Sunday, 2 October 2011

CCSVI: study that fails to reproduce Zamboni's findings is now in print

Tsivgoulis et al. Extracranial venous hemodynamics in multiple sclerosis: A case-control study. Neurology. 2011 Sep 27;77(13):1241-5.

"This paper is now in print; I thought it may be worth reminding readers of its findings."

Background: A chronic state of impaired cerebral and cervical venous drainage, termed chronic cerebrospinal venous insufficiency (CCSVI), has recently been implicated in the pathogenesis of MS. The researchers performed a color-coded Doppler sonography case-control study to externally validate the CCSVI criteria.


Methods: They prospectively evaluated consecutive patients with clinically definite MS and healthy volunteers using extracranial and transcranial color-coded Doppler sonography. The recently developed neurosonology criteria for CCSVI detection were used for interpretation of ultrasound assessments. The presence of venous reflux in cervical veins was assessed both in the sitting and upright position during a short period of apnea and after Valsalva manoeuvre (straining to increase the pressure in the lungs).

Results: They recruited 42 patients with MS (mean age 39 ± 11 years, 17 men) and 43 control individuals (mean age 38 ± 12 years, 16 men). Very good/excellent intrarater and interrater agreement (κ values 0.82-1.00) was documented in 3 out of 5 CCSVI criteria. There was no evidence of stenosis or nondetectable Doppler flow in cervical veins in patients and controls. Reflux in internal jugular vein (IJV) was documented in 1 patient (2%) and 1 control subject (2%), both in sitting and supine posture during breath holding. After performing Valsalva maneuver to increase the pressure in the lung, they documented the presence of IJV valve incompetence in 3 patients with MS (7%) and 4 healthy volunteers (9%; p > 0.999).

Conclusions: With established reproducibility of venous ultrasound testing, these data argue against CCSVI as the underlying mechanism of MS. Without further independent validation of CCSVI, potentially dangerous endovascular procedures, proposed as novel therapy for MS, should not be performed outside controlled clinical trials.

"I have now lost count of all the studies that have not been able to reproduce Zamboni's data. Do we still need more data? It is becoming increasingly clear that CCSVI does not exist as a disease entity."

32 comments:

  1. Dr. Zamboni clearly stated that Valsalva manoeuvre was NOT to be used, so why was it used in this study; this most certainly was NOT done by anyone who has been trained properly to detect CCSVI.

    As a person who has had the treatment to correct CCSVI, I can tell you first-hand of its benefits.

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  2. thousands worldwide have benefitted with a much better quality of life.Its not a cure as many journalists beleive who have not done their research properly at all

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  3. Perhaps a study that actually uses the Zamboni protocol would come to a different conclusion. I say that, because the treatment worked brilliantly for me and countless others. The question should not be whether it works or not, but how we can make the results last. Stent use has complications and even with stents, re-stenosis is a given eventually.

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  4. The neurologists are not able to do the ultrasound for CCSVI.
    They don't understand anything about the veins.
    They are only interested in drugs.

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  5. CCSVI is the biggest hoax of 2009-2011.

    It's a complete placebo effect. It works because you're fooled in to thinking it works.

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  6. My husband has had MS for 33 years. His condition has been severe for several years. His IJV were 100% stenosed. His azgos vein 85-90% stenosed. The edema in his hands disappeared immediately as venus blood began to flow. He has had relief from 6 or seven or his sypmtoms.

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  7. I would like to see both the credentials of the person/peope who designed and performed the study as well as their financial tracking. i.e. do they get money or subsidies from pharma? Full disclosure please!

    Also, to the person who stated this is a placebo I would like to know why the DMD's aren't also a placebo effect and why their placebo effects aren't as good as CCSVI's?

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  8. Re: "I would like to see both the credentials of the person/peope who designed and performed the study as well as their financial tracking. i.e. do they get money or subsidies from pharma? Full disclosure please!"

    The following is copied from their paper:

    Disclosure: The authors report no disclosures.

    AUTHOR CONTRIBUTIONS

    Dr. Tsivgoulis: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, study supervision. Dr. Mantatzis: drafting/revising the manuscript, contribution of vital reagents/tools/patients. Dr. Bogiatzi: analysis or interpretation of data, acquisition of data. Dr. Vadikolias: drafting/revising the manuscript, study concept or design. Dr. Voumvourakis: drafting/revising the manuscript, acquisition of data. Dr. Prassopoulos: drafting/revising the manuscript. Dr. Piperidou: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, statistical analysis. Dr. Heliopoulos: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, statistical analysis.

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  9. Re: "Also, to the person who stated this is a placebo I would like to know why the DMD's aren't also a placebo effect and why their placebo effects aren't as good as CCSVI's?"

