Turf War

If all you read are neurological journals, you would assume CCSVI research is over and done. But CCSVI venoplasty studies are continually being published in peer-reviewed vascular journals---and the results are encouraging.


Here is a recent study from a university cardiovascular disease center, published this month in the Journal of Cardiovascular Interventions--looking at quality of life (QOL) one year after treatment to relieve venous stenosis.

Does an Endovascular Procedure Improve the Quality of Life in Patients with Multiple Sclerosis
http://interventions.onlinejacc.org/article.aspx?articleid=2492262

There were 94 MS patients tested for CCSVI (22 RRMS, 44SPMS and 26PPMS). 2 patients did not present with any vascular abnormality (that's 2%) and were not treated. Most patients had left IJV stenosis. The more disabled patients were, the more areas of venous abnormalities which needed treatment. The remaining 92 patients were all treated with balloon venoplasty.

By treating the venous abnormalities, cerebral venous drainage was increased.

There was a reduction in bladder disfunction, reduction in fatigue, improvement in disability and QOL for all of the treated patients, and these 4 parameters were maintained a year after treatment.There are other papers showing similar positive results after treatment. You will note that most are published in vascular journals, because this is a vascular treatment for a vascular problem.

Here are the some of the most recent ones on successful treatment for CCSVI:

http://www.ncbi.nlm.nih.gov/pubmed/24531803
http://www.pagepressjournals.org/index.php/vl/article/view/vl.2014.3854
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061177/
http://www.ncbi.nlm.nih.gov/pubmed/24806325


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Why don't we hear about these published CCSVI studies? Primarily because MS immune modulating drugs are a $20 billion dollar a year business.  Yes, that's $20 BILLION dollars....with a B.   And this kind of money has created a disastrous turf war.
The value of the multiple sclerosis therapeutics market will rise slowly from $17.2 billion in 2014 to approximately $20 billion by 2024, at a Compound Annual Growth Rate (CAGR) of 1.5%, according to research and consulting firm GlobalData.
http://www.fiercepharma.com/press-releases/multiple-sclerosis-treatment-market-value-reach-20-billion-2024-says-global-0


We have known about this dilemma in medical research for decades. Vascular departments at universities simply do not receive the grant and pharma funding which is readily available to neuroimmulogical departments for drug development.  This has lead to an imbalance of power, and a betrayal of multiple sclerosis patients.


Read "Social constructionism and medical sociology: a study of the vascular theory of multiple sclerosis" a paper specifically addressing this divide, which was published in 1988.

http://onlinelibrary.wiley.com/doi/10.1111/1467-9566.ep11340153/abstract


brief excerpts below:


"A recent debate surrounding the pathogenesis of multiple sclerosis is analysed in terms of the skills, interests and backgrounds of the medical personnel involved. It is noted that the proponents of the vascular theory possess developed expertises in interpreting disease in structural, vascular terms, whereas their opponents' skills lie in immunology or neurology. Different observers have produced different conceptions of the disease because modes of observation, and the points from which observation takes place, differ. It is also noted that the debate over the causation and treatment of MS has occurred between a large and powerful social group (neurology) and a weak and marginal one (vascular specialists). The effects of this power inequality on the production an assessment of knowledge about MS are investigated. "


The paper goes on to discuss the very real turf war between vascular researchers and neuroimmunologists:

VASCULAR:

"Support for the idea of early vascular involvement in the aetiology of MS has also come from researchers working with the tomographic scanner. One of the standard techniques used in sectional radiography is a process whereby a radio-opaque dye is injected into the bloodstream, thus enabling any leakage through the walls of the blood-vessels to be readily observed. In other words tomographers possess well-developed skills in the study of lesion events within the vascular system. When these skills have been applied to the investigation of MS they have revealed fresh vascular features. "

"The dominant anatomic feature of multiple sclerosis is the relation of plaques to the venous component of the vascular system. The plaques, at least in the early stages, are almost always perivenular, extending as slender sleeves of demyelination. "


VS. NEUROLOGY:

"Furthermore, the clinicians who treat MS patients have always been neurologists - who tend routinely to conceive of MS as being essentially, as well as symptomatically, a neurological disorder.

Also the therapeutic implications of the auto-immune theory are generally pharmacological - involving modes of treatment with which most neurologists are already very familiar and in which they possess developed skills. A new drug treatment for MS, even the trial of a new drug, could be accommodated into existing clinical routines with little difficulty."



It is now almost 30 years since this paper was written. And very little has changed in mainstream MS treatments.
Not since Dr. Zamboni's discovery of CCSVI, Dr. Michal Schwartz's discovery of the brain's protective immune system, Dr. Jonathan Kipnis' discovery of the brain's lymphatic vessels which rely on veins, The Gladstone Institute's revelation that a singular drop of blood in brain tissue creates MS lesions, or Dr. Yulin Ge's visualization of microbleeds in the MS brain with 7T MRI.


