Aug 02 2010

CCSVI – The Importance of Replication

Scientists and skeptics are familiar with this pattern – a preliminary study suggests a wildly new understanding of a scientific or medical question. The scientific community is cautiously skeptical but interested. The press proclaims a stunning breakthrough, and the public is briefly fascinated. If the new discovery concerns a medical treatment, the community of those affected become fixated on the potential new “cure”, and many start demanding treatment based solely on the preliminary evidence. But then the wheels of research begin to grind and, more often than not (because that is the nature of discovery) the new idea turns out to be wrong – it fails the critical step of replication.

Then one of two things will happen: either the new idea or treatment will fade, becoming little more than a footnote in the history of science, or a subculture will persist in believing in the treatment and will dismiss contrary evidence and mainstream rejection as a conspiracy. Which course the new idea will take seems to depend largely on the original scientist – if they accept the new evidence and abandon their claims, it will likely fade. If they refuse to give up in the face of new evidence, then a new pseudoscience will likely be born.

We have seen this pattern play out with Laetrile, psychomotor patterning, cold fusion, and many other ideas.

Now we are in the midst of this pattern playing itself out yet again – with the Zamboni treatment for multiple sclerosis (MS). Dr. Zamboni is an Italian neurosurgeon whose wife has MS. He sought out to find a cure, and eventually discovered that patients with MS have a blockage in the venous drainage of their brains, a condition he termed “chronic cerebrospinal venous insufficiency” (CCSVI). He further claims that MS can be treated, even cured, by opening up the veins that drain the brain with either angioplasty or stenting. Many MS patients have been interested in this potential new treatment, and many have even undergone treatment.

The neurological community is, to say the least, skeptical – but interested. There are many red flags of crankery in CCSVI, however. First, it may make for good story telling, but it is a bit curious that a neurosurgeon set out to discover a treatment for MS and found a neurosurgical one – even though there was no prior suggestion that this would be the case. Further, we have decades of research that tell us that MS is primarily an autoimmune disease – the patient’s immune system is attacking their own central nervous system. It is true that inflammatory plaques tend to occur around veins, but that is explained by the fact that blood vessels allow immune cells access to the central nervous system.

And finally Zamboni found in his own research that his criteria for CCSVI has 100% sensitivity and 100% specificity for MS – which triggers the “too good to be true” red flag. It is rare (perhaps nonexistent) to find a test in medicine that is correct 100% of the time, with no false positives or false negatives. These kinds of results strongly suggest experimenter bias.

Zamboni presented his research at the latest meeting of the American Academy of Neurology. I was not present, but I have spoken to some colleagues who were – the buzz is that Zamboni’s presentation was not impressive, and he came off as a bit of a crank. This by itself does not mean much – it’s more about personality than data – but it’s not surprising given the pattern I have outlined above.

The only reasonable response to such claims is cautious interest, and that is exactly what the medical community has done. In general most neurologists acknowledge that Zamboni’s claims need to be replicated and researched. Perhaps he is on to something, even if he is overstating the claims. Perhaps the perivenous inflammation of MS leads to CCSVI which exacerbates MS. Maybe Zamboni has found a piece to the puzzle, even if he has not solved the whole thing in one fell swoop.

Well now we have two independent replications of Zamboni’s research published in the latest issue of the Annals of Neurology – and both are completely negative. The first is a German study by Florian Doepp et al, using ultrasound to test the CCSVI criteria in 56 MS patients and 20 controls. They found almost completely negative results (one MS patient met one criterion, but not the others) – no signs of venous blockage in the MS patients.

The second study is a Swedish study by SundstrÃm et al (“Venous and cerebrospinal fluid flow in multiple sclerosis – a case-control study.” Peter SundstrÃm, Anders WÃ¥hlin, Khalid Ambarki, Richard Birgander, Anders Eklund and Jan Malm. Annals of Neurology) – not yet available online. This study used MRI scanning to assess blood flow in the internal jugular vein in 21 MS patients and 20 controls, and also found no difference.

