MS as a Vascular MS as a Vascular Disease: Disease:

Background and Background and HistoryHistoryMarie Rhodes RNMarie Rhodes RN

Is MS proven Is MS proven to be a primary to be a primary

autoimmune autoimmune diseasedisease??

Barnett M, Prineas J. 2004. “Relapsing Barnett M, Prineas J. 2004. “Relapsing and remitting multiple sclerosis: and remitting multiple sclerosis: pathology of the newly forming lesion.” pathology of the newly forming lesion.” Ann NeurolAnn Neurol. Apr;55(4):458-68. . Apr;55(4):458-68. PMID:15048884PMID:15048884

““The earliest change observed in the lesions examined in

this study was widespread oligodendrocyte apoptosis in

tissue in which T cells, macrophages, activated microglia,

reactive astrocytes, and neurons appeared normal.”

Oligodendrocyte loss and myelin Oligodendrocyte loss and myelin breakdown with microglia scavenging breakdown with microglia scavenging and subsequent immune cell and subsequent immune cell recruitment; the Barnett and Prineas recruitment; the Barnett and Prineas model.model.

Microglia

Oligo

Nerve cell with damaged myelin

Recruited Immune System Cells

ReplicationReplication Barnett M, Sutton I. 2006. “The pathology of Barnett M, Sutton I. 2006. “The pathology of

multiple sclerosis: a paradigm shift.” multiple sclerosis: a paradigm shift.” Curr Curr Opin Neurol.Opin Neurol. Jun;19:242-47. PMID:16702829 Jun;19:242-47. PMID:16702829

Barnett M., Henderson A, Prineas J. 2006. Barnett M., Henderson A, Prineas J. 2006. "The macrophage in MS: just a scavenger "The macrophage in MS: just a scavenger after all?" after all?" Mult SclerMult Scler. Apr;12(2); 121-32. . Apr;12(2); 121-32. PMID:16622941PMID:16622941

Barnett M, Parratt J, Prineas J. 2009. Barnett M, Parratt J, Prineas J. 2009. “Multiple sclerosis: Distribution of “Multiple sclerosis: Distribution of inflammatory cells in newly forming MS inflammatory cells in newly forming MS lesions.” lesions.” Ann Neur. Ann Neur. Dec;66:739-753. Dec;66:739-753. PMID:20035511PMID:20035511

Barnett M, Parratt J, Pollard J, Prineas Barnett M, Parratt J, Pollard J, Prineas J. 2009. “MS: is it one disease?” J. 2009. “MS: is it one disease?” Int Int MS JMS J. Jun;16 (2):57-65 PMID: . Jun;16 (2):57-65 PMID: 1967136919671369

Henderson AP, Barnett MH, Parratt Henderson AP, Barnett MH, Parratt JD, Prineas JW. 2009. Multiple JD, Prineas JW. 2009. Multiple sclerosis: distribution of inflammatory sclerosis: distribution of inflammatory cells in newly forming lesions. cells in newly forming lesions. Ann Ann NeurolNeurol Dec;66(6):739-53. Dec;66(6):739-53. PMID:20035511PMID:20035511

These papers have been cited These papers have been cited numerous times by other researchers.numerous times by other researchers.

Chaudhuri A. 2004. “Multiple sclerosis is Chaudhuri A. 2004. “Multiple sclerosis is not to an auto immune disease." Comment not to an auto immune disease." Comment in in Arch NeurolArch Neurol. Oct;61(10):1610-12. . Oct;61(10):1610-12. PMID:15477520PMID:15477520

Behan P, Chaudhuri A. 2002. “The Behan P, Chaudhuri A. 2002. “The pathogenesis of multiple sclerosis pathogenesis of multiple sclerosis revisited.” revisited.” J R Coll Physicians Edinb. J R Coll Physicians Edinb. 32(4):244-26532(4):244-265

Roach E. 2004. “Is multiple sclerosis an Roach E. 2004. “Is multiple sclerosis an autoimmune disorder?” autoimmune disorder?” Arch NeurolArch Neurol. . Oct;61(10):1615-6. PMID:15477522Oct;61(10):1615-6. PMID:15477522

Tsutsui S, Stys P. 2009. “Degeneration Tsutsui S, Stys P. 2009. “Degeneration versus autoimmunity in MS.” Comment in versus autoimmunity in MS.” Comment in Ann Neurol.Ann Neurol. Dec;66(6):712. Dec;66(6):712. PMID:20033985PMID:20033985

Is MS autoimmune?Is MS autoimmune?

MS an inflammatory disease of unknown MS an inflammatory disease of unknown origin. The inflammation is indisputable, but origin. The inflammation is indisputable, but the cause of the immune system activity is still the cause of the immune system activity is still unproven.unproven.

