And once again CCSVI fails to prove itself...

It always blows my mind that people in favour of CCSVI say, "Follow the money" and blame big pharma - well, what about the docs who are making millions on this procedure?

Highlights mine...

Vein Surgery for MS Fails in First Controlled Trial

This report is part of a 12-month Clinical Context series.

By John Gever, Senior Editor, MedPage Today

Published: March 15, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

• Outcomes in multiple sclerosis patients were not improved with a controversial surgical procedure to improve blood flow in cerebrospinal veins.
• The findings were especially notable because they represent the first report of a randomized, controlled, double-blind trial of the procedure, percutaneous transluminal venous angioplasty.

SAN DIEGO -- Outcomes in multiple sclerosis patients were not improved with a controversial surgical procedure -- percutaneous transluminal venous angioplasty -- to improve blood flow in cerebrospinal veins, results of a small, double-blind, controlled trial indicated.

Among nine patients who underwent the venoplasty to clear blockages, clinical outcomes and brain lesion measures were generally worse after 6 months than in the 10 patients who received a sham procedure, Adnan Siddiqui, MD, of the State University of New York at Buffalo, and colleagues found.

Patients in the active-treatment group had a total of four clinical MS relapses during follow-up, compared with one relapse in the control group. MRI lesion volumes and numbers also were no better and, for some measures, showed strong trends toward worsened disease activity in the patients undergoing venoplasty.

Data from the study were released in advance of Siddiqui's formal presentation next week at the American Academy of Neurology's annual meeting here.

The findings were especially notable because they represent the first report of a randomized, controlled, double-blind trial of the procedure -- and also because Siddiqui and co-principal investigator Robert Zivadinov, MD, also of the University at Buffalo, have been more accepting than most U.S. neurologists of the theory underlying the venoplasty procedure.

That theory goes under the name of "chronic cerebrospinal venous insufficiency" or CCSVI. It gained worldwide prominence in 2009 when Paolo Zamboni, MD, of the University of Ferrara in Italy, reported that every MS patient he examined showed blocked veins and reduced blood flow out of the brain, whereas none of the healthy controls showed such abnormalities.

Moreover, Zamboni asserted that venoplasty in his MS patients led to dramatic relief of symptoms, amounting to a virtual cure in many of them.

But attempts to replicate the findings of Zamboni's uncontrolled, unblinded study in other settings have often failed, with neurologists elsewhere reporting either that they found CCSVI only rarely in MS patients, and/or that it was no more common in MS patients than in controls.

In the largest CCSVI study to date, conducted in Italy and using blinded central interpretation of the ultrasound scans, only 3% of MS patients and a slightly smaller percentage of controls were found to have the condition. The finding led the Italian Multiple Sclerosis Society to declare CCSVI effectively nonexistent as a cause of MS.

Nevertheless, a small industry centered on the theory has flourished, especially in Latin America, where endovascular surgeons perform venoplasty on MS patients wealthy enough to afford it -- despite official recommendations from neurology groups that such procedures hold many risks and no proven benefits.

Zivadinov, in an interview with MedPage Today last year, said that patients should undergo the procedure only in the context of a clinical trial. That was also the message Siddiqui conveyed with the results of their team's current study.

"This is not the last word on this endovascular treatment for MS," Siddiqui said in a press release. "This is the first word because this was the first double-blinded, randomized, sham-controlled trial on the subject. However, these findings lead us to caution strongly against the general acceptance of this invasive procedure for MS patients."

In the study, called PREMISe (Prospective Randomized Endovascular Therapy in MS), an initial 10 patients underwent the venoplasty procedure as a phase I safety test, with no serious adverse events noted.

For the phase II efficacy trial, Siddiqui and colleagues recruited 20 patients to be randomized to the active procedure or to a sham in which patients were catheterized but no venoplasty was performed. Only the interventional surgeon -- not the investigators who evaluated outcomes -- was aware of treatment assignments.

Patients had received an initial diagnosis of CCSVI on the basis of imaging studies as well as confirmed MS of the active-relapsing, secondary progressive, or progressive-relapsing forms. Patients had EDSS disability scores of no more than 5.5.

After catheterization, all patients in both arms were confirmed by the investigators to have CCSVI using catheter venography to establish luminal diameter reductions of at least 50% in the azygous or internal jugular veins. Venography findings had to be confirmed with intravascular ultrasound.

One patient in the phase II study was found not to meet criteria for CCSVI during this procedure and was excluded, leaving 10 in the sham group and nine in the venoplasty group.

Mean EDSS scores were 3.9 in the phase II patients, with median disease duration of 9 years (range 2 to 31). Mean age at disease onset was 35; at enrollment, mean age was 46.

Besides relapses, Siddiqui and colleagues examined other clinical outcomes including EDSS score, 6-minute walk distances, and Multiple Sclerosis Functional Composite score.

