MS appears to be related to venous flow abnormality of ...

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

MS appears to be related to venous flow abnormality of ...

Postby sbr487 » Mon Oct 04, 2010 3:58 am

A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die and a new generation grows up that is familiar with it
- Max Planck
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Re: MS appears to be related to venous flow abnormality of .

Postby 1eye » Tue Sep 13, 2011 6:53 pm

Dr. Simka has not wasted any time capitalizing on this discovery, I'm sure pleasing many. Note that shear stress reduces, causing the breach of the BBB in this scenario, when flow is slow. Flow directly in the narrowed vessel will be faster, but if enough resistance happens, the flow will be slower upstream of the narrowing (in the brain) and disrupt the BBB, as well as starving the brain of food and oxygen. Isn't the increased ICAM-1 also a target of Tysabri?

Perhaps exercise can restore some of the shear stress and flow.
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Re: MS appears to be related to venous flow abnormality of .

Postby PointsNorth » Wed Sep 14, 2011 11:46 am

Hey 1eye, I ain't no expert in fluid dynamics, but wouldn't a narrowing just cause blood to flow faster thru a narrowing but not necessarily affect total volume of blood? From a presentation that Dr. Arata recently gave he said that vein narrowing doesn't necessarily result in reflux or limit volume of flow. I remember BourNouelli's theory (more Italians!).

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Old paper from 2008

Postby MarkW » Wed Sep 14, 2011 2:38 pm

I think Prof Zamboni's more recent papers are more useful than this one.
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Re: MS appears to be related to venous flow abnormality of .

Postby Cece » Wed Sep 14, 2011 6:06 pm

PointsNorth wrote:Hey 1eye, I ain't no expert in fluid dynamics, but wouldn't a narrowing just cause blood to flow faster thru a narrowing but not necessarily affect total volume of blood? From a presentation that Dr. Arata recently gave he said that vein architecture doesn't necessarily result in reflux or limit volume of flow. I remember BourNouelli's theory (more Italians!).

PN

We need more experts in fluid dynamics around here! I would like to learn everything....

Pre-procedure, at my first ultrasound here in MN, my right jugular was observed to have very rapid flow. It makes sense how an increase in velocity could counter to some degree for a stenosis. It's still hard to think of how flow disruptions could occur in the absence of luminal or structural abnormalities, but I could consider the argument that if the vein is stenosed but the flow is not disrupted (because it flows at a higher velocity or because it is carrying an appropriate amount of flow for the area of the stenosis), then CCSVI is not present despite the stenoses.
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Re: MS appears to be related to venous flow abnormality of .

Postby Cece » Sun Sep 18, 2011 11:30 am

MS appears to be related to venous flow abnormality of the brain with secondary brain autoimmunity
Steven R Brenner, physician

Dept. Neurology St. Louis VA Medical Center and Dept. Neurology & Psychiatry at St. Louis University

Dear Editor,

I read the article by Zomboni (1) with interest, with respect to the interaction of the cerebral venous system and central nervous system in development of multiple sclerosis (MS).

An interaction between the central nervous system and venous system has been observed previously in MS lesions by F. A Schelling (2) who initially observed “striking widening of the main venous passageways in the skulls of victims of multiple sclerosis”, and observed venous involvement in the development of cerebral lesions of multiple sclerosis. His supposition was lesions of MS are due to venous back jets from intermittent rises in pressure in the large collecting veins of the neck and especially the chest (2) and noted that Beno Schlessinger, in 1939, while injecting the straight sinus under heavy pressure, noted the extravasations produced around the lateral ventricles “closely stimulate the distribution and even shapes of plaques in multiple sclerosis”.

Certainly venous involvement is distinctive in MS plaques, which usually are perivenous in location, especially in the brain.

The venous outflow obstructions noted by Zamboni (1) appear significant in the development of multiple sclerosis, however their origin remains uncertain. Possibly they are developmental, although an underlying abnormality of the venous wall could also lead to development, especially since MS more commonly develops during adult life, and possibly there is more than one etiology since MS is variable in symptomatology.

