MS as a Vascular Disease: Background and History

1. MS as a Vascular Disease: Background and History Marie Rhodes RN Second person treated for CCSVI at Stanford & Author: CCSVI as the Cause of Multiple Sclerosis Due out April 19, 2011

2. Three Topics Tonight: • Is MS autoimmune? • What is venous disease? • Is there historical evidence for venous issues in MS?

3. Autoimmune Theory for MS: • Viruses and genetics combine to “program” the immune system to attack the myelin in the brain. • The nerves cannot function without myelin. • Immune system cells called T cells are the ones that are accidentally programmed to attack the myelin, and inflammation from that activity damages other brain cells like oligodendrocytes and nerves. • The best way to cure MS is to suppress the immune system so it can’t function normally and thus stop the attacks.

4. Is MS proven to be a primary autoimmune disease?

5. Young MS patient died hours into a relapse. • Autopsy showed death of oligodendrocyte followed by myelin degeneration. • There were no T cells or B cells at the site of the dead oligodendrocyte. • The immune system was just beginning to respond to clean up the dead tissue. • Barnett M, Prineas J. 2004. “Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion.” Ann Neurol. Apr;55(4):458-68. PMID:15048884

6. Hypothesis: Oligodendrocyte loss and myelin breakdown with immune system cleanup. Image by Marv Miller from “CCSVI as the Cause of Multiple Sclerosis” Nerve cell with damaged myelin Vein Oligodendrocyte Microglia Recruited Immune System Cells

7. “The cause of multiple sclerosis (MS) and its pathogenesis are unknown…We propose that MS is not an autoimmune disease but a genetically determined disorder characterized by metabolically dependent neuro-degeneration.” • Behan P, Chaudhuri A. 2004. “Multiple sclerosis is not an auto immune disease." Comment in Arch Neurol. Oct;61(10):1610-12. PMID:15477520

8. “Importantly, despite even potent modulation of the immune system, which results in profound reduction of inflammatory lesions, the effect on long-term disability and progression is not as robust as we would expect or hope for, and treatment of progressive disease has thus far been a failure” • Tsutsui S, Stys P. 2009. “Degeneration versus autoimmunity in MS.” Comment in Ann Neurol. Dec;66(6):712. PMID:20033985

9. Is MS autoimmune? • MS an inflammatory disease of unknown origin. • Standard MS therapies reduce inflammation, and much of MS damage is caused by inflammation itself regardless of cause; relapses and inflammatory lesions are reduced with these therapies even though the trigger of the inflammation is unknown. Autoimmune or Degenerative: both are unproven theories. The question is “which is first?”

10. What is known about Chronic Venous Disease?

11. Current Understanding of CVD Pressure in the vein is increased either by reflux or a blockage This alters the endothelium (lining of the vein) and it becomes leaky. Pressure inside the vein exceeds normal tissue pressure outside and fluid leaks out— “puffy ankles”. If this continues red blood cells leak out as well. The immune system activates in part to remove iron left by dying red blood cells, and in part because the endothelium is damaged.

12. Most of the damage to leg tissue is caused by immune system activity. All of these problems combine so that the tissue has poor blood flow which worsens the problems. CVD may be thought of as an inflammatory disease: some researchers are suggesting drugs that suppress immune system activity may reduce the damage. Repairing the blocked vein often results in healing of the lesion, though the area may remain very scarred. Bergan J, Schmid-Schönbein GW, Smith PD, Nicolaides AN, Boisseau MR, Eklof B. 2006. “Chronic venous disease.” N Engl J Med. Aug 3;355(5):488-98. PMID: 16885552

13. CVD Immune Cell Cascade with Reflux Image by Marv Miller from “CCSVI as the Cause of Multiple Sclerosis” Immune cells Refluxing blood in stenosed vein Red Blood Cells

14. Paolo Zamboni, MD • Leading venous researcher. • His wife got MS in 1995. • Noticed that MS has important features in common with venous disease, especially fibrin cuffs, iron and the way the lesions develop. • Investigated the idea and in 2006 presented his findings at the Royal Society of Medicine.

15. From: Zamboni P. 2006. “The Big Idea: Iron dependent inflammation in venous disease and proposed parallels to MS.” J R Soc Med. 2006 Nov;99(11):589-93. PMID:17082306

16. Further Zamboni Studies • Dr. Zamboni and his team of researchers evaluated nearly 700 people over three studies and discovered that MS patients had blood flow differences when compared to normal people. • Recently their landmark study involving 550 patients and 12 clinical centers was approved. Called BRAVE DREAMS, it will perform treatment on patients and document outcomes. End point: one year. • Other researchers are trying to design studies that help clarify the blood flow issues in MS patients.