None of these measures changed significantly from baseline in either group, and there were no between-group differences, the researchers indicated.

In addition to the lack of apparent clinical improvement in patients undergoing the procedure relative to controls, there was no sign that the venoplasty improved blood flow.

Both groups showed increases in venous sufficiency from baseline, according to the researchers' hemodynamic measurements, but they were virtually the same (P=0.894)

MRI measures also did not favour the venoplasty group:

• Mean cumulative new T2 lesions: 0.3 sham, 2.2 venoplasty (P=0.07)
• Mean T2 lesion volume change: -4.7% sham, 13.9% venoplasty (P=0.04)
• Mean cumulative T1 lesions: 0.2 sham, 0.8 venoplasty (P=0.14)
• Mean T1 lesion volume change: -14.6% sham, -10.2% venoplasty (P=0.81)
• Mean cumulative contrast-enhancing lesions: 0.3 sham, 2.4 venoplasty (P=0.06)

One serious adverse event was seen during the randomized phase, but Siddiqui and colleagues determined that it was not treatment-related: a cardiac event treated with a pacemaker.

A single case of swelling and soreness in the neck was considered treatment-related. However, it was rated nonserious as it did not require additional treatment, the researchers indicated.

"Our strong recommendation to patients and to practitioners, who have, in earnest, been seeking betterment for their disease and a cure for MS is that they should instead consider enrolling in trials, rather than undergoing these procedures on a fee-for-service basis," Siddiqui said in the press release.

The study was funded by Kaleida Health, the Direct MS Foundation (Canada), Volcano, ev3 , Codman & Shurtleff, the Jacquemin Foundation, and individuals.
Siddiqui reported relationships with Hotspur, Intratech Medical, Stimsox, Valor, Concentric, ev3/Covidien, GuidePoint, Penumbra, Genentech, Abbott, and Neocure. Other study investigators reported relationships with Teva, Biogen Idec, EMD Serono, Bayer, Genzyme-Sanofi, Novartis, Bracco, Questcor, Shire, Novartis, Actelion, Allergan, Nelezza, Pfizer, St. Jude Medical, Toshiba, Boston Scientific, Cordis, Micrus, W.L. Gore, and numerous other drug and device companies.

Primary source: American Academy of Neurology
Source reference:
Siddiqui A, et al "Percutaneous transluminal venous angioplasty (PTVA) is ineffective in correcting chronic cerebrospinal venous insufficiency (CCSVI) and may increase multiple sclerosis (MS) disease activity in the short term: Safety and efficacy results of the 6–month, double–blinded, sham–controlled, prospective, randomized endovascular therapy in MS (PREMiSe) Trial" AAN 2013; Abstract P04.273.

---

Pain and MS, including those with an axe to grind

Oh legs. Legs'o'mine. Couldja leave me alone just for a leetle while?
I still don't get it - why is there so much numbness plus so much pain? Surely they should block one another out?
But no, here I cringe, legs repositioning every few minutes while I struggle to feel my fingers on the keys.
I do wish I understood this disease better. I wish anyone understood it better.
And thanks, CCSVI advocates for once again sending me an unnecessarily long and gruesome post to my CCSVI, the terrible temptations post. Every few months you send me one. It's tedious.It's advertising, pure and simple. Usually I delete the comments, made as they are by some mailing robot that spasms, like my legs, unexpectedly, and shoots out blather.
I've decided to allow this one because we are at the point of doing a study here in Canada that looks like it will be carefully designed enough to actually give us some answer, unlike all the observational studies done before. This study will assign patients with venous "obstructions" to control and experimental groups and do mock procedures on the controls. Everyone involved will be blinded as to who got what procedure. then, a year later, the groups will be switched, so everyone will end up with the procedure (important as it is an invasive experiment) and the same person can be evaluated throughout the experiment for effects. I don't know if they are following the procedures with physical therapy, my own personal thought about how the benefits are accrued from the procedure.
So in two years, we should have some hard research results.
Best thing is that the doc who is leading the study, while one of THOSE( neurologist) types, is also one of the most caring, considerate, and thoughtful neurologists I've happened to meet. I've worked with him on the Canadian MS registry project through CIHI and he is a good man, not given to self-aggrandizement, prone to listening to ideas, and open and easy to speak to. I'm hoping the centre in Montreal is going to be led by my other favourite neurologist, another gem of a doc. I'd mention their names but I don't want them to be swamped with people demanding care to the point they burn out. Nice neurologists are not common out there. tremendously smart and knowledgeable ones, yes, but pleasant and friendly, not so much.
Perhaps, unlike my numbness and pain, niceness and smartness don't normally occur together.

But in some lucky or unlucky instances, they do.

Why all the fury about CCSVI?

Whew. Apparently there will be an announcement about CCSVI made by the NL Health Minister at noon today.

