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CCSVI Update

I have been following the story of Dr. Zamboni, an Italian vascular surgeon who claims that multiple sclerosis (MS) is primarily caused by blockages in the veins that drain blood from the brain. This results in backup of blood in the brain, leading to inflammation around the blood vessels and MS. He sought to find the cause and cure for MS because his wife suffers from this disease – and he claims to have found one in his own specialty.

New ideas are presented in science and medicine all the time. This is healthy and necessary – we have to keep churning the pot so that new ideas can emerge and our thinking does not become calcified. But science is both a creative and destructive process, and most new ideas fall victim to the meatgrinder of research and peer-review. Ideally this process will take place mostly within the halls of science, and then those ideas that survive at least initial examination will start to penetrate the broader culture.

This is not what often happens today, however. With the internet and mass media, preliminary speculative studies are often presented to the public as if they are a stunning breakthrough. When the scientific community responds with their typical and completely appropriate skepticism, this may lead some to think that they are being stodgy or dogmatic, or even that a cover-up is in the works. The originator of the speculative claim is usually portrayed as a brave maverick, although sometimes the story can be framed as, “Brilliant scientist or dangerous crank? You decide.” When the topic is a new medical treatment, the stakes can be quite high. In this case many patients with progressive MS are seeking treatment with the so-called liberation procedure to treat the highly speculative CCSVI as an alleged cause for their MS.

This story has all the makings of the kind of scientific and medical drama the mass media loves. While the controversy rages, the science is quietly being done in the background, and the results are not heading in a favorable direction for Zamboni. A recent study, the largest to date, drives a further stake into the heart of CCSVI as a cause of MS.

First, let us consider how to approach Zamboni’s claims. His data suggests that nearly 100% of patient with MS have CCSVI (detectable blockages in the veins that drain the brain) while 0% of non-MS patients do. This kind of evidence is correlation only, and does not prove (even if it might suggest) causation. Before we leap to treatment, the cautious scientific approach is to first confirm the correlation with replication. If the correlation holds, then studies need to be done that can shed light on causation – does the pattern of correlation fit the hypothesis that CCSVI causes MS, rather than MS causing CCSVI or both correlating with some other factor. Finally, before treating CCSVI, we would need to study this treatment directly in specific types of MS.

Proponents of the liberation procedure are skipping over all these research steps, and then use anecdotal evidence to support claims of efficacy. This is a story we have seen before, and it usually does not turn out well. Getting back to the first step – how have attempts to replicate the correlation been going?

Last August I described the first four attempts at replication, three of which yielded negative results. Just last month I wrote a following up where I described three further studies of CCSVI – all negative. This month two more relevant studies have been published. The first compared 20 MS patients to 20 healthy controls, and found:

Only one healthy control and no MS patients fulfilled at least two criteria for CCSVI. Conclusions This triple-blinded extra- and transcranial duplex sonographic assessment of cervical and cerebral veins does not provide supportive evidence for the presence of CCSVI in MS patients. The findings cast serious doubt on the concept of CCSVI in MS.

Last week the largest CCSVI study was published, a study that enrolled 499 subjects, and compared MS patients to patients with other neurological disease (OND) and to healthy controls (HC). They found:

RESULTS: CCSVI prevalence with borderline cases included in the “no CCSVI” group was 56.1% in MS, 42.3% in OND, 38.1% in CIS, and 22.7% in HC (p < 0.001). The CCSVI prevalence figures were 62.5% for MS, 45.8% for OND, 42.1% for CIS, and 25.5% for HC when borderline cases were excluded (p < 0.001). The prevalence of one or more positive VH criteria was the highest in MS (81.3%), followed by CIS (76.2%), OND (65.4%), and HC (55.2%) (p < 0.001). CCSVI prevalence was higher in patients with progressive than in nonprogressive MS (p = 0.004).

CONCLUSIONS: Our findings are consistent with an increased prevalence of CCSVI in MS but with modest sensitivity/specificity. Our findings point against CCSVI having a primary causative role in the development of MS.

These findings are interesting – they do not entirely rule out a correlation between CCSVI and MS. However, the results are very ambiguous. There is a statistical correlation between MS and CCSVI, but there is also a correlation with other neurological diseases – with very different histories and probable causes than MS. CCSVI was also found in a quarter of healthy controls. So CCSVI is not specific to MS, and almost half of MS patients do not meet criteria for CCSVI.

