The Drug/MRI Fallacy

[centenarian100]

This discussion reminds me of the Tobacco companies who resisted responsibilty by stating that there was no scientific proof that cigarettes caused lung cancer or heart disease.

This isn't a fair analogy because there was a proven very strong association between smoking and lung cancer that nobody could question. The association between CCSVI and MS is not consistently reproducible.

Check out the development of Stents and Interventional Radiology, a relatively new specialty. I don't think the FDA limited development of the specialty.

Again, I don't think this is a fair comparison because no one is challenging the fundamental principle behind many of the procedures that they do. For instance, no one is challenging that arterial occlusion by a thrombus is related to acute stroke or that dural venous thrombosis is contributing to venous hemorrhage. Even in these cases, I think it is important for randomized controlled trials be done before these treatments become widely used.

Why? Because sometimes things aren't as merry as they seem. Check out this famous trial on acute stroke intervention: http://www.nejm.org/doi/full/10.1056/NEJMoa1214300

What if these procedures become too widely used before they are proven to be effective? The result is an enourmous cost, a lot of side effects, no net benefit to the stroke victims.

In this case, nobody is challenging the relationship between arterial occlusion and brain infarction.

Centenarian, it's a question of CHOICE. If someone chooses to take any drug they want, fine. But I should have the choice of venoplasty by a competent experienced Interventional Radiologist paid for by my insurance company (which was possible before the FDA declared the procedure "experimental" May 2012). Right now the FDA is fast tracking new drugs.

I understand the political appeal of choice, but I actually strongly disagree with your position. Of course you feel that you have the right to access to liberation paid for by your insurance company...because you feel that the treatment is effective. You are convinced by the observational studies. You are convinced by the anecdotes. You are convinced by the underlying concept. But of course anyone can believe in any treatment for any condition.

"I want my insurance to pay for experimental chemotherapy for my glioblastoma."
"I want monthly screening full body MRIs because my mother died of cancer."
"A want full exome sequencing out of curiousity"
"I want acupuncture"
"I want to see 10 different specialists because I'm a hypochondriac"

Do we just give everything to everyone? Is this a pragmatic approach to medicine from a community perspective?

Of course not.

You're not the only person on the planet. There are other people with other medical problems. There are lower middle class people who cannot afford health insurance due to outrageous costs who develop hypertensive nephropathy which could have been easily prevented.

The only reasonable way to adjudicate what constitutes medical need and what does not is based on current standard of practice and best available evidence. Most neurologists and most interventional radiologists simply do not believe that liberation is the standard of care. If they did, health Canada would pay for the procedure.

If you want a non-standard of care experimental treatment, you should have to pay cash for it.

You have right to free liberation like I have a right to a free ferrari.

I call this Luddite médicine.

excellent use of "Luddite," but I still disagree

[centenarian100]

You see 'doc the width of my veins are just unfashoinably narrow..."

Haha

[DrGeoff]

The polarization evident in this thread was, I suppose, inevitable.
Right now we are at a point where some people have shelled out the big money, had the procedure, and reported mixed benefits; and on the other side are those who have seen all the conflicting research studies and said to themselves "No Way"

CCSVI does have a number of problems, but the biggest one is its public image.
Right after Zamboni's initial report, the "only in it for the big bucks" section of the medical fraternity started to offer the procedure. Never mind that it was only an experimental idea at that stage - it was available all over Europe and India. That would have influenced everyone who wanted to see some more evidence first.

Next, there is no standardized method for testing for CCSVI. I quote the MS Society of Canada:
"imaging for CCSVI is not standardized at this time"
and that is on their CCSVI information page, marked 2014.
A good testing method must handle individuals that are both upright and prone, and it must give a good discrimination between those with CCSVI and those who do not have it.

After this, then it should be possible to determine if there is any connection between CCSVI and MS. This would need to involve sufficient people that there would be a clear distinction between the population at large and the MS population. If there is such a connection, research should then address the question of directionality: whether CCSVI causes MS, or the reverse. Right now, there is no evidence either way, and of a starting point for some conclusive research. What we do have is a situation where each research report contradicts the one before.