Instantly the chatter lines light up. The CCSVI advocates are hollering again. They yell, they tirade, they do personal attacks on neurologists, the MS Society, the people who work at the MS Society, drug representatives, cardiologists, radiologists, that guy that's walking by the window, anyone who doesn't eat pasta, that annoying mosquito.

It's like as soon as you mention those four initials, you've poured alcohol on a fire.
From my way of thinking, I don't find such ranting persuasive. The pro-CCSVI people are sounding more and more like a cult of late.

We've seen this before, folks. Remember laetrile?

I don't know what will transpire regarding CCSVI and MS. I hate the medications we have to take that we aren't sure will do anything and that cost us a lot in terms of money and side effects (potential and present). I hate the fact that I have to take medications at all. I particularly hate that Copaxone has been fined for overcharging and they, TEVA, just wandered out of the discussion, grinning and patting their fat wallets. While gesturing with their other middle finger.

(But then, I have high cholesterol, too, and pay into Crestor's vast resources while eating potato chips. Thus supporting TWO evil industries. I feel kind of silly grousing about big pharma when I lack the self control to avoid them.)

But interventional radiologists are making money on this, too. They have better press at present, true, and maybe that's because a great many neurologists are, unfortunately, just not nice. Or they are frustrated dealing with a chronic disease for which they have no real hope or answer, despite years of research on it. Brains are, apparently, complicated. Immune systems even more so. Who designed this system, anyway?

In any case, the jury is still out. We're devoting resources to investigating this CCSVI thing, that, unfortunately, doesn't seem to be coming back with positive answers for many.

And any who raise a cautionary hand are being demonized.

This is a confusing disease. It's awful and hopeless and expensive and leads many to suicide. How about stepping back and stopping the attacks, eh, CCSVIers? I, for one, would be more tempted to listen. Right now I wish the whole thing would go away.

Oh CCSVI - why won't you die???? Maybe if we inject you with stem cells....

Every once and awhile, some search engine finds my blog and I get dive bombed by CCSVI protagonists. This time I also got messages from those recommending stem cell transfusions. Which, I must quickly add, have even less science support than CCSVI does, and which have been tied to rather severe side effects, unlike CCSVI overall (though don't get me started about stenting, which seems to have a shockingly high fatality rate, or the rate of restenosing, which also seems unacceptably high)
Strangely, these dive bombings come from places where neither procedure is allowed on the countries' own people.

What does that tell us?

I dunno, but my "sucker alert" becomes activated. You know - that little beeping sound that tells you there are people out there seeking to take advantage of desperate folks with deep pockets - or worse still, desperate folks with shallow pockets, who go broke trying to cure this dratted disorienting disabling disease.

Now, I can understand the desperate people. I've been there. Heck, I already have my suicide plan in place and review it regularly. Not for use now, I add - heck, I can't even decide if I should get rid of my dog. No, it's for later. Just in case.

I don't understand the people on the other side. The ones who seem willing to rip off sick people for unproven and even dangerous therapies (by this I mean stem cell treatments and stenting).

The pro-CCSVI people go on about how big pharma loves we MS endurers cos they make tons of money off of us. Well, follow the money, people. Look at what CCSVI has brought providers. Look at what repeated treatments bring them. Look at how they treat and then send any complications back home where they don't have to pay the costs. Just saying'.

I know, some people say they've had wonderful results from CCSVI. And they may well have. God love 'em. And I'm happy for them. I'm less happy about the paranoid rantings against anyone who raises a question about the procedure - that just makes we MS people sound like crazy people and I have had my care suffer because of this.

Me, I'm waiting for the science. And yes, each and every day I lose a bit. Like sands through an hourglass, as the old soap used to say, my abilities slip endlessly through the narrow neck of no return. I exercise my body and my mind in an attempt to stall the flow. I take my medicines like a good patient, most of the time. But I'm not a pawn of big pharma and I fight taking any extra meds. I do my research and am glad I took the time to study nursing and epidemiology and health policy so that I can, in fact, usually understand what I am reading.

I know the tipping point may be just around the corner, where I can no longer walk dependably. But it's not intolerable yet. I am alone, so must learn to be dependent, and this is killing my soul. Or making it grow. I haven't figured that part out yet.

I'm not yet willing to give some manipulative money grubbing individual my carefully saved thousands of dollars for a treatment that may well not work, only to be left with not enough money to afford the wheelchair I will now need. I've seen far too much of that out there, and it breaks my heart.

If I do eventually succumb to temptation and try out CCSVI, there's no way I'd agree to stents. There's nothing good to say about them.

And I damn well will not give my money to someone who plans to inject me with stem cells - those cells that can turn into ANYTHING and that don't show any promise unless you actually kill off all the regular immune system in your body. Even then, the risk of death is high high high.

Listen to your sucker alert, will you? Let's stay safe out there.

Black Holes in my brain...or, do we actually know ANYTHING about MS at all?

