FROM MS ANSWERS.CAhttp://www.msanswers.ca/QuestionView.aspx?L=2&QID=3403
What steps would be required before a treatment for CCSVI (Chronic Cerebrospinal Venous Insufficiency) would be declared safe and recommended?
How long does it typically take to become available in Canada?
The theory that chronic cerebrospinal venous insufficiency may play a role in MS has generated a huge amount of interest after the media reported on the work of an Italian researcher, Dr. Zamboni. He reported that abnormalities in the major veins draining the brain and spinal cord (the internal jugular and azygos veins), were always narrowed in people with MS, and were never narrowed in people without MS, and that opening these areas of narrowing might result in benefit.
Other researchers are now working hard at trying to quickly replicate and determine the significance of his findings.
Firstly, researchers have been trying to confirm the existence of these proposed venous abnormalities and then to determine how these abnormalities might contribute to the MS disease process.
The group of researchers at the Buffalo Neuroimaging Analysis Center recently announced their results with the first 500 patients studied with the same technique employed by Dr. Zamboni (Combined Transcranial and Extracranial Venous Doppler Ultrasound). They have just announced the preliminary results and plan to present more detailed results at the American Academy of Neurology meeting in Toronto in mid April. They used Dr. Zamboni's technique to determine the presence of venous abnormalities in people with MS and age matched "controls" (people without MS). They used Dr. Zamboni's criteria for considering someone to have CCSVI. They reported that the abnormalities were present in 55% of people with MS and 26 % of the people without MS. Another 10 % of MS patients were "borderline". This is quite different than Dr. Zamboni's results of finding the abnormality in 100% of people with MS and 0% of controls. It raises the possibility that the venous abnormalities may be associated with, or a risk factor for MS, rather than a cause, although this hasn’t yet been determined with certainty. Thanks to an increase in funding generated by interest in the topic from people across North America, other groups across Canada and the U.S. also have studies planned or underway to investigate the presence of and significance of venous abnormalities in MS.
All of these results are eagerly anticipated to help us define exactly what the relationship is between these venous abnormalities and MS. There are many questions left to be answered including (as just a small sampling): are these areas of narrowing true constrictions or simply areas of variable collapsing and expansion normally seen in veins, how could these venous abnormalities contribute to MS, how can we explain the absence of venous abnormalities in a significant proportion of people with MS if it really contributes substantially to the disease, why do some people with these venous abnormalities not develop MS (a full 26% of the non-MS population in the Buffalo study), how come people with venous abnormalities after procedures like the insertion of a central line in the jugular vein not develop MS even though their internal jugular vein can become closed off, how could the four patterns of venous abnormalities described by Dr. Zamboni account for the tremendous variability in the disease, how do the venous abnormalities tie in with the known effect of vitamin D levels on the population risk of MS, how come immunomodulatory and immunosuppressive therapies work in MS if it is a blood flow problem, why do we see the immune abnormalities in the blood and spinal fluid of people with MS if it’s a vascular problem and many, many others.
Dr. Zamboni also reported on a small study of 65 people, 35 with relapsing-remitting MS and 30 with progressive forms of MS (20 with secondary progressive MS and 10 with primary progressive MS), in which he used a balloon catheter inserted into these veins, and by inflating the balloon, reversed the narrowing (venoplasty). He reported his results in a paper published in the December issue of the Journal of Vascular Surgery. The procedure was successful at keeping the azygous open in most cases, although a stent was used in one case to keep it open. In the internal jugular vein, the re-narrowing rate was 47 % over the subsequent months and required that the procedure be re-done. He could not use a stent in this vein as the currently available stents (designed for arteries not veins) were felt to be at high risk for migrating, which can cause life threatening side effects.
