Thursday, 17 May 2012

CCSVI and MS: no meaning, no fact

Epub ahead of printBaracchini et al. CCSVI and MS: no meaning, no fact. Neurol Sci. 2012 May 9.

A condition called "chronic cerebrospinal venous insufficiency" (CCSVI) has been postulated to play a role in the pathogenesis of multiple sclerosis (MS). This hypothesis implies that a complex pattern of extracranial venous stenosis determines a venous reflux into the brain of MS patients, followed by increased intravenous pressure, blood-brain barrier breakdown and iron deposition into the brain parenchyma, thus triggering a local inflammatory response. In this review, we critically analyze the scientific basis of CCSVI, the current literature on the relationship between CCSVI and MS, as well as the ultrasound methodology that has been claimed to provide evidence of impaired cerebral venous drainage. We show that no piece of the CCSVI theory has a solid supportive scientific evidence. The CCSVI appears to be a rather alien condition and its existence should be definitely questioned. Finally, no proven (i.e., based on strict scientific methodology and on the rules of evidence-based medicine) therapeutic effect of the "liberation" procedure (unblocking the extracranial venous obstruction using angioplasty) has been shown up to date.


"Interesting that this has been written by an Italian group; Italy remains in the eye of the storm."

29 comments:

  1. Bin here we come.
    I have been saving these until end of month more to follow.

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  2. I agree with the title 100%, because this is what happens (100% of the time) when research is ignored. Currently there are over 200 peer-reviewed abstracts and papers at ccsvi.org. Recommend reading Canada's response to the FDA (today) by CCSVI Ontario ... much detailed information in the letter that sumarizes the current situation in Canada and USA.

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  3. It's amazed me from the beginning that even skeptics of the theory of ccsvi agree to the need for clinical trials when the crucial point of the entire situation is that not long ago shared total obscurity along with the thousands of other theories of possible MS causes and treatments.

    The only thing to eventually distinguish the theory of ccsvi from the thousands of other theories was that Dr Zamboni announced to the world that his studies showed a 100% association between his claimed diagnostic criteria for MS and 0% association among people who don't have MS.

    Unfortunately it soon became evident that Dr Zamboni's figures were way off to the point that can only be explained as the product of incompetence or dishonesty.

    With it soon being obvious that the theory of ccsvi had risen to the world's attention without legitimate grounds and through false pretenses the theory of ccsvi should have sunk back into deserved obscurity as any other theory found to be without merit would have, but this is the age of the internet and an out of work nurse and a California housewife with internet skills made the promotion of the theory of ccsvi their mission in life, despite the dearth of supporting evidence for the theory of ccsvi, they've been amazingly successful in their mission.

    I've often read ccsvi proponents wondering why the medical establishment isn't taking the theory of ccsvi seriously and as mentioned above I think it really involves that in the minds of most people of science ccsvi long ago proved itself without merit and sunk back into obscurity as justified due to it's rise to "fame" under false pretenses.

    The theory of ccsvi deserves further clinical trials no more than any of the other thousands of theories waiting patiently in the wings.

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  4. I totally agree with what Robert above says.

    When CCSVI first became news I was as excited as anybody, because who wouldn't welcome a miracle cure?

    I thought the 100% association was very convincing and I told everybody about CCSVI and set up Google Alerts and read every bit of CCSVI news for many months. But as Robert says 'it soon became evident that Dr Zamboni's figures were way off'

    The neuro's reaction also helped to change my mind. He said it doesn't mean much that some patients got better because he has had patients getting better after bee sting therapy and various other things

    I got even more doubtful after watching & reading Ben Goldacre on the placebo effect (Prof G's recommendation)

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  5. Anonymous
    The paper described meticulously examimes the available evidence and comes to the conclusion that there is no evidence for ccsvi. Furthermore it indicates where Dr Zamboni has been "economical with the actualite".
    There is no point in reading anything from ccsvi.org or CCSVI Ontario as these are hopelessly biased sites, which do little more than encourage desperate people to part with significant amounts of cash for no proven gain.

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  6. naysayers do the research

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  7. I don't believe in CCSVI but I can't overlook the benefits MSers get from a treatment even if it is only temporary or due to a placebo effect.