The longer I have this disease, the more discouraging it becomes. Not so much because it's a stinky disease and has its hateful bits, but because the more I look at the research, the more I realize we actually have no idea at all about what goes on with it, despite years and years of research.
I just finished reading this report (http://brain.oxfordjournals.org/content/126/8/1782.long)
about the black holes (so termed) that form in our brains over time. I had thought I was told they were permanent, visions of brain death and atrophy.
However, this study talks of how they can revert. Huh? And of course there is no association between the number of them and disease progression except in that overall brain atrophy is linked with physical and cognitive decline. At least I think that is what I understood, given that my brain doesn't seem to be functioning so well today. It's squinting, trying to focus. Brain squinting is an odd sensation. I used to be a hyper-intelligent mega-being with delusions of grandeur. Now I'm just deluded.
So, to summarize what I know about MS:
1. the disease modifying drugs we all take every day don't actually prevent progression of disease, they just modify how it presents itself - i.e. fewer acute attacks - but still the disease goes on ever on in our nervous systems. The drug companies want to tell us they delay progression, but I'm not seeing it in the research. So, after years of injecting myself with this drug, I have absolutely no proof that it's doing anything for me except bettering my injection skills and helping me learn how to needle felt.
2. Cognitive changes and mood changes are very poorly understood and rarely dealt with, as is pain. So we wander about, foggy and groaning until someone takes pity on us and feeds us chocolate.
3. What used to be an indicator, number of brain lesions, is apparently totally unconnected to disease activity and it is really the silent inflammation that causes the problems. Of some part of the brain as yet uncertain. Maybe glial cells. Maybe that bubble gum I inhaled as a child. Who knows.
4. We have no idea what causes the inflammation, what makes it worse, what makes it better, or what causes it to start in the first place.
5. The only way to treat the disease is symptomatically with ever more intrusive treatments, appliances, care, limitations. The thought of a scooter was cool when I didn't see it lurking around the corner. Let's not talk about Depends, shall we, until Victoria's secret makes some?
6. We used to think that MS was unknown in people who get a lot of sun, but now we are finding fresh cases that have had MS for years and who have only just moved north from the equator. So maybe the Vitamin D thing isn't right, either.
7. Practically EVERYONE gets Epstein-Barr virus at some point  (though it's one of those things that is implicated in many diseases) so why do some get this, some get non-Hodgkins lymphoma, etc? Is there an infectious cause? Who knows?
8. CCSVI's hypothesis isn't proven, but some people get benefit from having their veins plunged. No one knows why. No one knows why not. Everyone knows stents are dangerous, but people are still getting them. There is no logic in this disease anywhere, except the logic of the market.
9. Completely killing your bone marrow and starting fresh with a new lot of cells seems to help - but for how long? No one knows.
10. Apparently zapping your brain deep inside can help with cognitive problems, but it also helps with depression, which can lead to cognitive problems. Chicken and egg, people. It's always chicken and egg.
11. The only certain thing, MAYBE, is that we are losing myelination of our nerves. But are we really? Since most of the research is done on mice and cadavers, I'm not so sure even that is true, and as I'm still alive, and not a rodent, I'll never know til too late.

Is it any wonder we get depressed?
Ach, the hell with it. It's obviously time to stop looking at the research. It makes my brain ache, and I know that can't be good.

CCSVI and the lure of the "benign"

One of the points CCSVI advocates make is that the treatment is benign, that there are few, if any risks, that it may as well be done as not.
I'm a nurse and I have to tell you the thought of introducing a catheter to any part of my body (but especially the vascular system) fills me with a bit of fear.

I know I'm a chicken. All of my rellies died of cancer (just about) by the time they hit 60.  So the fact that I am on a long term immune system modulator gives me pause, lemme tell you. Every time I inject the copaxone, I think about how a. they are not completely certain how it works, b. it doesn't seem to slow the eventual progress of the disease, just reduce flare-ups and maybe lesions, which everyone agrees don't really predict disease outcomes, c. how since I've been on it, my body doesn't swell up with mosquito bites any more and how weird that is and how there may well be cancer cells sneaking around my body at this VERY MINUTE looking for a good place to lodge and grow, happy and healthy.

I'm on an antidepressant, too - started before my diagnosis, and it's supposed to be doing something for me but again, no one knows what, or whether the depression is caused by the MS or just a reaction to it or to the constant pain, or whatever.  I've withdrawn from antidepressants before and it is some scary stuff, believe you me. They obviously do something altering to your brain and I'd feel a whole lot better if somebody could show me the "insert tab a into slot b" directions for how it worked. But they can't.

Why does the thought of a catheter thingie seem more risky than these steps? Well, I've seen the damage from bad insertion of things (some jokesters might say  - like my kids...- but I love them, so perhaps not..) I know that whenever you put something into your body of the metal or unnatural kind, in places where things are not usually put, you get some damage.  Could be little damage, and worth the risk - such as when you get a screening colonoscopy (which also result in some poor outcomes, however) - given the risk of the alternative. Placing a stent in your heart, for example, is not just one of those things you get done cheerily and wander off to be your regular self.  There is damage caused by the manipulation of tissue that is normally protected.