Any discussion of the merits of any particular clinic should wait until the preceding issues have been addressed.

[centenarian100]

Thank you for your comments Dr Geoff

I think that Zamboni himself is indirectly the reason for the controversy.

Lets say that Zivadinov was the first to publish his diagnostic study reporting a modest correlation between CCSVI and MS. His study was of far superior methodology and had far more plausible results. The medical community would have been interested, and the fanaticism amongst patients wouldn't have developed.

Obviously, Zamboni's results were absurd and could not be duplicated with good methodology, so the medical community backlashed against the patient fanaticism.

In addition, in my opinion Zamboni's criteria for CCSVI are silly because of the known high variance in head and neck venous anatomy. Venous pressure and flow would be more reasonable markers. Tons of people have a right or left internal jugular occlusion secondary to a central line catheter and don't develop any problems because they have adequate collaterals and normal central venous pressure and flow. Abnormal flow and pressure in the veins of the brain, optic nerve, and spinal cord is the only thing that could conceivably cause central nervous system disease. The spinal cord cannot see what is going on in the azygous vein. It only "cares" about its own local venous environment (which may or may not be influenced by anatomical abnormalities in the azygous vein)

To make an analogy to cardiology, a chronic coronary artery stenosis or occlusion is not necessarily functionally significant. Functional significance can be inferred by angina/anginal equivalents, dynamic EKG changes on stress testing, and myocardial perfusion studies (for instance). It is not recommended to treat a coronary artery anatomical lesion which is not causing functional cardiac perfusion problems. Even in stable angina (where a stable stenosis causes a fixed degree of functional ischemia), the randomized trials (i.e. the courage trial) was not successful except in symptom relief.

Because zamboni's criteria for CCSVI caught fire, no one pursued more reasonable markers of CCSVI which could be a medically important condition (though not necessarily related to MS)

[DrGeoff]

Just one other thought:
If (and I really do mean if) there is a correlation between MS and CCSVI, and the mechanism is considered to be that the reduced cerebral drainage is preventing a good supply of freshly oxygenated blood to the brain, then why not put things together with another treatment (which is also untested but which has good user reports)?

I am thinking here of HBO. Some people try it and swear by it, others say never again. But if HBO delivers a good supply of freshly oxygenated blood to the brain, and the "Liberation" procedure does exactly the same thing, then surely someone is capable of adding one and one to get two. Or, maybe, the enthusiasts for each treatment have closed their minds to anything else.

Perhaps this could get Zivadinov's attention and then we might really get somewhere.

Geoff

[Kronk]

I am thinking here of HBO. Some people try it and swear by it, others say never again. But if HBO delivers a good supply of freshly oxygenated blood to the brain, and the "Liberation" procedure does exactly the same thing, then surely someone is capable of adding one and one to get two.

HBO Treatments in MS
http://www.ncbi.nlm.nih.gov/pubmed/20415839

I am thinking along the same lines, you would think blood thinners would allow blood to pass more freely through the veins. I think the issue is more with the blood and less with its pathways. There have been many studies showing that MS patients have too much Saturated Fat in plasma. Saturated fat in the cell membrane limits interaction with peptides, hormones, and basically all other functions that require a receptor to connect with its activator. Spinal fluid in MS patients has about 60% more histamine than healthy controls, but HMT its active agent is severely reduced. Meaning we are unable to use histamine so our body is trying to produce an excess of it. Much like how bodybuilders block estrogen to get the body to produce more testosterone which the body tries to convert to estrogen. Histamine and Thrombin have been shown to increase and sustain holes in the BBB.

Really I think the CCVSI is directing research in the wrong direction... of course I hope I am wrong and it turns out to be the cure...

[HarryZ]

Obviously, Zamboni's results were absurd and could not be duplicated with good methodology, so the medical community backlashed against the patient fanaticism.

I don't know if you saw CTV's initial interview of Zamboni in Canada but he basically said this is what I found and I know this requires a lot of research.