MS standard therapies reduce inflammation, MS standard therapies reduce inflammation, and much of MS damage is caused by and much of MS damage is caused by inflammation itself regardless of cause. inflammation itself regardless of cause. Therefore relapses and inflammatory lesions Therefore relapses and inflammatory lesions are reduced with these therapies even though are reduced with these therapies even though the cause of the inflammation is unknown.the cause of the inflammation is unknown.

What is What is known about known about

CVD?CVD?

Chronic Venous DiseaseChronic Venous Disease

Bergan J, Schmid-Schönbein GW, Bergan J, Schmid-Schönbein GW, Smith PD, Nicolaides AN, Boisseau Smith PD, Nicolaides AN, Boisseau MR, Eklof B. 2006. “Chronic venous MR, Eklof B. 2006. “Chronic venous disease.” disease.” N Engl J MedN Engl J Med. Aug . Aug 3;355(5):488-98. PMID: 16885552 3;355(5):488-98. PMID: 16885552

Review of current understanding in Review of current understanding in the field of vascular medicine.the field of vascular medicine.

Veins become stretched out.Veins become stretched out. Stretched or vericose veins are under increased Stretched or vericose veins are under increased

pressure.pressure. Pressure inside the vein exceeds normal tissue Pressure inside the vein exceeds normal tissue

pressure outside and fluid leaks out— “puffy pressure outside and fluid leaks out— “puffy ankles”.ankles”.

If this continues red blood cells leak out as If this continues red blood cells leak out as well.well.

The immune system activates in part to remove The immune system activates in part to remove iron left by RBC’s. iron left by RBC’s.

Much of the damage to leg tissue is caused Much of the damage to leg tissue is caused by immune system activity. by immune system activity.

If lesions develop venous insufficiency is If lesions develop venous insufficiency is present.present.

CVD may be thought of as an inflammatory CVD may be thought of as an inflammatory disease.disease.

CVD Immune Cell Cascade with RefluxCVD Immune Cell Cascade with RefluxImage by Marv Miller from “CCSVI as the Cause of Multiple Sclerosis”Image by Marv Miller from “CCSVI as the Cause of Multiple Sclerosis”

IronironImmune cells

Red Blood Cells

Refluxing blood flow in a varicose vein

Paolo Zamboni, MDPaolo Zamboni, MD Professor of Medicine at University of Ferrara, Professor of Medicine at University of Ferrara,

Italy.Italy. Director of the Vascular Diseases Center.Director of the Vascular Diseases Center. Graduated in ’82 as a doctor, then completed a Graduated in ’82 as a doctor, then completed a

general surgery internship through ’87. He general surgery internship through ’87. He then went on to a fellowship at the Vascular then went on to a fellowship at the Vascular Surgery Center at UCSF.Surgery Center at UCSF.

He is a prominent researcher in the vascular He is a prominent researcher in the vascular field and the recipient of numerous awards for field and the recipient of numerous awards for his work.his work.

His wife was diagnosed with MS in 1995His wife was diagnosed with MS in 1995

From: Zamboni P. 2006. “The Big Idea: Iron From: Zamboni P. 2006. “The Big Idea: Iron dependent inflammation in venous disease and dependent inflammation in venous disease and proposed parallels to MS.” proposed parallels to MS.” J R Soc MedJ R Soc Med. 2006 . 2006

Nov;99(11):589-93. PMID:17082306Nov;99(11):589-93. PMID:17082306

Do Zamboni’s Do Zamboni’s ideas have any ideas have any

support in support in standard MS standard MS literature?literature?

Jean Martin CharcotJean Martin Charcot The “Father of The “Father of

Neurology”Neurology” In the 1860’s he In the 1860’s he

documented a case documented a case of MS including an of MS including an autopsy of her brain autopsy of her brain after death.after death.

He noted vascular He noted vascular changes and changes and decided they were a decided they were a result of her result of her disease process.disease process.