I've always had troubles with my neck, being a short person with significant stenosis and a lesion or two back in the spinal column. I fear chiropractors manipulating there ever since I heard of strokes caused by neck manipulation. So the thought of a snaky tube going up through those vital spaces fills me with fear.

And yet, the thought of a potential cure for the awful symptoms I live with every day is tempting. Being part of the study that is being done on all those here in Canada who are being followed up for the "treatment" interests me, too - after all, some days I don't feel I am much use except as a medical curiosity.  Every day I take up my arms in battle against MS.  Sometimes it is wearying.

But I've never viewed the procedure as benign.  And of us who have had urinary tract infections after a catheterization know of the risk of introducing illnesses.  Many people coming back from India where they have had medical care end up bringing along a superbug with them, which then spreads throughout our hospitals. And others have other bad results, from spasms to neck problems to this latest report - death by stroke.

This poor woman.  She was basically healthy, had symptoms that were nasty, and the certainty that they would most likely get worse.  But the hope of this "benign" procedure was held out to her  - and she chose it - and she lost, horribly. I know everyone has the choice in this case, but isn't there some responsibility for the medical profession to give the right advice? And maybe she received all the information and decided to continue, I don't know. But if you read the article, some interventional radiologists don't think they should be offering an untested procedure.

Brant-Zawadzki refuses to do the procedure even though people with MS are clamouring for it.

"I do think that physicians themselves believe they're helping these patients, but unconsciously there's an enablement going on of what could become self-harmful, if not a truly self-destructive process."

http://www.cbc.ca/news/health/story/2011/07/08/multiple-sclerosis-ccsvi-death.html

I've met a lot of people with chronic illnesses who do become self-harming with the various treatments they take - before I was diagnosed, I was told I had fibromyalgia.  One of the members of the support group was choking back guafenisin to treat herself based on a protocol someone had created - a dangerous idea, as the side effects are grim. Others are taking opiates for the pain, gradually increasing the doses until they become at risk of falling or doing damage to others.

It sucks having a chronic, incurable disease.  We all want a magic pill.  But we need to be sure it isn't more of a Snow White apple, laced with more poison than benefit.

My deepest sympathies to Maralyn Clarke's family.

A positive outcome from the CCSVI urgency?

Good news today from the worlds of MS research. As a doubter of the CCSVI hypothesis (but still interested in hearing about it, as aren't we all!), I was excited to see that research in other areas is stepping up as well. An evil drug company is collaborating with the UK National MS Society to work on research that focuses on neurprotection and repair, two areas I find most valuable. And fascinating. And perhaps globally useful for other forms of brain damage...

The funding is for innovative research, and given to universities and non-profits as well as a separate fund for for-profit agencies focused on making medications that will give money.  The innovations in research funding is the sort of program that allows university researchers to explore new realms and perhaps come up with results that answer more than the initial question.

I'm also interested to hear about the areas of research - while they are looking at the causes of the inflammation occurring in MS, they also seem further ahead than I knew.  I didn't know we had knowledge of the ion channel changes or the sodium/calcium exchanger roles in MS. Fascinating stuff, if you like the biochemistry side of things, and a real source of hope if they can fix these cellular changes. Who knows if CCSVI helps these changes occur, but since the procedure seems to be limited in its effect, and require re-treatment, wouldn't it be nice if we could treat the outcomes, biochemically, of whatever changes are going on in the brain, whether infectious or not?

I dunno, but I am encouraged there is progress going on in all sorts of areas of MS research and that everything, from the large interventions to the tiny ones, is being examined. Maybe all the press about CCSVI helped, though this collaboration was created before Dr. Zamboni's study was released. Let's hope all the noise leads to increased and improved research in all areas of MS. (Bolding is mine)

http://www.prnewswire.co.uk/cgi/news/release?id=326120

Merck Serono and Fast Forward Announce Recipients of Funding for Multiple Sclerosis Research

GENEVA, June 30, 2011 /PRNewswire/ --

• Merck Serono and Fast Forward Provide Funding of Over $1 Million to Accelerate Early Stage Research in Multiple Sclerosis

Merck Serono, a division of Merck KGaA, Darmstadt, Germany, and Fast Forward, LLC, a not-for-profit organization established by the American National Multiple Sclerosis Society, today announced the second group of recipients to receive funding through their collaboration, which is designed to speed research advances in mutually selected, high potential areas of multiple sclerosis (MS) research.  

The awards total over $1million and will be distributed from two funds created by Merck Serono and Fast Forward to encourage early stage drug discovery for MS: the Accelerating Commercial Development Fund which is allocated to development programs for for-profit entities and the Accelerating Innovation Fund which is allocated to innovation projects and available to university-based investigators and seed-stage for-profit entities.