The vascular connection to MS is still being swept under a very large $20 billion dollar rug.
MS has a quantifiable vascular component. However, I'm not planning on blogging about this for 20 more years.  Jeff's doing well, now nine years past an MS diagnosis with no disease progression. He has returned to his performing and conducting, as well as increasing his compositional output. We've been traveling the world, and enjoying his renewed health and vigor. His brain is healthier than it was when he was diagnosed with MS in 2007 and treated for CCSVI in 2009---with a reversal of gray matter atrophy and remyelination of his cervical lesion documented on MRI.

He is very fortunate, and he is not alone.

Let's hope that all of us, working together, can change MS research and treatment.

Coming up---information on an opportunity to donate to CCSVI Alliance's matching donation drive, and double your dollars to fund neurovascular research.


Joan

   

Ending a "Misadventure"

The following is an open letter to Dr. Dennis Bourdette in response to his editorial in the June 2014 issue of Neurology, entitled Venous Angioplasty for "CCSVI" in multiple sclerosis: ending a therapeutic misadventure.  This open letter has been sent to his university, as well.  I hope to continue a dialogue with the CCSVI advocacy community and neurology.



Dear Dr. Bourdette--


I was disappointed to see that your comments in Neurology only focused on one half of the two phases of the BNAC PREMiSe CCSVI trial.  The first phase, which has been largely ignored by the press and neurology,  was a case controlled study of venoplasty in 15 patients with RRMS.  Eight patients were treated with venoplasty to repair CCSVI, and the other seven had delayed treatment after 6 months.  There was an immediate improvement in cerebrospinal fluid flow in the treated group, a lessening of lesions on MRI, while the delayed treatment group showed continued MS progression, more lesions and altered CSF hemodynamics.  This phase of the study showed venoplasty, when able to restore venous flow to >75% of capacity,  created a measured improvement of CSF flow and better parenchyma venous drainage, which continued on for twelve months after treatment.   It was published in The Journal of Vascular Interventional Radiology.  (1)  Important to note that Phase 2 of PREMiSe DID NOT restore venous flow to >75%.. In fact, it only restored venous flow to 50%, and was a failure of treatment.  There are many more published studies finding a connection of CCSVI and MS and improvements after successful treatment, and they appear mainly in vascular journals and are ignored by neurology. This disconnect has become increasingly frustrating to those of us whose lives depend on the future of MS research.

As a neurologist with an endowed chair from the Swank Family Foundation, I'm sure you are well-versed in the vascular component of multiple sclerosis.  Dr. Roy Swank was documenting  "capillary fragility"  in Neurology's pages in 1958.  He found systemic subcutaneous hemorrhages in his MS patients, decades before the science of the endothelium.(2)  He also noted hypercoagulation, platelet abnormalities, and slowed cerebral blood flow in MS.(3)  Today, we understand much more about how the vasculature is involved in MS. (4)  To label research into CCSVI and the extracranial venous system as a "misadventure" is to do science a great disservice. 

In spite of the accumulating links of MS to cerebral hypoperfusion (5) and recent research as to how the vascular endothelium controls cerebral blood flow and neuronal health (6), neurological researchers remain wedded to Dr. River's EAE murine model of 1935.  This allegiance to EAE is a stranglehold far more damaging than Charcot's harness. (7)  The tragedy of PML occurred in patients receiving Tysabri infusions only because mice cannot be infected by the JC virus.  The murine model testing of Tysabri could not foretell the deadly results in humans. (8)  The mouse model of EAE is not spontaneous nor does not remit, as MS develops, relapses and remits in humans.(9)  It is time to admit that the EAE mouse model, while somewhat effective for testing immune modulating pharmaceuticals, is not helping us understand the disease process we call multiple sclerosis.  Nor is it addressing MS disability progression linked to gray matter atrophy.  

I am married to a man diagnosed with MS in 2007.  Due to his severe presentation, he was told not to expect many more days of mobility.  At the time, I noted vascular issues, including a petechial rash--the same rash Dr. Roy Swank had documented.  My husband also presented with extreme hypercoagulation and high liver enzymes.(10)  By making the connection of his disease to his vascular system, I was able to piece together peer-reviewed and published research to address these factors. Since his diagnosis seven years ago, he follows a diet and active lifestyle based on Dr. Swank's program-- combined with modern research into endothelial health and EDRF (nitric oxide), published by Dr. John Cooke, author of The Cardiovascular Cure. (11) 

He had venoplasty at Stanford University over five years ago, to resolve a severe stenosis in his left jugular vein and dural sinus. (12) Since this successful endovascular treatment, which is approved for dural sinus stenosis (13), his gray matter atrophy has reversed, as documented on MRI. This fact makes it difficult to claim his improvements are due to placebo.  He jogs, skis, mountain bikes, hikes and works full days.  Not bad for a 51 year old man with MS.  Since venoplasty, his heat intolerance is gone, his cognitive fog and fatigue hugely reduced.  His bladder issues and spasms have remitted. He no longer has central sleep apnea.  He has had no further lesions or MS progression.  And yes, he is a wonderful anecdote; as are the thousands of other MS patients who have received venoplasty and had benefit.  Or the thousands of other patients, like Dr. Terry Wahls and Dr. George Jelinek, who have changed their diets, increased aerobic exercise, stopped smoking, utilized UV ray therapy, and found hope in "alternative" cardiovascular treatments.

