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

Is it all about the poo?

My brother sent me on this podcast http://feedproxy.google.com/~r/freakonomicsradio/~5/VZ-2GFkkQrU/freakonomics_podcast030211.mp3  from freakonomics radio about how a man with MS was "cured" by getting a fecal transplant.  Apparently, if we have bad germs in our guts, we can get some good germs from someone else's poo and allow them to inhabit our guts.  This will remove the harmful bacteria that live there and therefore return us to health. Assuming they beat up our bacteria and take over.

It's an interesting point.  If we are, as described in the podcast, 10% us and 90% bacteria, there's something to be said about reorganizing our friendly colonists (pun intended) to be more friendly. And, after all, that discovery of H. Pylori and ulcer causation revolutionized the treatment of ulcers.

And, truth be told, there is much research to indicate that MS is probably infection-related, given that it involves an autoimmune response that must be triggered somehow.

I'm not sure about having a poo transplant, though. There's a lot of nasty stuff in poo, much of it I would not want to visit.  Montezuma's revenge, cholera, who knows what else. I'm reminded of the rabbits of Australia - brought on for hunting, reproduced like mad, then they had to treat the rabbit problem, and lost control of that, too.

And I can't help but wonder if some of the same magic thinking is going on here that hangs around those in support of cleanses. Our digestive tract is full of little creatures that change and reproduce and wriggle about depending on what environment we give them. I think they'd be hard to manage long term.

The fellow they interviewed said that he was all better after his treatment, but time will tell. Relapsing-remitting MS is a trickster that way - you can think you have it beaten and then it sneaks up on you from behind (har har). I hope he stays well. But it's another tale of anecdote not making scientific proof.

I'm not signing up for the randomized controlled trial, though.
Ewwww.

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.