Given the other negative studies, these results cannot be taken at face value but have to be put into context of the other research. At this time we can say that there might be a correlation, but it’s weak. It’s also still possible there is no correlation, and since there are some contradictory results more research would be helpful.

Even if there is a partial correlation, this study argues strongly against CCSVI being a significant cause of MS – if 44% of MS patients do not have it, and 42% of patients with OND do have CCSVI but not MS. This could mean that CCSVI only causes a subset of MS, or that it is a risk factor but not a direct cause. Or it could mean that MS (and apparently other diseases) cause CCSVI. This is plausible – we can imagine that the chronic inflammation caused by MS damages the veins over time resulting in CCSVI. It is even possible that this, in turn, will cause its own symptoms or worsen the MS and therefore treating it may be beneficial. This is all just speculation, however. In this case the phrase, “more research is needed” is appropriate.

One other recent study, that I have not written about previously, is worth mentioning. In this study researchers looked specifically at subjects at the very onset of their MS. If CCSVI causes MS then it should precede MS. They found no correlation, and concluded:

Our findings do not support a cause-effect relationship between CCSVI and pMS. Further studies are warranted to clarify whether CCSVI is associated with later disease stages and characterizes the progressive forms of MS.

Conclusion

With these latest studies the correlation between CCSVI and MS seems shaky – nonexistent to weak, but not entirely ruled out. That CCSVI is a significant cause of MS is even weaker. It cannot be ruled out as a late stage contributor, or a cause in a subset of MS patient, but neither is it established as a contributing cause at all, and the evidence is largely against it.

There is so far no controlled blinded studies of the liberation procedure in patients with CCSVI and MS. There is a controversy as to whether or not such studies would be ethical and appropriate. It would be getting ahead of the more basic research – we should determine that a phenomenon exists and is causative before studying a treatment of it. However, hype has generated great interest in the liberation procedure, and it is being done in various clinics. This is the Catch-22 that the modern information age has created for ethical medical researchers.

In a perfect world clinical trials of the liberation procedure would wait for more confirmatory studies, but we do not live in a perfect world. We may need to at least study those patients who are seeking out the treatment anyway, and provide useful data that future patients and practitioners can use to guide their decisions.

Posted in: Neuroscience/Mental Health

Leave a Comment (8) ↓

8 thoughts on “CCSVI Update

  1. colros says:

    You have to read more than the abstract of the Buffalo paper to see the problems with the study. I have uploaded it to my dropbox in case you can’t access it.

    http://dl.dropbox.com/u/4089353/Neurology-Zivadinov-CCSVI.pdf

    From the Methods section:

    “As in any case-control study that includes disabled patients vs HCs, blinding was a challenge in the CTEVD [combined transcranial and extracranial venous echo-color doppler] study.”

    Zivadinov is admitting that he didn’t use adequate blinding. Recorders and interpreters of the data could easily have gotten hints of the patients diagnosis. It is well-known that observers often subconsciously manipulate data collection and bias interpretation of it to get the answer they want. At the very least he should have used different data analyzers who had never seen the subject and were completely blinded to the diagnosis. So it’s not surprising that Zivadinov found more “CCSVI” in MS patients, unlike the numerous other well-blinded studies that find no correlation. Rigorous blinding is essential in these sorts of studies.

    We can now state beyond a reasonable doubt that “CCSVI” does not exist as a disease. It is just a name for the normally large variations in head and neck venous anatomy some of which Zamboni selected to be associated with MS in his initial unblinded study.

    “Liberation” is a scam and should be banned by every ethical medical organization.

    I was very surprised to see that even at presumably respectable medical school like the Baylor College of Medicine a Dr. Peter Lin is trying to profit from the scam.

    http://www.debakeydepartmentofsurgery.org…

  2. S.C. former shruggie says:

    Thank you for the update, Dr. Novella. A lot of MS patients here in Canada got caught up in the premature promotion of this treatment, including members of my family. Our government tried to encourage people to wait for further confirmation, but to no avail. MS sufferers died or were seriously injured seeking surgery abroad.

  3. egrrrl11 says:

    Thank you for following this – i have a brother in law with MS who has been looking for information on this treatment and is having a hard time finding anything other than places wanting to sell it to him. I will link him to your posts.