Where is the intellectual curiosity of neurologists?  Why the continued disassociation of the brain with the cardiovascular system and blood vessels?  

It is time to admit---neuroimmunology has failed MS patients.  This is exactly why so many patients and caregivers are turning to treatments outside the EAE autoimmune paradigm.  Neurologists must reach out, across academic silos, to include the new research of the endothelium and the vascular component of MS.  CCSVI investigation is only just beginning.  Neurology has had eighty years of EAE, and many, many failures.  The vascular endothelium and extracranial venous system deserve a bit more time and effort, before you proclaim the exploration over.

I invite a dialogue, Dr. Bourdette-- and would be happy to share your thoughts on this letter- in my blog and with the online CCSVI community.  I also invite you to consider the continuing research of the International Society for Neurovascular Disease. (14)

most sincerely,

Joan Beal

Disclosure:  Joan Beal is not a doctor.  She receives no money for her MS advocacy work.  She funds her own endeavors.  Her personal reward is seeing her husband thriving.  She writes about current MS research on her blog, Multiple Sclerosis-the vascular connection.  Joan's theory of MS is that it is a disease of endothelial dysfunction, cerebral hypoperfusion and reperfusion injury, and she invites researchers to consider the scientific evidence. Multiple Sclerosis--the vascular connection: Multiple Sclerosis -- Hypoperfusion/Reperfusion Theory

References:

1.  Zivadinov R, Magnana C,  Galeotti R, Schirda C, Menegatti E, Weinstock-Guttman B, Marr K, Bartolomei I, Hagemeier J, Maiagoni AM, Hoinacki D, Kennedy C, Beggs C, Salvi F, Zamboni P    Changes of cine cerebrospinal fluid dynamics in patients with multiple sclerosis treated with percutaneous transluminal angioplasty: a case-control study.  Journal of Vasc. Interv. Radiology 2013 Jun;24(6):829-38. 

2. Swank RL. Subcutaneous hemorrhages in multiple sclerosis. Neurology. 1958; 8: 497-498. 

3.. Swank RL: Plasma and multiple sclerosis - past and present; in: Multiple Sclerosis: Immunological, Diagnostic and Therapeutic Aspects. London, John Libbey Eurotext, 1987, pp 217-220.

4.. D'haeseleer M., Cambron M., Vanopdembosch L, De Keyser, J.  Vascular aspects of multiple sclerosis.Lancet Neurology. 2011 Jul;10(7):657-66. 

5. Narayan P, Zhou Y, Hasan K, Datta S, Sun X, Wolinsky J.  Hypoperfusion and T1 hypointense lesions in white matter in MS.  Multiple Sclerosis Journal.  March 2014 vol. 20 no. 3365-373

6. Brenda R. Chen, PhD; 

Mariel G. Kozberg, MPhil; 

Matthew B. Bouchard,   PhD;

Mohammed A. Shaik, BS; 

Elizabeth M. C. Hillman, PhD     

Vascular Medicine-A Critical Role for the Vascular Endothelium in Functional Neurovascular Coupling in the Brain.   J Am Heart Assoc. 2014;3:e000787  


7. Behan, P Chaudhuri, A.  EAE in not a useful model for demyelinating disease.   Multiple Sclerosis 

and Related Disorders.   01/2014


    Behan, P Futility of the Autoimmune orthodoxy in MS research.  Expert Rev. Neurother. 10(7), 1023–1025 (2010)  


8. Steinman, L  Zamvil, S  Virtues and Pitfalls of EAE for the development of therapies for multiple sclerosis, TRENDS in Immunology Vol.26 No.11 November 2005

9. Gold, R Linington, C Lassman, H.  Understanding pathogenesis and therapy of MS via animal models: 70 years of merits and culprits in EAE research.  Brain  doi:10.1093  2006.

10. Tremlett H, Seemüller S, Zhao Y, Yoshida EM, Oger JD, Petkau J.    Liver test abnormalities in multiple sclerosis: findings from placebo-treated patients.  Neurology. 2006 Oct 10;67(7):1291-3.  

11. Cooke, JP. Therapeutic interventions in Endothelial Dysfunction.  Clin. Cardiol. Vol. 20 (Suppl. II), II-45–II-51 (1997)

12. Dake MD,  Dantzer N, Bennett WL, Cooke, JP.   Endovascular correction of cerebrovenous anomalies in multiple sclerosis: a retrospective review of an uncontrolled case series.   Vascular Medicine 2012 Jun;17(3):131-7. doi: 10.1177/1358863X12440125. E2012

13. Arac, A  Lee, M  Steinberg, G   Efficacy of endovascular stenting in dural venous sinus stenosis   Neurosurg Focus 27 (5):E14, 2009 

14.  www.isnvd.org