Venous obstruction may lead to decreased cerebrospinal fluid reabsorption with subsequent toxicity to neuronal structures from retained CSF components. Additional injury would occur subsequent to breakdown of the blood brain barrier from intermittent elevation of venous pressure injuring capillary and venule endothelium, with secondary development of autoimmunity to brain components following exposure to the systemic immune system, which is ordinarily barred from the central nervous system. After autoimmunization to brain components, MS could transition from a initial abnormality of venous drainage to a secondarily progressive autoimmune disease.

This is from 2009, but Dr. Brenner raises some interesting points from the neurological perspective.

Is CCSVI developmental aka congenital in origin, or is there an underlying abnormality that leads to later development of CCSVI, or possible both, which could begin to explain some of the variability of MS?

If venous obstruction also obstructs the resorption of CSF, since CSF drains into the dural sinuses through arachnoid granulations (does it drain elsewhere too?), and the dural sinuses lead directly into the jugulars and blockages there can lead to slow or refluxing flow that affects the CSF drainage, that means we are left with poorly drained CSF, leading to increased toxicity to delicate brain tissue.

Additional injury occurs through the intermittent elevation of venous pressure within the capillaries and venules, to which Dr. Tucker and Dr. Beggs have both recently drawn attention.

Secondary development of autoimmunity can occur, as the weakened capillary endothelium allows leukocytes gain access to the brain. The blood brain barrier is there for a reason, it is not by chance that the endothelium of the capillaries of the brain has those extreme tight junctions, and we get to live the results of that BBB being weakened. Dr. Brenner uses the words 'secondarily progressive' autoimmune disease, does that mean he is suggesting that this secondarily acquired autoimmunity marks the change from relapsing-remitting MS to secondarily progressive MS? I don't think this quite fits. Relapsing-remitting has a strong role for the immune system; secondarily progressive does not much involve the immune system, since the DMDs no longer do much for SP the way they do for RR. I find it more likely that SP is a result of the accumulation of axonal damage and the natural consequences of aging meaning that the brain can no longer heal and recover the way it could when we were twenty.
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Re: MS appears to be related to venous flow abnormality of .

Postby marcstck » Sun Sep 18, 2011 7:31 pm

Cece wrote:

Secondary development of autoimmunity can occur, as the weakened capillary endothelium allows leukocytes gain access to the brain. The blood brain barrier is there for a reason, it is not by chance that the endothelium of the capillaries of the brain has those extreme tight junctions, and we get to live the results of that BBB being weakened. Dr. Brenner uses the words 'secondarily progressive' autoimmune disease, does that mean he is suggesting that this secondarily acquired autoimmunity marks the change from relapsing-remitting MS to secondarily progressive MS? I don't think this quite fits. Relapsing-remitting has a strong role for the immune system; secondarily progressive does not much involve the immune system, since the DMDs no longer do much for SP the way they do for RR. I find it more likely that SP is a result of the accumulation of axonal damage and the natural consequences of aging meaning that the brain can no longer heal and recover the way it could when we were twenty.

As we've discussed before, there is a distinct possibility that the reason the DMDs don't work once the disease progresses to SPMS is because they don't cross the blood brain barrier, and recent evidence indicates that a rogue immune system develops within the CNS of SPMS (and possibly PPMS) patients. This would explain the success some have had treating progressive patients with it intrathecal methotrexate, and in fact the NIH is currently conducting a study using intrathecal Rituxan to treat SPMS patients. This all goes back to the tertiary lymphatic organ discussion we had several months ago.

I believe what the author is referring to is the fact that once such an autoimmune engine has been started, eliminating the key that started it will no longer relieve the disease. In other words, there is a window, before SPMS sets in, when systemic treatment of any kind is much more likely to be effective, because once the self-contained autoimmune process develops within the CNS, systemic remedies would be of little or no efficacy. Treatment modalities specifically targeted within the CNS need to be developed.
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Re: MS appears to be related to venous flow abnormality of .

Postby Cece » Sun Sep 18, 2011 7:54 pm

If there is a tertiary lymphatic system in SPMS or PPMS, then what about Tysabri? Tysabri causes the BBB to be so impervious to leukocyte crossing that the JC virus can get out of control within the brain, leading to PML. But Tysabri would have no impact on a rogue tertiary lymphatic organ within the brain. If it exists, wouldn't we see more cases of PML in RR (since they'd lack this tertiary immune system) and fewer cases of PML in SPMS and PPMS (since the tertiary system would render them some protection)?
I believe what the author is referring to is the fact that once such an autoimmune engine has been started, eliminating the key that started it will no longer relieve the disease.