Unfortunately, the way it was done turned out to be a big mistake! In most cases, this kind of result in such a small group of people involving something radically different in MS, should have been presented to a peer reviewed medical journal. But those in medicine and having any kind of understanding in the world of MS research would probably have known what kind of negative reaction this would get and it would have likely been stifled.

But now his initial results were broadcast to the world and the reaction it got from MS patients was uncontrollable. We all know how it has panned out since.

[cheerleader]

Dr. Geoff--Dr. Yulin Ge's (from NYU) research presented at the ISNVD conference showed reduced O2 utilization in the MS brain. (p. 43 + 45) He showed how iNOS could be a potential complication. HBOT might be an effective treatment, but if the MS brain cannot utilize the O2 already present---I'm not sure how increasing oxygen amounts would help-- Many researchers are now looking at how cerebrospinal fluid is affected by venous return, and how increases in intracranial pressure compromise the brain's endothelial cells and the blood brain barrier. (p. 40-42) To read all of the abstracts from the ISNVD conference, here is the catalog. I highly recommend you check out the presentation and abstracts. It was a fascinating conference. http://www.isnvdconference.org/images/I ... _2014_.pdf

Harry--Dr. Zamboni's research was peer-reviewed and published in the Journal of Neurology, Neurosurgery and Psychiatry. Stanford University would never have given me the time of day if it wasn't peer-reviewed science.
http://jnnp.bmj.com/content/80/4/392.full

The ISNVD (International Society for Neurovascular Disease) is comprised of dozens of internationally recognized researchers, who are publishing in peer-reviewed medical journals on the vascular connection to diseases of neurodegeneration, and carrying on the CCSVI exploration. http://www.isnvd.org

The research is far from over---and to imply that this has been a failure is simply not true. I saw three of Dr. Dake's original patients at the ISNVD conference, as well as other treated patients. All were active, completely mobile and have had no MS progression and a reversal of MS symptoms. Dr. Zamboni's discovery has been life-changing for them, and their improvements are being followed on MRI and thru EDSS evaluation. My husband's gray matter atrophy has reversed, and his case is being documented. Elena Zamboni remains MS progression free, now seven years past her treatment. The next step is to find out which patients will benefit the most from venoplasty. But people with MS have been scientifically shown to benefit from cessation of smoking, better nutrition, exercise, vitamin D/UV rays and other cardiovascular measures. Just because the research is not complete does not mean it is falacious. The ISNVD (including Zivadinov, Dake, Zamboni, Haacke, Ge, Chung, Begg and others) is not putting this research aside.

cheer/Joan
http://ccsviinms.blogspot.com/2014/02/i ... cture.html

[HarryZ]

Harry--Dr. Zamboni's research was peer-reviewed and published in the Journal of Neurology, Neurosurgery and Psychiatry. Stanford University would never have given me the time of day if it wasn't peer-reviewed science.
http://jnnp.bmj.com/content/80/4/392.full

Hi Cheer,

Prior to Zamboni's CTV interview in Nov 2009, very few people had ever heard of his study results. You would ask the question as to why not but like I pointed out earlier, this was a huge deflection from the accepted MS theory and I doubt anyone in the world of neurology wanted to stick their neck out and run with it.

I'm sure he would have been frustrated at the lack of any progress in getting this news out so he turned to that interview with CTV. I probably would have done the same had I'd been in his shoes. But now you had this incredible bit of news being eventually released globally and we all know what happened afterwards. The pro and con forces have been slugging it out ever since.

Should Zamboni have taken a different route? I don't know but the battle that resulted was not good for anyone. That's why I said it was a mistake. Would things have happened differently had he handled it differently? Don't have the answer to that one.

[cheerleader]

Harry-- I need to clear some things up for you.