    So I thought "what could be a good explanation why it works" and came across a theory of an "reverse Uhthoff phenomenon".

    The idea of CCSVI is that blocked veins cause a reduction blood flow through the vessels. By dilating the veins or placing a stent within the vein it is ensured that the blood flow is set back to a normal value.
    A blocked vein may cause a reduced blood flow (always mentioned by Dr. Zamboni, but not much people seem to take notice of this). If you have a reduced blood flow the temperature increases slightly within the blood vessels.
    This may cause a gain of symptoms even if the patient doesn't feel anything. Also it may increase the local count of leucocytes (lymphozytes).

    If the outer temperature increases, the body can't lower the local temperature due to the blocked vein and cause what is known as "Uhthoff phenomenon".
    If the vein is then dilated and the blood flow is set back to a normal value, the temperature is decreased.
    With the decrease of the temperature the symptoms also fade.
    So that's why I call CCSVI a "reversed Uhthoff phenomenon".
    This is a very mechanic look at the process taking place. But it may explain what is happening.
    Please keep in mind that the increase in temperature might be very low and local (0.2 - 1.5°C) but at a constant level.

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  8. Reference number [6] of the article by Baracchini et al is the following:

    http://onlinelibrary.wiley.com/doi/10.1002/ana.22228/pdf

    "No Evidence of Chronic Cerebrospinal
    Venous Insufficiency at Multiple Sclerosis Onset"

    In there, Baracchini tells the story of performing 10 venographies and finding only one problem, a hypoplastic right internal jugular vein. By that he concludes that ccsvi is non-existent.

    However, the writers include an image of a venogram that seemed normal to them, despite an abnormal ultrasound. You can check it out, Figure 3. You might show it to a vascular expect too. You will clearly see that there is a horizontal obstacle (immobile valves) that prevent the contrast media from flowing down. You will also see that there is no stenosis on the vein walls themselves. On the contrary, the vein is distended in the valve area (due to flow congestion) and has the shape of a pear.

    So, Baracchini presented a problematic vein as normal and convinced you that there is no ccsvi. This is a very low quality research you base your arguments on to.

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  9. Re: "Reversed Uhthoff phenomenon"

    I am not aware of any evidence for this, but it needs exploring. You may be interested to know that the cavernous sinus that drains in the internal jugular vein acts as a heat exchanger cooling blood in the carotid artery. This is very important in ungulates (antelope, etc.), but is rudimentary in humans. It is called a carotid rete.

    You can read more about it on our Teach Neurology site: https://sites.google.com/a/giovannoni.net/teach-neurology/7-evolutionary-neurology/evolutionary-neurology/paranasal-sinuses

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  10. Vasilis Vasilopulos
    Regarding low quality research, the pro-CCSVIers have set a very low bar.
    Now PLEASE stop wasting our time. There are many other sites where your "wisdom" may be appreciated but not here. Thanks.

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  11. Can we trust doctors (earning probably £200,000 a year) who do not even know what post mortem and MRI evidence proves about how our lesions form. They do not even know about the doctors who have been warning for many years that MS is not an immune disease (they didnt know about CCSVI either but at least the other doctors know MS lesion formation has nothing to do with immune inflammation!!) That is what I find most shocking about neurologists in this country - they are brainwashed robots blindly doing what neuroimmunologists tell them to do for their £200,000 a year plus 'finders fees' for putting US on any old chemo drug trial... Breathtaking they get away with it.

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  12. Re: "Can we trust doctors earning probably £200,000 a year."

    If only; the average consultant neurologist in the UK earns half that. Why should what we earn affect trust? Does earning money make people untrustworthy? I feel another pointless philosophical debate emerging.

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  13. Re: "... who do not even know what post mortem and MRI evidence proves about how our lesions form."

    If you know the answer to this please share it with us. Even experienced neuropathologists don't know exactly how MS lesions develop, hence the ongoing debate in the field.

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  14. Re: "...at least the other doctors know MS lesion formation has nothing to do with immune inflammation!!"

    What is the evidence for this? Even in the Prineas early lesion there is lots of antibody deposition and complement activation products with some low grade T cell infiltration. These are all signs of inflammation.