Pathology of MS lesion as Pathology of MS lesion as noted by Jean Martin noted by Jean Martin

Charcot 1863Charcot 1863 ““Specific features: in the ventricular wall a Specific features: in the ventricular wall a

massive lesion can be seen to undulate outwards massive lesion can be seen to undulate outwards into the cerebral hemisphere; it into the cerebral hemisphere; it embeds major embeds major venous blood vessels, attended by uneven venous blood vessels, attended by uneven widening of the perivascular spacewidening of the perivascular space.” (F A .” (F A Schelling, 2003)Schelling, 2003)

Dr. E. Rindfleisch 1863Dr. E. Rindfleisch 1863 "If one looks carefully at freshly altered parts "If one looks carefully at freshly altered parts

of the white matter ... one perceives already of the white matter ... one perceives already with the naked eye a red point or line in the with the naked eye a red point or line in the middle of each individual focus,.. the lumen of middle of each individual focus,.. the lumen of a small vessel engorged with blood ... All this a small vessel engorged with blood ... All this leads us to search for the primary cause of the leads us to search for the primary cause of the disease in an alteration of individual vessels disease in an alteration of individual vessels and their ramifications; All vessels running and their ramifications; All vessels running inside the foci, but also those which traverse inside the foci, but also those which traverse the immediately surrounding but still intact the immediately surrounding but still intact parenchyma are in a state characteristic of parenchyma are in a state characteristic of chronic inflammation." chronic inflammation."

Comment in Archives of Pathological Anatomy and Physiology 1863;26:474-483Comment in Archives of Pathological Anatomy and Physiology 1863;26:474-483

Tracy J. Putnam MDTracy J. Putnam MD

Dr. Putnam designed Dr. Putnam designed many experiments many experiments around the idea that around the idea that MS was a vascular MS was a vascular disease. disease.

One of 20 founding One of 20 founding NMSS neurologists.NMSS neurologists.

Because of his work, MS Because of his work, MS was commonly thought was commonly thought to be vascular in the to be vascular in the ’50’s.’50’s.

Putnam’s ExperimentsPutnam’s Experiments

He occluded the neck veins in dogs then He occluded the neck veins in dogs then documented the development of lesions in documented the development of lesions in their brains. their brains.

Experimented with blood thinners which Experimented with blood thinners which provided modest improvement in symptoms.provided modest improvement in symptoms.

Wrote a manual for the NMSS stating MS was Wrote a manual for the NMSS stating MS was vascular.vascular.

Was unable with technology of the time to Was unable with technology of the time to evaluate blood flow in living people but evaluate blood flow in living people but believed until the end of his life that MS was believed until the end of his life that MS was vascular.vascular.

Replication of Putnam’s Replication of Putnam’s workwork

Dow and Burglund. 1942. “Vascular Dow and Burglund. 1942. “Vascular pattern of lesions of multiple sclerosis.” pattern of lesions of multiple sclerosis.” Arch Neurol Psychiatry. 1942;47(1):1-18 Arch Neurol Psychiatry. 1942;47(1):1-18

Zimmerman, H, Netsky, M. 1950. “The Zimmerman, H, Netsky, M. 1950. “The pathology of multiple sclerosis.” Res. pathology of multiple sclerosis.” Res. Publ. Ass. Nerv. Ment. Dis. New York Publ. Ass. Nerv. Ment. Dis. New York 28, 271--312 28, 271--312

Confirm vascular issues but suggest Confirm vascular issues but suggest clots not as important as Putnam clots not as important as Putnam thought.thought.

Related Research in the Related Research in the 50’s: Vasodilators50’s: Vasodilators

Brickner R. 1953. “Essential precautions Brickner R. 1953. “Essential precautions in treatment of new phenomena in multiple in treatment of new phenomena in multiple sclerosis.” sclerosis.” AMA Arch Neuro PsychAMA Arch Neuro Psych. . Oct;70(4):483-8. PMID:13091497Oct;70(4):483-8. PMID:13091497

Jonez H. 1952. “Management of multiple Jonez H. 1952. “Management of multiple sclerosis.” sclerosis.” Postgrad MedPostgrad Med. 1952;2:415-22. 1952;2:415-22

These vasodilators did not change the These vasodilators did not change the disease course in spite of temporary disease course in spite of temporary improvements.improvements.

Why did this model lose Why did this model lose stature as the favored stature as the favored

model?model? Blood thinners and vasodilators were Blood thinners and vasodilators were

only modestly helpful at best.only modestly helpful at best. Research was severely limited by a Research was severely limited by a

lack of technology.lack of technology. The budding field of immunology The budding field of immunology

seemed to promise to offer a better seemed to promise to offer a better way of looking at MS by evaluating way of looking at MS by evaluating the obvious inflammation and immune the obvious inflammation and immune system activity by looking at animals.system activity by looking at animals.

Newer Venous Findings Newer Venous Findings Fog T. 1965. “The topography of plaques in Fog T. 1965. “The topography of plaques in

multiple sclerosis.” multiple sclerosis.” Acta Neurol ScandActa Neurol Scand. . 1965;15:1-161 PMID:52137271965;15:1-161 PMID:5213727

Fog T. 1963. “On the vessel-plaque relations Fog T. 1963. “On the vessel-plaque relations in the brain in multiple sclerosis.” in the brain in multiple sclerosis.” Acta Acta Psychiat Neurol ScandPsychiat Neurol Scand. 1963; 39, suppl. 4:258. 1963; 39, suppl. 4:258

Dr Fog dissected MS lesions and discovered Dr Fog dissected MS lesions and discovered they follow the vein closely expanding in they follow the vein closely expanding in successive waves countercurrent to blood successive waves countercurrent to blood flow.flow.