A year before CTV did their story, I sent the published research to my endothelial research contact at Stanford, Dr. John Cooke. We had been corresponding on the vascular connection in MS, before I'd seen Dr. Zamboni's publications. Dr, Cooke said he'd get some more opinions, and he gave the paper to his colleagues, including Dr. Dake. That's why Dr. Dake met with Dr. Zamboni at the Charing Cross Vascular Convention, and then asked Jeff to come to Stanford to be tested for CCSVI. Jeff was treated in May 2009, many months before the CTV special. We were actually interviewed in Part 2. Dr, Zamboni was not looking for publicity, he wanted to get other universities involved in the study of venous hemodynamics and MS. He was not "frustrated at the lack of progress"---BNAC was already collaborating with him on studies, as was Dr. Dake and other Italian sites. Let's get the facts straight....they are all here, in print, on this site, preserved, because This Is MS is where the discussion started. I really want people to know the facts, not just some random opinions, or story-telling.

All of us hoped to get interdisciplinary groups doing this research. Dr. Zamboni was working with neurologists in Italy and the US, and Dr. Dake approached many neurologists for help in doing a study. None of could have forseen the pushback, or medical tourism. I actually started my Facebook page in August of 2009 to get patients to "go local"-- I recommended pwMS bring the research to their local universities for testing and not travel anywhere to be treated, because it was important to stay close to home and work with local physicians if they decided to pursue treatment. We were all simply interested in contributing to the understanding of MS. Hindsight is 20/20, but let's not rewrite what happened.
Here is where I first wrote about Dr, Zamboni's CCSVI research---December, 2008. It's all here--the whole story.
http://www.thisisms.com/forum/chronic-c ... c6488.html
cheer

[HarryZ]

Hi Cheer,

I'll agree that there was activity taking place with Zamboni's CCSVI work for about a year but other than the inner circles of those involved, who knew about it on a large spectrum? News of something on that nature should have been circulating faster than what it was.

Zamboni goes on CTV, has the interview and within a short period of time the whole world knows about it. And the battle began with the opponents knowing very little if anything about the science behind it. I can remember seeing the interview and saying to myself at the time.." oh is this going to create a battle storm. I can imagine the established world of MS medicine is already circling the wagons." And they were and continue to do so.

Some of the attacks on Zamboni were personal and uncalled for but that is how some of his opponents operate. How sad.

[cheerleader]

Harry---about "news of that nature circulating" is simply NOT true. Dr. Zamboni had been working on his research at the University of Ferrara for many years, starting with the "Big Idea" paper on the parallels of iron deposition in MS and venous insufficiency. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633548/
Just this month, a new paper from Canadian molecular biologists looking at this very connection Zamboni posited in '06 finds--

..abnormal iron deposits are found in and around multiple sclerosis (MS) lesions that themselves are closely associated with the cerebral vasculature. However, the origin of this excess iron is unknown, and it is not clear whether this is one of the primary causative events in the pathogenesis of MS, or simply another consequence of the long-lasting inflammatory conditions. Here, applying a systems biology approach, we propose an additional way for understanding the neurodegenerative component of the disease caused by chronic subclinical extravasation of hemoglobin, in combination with multiple other factors including, but not limited to, dysfunction of different cellular protective mechanisms against extracellular hemoglobin reactivity and oxidative stress. Moreover, such considerations could also shed light on and explain the higher susceptibility of MS patients to a wide range of cardiovascular disorders.

http://www.ncbi.nlm.nih.gov/pubmed/24504127

We forget that before the internet became a means of patient communication, most MS research simply stayed in medical journals and at conferences--unless universities sought PR. Zamboni did not seek PR, he simply kept publishing and sharing at vascular conferences, like the Charing Cross. Other vascular researchers, like Marian Simka in Poland, were looking at Dr. Zamboni's findings. And Canada is not the whole world. Yes, the CTV story was a big story for your country, and you're right, it did feed controversy by putting neurologists on the defensive, without fully understanding the science. The ISNVD continues to publish on the venous hemodynamic connection to diseases of neurodegeneration--with or without publicity, or MS specialists. The science continues--no matter what patients and caregivers say on an internet forum. Thomas River's EAE model has had almost 70 years--I think understanding the vasculature via doppler, 7T MRI, MRV, SWI, SPECT, BOLD and new imaging technologies should get some time, too.
http://www.isnvd.org
cheer