The study design was a non-randomized open label study without a control group, and such studies in MS can be hypothesis generating but are fraught with potential problems, as he clearly acknowledges in his conclusions (stating the design creates "a great potential for bias"). Nevertheless, it was a start in examining the theory. In terms of the results of the study, there was no statistically significant difference in the annualized relapse rate but relapsing-remitting MS patients were more likely to be relapse free than in the year prior to the study (27% versus 50 % relapse free). There was a reported reduction in gadolinium enhancement on MRI in those with relapsing remitting MS. People with RRMS also reported an improvement in quality of life. There were a number of challenges in interpreting the results. Most importantly, there was no control group. This is critical in MS studies, as in most clinical trials, even the group of people who do not get the treatment (placebo group) do better than they did the year prior to study entry, and if a treatment works, it must be found to produce a benefit significantly better than that seen in the placebo group. How relapses were defined in the year prior to and after the treatment was not explained, although this can significantly affect the reported relapse rates. The MRI scans were not done on any particular schedule and on different scanners, so the MRI portion is also tricky to interpret. Most of the relapsing remitting patients were also being treated with the current disease modifying therapies (a point somehow left out of the recent media reports of the treatment), so it is also difficult to separate out what factors might have been responsible for any improvement in disease activity. The measure used to measure disability was also one that is known to have a significant practice effect, which was not accounted for in the way it was administered in this study, so it was not possible to know if any early improvement was due to the practice effect or to a true treatment effect. Unfortunately the results were not very encouraging in those with progressive forms of MS, with only a weak inconsistent effect on quality of life but with no real benefit seen on other measures.
In the published report of his study, the conclusion reached by Dr. Zamboni was that his results warranted further study with a randomized double blind study of the treatment as an add-on therapy to current disease modifying therapies in relapsing-remitting MS. That means it would be tested in people with relapsing-remitting MS on one of the current disease modifying therapies and that half would get venoplasty and the other half would not. The two groups would then be compared with neither the examining neurologist nor the person themselves knowing whether or not they actually had the veins opened. It could then be determined whether there was a benefit to the procedure above the placebo effect. Subjects would also be followed closely to determine any risks associated with the procedure.
Although there were no serious side effects in Dr. Zamboni’s study, there was quite a high rate of recurrence of the vein narrowing. On the other hand, we now know from the experience at Stanford, that there can be significant risks to using stents to keep veins open. With their technique, there was one death and one case in which the stent migrated into the heart requiring emergency surgery, so clearly a safer approach is needed. In fact, their research was halted because of these serious adverse events. The treatment studies that are planned will help to define the risks of whatever approach is being tested. For now, it is generally agreed that venoplasty only be done as part of a controlled clinical trial, as would be the case for any new proposed treatment.
Although most researchers are focused on trying to whether the reported imaging abnormalities truly result in altered blood flow patterns and to determine the nature of the relationship between these venous findings and MS, there are others moving ahead already with clinical trials to test in a randomized study whether or not there really is a benefit to opening up the veins and how best to keep them open. Researchers in Buffalo have announced the initiation of a treatment trial and other groups have also indicated their intention to consider such studies. These planned treatment studies will attempt to define what the true benefits are from this treatment and will also better define the risks of different approaches. It will probably be tested first in those with relapsing-remitting MS as suggested by Dr. Zamboni. If it does indeed have a benefit in relapsing-remitting MS, then I would expect it would also be tested in progressive forms of the disease as his study was too small to draw a firm conclusion of lack of benefit in progressive MS.
In order for a treatment to be made available in Canada through public health care, there must be evidence from properly done clinical studies that:
1) the treatment provides a significant benefit over and above the placebo effect (comparing people actually having the procedure to those who just think they had it) and
2) that the potential benefits outweigh the potential risks.
Clinicians and researchers who work in the field of MS are keen to leave no stone unturned in the quest to end MS. Given the interest in this subject, which helps make research funds available to study it, research is likely to move ahead quite quickly in this area. Keep posted on the MS Society website for reports on developments in this and other areas of research as they become available.
DISCLAIMER: Please be aware that this information does not necessarily represent the opinion of the MS Society of Canada, and is not intended as medical advice. For specific advice and opinion, always consult a physician.