    Absolutely; that is why trials are randomised double-blind and placebo-controlled. The blinding and randomisation takes care of the placbo effect that occurs in all trials. Unfortunately, the CCSVI'ers don't appreciate this, which is makes it impossible to interpret their data. This is all explained in Bad Science, by Ben Goldacre; a book I recommend everybody should read particularly if you are following CCSVI saga. It is amazing how history repeats itself.

    Thanks for commenting with a name and not as anonymous, it makes a difference.

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  10. The pathogenic role of cerebral venous insufficiency in MS is not Zamboni's invention. Dr Franz Schelling has elaborated on this subject years before the emergence of CCSVI. Not to mention Tracy Putnam's experiments back in 1937. Are you familiar with all these?

    On the other hand, how can you still support the autoimmune hypothesis after the overwhelming evidence against it, as reflected in the work of numerous researchers: Lumsden, Barnett, Prineas, Chaudhuri, Behan?

    Why do you regard the animal model EAE as analogous to MS, though it mostly resembles ADEM?

    How can you explain the formation of Dawson's fingers under the autoimmunity axiom? Dr Clive Beggs had no difficulty in doing it as a clear consequence of CCSVI.

    Why do you insist on the value of any conclusion derived from ultrasound, since the golden standard for finding venous flow problems is now invasive venography plus IVUS?

    And last but not least, have you heard that Parkinson's disease is most probably the neurological aftermath of a mechanical compression of the brain by a certain artery (Peter J Jannetta)?

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  11. Re: "Dr Franz Schelling has elaborated on this subject years before the emergence of CCSVI. Not to mention Tracy Putnam's experiments back in 1937. Are you familiar with all these?"

    I am aware of it; Alastair Compston discussed it at a meeting several months back. I seem to recall however that the theory predates Schelling. However, Zamboni's theory evokes iron deposition. Not aware of Tracy Putman's work; is it relevant?

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  12. Re: "How can you still support the autoimmune hypothesis?"

    I never have; the autoimmune hypothesis can't explain MS. I think MS will most likely turn out to be an infectious disease.

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  13. Re: "how do you regard the animal model EAE as analogous to MS, though it mostly resembles ADEM?"

    I don't; I agree it is like ADEM. However, some EAE models allow you to study and screen therapeutic agents; for example anti-spastic therapies and possibly neuro-protective therapies.

    It is quite clear you don't know me very well and haven't read my work and ideas; you seem to have gotten everything wrong about me so far.

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  14. Re: "How can you explain the formation of Dawson's fingers under the autoimmunity axiom?"

    I haven't made any claims about Dawson's fingers.

    "Dr Clive Beggs had no difficulty in doing it as a clear consequence of CCSVI."

    I suppose Dr Beggs can explain the genetics, latitudinal effect, OCBs, month-of-birth, sex ratio, migration effect, ectopic B cells follicles, gray matter pathology and the EBV-smoking-vD association by CCSVI.

    I would recommend that you apply modern causation theory to CCSVI; you may then begin to realise that not only is CCSVI a non-disease, but it simply can't explain anything about MS.

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  15. Re: "And last but not least, have you heard that Parkinson's disease is most probably the neurological aftermath of a mechanical compression of the brain by a certain artery (Peter J Jannetta)?"

    Not sure about this! As far as I am aware Parkinson's disease is misnomer; it is now a syndrome with 18+ genetic causes and a potentially large number of other causes. However, I assume you are referring to Lewy body positive disease. If you are you should read Braak's theory of the disease. In a meta-analysis we are completing on PD, trauma does not come up as a risk factor. I therefore would appreciate it if you could refer to the relevant publications. Thanks.

    This discussion is irrelevant as this blog focuses on MS.

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  16. Re "I never have; the autoimmune hypothesis can't explain MS. I think MS will most likely turn out to be an infectious disease."

    So, there is nothing wrong with the immune system. Then why use immunomodulators and immunosuppressors? Why not antibiotics?

    Any particular bug in mind? I hope not EBV (http://brain.oxfordjournals.org/content/134/9/2772.abstract)

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  17. Re "I don't; I agree it is like ADEM."
    Re "I haven't made any claims about Dawson's fingers."

    So, why are there Dawson's fingers in MS but not in ADEM?

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  18. Re: "So, there is nothing wrong with the immune system. Then why use immunomodulators and immunosuppressors?"

    A misquote; I never said there was nothing wrong with the immune system.

    Often in infectious diseases the immune response to the organism causes the damage; so immunomodulators and immunosuppressive therapies will work.

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  19. Re: "Why not antibiotics?"