Conclusion

These two studies are not going to be the final word on CCSVI and MS, but they are very important in signaling a note of caution to patients and clinicians about this new hypothesis. The treatment for CCSVI is invasive and has serious risks, and should not be undertaken lightly. I agree with the current consensus that evidence for CCSVI is too preliminary to warrant treatment, especially given the risks.

I do wish that the media and public would learn the more general lesson here – new dramatic ideas in science, especially those that seem to go against established knowledge, are likely to turn out to be wrong when the dust settles. It is partly the job of the skeptical community to provide cultural memory of such events – so the next time a lone scientist or doctor claims to have made a revolutionary breakthrough that seems a bit dubious, it is the skeptics who will be there to say – remember Zamboni.

32 responses so far

32 thoughts on “CCSVI – The Importance of Replication”

  1. Nige says:

    I think all this false hope coming from preliminary experiments is the victim of bad science reporting. If the journalist stressed that the research hasn’t been confirmed by supporting studies then hopefully that would curb over enthusiastic responses by the public (or is that wishful thinking?).

  2. titmouse says:

    In a nutshell, Zamboni is guessing MS is due to cerebral venous insufficiency.

    I wonder if he thought to recommend elevation of the head first before proposing surgery.

  3. SARA says:

    I wonder how often a scientist, especially a scientist who is so invested like Zamboni, is effected by the priming of an idea. There are studies that show that we will defend a misinformation about ourselves, even if we never created the misinformation but are convinced we did. In fact we don’t even consider it misinformation, we just adapt and rationalize.
    So suppose a scientist gets his first data return (which is unfortunately an anomaly but he doesn’t know it) and it shows him something he wants to believe. Now he perceives all other returns are that same result, for the same irrational reason that we defend misinformation we never told in the first place.

    I think it would be a fascinating social study to somehow study scientist in that realm. How far could a scientists delude herself if she were invested in the result? Would she even be conscious of any manipulation of data?

  4. ADR150 says:

    I saw the NYT article about this procedure a couple weeks ago and had a similar reaction, Steve.

    It seems reasonable, though, that as the NYT piece states “Dr. Zamboni himself has said that the procedure should not yet be done outside of studies. He said in an interview that he was conducting research only and had turned down thousands of requests from people wanting to go to his clinic at the University of Ferrara.”

    Doesn’t sound like he’s going off the deep end just yet.

  5. JoanneBB says:

    In Canada, Saskatchewan is funding trials, and is encouraging other provinces to jump in as well.

    http://www.nationalpost.com/news/canada/urged+join+trials/3341298/story.html

  6. Trevor Systema says:

    Dr. Steven Novella

    I read your article
    CCSVI – The Importance of Replication

    I was not impressed as there are many mistakes
    the main one being that CCSVI is new is is not new!
    you just did not know

    it is a pity that you do not research very well and then write to soon or talk about things you don’t understand

    The venous connection to MS- a timeline
    To those doctors who insist the venous connection to MS is an unproven theory, I offer a timeline of doctors who might beg to differ.

    1863 Rindfleisch
    Dr. E. Rindfleisch noticed that, consistently in all the autopsy specimens of MS brains he viewed with his microscope, a vein engorged with blood was present at the centre of each lesion.

    Rindfleisch wrote:
    “If one looks carefully at freshly altered parts of the white matter … one perceives already with the naked eye a red point or line in the middle of each individual focus,.. the lumen of a small vessel engorged with blood … All this leads us to search for the primary cause of the disease in an alteration of individual vessels and their ramifications; All vessels running inside the foci, but also those which traverse the immediately surrounding but still intact parenchyma are in a state characteristic of chronic inflammation.”

    Rindfleisch E. – “Histologisches detail zu der grauen degeneration von gehirn und ruckenmark”. Archives of Pathological Anatomy and Physiology. 1863;26:474–483.

    1930s Putnam
    Dr. T. J. Putnam researched lesions and noted that thrombosis of small veins could be the underlying mechanism of plaque formation-
    Putnam, T.J. (1937) Evidence of vascular occlusion in multiple sclerosis

    1942 Dow and Berglund
    Dr. Robert Dow and Dr. George Berglund continue on with Dr. Putnam’s research and continue finding venous connections to MS lesions.
    VASCULAR PATTERN OF LESIONS OF MULTIPLE SCLEROSIS Arch Neurol Psychiatry. 1942;47(1):1-18.