    In the van der valk pre-MS lesion there is prominent microglial activation. Another sign of inflammation.

    What is known is that in all these early MS lesions there are no signs of venous stasis or slow flow. So we are pretty confident that the venous flow hypothesis is unlikely.

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  15. Re: "... for putting us on any old chemo drug trial... Breathtaking they get away with it."

    The only old chemo drugs we use are mitoxantrone and this is seldom used in the UK. Cladribine was repurposed as an oral formulation and this is not being taken forward. Alemtuzumab is a old oncology drug, but as it is not a chemo or chemical drug, but a biological it doesn't conform to this definition. May be you can clarify what you mean?

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  16. MD2, Prof GG, you still haven't made any comments on the vein image of the Baracchini venography. Figure 3, image B. Link:

    http://onlinelibrary.wiley.com/doi/10.1002/ana.22228/pdf

    The file has open access so anyone can see it. Professors, commenters of this blog, please take a look and write your opinion:

    Does the flow inside the vein look normal to you? Is this what you would expect to happen inside a 12mm wide vessel that drains the brain?

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  17. VV
    The reason we have not made any comments is that it is a waste of our time. Every negative CCSVI trial that comes out confirms this.

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  18. MD2, you only need 10 seconds to download the pdf and see the picture. I hope your readers are more willing to spend that amount of time.

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  19. If the author responds to your comment, you will get a response

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  20. ReRe: "Reversed Uhthoff phenomenon"

    I've taken a closer look on the cavernous sinus (wikipedia, mediacal books etc.).
    And I was surprised that this sinus is surrounded by a lot of nerves.
    Most of these nerves corelate with MS symptomes.

    Are there any data availible on how nerves react if the temperature gets too high?

    Because I remember an article of a Japanese company who invented a brain cooling device for their engineers so they wont get too tired too soon. It only cools about 3°C.

    Greetings

    Marc

    (english is not my mother tongue)

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  21. Re: "Are there any data availible on how nerves react if the temperature gets too high?"

    The sodium and other channels malfunction; demyelinated nerves stop conducting and others become overactive. This is why you get pyrexial convulsions with very high temperatures.

    High temperatures are not good for you!

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  22. Re: reversed Uthoff, temperature, nerves

    Thanks for the info!

    I am not a medical or biological educated person. But this sounds very interesting although I don't believe in CCSVI.
    This is the first time I read about this and it makes a bit of sense.

    I haven't read about cavernous sinus and the nearby nerves in any CCSVI article yet.

    Is there anything besides genes, antibodies etc. which makes this thesis obsolete?

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  23. Re: "Is there anything besides genes, antibodies etc. which makes this thesis obsolete?"

    Yes, causation theory and epidemiology. CCSVI does not tick any of the boxes for causation and it can't explain the epidemiology of MS, i.e. the worldwide distribution of the disease.

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  24. Dear Prof. G.

    thanks for the time and the intersting facts.

    So it's a classical causation/correaltion issue.
    It looks like CCSVI is causing MS, but it only correlates.
    And it only correlates with a part of MSers.

    Like global warming is caused by less pirates sailing the seas.
    It looks good, sounds good and it also may make a bit of sense but it has nothing to do with it.

    This is something I can tell other MSers if the topic comes up.
    I just needed this last piece of the puzzle. Now my disblieve in CCSVI has turned to knowing that CCSVI doesn't cause MS.

    Thanks a lot! Your time effort and information is much appreciated!! :)

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  25. Re: "Thanks a lot! Your time effort and information is much appreciated!"

    One of the reasons I started this blog was to counteract misinformation, in particular that around CCSVI.

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  26. An MS friend of mine had the procedure last year. It had the immediate effect of taking away her severe fatigue. She still gets tired but has lost the overwhelming feeling which compelled her to lie down immediately and sleep for hours on end. She was hoping for an effect on her walking, which hasn't happened but at least she can last the day.

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  27. "it can't explain the epidemiology of MS, i.e. the worldwide distribution of the disease. "

    Nothing can adequately explain that distribution. There are more direct and tangible characteristics of MS that should be explained prior to such a vague and error prone observation as worldwide distribution. Periventricular distribution of cerebral lesions, for example.

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