    I learnt in 3rd year medical school that you have to know what bug you are treating, or have a good idea of what the most likely bug is before prescribing antibiotics. So that's why I won't prescribe antibiotics.

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  20. Re: "Any particular bug in mind? I hope not EBV (http://brain.oxfordjournals.org/content/134/9/2772.abstract)."

    Yes EBV and possibly HERVs. You should read the literature you may be surprised.

    The Brain article refers to EBV infection in the brain of MS'ers and not to EBV and its association with MS; I suggest you read it properly so that you don't quote it out of context again.

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  21. Re: "So, why are there Dawson's fingers in MS but not in ADEM?"

    Disease are defined as clinico-pathological correlates. It is clear that ADEM and MS are not the same disease so I am not surprised that you don't find Dawson's fingers in ADEM.

    When we establish the cause of MS, i.e. ticked all of Bradford-Hills criteria of causation, Dawson's fingers will be explained. The cause of MS has to explain everything, not just parts of the disease.

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  22. Re "I suppose Dr Beggs can explain the genetics, latitudinal effect, OCBs, month-of-birth, sex ratio, migration effect, ectopic B cells follicles, gray matter pathology and the EBV-smoking-vD association by CCSVI.
    "

    Excluding the non-MS-specific OCBs and the EBV association (see link above) the rest remind me of all the factors affecting venous insufficiency of lower extremities. Now, why is that?

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  23. Re "This discussion is irrelevant as this blog focuses on MS"

    http://www.pagepress.org/journals/index.php/ni/article/view/ni.2011.e7

    no more comments

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  24. Re "The Brain article refers to EBV infection in the brain of MS'ers and not to EBV and its association with MS; I suggest you read it properly so that you don't quote it out of context again."

    From the abstract: "Recent epidemiological and immunological studies provide evidence for an association between Epstein–Barr virus infection and multiple sclerosis, suggesting a role of Epstein–Barr virus infection in disease induction and pathogenesis. A key question in this context is whether Epstein–Barr virus-infected B lymphocytes are present within the central nervous system and the lesions of patients with multiple sclerosis".

    So, its not entirely out of context after all.

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  25. Re "When we establish the cause of MS, i.e. ticked all of Bradford-Hills criteria of causation, Dawson's fingers will be explained"

    I'll take this as a "I haven't the slightest idea why and how Dawson's fingers emerge in MS".

    Perhaps you would agree with Dr. Franz Schelling when he says that Dawson's fingers are SPECIFIC TO MS and are therefore worth the investigating priority.

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  26. Re: " "Recent epidemiological and immunological studies provide evidence for an association between Epstein–Barr virus infection and multiple sclerosis, suggesting a role of Epstein–Barr virus infection in disease induction and pathogenesis. A key question in this context is whether Epstein–Barr virus-infected B lymphocytes are present within the central nervous system and the lesions of patients with multiple sclerosis"

    In the diseases in which we know the cause and that has OCBs the majority of the bands, if not all, react with the causative agent. Which is why I don't think EBV is necessarily the causative agent. In MS very few of the bands react against EBV antigens. However, EBV may be working up stream of another virus the so called dual viral hypothesis.

    Finally, the CNS EBV infection hypothesis is still running; we have a paper in press in Neurology with some additional findings.

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  27. Re: "no more comments"

    The Braak hypothesis:http://www.ncbi.nlm.nih.gov/pubmed/19846332

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  28. Re: "Excluding the non-MS-specific OCBs and the EBV association (see link above) the rest remind me of all the factors affecting venous insufficiency of lower extremities. Now, why is that?"

    But you are ignoring the fact that outside of Zamboni's group, and that group in Buffalo with whom he collaborates, the evidence that CCSVI exists is not there. In addition the pathology of chronic venous hypertension is very different to the MS pathology; in particular you don't get Dawson's fingers that are inflammatory.

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  29. Re "Yes EBV and possibly HERVs. You should read the literature you may be surprised."
    Re "Which is why I don't think EBV is necessarily the causative agent"

    You got me confused.

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  30. Re "But you are ignoring the fact that outside of Zamboni's group, and that group in Buffalo with whom he collaborates, the evidence that CCSVI exists is not there"

    Nobody can be forced to see something he does not want to see. Tsivgoulis et al admit that they looked up only 3 out of 5 CCSVI criteria. They say they had a good reason for that. Maybe. But then what they did should not be called CCSVI investigation.

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  31. Re "in particular you don't get Dawson's fingers that are inflammatory."

    I agree. Iron deposition can not lead to Dawson's fingers. But hindered CSF flow combined with flow obstacles in cerebral draining paths can cause injurious venous blood flow inversions consistent with the migraine-exertional headaches that MS patients often describe.

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