Merck Serono and Fast Forward distributed a call for proposals to fund projects focused on central nervous system neuroprotection and/or repair strategies. These priority areas were determined by a joint steering committee comprising Fast Forward staff and representatives from Merck Serono.

The following organizations will receive funding:

Under the Accelerating Innovation Fund:

Howard Florey Institute, Carlton, Victoria, Australia (Project Director - Bevyn Jarrot, Ph.D.) will receive $275,000 over 12 months to advance the development of molecules that target Na_v 1.6 ion channels. In MS, there is a change in these ion channels, which contributes to abnormal nerve function. This project will focus on molecules which could potentially prevent this abnormal function, thereby protecting axons from further damage.

The Gladstone Institutes /UCSF (Project Director-Katerina Akassoglou, Ph.D.) will receive $300,000 to conduct testing for the identification of small molecule inhibitors of microglial activation. Microglia are part of the resident immune system in the brain and spinal cord. Activation of microglia in MS is thought to contribute to the inflammation and nerve cell damage associated with MS.  In the funded studies, the investigators will focus on developing novel molecules that have the potential to inhibit the activation of microglia in MS.

Under the Accelerating Commercial Development Fund:

Axxam SpA, Milan, Italy (Project Director -Michela Stucchi, Ph.D.) will receive $430,590 over 18 months to advance the development of small molecules that target the sodium-calcium exchanger NCX1 on axons. NCX1 functioning in reverse mode is thought to cause nerve cell death in MS. Axxam is developing molecules to prevent NCX1 activation and thus prevent axonal injury and ultimately clinical disability in MS.

"We are pleased to announce the 2011 funding recipients who will work to advance exciting early-stage projects in MS," said Dr. Bernhard Kirschbaum, Merck Serono's Head of Global Research and Development. "We are committed to advancing research that has the potential to improve understanding of the disease, and ultimately result in the development of therapies to help people living with multiple sclerosis."

Merck Serono and Fast Forward entered into an initial two-year, worldwide agreement in March 2009, and recently extended the collaboration. As part of the up to $19 million collaborative agreement with Fast Forward, Merck Serono provided the majority of funding for the research awards, with Fast Forward contributing 10 percent of the total financing of the awards disseminated from each of the two funds.

"The potential of multiple sclerosis research currently in progress around the globe holds great promise for improving the quality of life for people living with multiple sclerosis," said Dr. Timothy Coetzee, Chief Research Officer at the American National MS Society and Fast Forward. We are pleased to have the opportunity to advance that promise through the continued collaboration between Fast Forward and Merck Serono. Our commitment to furthering research that will end multiple sclerosis remains steadfast, and we look forward to learning more from the results of these innovative research projects."

Photo from: http://gam3avoice.com/library/?tag=function-of-the-neuromuscular-junction

Reviewing the CCSVI research..

In my role as education person for the local MS Society, I've been called upon to try and figure out a presentation re: CCSVI.  The only problem is that little research has been completed to date.  There are status updates to the research funded by the MS Societies on their pages, but I went wandering through the other research looking for something else that might have been done.
Here are my conclusions:
Anyone associated with Dr.s Zamboni, Haacke, Simka, or their research institute have found that CCSVI has positive results.  Sample sizes are small, and my impression is that the several published papers resulted mainly from the same study set.
Anyone who is a neurologist finds no benefits from the CCSVI procedure. Their study sizes are also small, except for one study that looked for brain ferritin levels (following the iron damage hypothesis) which looked at 1408 patients with brain disorders and normals and found an increased amount of ferritin in people with various forms of MS and brain damage of other sorts.
Interestingly, studies by interventional radiologists also don't find a positive association between CCSVI treatment and MS improvement.
"Improvement" is, as has been said before, stated in terms of fatigue level improvement, some sensory improvement.  As someone who is dead tired all the time and numb from stem to stern, this sounds vaguely appealing, except for the costs. And the transience of the improvement. The study summaries are below.
The small sample sizes are a problem, as so much difference can be explained by random changes, especially in a variable disease like MS.  It's also a problem that most of the studies were unblinded - in other words, the experimenters knew who they were looking at.  This allows for bias and in fact, if you happen to have a vested interest in the results, like the neurologists who have invested years in the autoimmune theory, or the Zamboni group who are currently marketing the only machine capable of detecting the hard to find CCSVI (some conflict of interest there, methinks), bias comes in inevitably.
On the good side, the whole debate has increased interest in MS research.  On the bad side, several people have, for some unknown reason, decided the current researchers are not capable of doing a proper study, and so have stopped sending money to the MS Society.  Instead we should be sending more, and demanding unbiased studies, multisectorial, blinded, and large. We won't know for sure until we get those studies done. Until then, taking a stand is perhaps premature.

