CCSVI – Part 4
It has been seven years since Professor Paolo Zamboni presented what he called The Big Idea – that abnormalities in the flow of blood from the brain were the cause of multiple sclerosis (MS) (Zamboni P. J R Soc Med 2006; 99:589-593). Chronic cerebrospinal venous insufficiency (CCSVI) soon became an Internet phenomenon. Clinics around the world popped up to offer venous angioplasty to unclog blocked blood vessels, prompting thousands of people with MS to “get their veins done”.
Neurologists were taken by surprise and their response was a little flat-footed. But over the past few years, researchers from both sides of the CCSVI divide have been able to organize and publish over 50 studies. This is in addition to the dozens of reviews, guidelines (both pro and con), opinion pieces and stern warnings that have flowed through the pages of medical journals with no sign of insufficiency. Prof. Zamboni himself has coauthored some 38 papers relating to CCSVI.
The scorecard: About two dozen studies suggest that CCSVI is more common in people with MS compared to healthy controls. About the same number say the idea is bogus. And nine studies say that CCSVI may be more common but it has little or nothing to do with MS.
Some researchers who have been very open-minded about CCSVI now suggest that it has little or no impact on the development of disability (Weinstock-Guttman and colleagues. BMC Neurol 2012;12:26; free full text at www.biomedcentral.com/content/pdf/1471-2377-12-26.pdf). Nor does it appear that CCSVI has an impact on MRI lesions or tissue damage in the brain (Zivadinov and colleagues. AJNR Am J Neuroradiol 2012; epublished May 10, 2012). Others suggest that narrowing veins is largely due to getting older, but this doesn’t have much effect on the MS disease course (Lanzillo and colleagues. BMC Neurol 2013;13:20; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3577443/pdf/1471-2377-13-20.pdf). Others still have found that people with MS do tend to have abnormal blood flow, but isn’t related to their neurological function or disability progression (Garaci and colleagues. Radiology 2012;265:233-239). So CCSVI may or may not exist; and if it does exist, it may not be especially meaningful.
If CCSVI isn’t a direct cause of MS, does it make it worse? And, most importantly, does treating CCSVI make MS any better?
Enough people now have had their veins unblocked to give us some idea of the possible benefits and risks. The procedure is called PTA, for percutaneous transluminal angioplasty, which means that the balloon catheter passes through the skin and the lumen (the inner space of a blood vessel), is snaked to the blocked area, and the balloon is inflated to open up the blockage.
PTA is generally performed on arteries, but for CCSVI it’s used on veins. One problem is that after the balloon is deflated and removed, the veins often collapse (called re-stenosis). Several cases series have reported that this happens in up to 45% of people with MS undergoing PTA (Salvi and colleagues. Funct Neurol 2012;27:55-59; Kostecki and colleagues. Neuro Endocrinol Lett 2011; 2011;32:557-562). One solution is to insert a stent (a small tube) so the vein doesn’t collapse – although the use of stents has been strongly discouraged by the European Society of Neurosonology and Cerebral Hemodynamics (Baracchini and colleagues. J Neurol 2012;259:2585-2589). This is because of the risk of the stent becoming dislodged, migrating along the blood vessels and becoming lodged in the heart or lung.
So how have people fared after receiving PTA for their CCSVI? In Prof. Zamboni’s series of 29 people, he claimed that the relapse frequency and EDSS score (a measure of disability) generally improved in the two years following the procedure, although both relapses and disability got worse in about 14% of people (Salvi 2012). In a series of 331 people undergoing PTA in Poland, a number of complications were reported, including blood clots (about 1% of people), bleeding complications (about 2%), and heart rhythm disturbances (cardiac arrhythmias) (Ludyga and colleagues. Phlebology 2010;25:286-295). Other follow-up studies have also reported a problem with arrhythmias in about 1-2% of people (Petrov and colleagues. J Endovasc Ther 2011;18:314-323).
In Calgary, a high interest in CCSVI prompted researchers to form the Alberta Multiple Sclerosis Initiative, which collects information on PTA through online questionnaires and the group will be reporting its findings next week. In a review of Calgary hospital charts, five serious complications resulting from PTA have been identified, including one case of stent migration, one of nerve damage from the procedure, and two cases of blood clots (Burton and colleagues. Can J Neurol Sci 2011;38:741-746).
A U.S. study estimated that the risk of serious complications was about 1.6% (Mandato and colleagues. J Vasc Interv Radiol 2012;23:55-59). The researchers recommended heart monitoring during the procedure to identify people who develop arrhythmias, as well as ultrasound after surgery to detect potentially fatal blood clots.
The Italian Society of Neurology looked at the outcomes of 462 people with MS following PTA (Ghezzi and colleagues. Mult Scler 2013; epublished February 4, 2013). The rate of serious complications was about 3%, and included blood clots, atrial fibrillation, hydrocephalus (a buildup of fluid in the brain), epilepsy and stroke. One person died of a heart attack 10 weeks after the procedure.
There are no firm numbers for the number of deaths attributed to CCSVI. Four deaths are often cited (including two Canadians), but this is uncertain. There is even less certainty about the number of PTAs that have been performed worldwide, so there is no reliable estimate of the mortality risk.
Overall, PTA to treat CCSVI appears to be fairly safe. The risk of serious complications, such as stent migration, stroke, heart attack or clotting complications, is fairly low. To put things in perspective, the risk of death is probably lower than what is seen with Tysabri.
A risk of serious complications may well be worth it to some people – provided PTA has an impact on MS. But here the findings are very mixed. After analysing 462 cases, the Italian MS Society recently concluded that PTA had no impact on relapse rates or disability progression (Ghezzi and colleagues. Neurol Sci 2013; epublished January 25, 2013). Similarly, a study in Poland found no effect on disability progression (Kostecki and colleagues. Neuro Endocrinol Lett 2011;32:557-562). People generally reported that they felt better after the procedure, but this honeymoon effect was gone within six months.
The conclusions of a follow-up study in Kuwait, a popular destination for CCSVI treatment, were equally sobering. One year after the procedure, more people were experiencing relapses, there was more disease activity on MRI, and disability scores had generally worsened (Alroughani and colleagues. Int J Neurosci 2013; epublished February 4, 2013). It isn’t clear if PTA made MS worse. One-third stopped taking an MS medication after the procedure, but this didn’t appear to be the reason for the increase in relapses, MRI activity or progression. More studies will be needed to determine if PTA has the potential to worsen MS and, if so, how that occurs.
PTA studies thus far have not been the best quality (van Zuuren and colleagues. Cochrane Database Syst Rev 2012 Dec 12;12:CD009903). But the two large studies – the COSMO study of CCSVI and the BRAVE DREAMS trial of PTA – being planned are unlikely to provide definitive answers or convince the true believers (Comi and colleagues. Neurol Sci 2013; epublished January 24, 2013; Zamboni and colleagues. Trials 2012;13:183).
What is more likely is that CCSVI will fade from view over the next year or so as disenchantment with PTA sets in. The theory that CCSVI is a cause of MS has been largely debunked. Whether it contributes in some way to MS symptoms or progression is doubtful. Whether treating it produces any improvements other than a placebo effect remains to be seen.
There are some who will decide that PTA is their best option, which is their right; and unfortunately, that may be true. But the hope is that after this detour along the path of CCSVI, researchers will redouble their efforts to find effective treatments that prevent (or reverse) the long-term consequences of MS.
This concludes our series on CCSVI.
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