    1950 Zimmermann and Netsky
    Dr Zimmerman and Netsky carry on with Dow and Berglund’s research, and note that the lesions are indeed venous in nature, but not caused by small thrombosis as Putnam surmised.
    Zimmerman, H. M., Netsky, M. G.: The pathology of multiple sclerosis. Res. Publ. Ass. Nerv. Ment. Dis. New York 28, 271–312 (1950)

    1960s Fog
    Dr. Torben Fog, a Danish professor – noted that MS lesions are predominantly around the small veins. His subsequent study of 51 plaques from two cases of typical MS, making thin sections of the plaques and following their shape and course with direct drawings of each section, showed that most were prolongations of periventricular plaques, and that the plaques did follow the course of the venous system.

    Fog Torben, The topography of plaques in multiple sclerosis, with special reference to cerebral plaques. Acta Neurol Scand, 41,Suppl. 15:1, 1965)

    Fog T. On the vessel-plaque relations in the brain in multiple sclerosis. Acta Psychiat Neurol Scand. 1963; 39, suppl. 4:258

    1980s Schelling
    The story began in 1973, at the University of Innsbruck, when F. Alfons Schelling, M.D. began investigations into the causes and consequences of the enormous individual differences in the widths of the venous outlets of the human skull. The results of this study appeared, in 1978, in the official organ of the German-speaking Anatomical Societies, the “Anatomischer Anzeiger”.

    F.A. Schelling’s 1981 discovery, at the Hospital for Nervous Diseases in Salzburg, of a striking widening of the main venous passageways through the skulls in victims of multiple sclerosis were to occupy the author’s thoughts through the following decades of his quite diversified medical career. And in putting together, bit by bit, all the observations on the venous involvement in the emergence of the specific, and, in particular, cerebral lesions of multiple sclerosis, he was able to recognize their causes.

    “Unequal propagation of central venous excess pressure into the different cerebral and spinal venous drainage systems is the rule rather than the exception. The intensity of the forces thus to be exerted on vulnerable cerebrospinal structures by the resulting pressure-gradients in the craniovertebral space is unknown. There is a need to consider the various conditions which may cause individual proneness to heavier reflux into particular cerebral as well as epi- and subdural spinal venous compartments. An attempt is made to indicate eventual consequences of excessive retrograde dilatation especially of internal cerebral veins. The importance of elucidating the neuropathological and clinical implications of undue reflux into the skull or spine is deduced from the probability of relations between localized backflow into the craniovertebral space and unexplicated cerebrospinal diseases. In this regard the features of multiple sclerosis are discussed.”

    Damaging venous reflux into the skull or spine: relevance to multiple sclerosis.
    Schelling F.

    Here is Dr. Schelling’s website for more information. His book (available for free on his site) outlines the history of the connection of MS to the venous system. Dr. Schelling is a brilliant, kind and generous man. When he came public with his research, he was dismissed, ridiculed and mocked. I am so happy that he is able to now witness Dr. Zamboni’s technological corroboration of his findings. It was my pleasure and honor to meet him in Bologna, and to share his research with you.
    http://www.ms-info.net/evo/msmanu/984.htm

    as a final note I will be getting the liberation at the end of September I have had MS for 15 years 7 of my MS friends have been Liberated and are now all much better in fact far Greater than just a placebo effect.
    I was tested 7 months ago for stenosis and my left jugular is blocked, my own neurologist consultant was left with a headache after trying to argue his knowledge with me! he had had not even read Dr Zamboni’s Protocol I HAD! and he was trying to tell me what was in it!? and again I will tell you what I told Him IT IS NOT YOUR field ! you are not a cardiologist! end the procedure is completely safe and is done every day!
    again it is not your field of study you will be proven to be wrong more wrong than you are already. the autoimmune part of MS comes AFTER CCSVI not before

    Yours Trevor Robinson

  7. Trevor – I have researched this topic – reading everything published on medline. I never said in my article that the concept was entirely new – just that it is not established, and it isn’t. You are making claims based upon a small minority of the MS research, and ignoring the vast amounts of research that contradict your position.