Study/date	Blinded?	Number of participants	results
The perfect crime? CCSVI not leaving a trace in MS. J Neurol Neurosurg Psychiatry. 2011 Feb 4. [Epub ahead of print] Mayer CA, Pfeilschifter W, Lorenz MW, et al	Yes ++	20 MS, 20 controls	No retrograde blood flow Conclusions This triple-blinded extra- and transcranial duplex sonographic assessment of cervical and cerebral veins does not provide supportive evidence for the presence of CCSVI in MS patients. The findings cast serious doubt on the concept of CCSVI in MS.
Chronic cerebrospinal venous insufficiency and iron deposition on susceptibility-weighted imaging in patients with multiple sclerosis: a pilot case-control studyInt Angiol. 2010 Apr;29(2):158-75. Zivadinov R, Schirda C, Dwyer MG, Haacke ME, Zamboni P et al	No	16 RRMS 8 controls	All 16 MS patients fulfilled the diagnosis of CCSVI (median VH=4), compared to none of the HC Iron concentration measures were related to longer disease duration and increased disability as measured by EDSS and MSFC, and to increased MRI lesion burden and decreased brain volume.
CSF dynamics and brain volume in multiple sclerosis are associated with extracranial venous flow anomalies: a pilot study. Zamboni P, Menegatti E, Weinstock-Guttman B, , Zivadinov R. et al Int Angiol. 2010 Apr;29(2):140-8.	No	16 MS 8 controls	Vascular Hemodynamic changes occur more frequently in MS patients than controls. Altered VH is associated with abnormal CSF flow dynamics and decreased brain volume.
No Evidence of Chronic Cerebrospinal Venous Insufficiency at Multiple Sclerosis Onset Claudio Baracchini, MD,1 Paola Perini, MD,1,2 Massimiliano Calabrese, MD,1,2 Francesco Causin, MD,3 Francesca Rinaldi, MD,1,2 and Paolo Gallo, MD, PhD1	No	50 MS 60 global amnesia 60 healthy.	Our findings do not support a cause-effect relationship between CCSVI and pMS. Further studies are warranted to clarify whether CCSVI is associated with later disease stages and characterizes the progressive forms of MS.
Intracranial venous pressure is normal in patients with multiple sclerosis. Meyer-Schwickerath R, Haug C, Hacker A, Fink F, Seidel D, Hartung HP, Haupts MR.	No	29 MS 28 Controls 19 patients with increased intracranial pressure	There is no evidence of an increased intracranial venous pressure in MS patients.
Cardiovasc Intervent Radiol. 2011 Feb;34(1):1-2. Epub 2010 Dec 7. Cardiovascular and Interventional Radiological Society of Europe commentary on the treatment of chronic cerebrospinal venous insufficiency. Reekers JA, Lee MJ, Belli AM, Barkhof F.	No	Comment only	Thus far, no trial data are available, and there is currently no randomized controlled trial (RCT) in proress Therefore, the basis for this new treatment rests on anecdotal evidence and successful testimonies by patients on the Internet. CIRSE believes that this is not a sound basis on which to offer a new treatment, which could have possible procedure-related complications, to an often desperate patient population. PMID: 21136256 [PubMed - in process]
Nervenarzt. 2010 Jun;81(6):740-6. ["Chronic cerebrospinal venous insufficiency" and multiple sclerosis: critical analysis and first observation in an unselected cohort of MS patients]. [Article in German] Krogias C, Schröder A, Wiendl H, Hohlfeld R, Gold R.	No	?	The "venous hypothesis" is analyzed and evaluated with regard to the following aspects: first concerning the validity of published data, second with regard to the plausibility in view of the currently approved pathogenetic model of MS, and third with regard to the compatibility with preliminary neurosonological findings in a small but unselected cohort of patients at our department.The authors conclude that the "chronic cerebrospinal venous insufficiency (CCSVI)" cannot represent the exclusive pathogenetic factor in the pathogenesis of MS. In our cohort, only 20% of the patients fulfilled the required neurosonological features of CCSVI. So far, the pathogenetic relevance of these findings remains speculative. Thus, based on the current scientific position we cannot justify invasive "therapeutic" approaches, especially if they are performed outside of clinical trials.
Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. Worthington V, Killestein J, Eikelenboom MJ, Teunissen CE, Barkhof F, Polman CH, Uitdehaag BM, Petzold A. Neurology. 2010 Nov 2;75(18):1617-22. Epub 2010 Sep 29.	No	cross-sectional (n = 1,408) longitudinal (n = 29) patients with MS and a range of neurologic disorders.	Pathologic (>12 ng/mL) CSF ferritin levels were observed in 4% of the control patients (median 4 ng/mL), 91% of patients with superficial siderosis (75 ng/mL), 73% of patients with a subarachnoid hemorrhage (59 ng/mL), 10% of patients with relapsing-remitting MS (5 ng/mL), 11% of patients with primary progressive MS (6 ng/mL), 23% of patients with secondary progressive MS (5 ng/mL), and 23% of patients with meningoencephalitis (5 ng/mL). In MS, there was no significant change of CSF ferritin levels over the 3-year follow-up period. CONCLUSION: These data do not support an etiologic role for CCSVI-related parenchymal iron deposition
