacy and Safety of Extracranial Vein Angioplasty in Multiple Sclerosis: A Randomized Clinical Trial

Abstract

Importance: Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by restricted venous outflow from the brain and spinal cord. Whether this condition is associated with multiple sclerosis (MS) and whether venous percutaneous transluminal angioplasty (PTA) is beneficial in persons with MS and CCSVI is controversial.

Objective: To determine the efficacy and safety of venous PTA in patients with MS and CCSVI.

Design, setting, and participants: We analyzed 177 patients with relapsing-remitting MS; 62 were ineligible, including 47 (26.6%) who did not have CCSVI on color Doppler ultrasonography screening. A total of 115 patients were recruited in the study timeframe. All patients underwent a randomized, double-blind, sham-controlled, parallel-group trial in 6 MS centers in Italy. The trial began in August 2012 and concluded in March 2016; data were analyzed from April 2016 to September 2016. The analysis was intention to treat.

Interventions: Patients were randomly allocated (2:1) to either venous PTA or catheter venography without venous angioplasty (sham).

Main outcomes and measures: Two primary end points were assessed at 12 months: (1) a composite functional measure (ie, walking control, balance, manual dexterity, postvoid residual urine volume, and visual acuity) and (2) a measure of new combined brain lesions on magnetic resonance imaging, including the proportion of lesion-free patients. Combined lesions included T1 gadolinium-enhancing lesions plus new or enlarged T2 lesions.

Results: Of the included 115 patients with relapsing-remitting MS, 76 were allocated to the PTA group (45 female [59%]; mean [SD] age, 40.0 [10.3] years) and 39 to the sham group (29 female [74%]; mean [SD] age, 37.5 [10.6] years); 112 (97.4%) completed follow-up. No serious adverse events occurred. Flow restoration was achieved in 38 of 71 patients (54%) in the PTA group. The functional composite measure did not differ between the PTA and sham groups (41.7% vs 48.7%; odds ratio, 0.75; 95% CI, 0.34-1.68; P = .49). The mean (SD) number of combined lesions on magnetic resonance imaging at 6 to 12 months were 0.47 (1.19) in the PTA group vs 1.27 (2.65) in the sham group (mean ratio, 0.37; 95% CI, 0.15-0.91; P = .03: adjusted P = .09) and were 1.40 (4.21) in the PTA group vs 1.95 (3.73) in the sham group at 0 to 12 months (mean ratio, 0.72; 95% CI, 0.32-1.63; P = .45; adjusted P = .45). At follow-up after 6 to 12 months, 58 of 70 patients (83%) in the PTA group and 22 of 33 (67%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 2.64; 95% CI, 1.11-6.28; P = .03; adjusted P = .09). At 0 to 12 months, 46 of 73 patients (63.0%) in the PTA group and 18 of 37 (49%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 1.80; 95% CI, 0.81-4.01; P = .15; adjusted P = .30).

Conclusion and relevance: Venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS.

Trial registration: clinicaltrials.gov Identifier: NCT01371760.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Zamboni was the main author of the articles first describing chronic cerebrospinal venous insufficiency and its association with multiple sclerosis as well as the hypothesis of the potential anti-inflammatory action of venous outflow restoration. Dr Massacesi has received honoraria for speaking in scientific meeting or for participating on advisory boards for Genzyme, Biogen, and Roche and has received travel support for scientific meetings from Merck-Serono, Biogen, Teva, Genzyme, and Novartis. Dr Salvi is supported by a research grant from TEVA Company. No other disclosures were reported.

Figures

Figure.. Study Flowchart for Patients With Relapsing-Remitting Multiple Sclerosis

aIncludes 2 patients who received the sham treatment; one patient was included by mistake and the other was included because chronic cerebrospinal venous insufficiency was not confirmed on venography. CCSVI indicates chronic cerebrospinal venous insufficiency; MRI, magnetic resonance imaging.