[HarryZ]

Harry---about "news of that nature circulating" is simply NOT true. Dr. Zamboni had been working on his research at the University of Ferrara for many years, starting with the "Big Idea" paper on the parallels of iron deposition in MS and venous insufficiency. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633548/

I guess our definitions of what "news circulation" is, differ. While he may have been working on his theory for some time before the CTV interview, there was little known about CCSVI in MS circles outside of the people that he was dealing with at the time. I would imagine that since his work offered something totally different as to the established MS theory, the progress of it was very slow and cautious.

He goes on national tv and wham, the whole MS world knows instantly. You, I and everyone saw the reaction from this news and while it offered a glimmer of hope to MSers, it unleashed a nasty reaction from the established MS research group. Up until this time, if some of these researchers knew of his theory, they certainly weren't saying much publicly about it. But now the attacks were vicious and is something that may not have happened if the interview did not take place. That's all I'm saying is that it would have been interesting to see how CCSVI would have been handled had the interview not taken place and the work going on in the background continue as it had been.

We forget that before the internet became a means of patient communication, most MS research simply stayed in medical journals and at conferences--unless universities sought PR. Zamboni did not seek PR, he simply kept publishing and sharing at vascular conferences,

Yes I agree with you and felt strongly that Zamboni was just trying to create more interest in CCSVI research and even said so in the interview. I didn't think he was trying to seek PR at all but I felt he was going to get a lot of negative attention from his interview. And from what I remember, the details of the interview made it around the globe very quickly, both via the internet and news agencies. Doctors, like Freedman in Ottawa, publicly called him a "quack" which irked me big time! Uncalled for but nevertheless done and this is the kind of unplanned reaction that the interview brought.

[centenarian100]

I am thinking here of HBO. Some people try it and swear by it, others say never again.

Anecdotal evidence doesn't count.

Hyperbaric oxygen has already been looked at for MS with negative results:

http://www.ncbi.nlm.nih.gov/pubmed/7639061

rare but serious side effects have also been reported-pneumothorax, ear injury, etc (Bowling, 2007)

-C

[centenarian100]

Doctors, like Freedman in Ottawa, publicly called him a "quack" which irked me big time!

Obviously, it wasn't very nice or professional to call Dr. Zamboni a "quack," but Zamboni's original conclusion that there is a strong association between extracranial venous anomalies and multiple sclerosis is incorrect.

In that sense, Dr. Freedman has been vindicated.

Whether or not you believe that there is some relationship between CCSVI and MS is a matter of interpretation of available evidence and which studies you find most credible.

In the CCSVI alliance meta analysis (Read here: http://www.ccsvi.org/index.php/advanced ... svi-and-ms), they absurdly include zamboni's originally trial in their final results.

Cheer: Do you really believe the results in zamboni's original paper?-that there is an essentially perfect correlation between MS and CCSVI. If this were the case, it would be easily reproducible in blinded studies regardless of the definition of CCSVI or the experience of the investigators.

Here are the results from zamboni's paper:

http://jnnp.bmj.com/content/80/4/392/T3.expansion.html

Do you believe those results?

Like I said, I wouldn't necessarily discount zidavinov's results (which suggest a modest correlation between CCSVI and MS), but without hesitation, I would entirely discount Zamboni's original results. They are no longer credible given subsequent studies using better methodology.

I don't mean to say that Zamboni presented contrived data with plans to profit from the result. It may just be that he saw what he wanted to see in an unblinded study. He may have looked for abnormalities more persistently in MS patients and overinrerpreted normal variants (normal asymmetries, laminar flow, etc). In control patients, he may have blown off similar variants.

In a blinded study, you can let Zamboni himself analyze the ultrasounds, and I promise you he will not get the same results. He would either get a negative study or something similar to Zidavinov.

Like I said, Zamboni was ultimately bad for the CCSVI movement. He just created hype that could not be sustained.