    Further, your objections have nothing to do with the two new studies I was specifically discussing. These two studies are dead negative, and you cannot just dismiss them because you don’t like the results.

    I will also point out that anecdotal evidence of a benefit is not compelling, and it absolutely can be placebo effects or other artifacts. We will have to wait for clinical trials to see if there is any real effect from angioplasty or stenting.

  8. taustin says:

    My mother had MS for 35 years, and IMO, one must be very careful about placebo effects with it. MS is not one single, always-the-same thing; it manifests itself differently in every patient, and patient attitude can make a huge, huge difference in many cases (my mom included). On good days, you’d hardly know she had it; on bad days, she should barely walk. A good deal of my father’s care for her, for all those years, was protecting her from stress, and it improved her life enourmously.

    Placebos can be useful, when quality of life is so variable, but it’s not medicine.

  9. Edward says:

    Thank you, Dr. Novella!

    I’m a skeptic with multiple sclerosis. Over the decades I’ve seen everything from magnets and magical shoes, special diets involving fats and “the Paleolithic diet” promoted by everyone from the very well-meaning but naïve to the scientifically trained who decide that and they can trawl through the data of abandoned hypotheses and find some magical cure that was somehow overlooked/ignored/hidden/whatever by the scientists like yourself whose field of study this really is. Argument from authority seems more proof to many than logical fallacy. I appreciate your discussion of this. You will, of course, invite more logical fallacies. Ad hominem already noted.

    I was about to write you and ask that you comment on CCSVI because, of course, I have received the expected e-mails and questions from well-meaning friends and others with MS. I have explained my caution, my skepticism. I very much hope they will better understand when they read your blog post.

    Now, I think I have an episode of SGU catch up on.

    Kindest regards

  10. John Ellis says:

    FYI a nice study recently appeared in the BMJ on how small studies exaggerate the benefits of treatment.
    http://www.bmj.com/cgi/content/full/341/jul16_1/c3515

  11. mikenz says:

    The 4th World Congress on Controversies In Neurology (CONy)
    (Barcelona, October 28-31, 2010) has a nice format debating current contentious issues in neurology. By coincidence, just saw today in my inbox that one of the debates is:

    Debate: Does chronic venous insufficiency play a role in MS pathogenesis?
    Yes: P. Zamboni, Italy
    No: O. Stuve, USA
    Commentator: A. Miller, Israel

    Cheers,

    Michael MacAskill

  12. Al Morrison says:

    I’m curious, in how many independent experiments does the null hypothesis have to be supported before we can reject the original hypothesis? I am (because I am not qualified or knowledgeable) not suggesting two studies reach this threshold for CCSVI. There must be a point at which we can safely say the hypothesized relationship has failed across enough varied paradigms to be deemed falsified.

    With medicine the stakes are high. One would hate to be premature and miss a potential diagnostic or treatment regimen. However, the funding is not unlimited, nor are the number of research hours.

    Both the sufferers/fundraisers and the researchers should have input; however, the question is, to what degree.

    Interested in feedback. Thanks.

  13. SteveA says:

    Trevor Systema: “and again I will tell you what I told Him IT IS NOT YOUR field !”

    You’re not exactly brimming over with qualifications yourself, are you Trevor.

  14. BillyJoe7 says:

    “a preliminary study suggests a wildly new understanding of a scientific or medical question. The scientific community is cautiously skeptical but interested. The press proclaims a stunning breakthrough, and the public is briefly fascinated…But then the wheels of research begin to grind and, more often than not…the new idea turns out to be wrong ”

    This is probably also the origin of the following typical comment by a cynical member of the public: one week scientists are saying that X causes cancer and next week they are saying that it doesn’t.

  15. sgg333 says:

    BillyJoe: exactly!

    You know, the more I read, the more I really think the problem of overstating claims and the subsequent crushing of hope can be laid primarily at the feet of bad media reporting.

    I have my problems, on and off, with various branches of traditional media, but usually they come and go and there is still a net positive.