    It’s fascinating to me how this has played out in the media. I keep reading news stories where they interview 3 or 4 MS patients who have had the treatment, and it always seems to be one patient who found it ineffective, and the others claiming effects in areas that are highly susceptible to placebo (“I have more energy now”).

  4. ConspicuousCarl says:

    I have read a few reports suggesting that angioplasty might cause a small increase in the risk of stroke.

    If MS involves the blood-brain barrier becoming abnormally permissive, do people with MS have a higher-than-average risk of stroke following angioplasty?

  5. mxh says:

    “In a perfect world clinical trials of the liberation procedure would wait for more confirmatory studies, but we do not live in a perfect world. We may need to at least study those patients who are seeking out the treatment anyway, and provide useful data that future patients and practitioners can use to guide their decisions.”

    Actually, even after the study of these patients come out with no evidence for “liberation” working, people will be clamoring for it. Once the cat is out of the bag and people can profit off it, it’ll never go away.

  6. John says:

    What amazes me is the lack of regulatory control there is over surgical procedures as compared to drugs. Do they just label a surgery as “experimental”, have the patient sign a waiver and then do whatever they want?

    For instance, helminth therapy has had much better results in trials, yet it is (rightly, in my opinion) not yet approved to treat MS in the US. Angioplasty seems more radical to me, and yet it’s already being done to treat MS in multiple hospitals around the country.

    I’ve seen a few testimonials and anecdotal recovery stories post-”liberation”. Does anyone know if any of these have been patients with progressive MS? It seems like they don’t understand the nature of the disease, and all the stories are from patients with RRMS.

  7. Xanthippe says:

    Thank you for continuing to follow the research on CCSVI, Dr. Novella. Your blog is the only trustworthy source for me on this issue. I’m afraid that mxh is right, however. It bothers me that pro-CCSVI activists complain about “Big Pharma” making profits off of them, but there wasn’t a similar reaction to the news that Zamboni had submitted patents to detect CCSVI before the media reported on his discovery and failed to disclose this conflict of interest in his published research.

  8. Jpax says:

    I appreciate the informative overview of the current status of the CCSVI debate and research.

    I am really struggling with the entire story of CCSVI and MS, scientifically and personally.

    I have read all of Dr. Zamboni’s work as well as papers from other principal investigators and all the studies have flaws BUT… I do not believe MS is caused by CCSVI but there appears to be a subpopulation of MS patients who have significant blockage in not only the veins leading from the brain but in other areas of the body as well. This again does not mean that this caused the MS but may be a consequence of nerve damage and muscle spasticityor constantly clenched muscle tone. I agree there needs to be a blinded multicenter clinical trial to address CCSVI in MS patients. While a blinded study with MS patients may be difficult since the signs of MS cannot always be hidden, it can be designed (and usually is) so that those analyzing the data never see the patient – only the data. I would like to see studies that will investigate whether this is a subset of the MS population or a condition caused by MS.

    I am alarmed by the number of store front businesses opening up to provide CCSVI treatments for MS patients and I do hope that MS patients are very cautious is choosing endovascular surgical groups if they do decide to proceed with CCSVI treatment.

    As a scientist and MS patient I am truly torn over the CCSVI story. On one hand, I would volunteer immediately if/when a clinical trial becomes available in my area so as to contribute to the science of the CCSVI-MS connection. On the other hand, if I am diagnosed with CCSVI it is not a giant leap for me to take a chance that relieving the blockages will alleviate my MS symptoms and improve my quality of life. Until you live with MS daily and over a period of time you cannot appreciate the lure of a possible reprieve of alleviation of MS symptoms. Personally I don’t care of CCSVI causes MS or is caused by MS – if I have blocked veins coming from my brain I think I may want them to be repaired.restored.

    If you look at the numbers for the current MS disease treatments (interferon, copaxone, tysabri…) the clinical outcomes are not that impressive – slows disease progression in about 60% or less in most cases. There are a slew of pharmaceutical drugs and alternative therapies that over relief from MS symptoms but every MS patient knows that their nervous system is under attack and we are losing white & gray matter daily. It is no wonder that when the first reports from Dr. Zamboni were released the MS community grabbed on and wasn’t letting go.

    I think it is really important for those of us inside the MS community offer support to those around us who may rush to treatment. I only wish I had a solid opinion of my own! I can assure you I am in the process of formulating one and hope to come to some decision about my personal decision on CCSVI within the next month or so.

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