Yes, this is one of the most frustrating things about CCSVI treatment, that there are those for whom it is too little, too late, either due to severity of progression or something like this, a rogue tertiary lymphatic system in the brain itself.

Thanks for your thoughts, they are as always thought-provoking.
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Re: MS appears to be related to venous flow abnormality of .

Postby ikulo » Sun Sep 18, 2011 9:12 pm

Hi Mark,

could you link to more information on the 'rogue immune system' in CNS of SPMS? I'd be interested in reading more.

Thanks!
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Re: MS appears to be related to venous flow abnormality of .

Postby Cece » Sun Sep 18, 2011 10:02 pm

Here's a previous post from Marc on the subject:
chronic-cerebrospinal-venous-insufficiency-ccsvi-f40/topic17285.html#p171332

And some support for the existence of tertiary lymphoid systems:
During chronic inflammation, immune effectors progressively organize themselves into a functional tertiary lymphoid tissue (TLT) within the targeted organ. TLT has been observed in a wide range of chronic inflammatory conditions but its pathophysiological significance remains unknown. We used the rat aortic interposition model in which a TLT has been evidenced in the adventitia of chronically rejected allografts one month after transplantation. The immune responses elicited in adventitial TLT and those taking place in spleen and draining lymph nodes (LN) were compared in terms of antibody production, T cell activation and repertoire perturbations. The anti-MHC humoral response was more intense and more diverse in TLT. This difference was associated with an increased percentage of activated CD4+ T cells and a symmetric reduction of regulatory T cell subsets. Moreover, TCR repertoire perturbations in TLT were not only increased and different from the common pattern observed in spleen and LN but also “stochastic,” since each recipient displayed a specific pattern. We propose that the abnormal activation of CD4+ T cells promotes the development of an exaggerated pathogenic immune humoral response in TLT. Preliminary findings suggest that this phenomenon i) is due to a defective immune regulation in this non-professional inflammatory-induced lymphoid tissue, and ii) also occurs in human chronically rejected grafts.

http://www.plosone.org/article/info%3Ad ... ne.0011398

It is a good explanation for why the immune-modifying drugs stop working, once the RR phase is over.
Although it might give me nightmares.
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Re: MS appears to be related to venous flow abnormality of .

Postby ttucker3 » Mon Sep 19, 2011 12:40 pm

There seems to be a broad growing acceptance that a number of factors may contribute to the origins of multiple sclerosis. I would like to briefly touch on several possibilities.

Further to the hypothesis that chronic pulsatile reflux from a vein obstruction may give rise to acute localized hypertension in the cerebral venules (which in turn may give rise to a compromised blood brain barrier) here are some further observations.

There is a paper by Mahy, Tooke and Shore called “Capillary pressure during and after incremental venous pressure elevation in man” (1995) in which the peak pressure in the capillaries increased more than an induced increase in pressure in capillary bed’s vein. While this research was specific to the finger’s capillary bed, it seems not too unreasonable to extrapolate it to the cerebral capillary bed as well. This may mean that as the vein branches out into smaller venules, pressure is amplified somewhat as the reflux goes back up into the finer venules. (There is also probably another fluid dynamics phenomena happening here, in that as the vessels become finer and finer, blood probably flows more like catsup than water - which the fluid dynamicist would call non-newtonian flow). Such “pressure amplification” in the narrowing vessels would seem to accentuate the prospect for BBB disruption in the venule region and perhaps associated MS.

Another paper, by Lindenberg and Länne entitled “Sex-related effects on venous compliance and capillary filtration” (2006), also indicates that the vein’s compliance, which is the inverse of the elasticity, is about 50% less in women than men (ie. the elasticity of men’s veins is about 50% greater than that of women’s veins). Less female vein elasticity would mean that the lower portion of cerebral-spinal veins in women would have less capacity to store blood than men’ss veins and hence more blood and pressure would be pushed up into the venule region, thereby resulting in an increased pressure on the blood-brain barrier in women. Hence, less vein elasticity in women may lead to more BBB hypertension than in men and be a contributing factor to their greater per capita incidence of MS.