    But with “breakthrough” science reporting, I think the damage is consistent and many-fold.

    Think about it this way, some “big thing” is “discovered” (HIV treatment, Cancer breakthrough, etc, etc). Media covers it like crazy for a day or two. During the frenzy, scientists in the background waving their hands saying “you know there’s a lot of caveats here – we talk all about them in the paper!!” But, really, who cares what they think.

    Then, months later, it’s kinda walked back. It isn’t panning out, treatment in a human is far more difficult than in the mouse model, the drug has lethal effects, etc.

    In the inner worlds of science, this is nothing new, as you point out here as well.

    But there’s a serious repercussion caused by the media blowing up the balloon, then popping it on cue:

    It causes average folks to think that scientists don’t know what they’re doing.

    And if they don’t know what they’re doing, if anything reported today as “truth” (incorrectly, of course) could be called not-truth next week, why should anyone believe *anything* coming from the mouths of scientists. About *anything* – medicine, evolution, Pluto, some galaxy or a quark, etc.

    Because everyone’s trained to roll their eyes and say: “tomorrow, someone will say the opposite is true”.

    What’s particularly awful about this current situation is the ones getting blamed FIRST are the very scientists who are trying to avoid the whole over-hyping in the first place. But no one gets to see that.

  16. ccsvifab says:

    For an interesting view of a cardiologist on the CCSVI “theory” I suggest you read Dr. Colin Rose’s blog Panaceia or Hygeia, (Brad Wall, Saskatchewan Premier-Good Politician, Bad Scientist).

  17. montybissett says:

    Mr. Novella your conclusions on CCSVI are lame.

    1. Neurologists have no ideao the cause of M.S.
    2. Neurologists are prescribing drugs for a condition they don’t know the cause of.
    3. Zamboni has sAId many times he doesn’t know the cause of M.S.
    4. What he and many other Vascular Dr’s are saying the Angioplasty treatment is helping significant amounts of people.
    5. Sandy MacDonald a Canadian Vascular Dr treated 6 patients with the procedure and all found significant POSITIVE results.
    6. He then tested 200 more PATIENTS and found CCSVI in over 90% of them.
    7. The 2 studies you refernce don’t have a clue or the protocol to apply the testing for CCSVI.
    8. Just one drug Tysabri has caused the death of a significant amount of people.
    9. 58 more have brain abnormalities.
    10. The incidence of damage is increasing with time used.
    11. A Neurologist in San Diego is treating folks with CCSVI and having success.
    12. He also had his own son treated.
    13. There have been close to 1500 procedures worldwide and 2 cases of problems. None of them to do with Angioplasty. 1 due to taking wrong drug and another due to a stent moving.
    14. No deaths to Angioplasty recorded to date.
    15. How do you stack that up against Tsyabri.

    Ive noticed in the last few months of following this file that only the Neurologists are talking of Placebo, talking of danger, talking of false hope. The M.S Scoiety and Big Pharma and the Neuro’s are losing control of the folks with M.S. and it’s getting ugly. They say do no harm. I can’t imagine the harm that has been done by the drugs and the Neuro’s and the MS Society.
    Nobody is saying M.S. is caused by CCSVI. What 99% of the Neuro’s are saying is CCSVI isn’t the cause of M.S.

    It’s obvious we need an honest broker in the mix and that honest broker isn’t you and your gang. There are close to 25 Vascular Dr’s working on this issue around the world and I have a sneaky suspicion the harm that has been done to folks with M.S, is going to have a price tag put on it.
    Remember DO NO HARM

  18. shh92714 says:

    Excuse me, Doctor Novella, but did I read you correctly when you stated that Dr. Zamboni is a neurosurgeon?

    Let’s agree that that is the first inaccuracy in your article?

    You seem to take delight in stating “There are many red flags of crankery in CCSVI, however. First, it may make for good story telling, but it is a bit curious that a neurosurgeon set out to discover a treatment for MS and found a neurosurgical one – even though there was no prior suggestion that this would be the case.”

    In fact, Dr. Zamboni is a former vascular surgeon, one who can no longer operate because of a neurological condition affecting one of his hands. Thus, he has become an academician, a professor of vascular surgery.