Today, the fact that MS lesions surround a Today, the fact that MS lesions surround a vein is well known, but this fact is treated as vein is well known, but this fact is treated as unimportant to the autoimmune model: it is unimportant to the autoimmune model: it is assumed the changes in the veins are a result assumed the changes in the veins are a result of MS not the cause.of MS not the cause.

F. Alfons Schelling MDF. Alfons Schelling MD

Schelling F.A. 2003. Schelling F.A. 2003. Multiple Sclerosis: The Multiple Sclerosis: The Image and its messageImage and its message. (book available online). (book available online)

Dr. Schelling follows the history of venous Dr. Schelling follows the history of venous findings in MS from the earliest work in 1838.findings in MS from the earliest work in 1838.

He points out that numerous facts about MS He points out that numerous facts about MS cannot be accounted for by the autoimmune cannot be accounted for by the autoimmune model.model.

Example: MS lesions grow on veins of a certain Example: MS lesions grow on veins of a certain size and expand in successive waves size and expand in successive waves countercurrent to blood flow. EAE lesions do countercurrent to blood flow. EAE lesions do not expand in this way.not expand in this way.

Tan et al, 2006Tan et al, 2006 Because veins and venules are Because veins and venules are

ubiquitous, they traverse most other ubiquitous, they traverse most other types of disease processes. We types of disease processes. We incidentally used this technique in incidentally used this technique in patients with hypoxic ischemic white patients with hypoxic ischemic white matter lesions and found that, especially matter lesions and found that, especially in extensive lesions, veins could be in extensive lesions, veins could be identified within such lesions. identified within such lesions. However, However, in contrast to MS lesions, these white in contrast to MS lesions, these white matter lesions showed no relationship matter lesions showed no relationship to the shape and location of the veinsto the shape and location of the veins. .

Tan et al. 2000. “MR Venography of Multiple Sclerosis.” AJNR 21:1039-1042 Tan et al. 2000. “MR Venography of Multiple Sclerosis.” AJNR 21:1039-1042

BH Juurlink PhDBH Juurlink PhD

Juurlink B. 1998. “Juurlink B. 1998. “The multiple sclerosis lesion: initiated by a localized hypoperfusion in a central nervous system where mechanisms allowing leukocyte infiltration are readily upregulated? Med Hypoth

Speculates that MS is initiated by lack of blood flow which causes death of oligodendrocytes then myelin and a subsequent innate immune response.

Blood Flow is Slow in MSBlood Flow is Slow in MS Adhya S, Johnson G, Herbert J, Jaggi H, Babb Adhya S, Johnson G, Herbert J, Jaggi H, Babb

JS, Grossman RI, Inglese M. 2006. “Pattern JS, Grossman RI, Inglese M. 2006. “Pattern of hemodynamic impairment in multiple of hemodynamic impairment in multiple sclerosis: dynamic susceptibility contrast sclerosis: dynamic susceptibility contrast perfusion MR imaging at 3.0 T.” perfusion MR imaging at 3.0 T.” Neuroimage. Dec;33(4):1029-35. Neuroimage. Dec;33(4):1029-35. PMID:16996280 PMID:16996280

Blood flow in the brains of patients with MS Blood flow in the brains of patients with MS is half the speed that of normal people.is half the speed that of normal people.

Perfusion and oxygenation in the MS brain is Perfusion and oxygenation in the MS brain is poor.poor.

Venous RevivalVenous Revival Zamboni’s work brings the venous Zamboni’s work brings the venous

argument back to the forefront.argument back to the forefront. Today’s technology, used by Zamboni in Today’s technology, used by Zamboni in

his research, reveals blood flow issues in his research, reveals blood flow issues in MS that were not understood before.MS that were not understood before.

Research is just beginning to evaluate Research is just beginning to evaluate how to assess and treat these issues. It how to assess and treat these issues. It will be some years before best practices will be some years before best practices are understood even IF this is a are understood even IF this is a treatable issue.treatable issue.

Due out April 19thDue out April 19th 10% of my 10% of my

royalties go to royalties go to CCSVI Alliance.CCSVI Alliance.

Digital (ie Digital (ie Kindle) is less Kindle) is less expensive but expensive but more goes to more goes to CCSVI Alliance.CCSVI Alliance.