Vitamin D deficiency has also been associated with an increased incidence of MS. (See for example “Vitamin D intake and incidence of multiple sclerosis” by Munger, Zhang, O’Reilly et al, 2004) A paper recently presented at the 2011 American College of Cardiology meeting by Ibhar Al Mheid, provides evidence that Vitamin D deficiency is also associated with reduced blood vessel elasticity. Hence, vitamin D deficiency may also be a contributing factor to increasing BBB hypertension, its potential disruption and associated MS occurrence

Further, there is a paper by Kröger, Ose, Rudofsky et al called “Peripheral veins: influence of gender, body mass index, age and varicose veins on cross-sectional area” which indicates that varicose veins occur in women at approximately twice the per capita rate as men. Also, that the vein size in women is smaller than that in men and the vein elasticity for women is also less. In addition the most common cause of varicose veins is the malfunctioning of valves in the veins. In addition, there are associations between varicose vein occurrence, genetics and aging. Each of these varicose vein properties seem to be shared with those of the cerebral spinal veins now being associated with multiple sclerosis.

As a final note, other scientific papers that address the relationships of genetics and Epstein –Barr virus to MS indicate that these may have a deleterious effect on the health of endothelial cells (which go into making up the blood-brain barrier). Such effect may make the BBB more susceptible to disruption in the presence of venule hypertension.

All of the above taken together seems to provide some evidence that some combination of factors, starting with localized venule reflux hypertension, exacerbated by vein inelasticity associated with either gender or vitamin D deficiency, and genetics and latent Epstein-Barr virus infection may underlie MS. It seems unlikely that the combination would be the same for all individuals. However, since localized hypertension from reflux appears to be a common factor, this would seem to be a reasonable focal point for further research. The means to assessing which factor causes what contribution and under what particular circumstances could be addressed by application of computational fluid dynamics. This discipline would permit the experimentation with numerous combinations of factors, including amount of hypertension, elasticity of the veins and venules, compromise of the BBB from vitamin D deficiency and/or EBV. Seems like enough work for a dozen or so new PhD theses.
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Re: MS appears to be related to venous flow abnormality of .

Postby Nasti » Mon Sep 19, 2011 1:23 pm

Definition of the scientific revolution. Plus, it doesn't happen over night (unless all the old proponents die pretty fast) and it is completely and utterly different from the old definition (Galileo's Sun completely switched places with the Earth in the rotation who around who). And this is how progress happens. And we, the suffering, in this theory switching time, are just warriors (some veterans, some casualties) paving the way for the future not as unfortunate generations.
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Re: MS appears to be related to venous flow abnormality of .

Postby Cece » Mon Sep 19, 2011 1:41 pm

Thank you to Dr. Tucker for that summary. I don't think we've talked much about vein elasticity here, I wasn't aware of the gender differences in elasticity or what an effect it would have on reflux and BBB breakdown.

(edited for spelling, oh my!)
Last edited by Cece on Mon Sep 19, 2011 3:27 pm, edited 1 time in total.
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Re: MS appears to be related to venous flow abnormality of .

Postby Ruthless67 » Mon Sep 19, 2011 2:30 pm

I'm always excited when someone adds a piece to our puzzle. Every single piece is so important to the outcome.

I was not aware of the gender differences in elasticity, what a great new topic to explore. Good fodder for the upcomming Q & A session at the October 20th, CCSVI Alliance Satellite Session.

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Re: MS appears to be related to venous flow abnormality of .

Postby NHE » Tue Sep 20, 2011 4:33 am

Nasti wrote:Definition of the scientific revolution. Plus, it doesn't happen over night (unless all the old proponents die pretty fast) and it is completely and utterly different from the old definition (Galileo's Sun completely switched places with the Earth in the rotation who around who). And this is how progress happens. And we, the suffering, in this theory switching time, are just warriors (some veterans, some casualties) paving the way for the future not as unfortunate generations.


A little off topic and I don't mean to put Dear Galileo down, but I'm pretty sure that Copernicus was first to publish.


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