    Care to try again?

  19. John2 says:

    Montybisset, were you being deliberately insolent by referring to Dr Novella as Mr, or did you manage to have such a lax view of cactus that you managed to be wrong in the very first word which you posted?

    Your confusion between anecdote and peer reviewed published trial data would suggest the latter, but your later insults suggest the former.

  20. BillyJoe7 says:

    “Excuse me, Doctor Novella, but did I read you correctly when you stated that Dr. Zamboni is a neurosurgeon?…In fact, Dr. Zamboni is a former vascular surgeon,”

    But that actually works better:

    “There are many red flags of crankery in CCSVI, however. First, it may make for good story telling, but it is a bit curious that a vascular surgeon set out to discover a treatment for MS and found a vascular-surgical one – even though there was no prior suggestion that this would be the case.”

  21. titmouse says:

    Montybisset, were you being deliberately insolent by referring to Dr Novella as Mr, or did you manage to have such a lax view of cactus that you managed to be wrong in the very first word which you posted?

    Cactus?

  22. mindme says:

    1. Neurologists have no ideao the cause of M.S.

    So?

    2. Neurologists are prescribing drugs for a condition they don’t know the cause of.

    So? If double blind trials indicate the drugs can have effects on the symptoms, what of it then? I might not be able to cure a common cold but I sure do appreciate any drugs that alleviate a symptom.

    3. Zamboni has sAId many times he doesn’t know the cause of M.S.

    So?

    4. What he and many other Vascular Dr’s are saying the Angioplasty treatment is helping significant amounts of people.

    What Dr. Novella (who is Mr. Novella?) is saying is replication (an important feature of science and not anecdote telling) is showing something quite different.

    5. Sandy MacDonald a Canadian Vascular Dr treated 6 patients with the procedure and all found significant POSITIVE results.

    And Dr. MacDonald published this in which journal?

    6. He then tested 200 more PATIENTS and found CCSVI in over 90% of them.

    Have you considered you have the cause/effect chain reversed. Perhaps CCSVI is a symptom of MS but relieving that symptom has no effect on the progression of the disease.

    7. The 2 studies you refernce don’t have a clue or the protocol to apply the testing for CCSVI.

    In your medical opinion?

    8. Just one drug Tysabri has caused the death of a significant amount of people.

    A non sequitur. All drugs have risks. We have to balance the risks with the benefits. You don’t suppose a surgical intervention like angioplasty is risk free? If well designed trials indicate there are no benefits then the risks are pointless.

    9. 58 more have brain abnormalities.

    So?

    10. The incidence of damage is increasing with time used.

    What damage? Damage from what?

    11. A Neurologist in San Diego is treating folks with CCSVI and having success.

    And he published these results in what medical journal?

    12. He also had his own son treated.

    A meaningless anecdote.

    13. There have been close to 1500 procedures worldwide and 2 cases of problems. None of them to do with Angioplasty. 1 due to taking wrong drug and another due to a stent moving.

    So, there are risks.

    14. No deaths to Angioplasty recorded to date.

    The risks of death are low but angioplasty does have a .01% risk of death. Again, why go to the expense and risk (there are other serious risks you want to avoid aside from death) for a procedure that does not work?

    15. How do you stack that up against Tsyabri.

    Why does he have to “stack up”? What do you mean “stack up”?

  23. John2 says:

    Sorry, Titmouse, that was originally typed as “facts”, but I think that a typo followed by the ipad’s autocorrect gave cactus instead.

  24. a liberated guy says:

    Dear Dr. Novella do you know why there are dead negative? Read this (probably you already have):

    Dr Sclafani’s response

    11 August, 2010

    It is regretful that Drs. Doepp and co-authors’ attempt to reproduce Professor Zamboni’s discovery of a link between multiple sclerosis and disturbance of the outflow veins of the brain and spine has been unsuccessful.

