What are we to make of current developments in the theory of chronic cerebrospinal venous insufficiency (CCSVI), the theory that multiple sclerosis is caused by back pressure from narrowed veins taking blood back to the heart from the brain?
A brief history of CCSVI
Professor Paolo Zamboni, a vascular surgeon from the University of Ferrara, Italy, has turned the multiple sclerosis world on its head in recent years, postulating that this back pressure leads to blood leakage around small veins in the brain, iron deposition from the blood and subsequent inflammation, producing the typical lesions of MS. Zamboni’s motivation in proposing this hypothesis is clear.
His wife, Elena Ravalli, was diagnosed with MS in 1995 at the age of 37, and Zamboni was a vascular surgeon who had previously published extensively about venous back pressure causing inflammation and ulcers in the legs. His research team’s many publications have led to people with MS world-wide clamouring for access to angioplasty to open these venous narrowings.
CCSVI: is it a certainty?
But in my view, it is difficult to say with any certainty whether CCSVI is a real entity, and if so, what causes it, whether it causes MS, and what role angioplasty has to play in it, without further research. Much of the initial optimism about CCSVI has been thrown into confusion by two recent publications in Annals of Neurology. These two publications, one from Germany and another from Sweden, through different methodologies, found no real evidence of venous obstruction in people with MS compared to people without MS.
The whole CCSVI issue is clouded by conflict of interest. Conflict of interest in this case is when a researcher, research group, or commentator have a vested interest in the subject under study and are therefore potentially biased. Conflict of interest can come from many sources; it is commonly financial, such as when a researcher stands to profit from the product being researched (such as when a drug company conducts a clinical trial of a new agent they have developed); but conflict of interest can also be related to career advancement, or prestige, or relationships that researchers have.
Zamboni's conflict of interest
For instance with CCSVI, Zamboni has a clear conflict of interest in that his wife has MS. I understand that conflict perfectly, given that my mother died of MS. Personally, I find that such a conflict of interest can be very helpful, in that it often makes the researcher very passionate about the research, and more likely to persevere in the face of adversity.
But it can cloud the judgement of the researcher; I am aware that to some extent my conflict of interest produces a bias towards research that supports things that can be actively done to improve outcome, like diet, exercise, meditation, etc, whereas I tend to be biased against research that suggests such interventions are not helpful. But I try hard to remain objective.
Zamboni may well have similar bias towards finding a cure, and towards vascular techniques, and this may subtly influence his assessment of ultrasound scans, for example, when he knows that the person being scanned has MS. Those of us who use ultrasound daily know just how subjective and operator-dependent the interpretation of these scans is.
Some people with MS have argued that most neurologists have a conflict of interest against CCSVI because they have close ties to the pharmaceutical industry, and the possibility of angioplasty taking over from drug therapy as the main therapy for MS threatens them.
The myth of a 'cure'?
There may be some truth to this, although in my experience, most neurologists would be delighted if a cure was found for MS tomorrow, whether it was angioplasty or any other cure.
There may also have been subtle conflict of interest in the publication of the two negative studies in Annals of Neurology recently. The editor of Annals, Stephen L Hauser, who approved publication of the papers, was the neurologist who complained to Stanford University after one of his patients required open heart surgery to remove a stent that had dislodged from a cerebral vein after angioplasty for CCSVI.
It was this complaint that stopped Stanford’s angioplasty program for people with MS. Although the peer review process ensures that independent researchers assess the papers and provide a recommendation to the editor about publication, it is the editor’s call in the end whether the paper is published. As a journal editor myself, I am aware of the extent to which the editor has a guiding hand in what is published. One thing is sure: at the end of a lot of research, we will know whether CCSVI has any role in causing MS and whether venous angioplasty has any role in treatment.
True or false?
Fundamentally, CCSVI is either a real phenomenon or it is not, and a concerted research effort will answer that question, and we will know the answer for sure. For now, the Buffalo findings suggest it is real, with their results of 500 people, some with MS, some with no illness and others with other neurological diseases, showing that around 55% of people with MS had the criteria for CCSVI, about 22% of people with no illness had the criteria, and around 43% of people with other neurological conditions had the criteria.
But these findings are difficult to interpret given that they have not yet been published; also, they contradict the complete 100% association found by Zamboni between CCSVI and MS. But, they are far more believable; they suggest that the presence of venous abnormalities of the cerebral circulation may roughly double the risk of having MS or other neurological disease.
t will be important to see how the results are presented once the methodology of the study and its findings undergo rigorous peer review for publication. Now we have other studies from reputable groups of neurologists who have used similar or other techniques to try to demonstrate CCSVI but have been unable to find any evidence of it. It is difficult to summarise these conflicting data.
From the point of view of a specialist medical practitioner of over 30 years’ experience, an academic medical researcher, and a person with MS, with my own peculiar conflict of interest, I make the following observations.
Zamboni developed an ultrasound technique for finding venous abnormalities in the brain, found some abnormalities only apparent with this technique which he termed CCSVI, developed the criteria for its diagnosis, and developed a treatment. Other researchers investigating the condition have either found a significantly different incidence of CCSVI in MS or not found it at all.
This raises the question of the extent of the un-blinded observer bias in the ultrasound assessments of the people with MS in the early studies, and hence the reliability and validity of those early conclusions.
Consequently, I don’t have any idea whether CCSVI exists or whether it has any role in causing MS. I just don’t think we yet have enough data on which to base an opinion about this, and much of the data are conflicting. Further, I have no opinion about whether venous angioplasty is likely to be of any benefit in MS, even if it is shown that a person has CCSVI. The fact that in the only formal study of the procedure there was no difference in relapse rate for the group before and after the procedure is of concern. Further, the single death from cerebral bleeding and the serious side effect of a venous stent migrating to the heart, need to be weighed against any potential benefit.
As a person diagnosed with MS, I hope there is something to the CCSVI theory and that effective treatments for MS might become available as a result; as an academic researcher, I have to say it is important for us to be patient while the medical research community goes about studying this issue
. Certainly at the moment, along with the original CCSVI researchers, I would not advise anyone with MS to try angioplasty, except in the context of a properly run research study. We simply don’t know if it would work and what the side effects are likely to be, particularly long term (what would happen if venous constrictions get worse after being ballooned open for instance?: it appears they often re-develop quite rapidly).
Clinics are springing up charging a lot of money to have this procedure; judging by the location of some of these clinics, the medical standards involved in the procedure are questionable and the outcomes very uncertain. It is important for all of us involved with MS to keep an open mind about CCSVI, whatever our own particular conflict of interest.
CCSVI may well be an important part of the MS jigsaw, but until we have more information, it is not possible to say much more than that. We urgently need more research, and I strongly support governments, funding bodies and MS societies prioritising research funding to this area. With an appropriately concerted research effort, we should not have to wait too long to know the real answer.