Transcript MS as a Vascular Disease

MS as a Vascular Disease:
Background and History
Marie Rhodes RN
Is MS proven to be a
primary
autoimmune
disease?

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
“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 breakdown with
microglia scavenging and subsequent immune cell
recruitment; the Barnett and Prineas model.
Nerve cell with
damaged
myelin
Oligo
Microglia
Recruited Immune System Cells
Replication



Barnett M, Sutton I. 2006. “The pathology of multiple
sclerosis: a paradigm shift.” Curr Opin Neurol.
Jun;19:242-47. PMID:16702829
Barnett M., Henderson A, Prineas J. 2006. "The
macrophage in MS: just a scavenger after all?" Mult
Scler. Apr;12(2); 121-32. PMID:16622941
Barnett M, Parratt J, Prineas J. 2009. “Multiple
sclerosis: Distribution of inflammatory cells in newly
forming MS lesions.” Ann Neur. Dec;66:739-753.
PMID:20035511



Barnett M, Parratt J, Pollard J, Prineas J. 2009.
“MS: is it one disease?” Int MS J. Jun;16
(2):57-65 PMID: 19671369
Henderson AP, Barnett MH, Parratt JD,
Prineas JW. 2009. Multiple sclerosis:
distribution of inflammatory cells in newly
forming lesions. Ann Neurol Dec;66(6):739-53.
PMID:20035511
These papers have been cited numerous times
by other researchers.




Chaudhuri A. 2004. “Multiple sclerosis is not
to an auto immune disease." Comment in Arch
Neurol. Oct;61(10):1610-12. PMID:15477520
Behan P, Chaudhuri A. 2002. “The
pathogenesis of multiple sclerosis revisited.” J R
Coll Physicians Edinb. 32(4):244-265
Roach E. 2004. “Is multiple sclerosis an
autoimmune disorder?” Arch Neurol.
Oct;61(10):1615-6. PMID:15477522
Tsutsui S, Stys P. 2009. “Degeneration versus
autoimmunity in MS.” Comment in Ann Neurol.
Dec;66(6):712. PMID:20033985
Is MS autoimmune?

MS an inflammatory disease of unknown origin. The
inflammation is indisputable, but the cause of the
immune system activity is still unproven.

MS standard therapies reduce inflammation, and much
of MS damage is caused by inflammation itself
regardless of cause. Therefore relapses and
inflammatory lesions are reduced with these therapies
even though the cause of the inflammation is
unknown.
What is known
about CVD?
Chronic Venous Disease

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

Review of current understanding in the field of
vascular medicine.





Veins become stretched out.
Stretched or vericose veins are under increased
pressure.
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 RBC’s.

Much of the damage to leg tissue is caused by
immune system activity.

If lesions develop venous insufficiency is present.
CVD may be thought of as an inflammatory disease.

CVD Immune Cell Cascade with Reflux
Image by Marv Miller from “CCSVI as the Cause of Multiple Sclerosis”
ironIron
Immune cells
Red
Blood
Cells
Refluxing blood flow
in a varicose vein
Paolo Zamboni, MD





Professor of Medicine at University of Ferrara, Italy.
Director of the Vascular Diseases Center.
Graduated in ’82 as a doctor, then completed a general
surgery internship through ’87. He then went on to a
fellowship at the Vascular Surgery Center at UCSF.
He is a prominent researcher in the vascular field and
the recipient of numerous awards for his work.
His wife was diagnosed with MS in 1995
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
Do Zamboni’s ideas
have any support in
standard MS
literature?
Jean Martin Charcot



The “Father of
Neurology”
In the 1860’s he
documented a case of
MS including an autopsy
of her brain after death.
He noted vascular
changes and decided they
were a result of her
disease process.
Pathology of MS lesion as noted by
Jean Martin Charcot 1863

“Specific features: in the ventricular wall a massive lesion can be
seen to undulate outwards into the cerebral hemisphere; it
embeds major venous blood vessels, attended by uneven
widening of the perivascular space.” (F A Schelling, 2003)
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
Tracy J. Putnam MD
Dr. Putnam designed many
experiments around the
idea that MS was a
vascular disease.
One of 20 founding NMSS
neurologists.
Because of his work, MS
was commonly thought
to be vascular in the ’50’s.
Putnam’s Experiments




He occluded the neck veins in dogs then documented
the development of lesions in their brains.
Experimented with blood thinners which provided
modest improvement in symptoms.
Wrote a manual for the NMSS stating MS was vascular.
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.
Replication of Putnam’s work



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
Confirm vascular issues but suggest clots not as
important as Putnam thought.
Related Research in the 50’s:
Vasodilators



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
These vasodilators did not change the disease
course in spite of temporary improvements.
Why did this model lose stature as
the favored model?



Blood thinners and vasodilators were only
modestly helpful at best.
Research was severely limited by a lack of
technology.
The budding field of immunology seemed to
promise to offer a better way of looking at MS
by evaluating the obvious inflammation and
immune system activity by looking at animals.
Newer Venous Findings




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
Dr Fog dissected MS lesions and discovered they follow
the vein closely expanding in successive waves
countercurrent to blood flow.
Today, the fact that MS lesions surround a vein is well
known, but this fact is treated as unimportant to the
autoimmune model: it is assumed the changes in the
veins are a result of MS not the cause.
F. Alfons Schelling MD
Schelling F.A. 2003. Multiple Sclerosis: The Image and its
message. (book available online)
 Dr. Schelling follows the history of venous findings in
MS from the earliest work in 1838.
 He points out that numerous facts about MS cannot be
accounted for by the autoimmune model.
Example: MS lesions grow on veins of a certain size and
expand in successive waves countercurrent to blood
flow. EAE lesions do not expand in this way.

Tan et al, 2006

Because veins and venules are ubiquitous, they
traverse most other types of disease processes.
We incidentally used this technique in patients
with hypoxic ischemic white matter lesions and
found that, especially in extensive lesions, veins
could be identified within such lesions.
However, in contrast to MS lesions, these
white matter lesions showed no relationship
to the shape and location of the veins.
Tan et al. 2000. “MR Venography of Multiple Sclerosis.” AJNR 21:1039-1042
BH Juurlink PhD


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 MS

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

Blood flow in the brains of patients with MS is half the
speed that of normal people.
Perfusion and oxygenation in the MS brain is poor.

Venous Revival



Zamboni’s work brings the venous argument
back to the forefront.
Today’s technology, used by Zamboni in his
research, reveals blood flow issues in MS that
were not understood before.
Research is just beginning to evaluate how to
assess and treat these issues. It will be some
years before best practices are understood even
IF this is a treatable issue.
Due out April 19th


10% of my royalties
go to CCSVI
Alliance.
Digital (ie Kindle) is
less expensive but
more goes to
CCSVI Alliance.