    It is particularly unfortunate that the authors’ misunderstanding of Dr. Zamboni’s publications about this subject have led to their conclusions that “No cerebrocervical venous congestion in patients with multiple sclerosis” exists

    The authors mis-state several of the criteria for a positive ultrasound examination. They state that reflux must be present in both internal jugular veins or both vertebral veins. This is not accurate. Reflux in any one of these veins was considered a positive criteria by Zamboni.

    It appears to me that Dr Doepp and colleagues have tried to elicit reflux by testing for incompetent valves in the lower jugular vein. Incompetent valves result in reversal of blood flow from the heart back up into the jugular veins. They used the Valsalva maneurer, a technique to increase pressure in the chest that reverses blood flow. However, Zamboni explicitly states that one should assess flow “never in (by) a forced condition such as the Valsalva manoeuvre.”

    That the authors’ attempts were unsuccessful is not surprising. The ultrasound examination used by Zamboni is a simple one but the description of the technique has not been fully elaborated in his papers. Thus performance of the ultrasound by some investigators is often at variance and this may lead to differences of results. At my own institution, we were surprised that non-invasive testing by ultrasound did not correlate with the very obvious obstructive phenomena seen on catheter venography, which remains the Gold Standard of assessing veins. We also had difficulty identifying CCSVI on ultrasound, initially using the Valsalva maneuver during out testing. In fact we were able to find an obstruction in only one patient of twenty. It was only after being shown how to correctly perform this simple screening test by the Zamboni team during a visit to Ferrara, that we have become facile in detecting these abnormalities. It is clear that there is a learning curve to the use of this technique.

    Nor does this paper refute the concept of CCSVI. Doppler ultrasound is only a screening test for CCSVI. When Doppler shows signs of CCSVI, the gold standard test of catheter venography is indicated to detect the sites of potential obstruction.

    Doppler is not the definitive test of CCSVI because it cannot assess the azygous vein, an important contributor to cerebrspinal venous outflow resistance. Catheter venographies routinely show evidence of outflow obstructions. Sluggish flow, reversal of flow, extensive collateral veins, strictures, duplications, reversed valves, thickened incompletely opening valves and misplaced valves are among the many abnormalities seen in MS patients that we never see in patients without MS.

    The paper by Sundstrom and coauthors similarly rejected the CCSVI hypothesis by performing MR venograms and flow quantification in the neck. MR venography is suboptimal as a screening test because it underestimates and overestimates stenoses quite regularly.

    One can see from their illustrations two MRV images. It is noteworthy that neither image shows the portion of the jugular vein where lesions causing flow resistance are usually found: behind the clavicle as the vessel enters the chest. Both images show considerable collateral vasculature suggestive of CCSVI. Moreover the image on the right on page 258 purports to show a stenosis with an arrow. It is well known that most of the narrowings referred to by the white arrow are a common transient, non-stenotic narrowing caused by a true narrowing below the clavicle. Catheter venography shows abnormalities that cannot be detected by MRV.

    I was struck by the rapidity of publication of both articles. Surprising! Both papers were accepted within six weeks. I have never had such rapid decision, editing and publication of any of my more than 120 publications.

    This debate is going to be a challenging one. One side wants randomized prospective trials to prove efficacy.

    However while many proceduralists have noted sometimes impressive gains for patients, these proceduralists need to evaluate nuances of techniques before consensus can be built regarding the best approach to therapy. Only then can intelligent, carefully designed randomized prospective trials begin. Some who commonly perform randomized trials will try to reduce the work of those who will try to develop the best practices because they are not randomized. However, in my view this is a necessary initial step toward the final trials.
    —————————
    Yeah…dead negative…

  25. liberated – these studies definitely have limitations, which is why I said they will not be the final word.

    This is how science progresses – someone does a study, another group does another study – they argue about the details, then out of that argument better trials are designed until eventually you get definitive “consensus” trials that everyone can stand by. We are not there yet.

    You are assuming that Zamboni’s diagnostic methods are better. Perhaps they are more likely to produce false positives. It is still curious that his dramatic results are not easily found by similar techniques to look for insufficiency.

    I have no problem with pursuing an alternate hypothesis of MS. I just think the hype is premature. History dictates that the odds are heavily against such new ideas in medicine. So forgive some skepticism from those who have been through it many times before.

    All we want is evidence before hype.