No cerebrocervical venous congestion in patients with multiple sclerosis. Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ. Ann Neurol. 2010 Aug;68(2):173-83.	No	56 MS 20 Controls Sonography study, flow analysis, CCSVI criteria	Our results challenge the hypothesis that cerebral venous congestion plays a significant role in the pathogenesis of MS. Future studies should elucidate the difference between patients and healthy subjects in BVF regulation. No MS patient had >1 CCSVI criterion
Int Angiol. 2010 Apr;29(2):189-92. Chronic cerebro-spinal venous insufficiency: report of transcranial magnetic stimulation follow-up study in a patient with multiple sclerosis. Plasmati R, Pastorelli F, Fini N, Salvi F, Galeotti R, Zamboni P.	No	I patient	The demonstration of a modification of the cerebrovenous function with both clinical manifestation and via TMS suggests that the hampered cerebral venous return may contribute to the clinical course of MS.
Is chronic fatigue the symptom of venous insufficiency associated with multiple sclerosis? A longitudinal pilot study. Malagoni AM, Galeotti R, Menegatti E, Manfredini F, Basaglia N, Salvi F, Zamboni P. Int Angiol. 2010 Apr;29(2):176-82.	No.	31 fatigue testing 1, 6 and 12 mos post-procedure	The reestablishment of cerebral venous return dramatically reduced CF perception in a group of MS patients with associated CCSVI, suggesting that CF is likely the symptom of CCSVI. Note: Patients were identified as having CCSVI and Chronic Fatigue
Chronic cerebrospinal venous insufficiency and multiple sclerosis Omar Khan MD1,*, Massimo Filippi MD2, Mark S. Freedman MD3, et al ANN NEUROL 2010;67:286–290			In this Point of View, we discuss the recent investigations that led to the description of CCSVI as well as the conceptual and technical shortcomings that challenge the potential relationship of this phenomenon to MS. The need for conducting carefully designed and rigorously controlled studies to investigate CCVSI has been recognized by the scientific bodies engaged in MS research. At present, invasive and potentially dangerous endovascular procedures as therapy for patients with MS should be discouraged until such studies have been completed, analyzed, and debated in the scientific arena.
Venous and cerebrospinal fluid flow in multiple sclerosis: A case-control study .    Peter Sundström MD, PhD1,*, Anders Wåhlin MSc2, Khalid et al	No	21 MS 20 control	We found no differences regarding internal jugular venous outflow, aqueductal cerebrospinal fluid flow, or the presence of internal jugular blood reflux. Three of 21 cases had internal jugular vein stenoses. In conclusion, we found no evidence confirming the suggested vascular multiple sclerosis hypothesis. ANN NEUROL 2010;68:255–259
Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? T Ludyga *, M Kazibudzki *, M Simka * , M Hartel , M wierad *, J Piegza *, P Latacz *, L Sedlak * and M Tochowicz *	No	564 procedures in 331 MS patients with CCSVI	The procedures appeared to be safe and well tolerated by the patients, regardless of the actual impact of the endovascular treatments for venous pathology on the clinical course of multiple sclerosis, which warrants long-term follow-up.
No association of abnormal cranial venous drainage with multiple sclerosis: a magnetic resonance venography and flow-quantification study Mike P Wattjes1, Bob W van Oosten2, Wolter L de Graaf1, Alexandra Seewann2, et al	Yes	20 MS, 20 control MRV studies (magnetic resonance venography)	A completely normal venous anatomy was observed in 10 MS patients and 12 controls. Anomalies of the venous system (venous stenosis/occlusions) were found in 10 MS patients and eight healthy controls. An anomalous venous system in combination with associated alternative venous drainage was observed in six MS patients and five healthy controls. Flow quantification showed no venous backflow in any MS patient or control. Conclusions Findings suggestive of anomalies of the cranial venous outflow anatomy were frequently observed in both MS patients and healthy controls. Given the normal intracranial venous flow quantification results, it is likely that these findings reflect anatomical variants of venous drainage rather than clinically relevant venous outflow obstructions.
Iron and Neurodegeneration in Multiple Sclerosis Michael Khalil,1, 2 Charlotte Teunissen,2 and Christian Langkammer1 Multiple Sclerosis International Volume 2011, Article ID 606807,			In summary, increased iron deposition has been consistently reported to occur in MS, but its role in pathogenetic processes of this disease has not yet been completely clarified. Quantitative MRI and histopathologic analyses of postmortem MS brains should complement these     [9] studies.