17. Do Zamboni’s ideas have any support in standard MS literature?

18. Jean Martin Charcot, MD 1863 • The “Father of Neurology” • Documents widened veins and decided they were a result of the MS disease process

19. Dr. E. Rindfleisch 1863 • "If one looks carefully at freshly altered parts of the white matter ... one perceives already with the naked eye a red point or line in the middle of each individual focus,.. the lumen of a small vessel engorged with blood ... All this leads us to search for the primary cause of the disease in an alteration of individual vessels and their ramifications; All vessels running inside the foci, but also those which traverse the immediately surrounding but still intact parenchyma are in a state characteristic of chronic inflammation." Comment in Archives of Pathological Anatomy and Physiology 1863;26:474-483

20. Tracy J. Putnam, MD Dr. Putnam designed many experiments around the idea that MS was a vascular disease. One of 20 original NMSS neurologists.

21. Putnam’s Experiments • Dr Putnam: -occluded the brain’s venous drainage in dogs then documented the development of lesions in their brains. -experimented with blood thinners which provided modest improvement in MS relapse symptoms. -was unable, with technology of the time, to evaluate blood flow in living people but believed until the end of his life that MS was vascular.

22. Other 50’s Vascular Research • According to Brickner it was well known that vasodilators temporarily improved relapse symptoms (perhaps this explains the sudden release of symptoms in some patients after treatment?) • Debate of the 50’s centered around exactly how these vascular issues manifested and what to do about them using available tools. Dow and Burglund. 1942. “Vascular pattern of lesions of multiple sclerosis.” Arch Neurol Psychiatry. 1942;47(1):1-18 Zimmerman, H, Netsky, M. 1950. “The pathology of multiple sclerosis.” Res. Publ. Ass. Nerv. Ment. Dis. New York 28, 271--312 Brickner R. 1953. “Essential precautions in treatment of new phenomena in multiple sclerosis.” AMA Arch Neuro Psych. Oct;70(4):483-8. PMID:13091497 Jonez H. 1952. “Management of multiple sclerosis.” Postgrad Med. 1952;2:415-22

23. Immunology… • …is the study of the immune system and its related cells. • Got started in the late 50’s • Was the impressive science of the day: it was thought immunologists would be able to cure or manage all inflammatory diseases by managing the immune system. • Offered a huge advantage in that mice could be studied rather than people. • Bumped the venous model aside.

24. Newer Venous Findings • T. Fog dissected MS lesions and discovered they follow the vein closely expanding in successive waves countercurrent to blood flow. • MRI studies by Tan et al show that MS lesions are unique in following the shape of the vein. • Adhya et al show that blood flow and tissue perfusion is greatly reduced in MS patients. Fog T. 1965. “The topography of plaques in multiple sclerosis.” Acta Neurol Scand. 1965;15:1-161 PMID:5213727 Fog T. 1963. “On the vessel-plaque relations in the brain in multiple sclerosis.” Acta Psychiat Neurol Scand. 1963; 39, suppl. 4:258 Tan et al. 2000. “MR Venography of Multiple Sclerosis.” AJNR 21:1039-1042 Adhya S, Johnson G, Herbert J, Jaggi H, Babb JS, Grossman RI, Inglese M. 2006. “Pattern of hemodynamic impairment in multiple sclerosis: dynamic susceptibility contrast perfusion MR imaging at 3.0 T.” Neuroimage. Dec;33(4):1029-35. PMID:16996280

25. What does it mean? • It is possible that MS is a combination of venous and immune abnormalities. • Though it is not yet proven that CCSVI causes MS, logic suggests that if blood flow can be improved this should be helpful to the brain even if MS is autoimmune. • The plausibility of the theory and the fact that current therapies do not stop MS means we must investigate this thoroughly NOW. • Research is just beginning to evaluate how to assess and treat these issues. At this time it is best to remember that this model is still being investigated and it will be some time before anything is proven.

26. For more information: • Book due out April 19 • CCSVIbook.com this power point is on the site. • 10% of my royalties go to CCSVI Alliance to fund research. • Digital (ie Kindle) is less expensive but I give the same amount to research.