  26. ccsvifab says:

    Dr. Sclafani’s criticism of using MR to check venous anatomy of the head and neck is very strange, nebulous and seems to be grasping at straws. Dr. Sclafani does not provide references to support his opinions on the limitations of MR to assess veins. In two recent papers on imaging of Deep Vein Thrombosis (British Journal of Surgery 2008;95:137-146 and eMedicine Radiology April 10, 2009) Magnetic Resonance Venography was described as highly sensitive and relatively specific. In fact the British Journal of Surgery stated that MRV was more accurate than standard contrast venography or ultrasound in detecting pelvis vein thromboses. So why do proponents of the CCSVI hypothesis have so much difficulty MRV when it does not back up their findings? ( I can only imagine what Dr. Sclafani’s response would have been if Sundstrom’s paper had been supportive of CCSVI). The response by Dr. Sclafani as posted by a liberated guy reminds me of the garage dwelling invisible dragon as described in Carl Sagan’s Demon Haunted World. To paraphrase his example,
    “Sure MR is good at imaging other venous structures in the body but when researchers, other than me or my collaborators use it on the veins of the head and neck it becomes a useless method to investigate the pathology we say is there. So of course you will get negative results.”
    Of course as Dr. Novella points out we are still looking for the final word on this controversy, but we won’t get there by special pleading by the advocates of CCSVI when the evidence goes against them.

  27. ria_rokz says:

    Thank you for this article. It has reaffirmed why I don’t believe it is time for clinical trials of the procedure, and why I am skeptical of CCSVI in general. My opponents only use anecdotal evidence and conspiracy theories to back up their points. I am glad to see the scientific reasoning written so clearly.

  28. LarryG says:

    “Which course the new idea will take seems to depend largely on the original scientist – if they accept the new evidence and abandon their claims, it will likely fade. If they refuse to give up in the face of new evidence, then a new pseudoscience will likely be born.”

    In this case, the resulting psuedoscience requires treatments that people would only get by going overseas at the cost of tens of thousands of dollars (10K – 30K range, from many reports).

    Today, many patients can do it because they are helped by fundraisers and donations. Those will dry up if the treatment is proven ineffective.

    So, between the cost to the individual and the lack of outside help, I’m not sure it’ll survive quite the same way a cheaper treatment could…

  29. montybissett says:

    There are only 2 Neuro’s in the world who have stepped up to the plate for folks with M.S. Dr Sclafani and Dr Hubbard. Sclafani
    tried to actually derail Dr. Zamboni by sending him patients without M.S. to test. It is obvious 99% of Neuro’s can’t be anywhere near the CCSVI without Adult supervision. They just had a supposed expert panel in Canada tell the Gov’t not to do trials.
    2/3 of the panel were Neuro’s and all with ties to the drug companies. Some receiving millions of dollars of grants to study their drugs. Dr Novella this is one for the Vascular Dr’s. and the IR’s they will be the final judge of the procedure.
    They will find out if the procedure is safe and productive.
    By the way Dr. Hubbard and Dr. Zamboni both have huge conflict’s of interest. Dr Zamboni’s huge conflict was the love of his wife.
    Dr. Hubbards conflict was the love of his son.
    This is just another story to drive the Neuro’s crazy. Dr. Hubbard just treated his first Parkinson’s patient for CCSVI. I have to be honest I have no idea if the procedure helped. What i do know is the patient survived the UNBELIEVABLY DANGEROUS PROCEDURE. Keep up peddling the nonsense of false hope and placebo’s and the German and Swedish studies. Your definitely open minded and on the right track. There is 600,000 folks with M.S. that are counting on you giving a fair and balanced accounting. Hopefully you will study CCSVI and get back to the folks with some facts.

  30. colros says:

    Zamboni is not a neurosurgeon. He is a varicose vein surgeon. As Mark Twain said, to a man with a hammer everything looks like a nail. Zamboni was determined to find a venous cause for his wife`s MS.

    “CCSVI” is junk science. See my blog for details.

    http://medicalmyths.wordpress.com/2009/11/24/the-zamboni-myth-ccsvi-surreal/

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