Prospective randomized trial of venous angioplasty in MS (PREMiSe).
Siddiqui AH, Zivadinov R, Benedict RH, Karmon Y, Yu J, Hartney ML, Marr KL, Valnarov V, Kennedy CL, Ramanathan M, Ramasamy DP, Dolic K, Hojnacki DW, Carl E, Levy EI, Hopkins LN, Weinstock-Guttman B.
Neurology. 2014 Jul 29;83(5):441-9. doi: 10.1212/WNL.0000000000000638. Epub 2014 Jun 27.
We report the results of the investigation of safety and efficacy of venous angioplasty in patients with multiple sclerosis (MS) with findings of extracranial venous anomalies, considered hallmarks of chronic cerebrospinal venous insufficiency (CCSVI), in a 2-phase study (ClinicalTrials.gov NCT01450072).
Phase 1 was an open-label safety study (10 patients); phase 2 was sham-controlled, randomized, and double-blind (10 sham procedure, 9 treated). All study patients fulfilled venous hemodynamic screening criteria indicative of CCSVI. Assessment was at 1, 3, and 6 months postprocedure with MRI, clinical, and hemodynamic outcomes. Primary endpoints were safety at 24 hours and 1 month, venous outflow restoration >75% at 1 month, and effect of angioplasty on new lesion activity and relapse rate over 6 months. Secondary endpoints included changes in disability, brain volume, cognitive tests, and quality of life.
No perioperative complications were noted; however, one patient with history of syncope was diagnosed with episodic bradycardia requiring placement of a pacemaker before discharge. Doppler evidence-based venous hemodynamic insufficiency severity score (VHISS) was reduced >75% compared to baseline in phase 1 (at 1 month) but not phase 2. In phase 2, higher MRI activity (cumulative number of new contrast-enhancing lesions [19 vs 3, p = 0.062] and new T2 lesions [17 vs 3, p = 0.066]) and relapse activity (4 vs 1, p = 0.389) were identified as nonsignificant trends in the treated vs sham arm over 6 months. Using analysis of covariance, significant cumulative new T2 lesions were related to larger VHISS decrease (p = 0.028) and angioplasty (p = 0.01) over the follow-up. No differences in other endpoints were detected.
Venous angioplasty is not an effective treatment for MS over the short term and may exacerbate underlying disease activity.
Image: Jean-Marie Charcot's treatment for Parkinson's disease, the "fauteuil trepidant" (translation; shaking chair) or its portable version the shaking helmut. He devised this after observing that Parkinson's patients exhibited reduced symptoms after long carriage rides...lets just say the idea didn't take off. Which goes to show you that not everything you see is what it appears to be.
In short, this study found that there was no clinical improvement in those who participated.
Conversely they found that it may even worsen the disease. There were 20 patients in total in the phase 2 portion of the study: 4 relapses were in the treatment arm and 1 in the placebo/sham-arm, whilst 5 out of 9 patients in the treated arm showed new contrast-enhancing MRI lesions compared to 2 in the placebo/sham-arm.
It is not the first time that worsening disease activity has been noted, and has been reported in 4 other studies. It is thought that re-opening the veins may increase the perfusion of the micro-circulation of the brain, but inadvertently bring in more immune cells worsening the disease activity.
Was this study needed to be done? YES...
A double-blind placebo-controlled clinical trial needed to be done as their was uncertainty about the efficacy of venous angioplasty in CCSVI in MS.
But in order to do such a trial, "clinical equipoise requires that uncertainty exists about the efficacy of an intervention being studied in a clinical trial" - editorial comment.
But as the findings are negative, there is no longer this equipoise.....and further studies of this ilk cannot be justified on ethical grounds alone.
The numbers were small, but for a phase 1/2a interventional study this sample size is adequate. The placebo/sham arm patients still underwent the procedure, wherein an angioplasty balloon was inserted, but not inflated to achieve the dilatation as in the treatment arm. Therefore the risk of complication ~ 4% (4 in every 100) associated with cerebral angiograms still applies to the placebo/sham arm as well.
Infact, the argument works both ways, the authors assertion that angioplasty was performed safely in MS patients is also diminished by the small sample size.