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CCSVI: Can the Findings Be Reproduced?

Andrew A. Wilner, MD: Welcome to Medscape Peer to Peer. I'm Dr. Andrew Wilner, a neurologist from Newport, Rhode Island. We are here today in Honolulu, Hawaii, at the 63rd Annual Meeting of the American Academy of Neurology, and we will be discussing highlights of multiple sclerosis (MS) from the conference.

It is a pleasure to be speaking with Dr. Mark Freedman. Mark is Professor of Neurology at the University of Ottawa and Director of the Multiple Sclerosis Research Unit at the Ottawa Hospital General Campus, Ottawa, Ontario, Canada.

Dr. Freedman, thank you for joining us at Medscape. There is so much new in multiple sclerosis and we have been talking about it, but one of the topics I never seem to hear the end of is CCSVI. What is CCSVI, and why do I keep hearing about it?

Mark Freedman, MD: So much of this is being driven by hype, I think, from the patient standpoint, and [this is] really an example I think of where social media has really impacted medicine.

Dr. Wilner: So what is it again, this CCSVI?

Dr. Freedman: It is a term coined by an Italian researcher, Paolo Zamboni, a few years ago. Dr. Zamboni was a vascular surgeon specialist looking at venostasis, especially in legs. His technology, his skill, was using ultrasound and since MS plaques are perivenous, he thought that maybe they had something to do with the veins and venous drainage. This very loose association caused him to study a number of patients and come up with this theory called chronic cerebral spinal venous insufficiency, or CCSVI for short.

So this is, in fact, a theory, a theory of how this abnormality seems to associate with patients. And he went and did a study; not what we would call a regular study. It was pretty open-label and he took a bunch of patients who were willing, to some extent, to undergo venography and did ultrasound studies of their veins and decided on a series of criteria that would distinguish the MS patients from non-MS patients. His first claim was that he could find the abnormalities in 100% of patients.

Dr. Wilner: I remember being struck by that number. A study with 100% positivity!

Dr. Freedman: We learned in medical school that nothing is 100%, right? So that is the first red flag: 100% of patients.

Dr. Wilner: They had blockages in their neck, right?

Dr. Freedman: Stenoses, narrowings, blockages, abnormalities that might confer some kind of chronic backflow. How all of that transpires into MS? We are not there yet.

So 100% of patients, 0% of non-MS [patients], and so it's a theory. To corroborate a theory, you set out a null hypothesis and you try to disprove it. And so this is what has been done now by a number of different groups and nobody has been able to copy or reproduce his findings in a properly controlled and blinded study.

On top of that, [there are] a lot of claims that when you are pushing ultrasound devices onto the neck, a little pressure here and there can collapse a vein and natural structures like muscles.

Dr. Wilner: It is very operator-dependent.

Dr. Freedman: Very much. And so people have argued that maybe you are not able to copy his exact technique. So now we have heard from a couple of groups.

Dr. Wilner: There are reports at this meeting.[1,2]

Dr. Freedman: [There are] 2 reports at this meeting. One group reported using his machine -- the same technology - and they trained their technologist with him so that they are doing it exactly the way [Zamboni's group] does it. But they did it blindly so the technologist had no idea if patients had MS or not. They are all set up in advance and the person who is reading it or interpreting it has no idea -- so you can imagine all blinded, and when you do that nobody has CCSVI.

Dr. Wilner: Nothing, oh, my.

Dr. Freedman: But the tragic nature of this is that there were media claims that this was a cure. And this has spawned hundreds of locations around, unfortunately, the United States, Mexico, India, Bulgaria, and Poland. Everywhere has someone who is now willing to put in angiocaths and dilate to open up veins and try to treat MS. This is unbelievable.

The theory hasn't even been substantiated. The existence of the problem, if it is a problem, is called into question and most people think this is a normal variation in venous anatomy. Why would you treat that?

Dr. Wilner: Well, I guess this is very disappointing news for patients but a cautionary tale that preliminary results are preliminary and need to be [substantiated]. We were just talking earlier about when a drug is going to be FDA (US Food and Drug Administration] approved, there have to be 2 studies that are well reviewed. There is a reason for dragging out the scientific process.

Dr. Freedman: Yes, how come it doesn't apply to surgical procedures?

Dr. Wilner: I think there have been some fatalities as well associated with CCSVI.

Dr. Freedman: There is a report coming out in one of the Canadian journals of a whole list of complications that have ensued for people who have sought out this procedure from who knows where.

Dr. Wilner: I read somewhere that there are millions of dollars being spent currently in controlled trials to look at this.

Dr. Freedman: Probably. We are going to have the answer before the end of the year with proper investigation. These are not treatment trials. They are investigative trials along the line of what we have heard here, showing that when you control for everything else that the venous anatomy is probably no different in an MS patient than in someone who [does not have MS].

Dr. Wilner: So your advice to a neurologist or family physician when the patient comes and says, "I want to do this procedure," how should that doctor respond?

Dr. Freedman: I think it is a huge leap from "I think there is a problem, but nobody has proven it," to "let’s fix it." If it ain't broke don't fix it.

Dr. Wilner: So maybe some caution.

Dr. Freedman: Absolutely.

Predicting PML With Natalizumab

Dr. Wilner: Well, let's switch topics. I also read something about one of our best drugs, Tysabri®, or natalizumab -- it seems to work very, very well and yet there is this problem of PML (progressive multifocal leukoencephalopathy). And there may be a way to figure out who is going to get [PML] and who isn't, depending on JC virus testing.[3] Is that right?

Dr. Freedman: Right, so many of the cases have come, for instance, from Europe. There are not that many reported cases but they are growing all the time and over 100 cases have now been reported worldwide, or at least captured by the registries.

Dr. Wilner: How can you predict who is going to get it?

Dr. Freedman: You can't, but when you look and see what was more in [one] group than the other group, there is this history that they had been exposed to immunosuppressive drugs. I have always questioned that because most of the cases have come from Europe, and you know what the treatment was for MS 10, 20 years ago? Everybody got azathioprine and immunosuppressants. So is the fact that [there is] more PML in Europe just the association, or is it truly the immunosuppression?

If you look at patients who had serology at baseline before starting natalizumab for natural immunity to JC virus, the patients who had positivity are the patients who are more likely to have gotten [PML] because nobody who is negative for JC virus was at risk. At least this is the theory.

So if you have positivity, it means you have JC virus on board and you are a potential candidate for getting PML.

Dr. Wilner: And if you are immunosuppressed with the Tysabri, which is how it works, presumably.

Dr. Freedman: However, it is suppressing the very specialized response to this virus because we have never seen it with any other MS therapy. It is the only drug that I know of that has led to PML in multiple sclerosis patients.

Dr. Wilner: We haven't seen it with fingolimod, for example?

Dr. Freedman: Nothing. This was a first for them, so it is enticing to think that we have something that will screen a patient and will tell us absolutely no risk or risk. This is what is now being tested.

Dr. Wilner: So there is an assay?

Dr. Freedman: There is an assay that is now being tested to see if that is, in fact, true. I think we are making, again, a big leap if we say, rest assured if you are negative you are never going to get PML if you take natalizumab. I don't think we can say that yet, but that is the hope of this study.

Dr. Wilner: Okay, so again we will wait a little while and we will have more results maybe at ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) in October?

Dr. Freedman: I think as they collect this we will see more in about a year.

Dr. Wilner: Well, Mark, this has been very enlightening. Every year I learn more and more about multiple sclerosis, and I hope the other diseases catch up and that we have as many new treatments and potential cures and exciting ways to make patients better.

Dr. Freedman: I agree.

Dr. Wilner: So thanks for joining us on Medscape Peer to Peer. This is Dr. Andrew Wilner from the 63rd Annual Meeting of the American Academy of Neurology.

Dr. Freedman: Thanks, Andy.

They are investigative trials along the line of what we have heard here, showing that when you control for everything else that the venous anatomy is probably no different in an MS patient than in someone who [does not have MS].

So 100% of patients, 0% of non-MS [patients], and so it's a theory. To corroborate a theory, you set out a null hypothesis and you try to disprove it. And so this is what has been done now by a number of different groups and nobody has been able to copy or reproduce his findings in a properly controlled and blinded study.

Thanks Dr. Freedman for saying what many of us have been saying from the start.