Must read: JNNP eLetters for Zamboni's CCSVI article

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

Must read: JNNP eLetters for Zamboni's CCSVI article

Postby HappyPoet » Fri Jul 10, 2009 8:33 pm

Hello Everyone,

I'd like for my first thread to be a valuable contribution to your wonderful forum.

I have learned much, and my doctors and I (Albany, NY) are scheduling the necessary tests to see if I'm a potential candidate for CCSVI corrective measures.

I hope the JNNP-published eLetters (below) to the editors of JNNP regarding Prof. Zamboni's CCSVI article will make for interesting reading and discussion. I apologize if these have already been posted.

I feel like I already know many of you from my readings -- you're all the best!


~~~~~~~~ ... 164v1#4667

MS appears to be related to venous flow abnormality of the brain with secondary brain autoimmunity

16 June 2009

Steven R Brenner, MD
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.


1. P Zamboni, R Galeotti, E Menegatti, et al.
Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis.
J Neurol Neurosureg Psychiatry 2009; 80: 392-399.

2. F Alfons Schelling MD
Multiple sclerosis: The image and its message. The meaning of the classic lesion forms.
Available on line at URL:

No conflict of interest.


Chronic cerebrospinal venous insufficiency: a potential weakening factor of the blood-brain barrier

29 December 2008

Marian Simka,
Specialist in angiology
Department of Angiology,
Private Healthcare Institution SANA, Pszczyna;

Dear Editor,

Multiple sclerosis is believed to be an autoimmune pathology, yet the mechanisms triggering the disease remain elusive. Therefore, I read with great interest the paper by Zamboni and his team who investigated the venous hemodynamics in patients with multiple sclerosis. His findings that this disease might be attributable to venous refluxes shed new light on the facts that have been known for decades (1), but have been mostly ignored by the scientific community. It should be answered, however, how this pathological outflows in the extra- and intracranial veins could trigger autoimmune reaction.

The loss of integrity of the blood-brain barrier, which is primarily built by tight-junction complexes between adjacent endothelial cells of the cerebrovascular endothelium, is a hallmark of multiple sclerosis. In this context, parallels between multiple sclerosis and chronic venous insufficiency of lower extremities (which is also an endotheliocyte- focused pathology) could be helpful. Yet, it should be remembered that endotheliocytes building the blood-brain barrier highly differ from those in the periphery. Moreover, venous hypertension in cerebral and spinal veins is unlikely to disassemble the cerebrovascular endothelial barrier (2).

Indeed, although Zamboni has found increased venous pressure distally of venous stenoses, these pressure gradients were rather small. Thus, it is more likely that not venous hypertension, but pathological pattern of the blood flow-associated forces, decreased level of shear stress in particular, disassembles the blood-brain barrier and increases the transendothelial permeability.

It has been found that an enhanced expression of pivotal tight junction proteins: occludin and ZO-1 in the cerebrovascular endothelium was associated with reduced transendothelial permeability and it has been shown, moreover, that an increased shear stress, especially with pulsatile flow characteristics, upregulated these proteins (3). By contrast, loss of shear stress after flow cessation enhanced the blood-brain barrier permeability (4). Therefore, a reduced shear, for instance as a result of the refluxing venous blood flow, could potentially result in the weakening of the blood-brain barrier. This in turn could initiate an autoimmune attack against nervous tissue.

Several questions, though, should have been answered before multiple sclerosis was recognized as a fundamentally hemodynamic disorder. First, if intracranial reflux is indeed the trigger of multiple sclerosis plaques, and not an innocent bystander. This will require additional studies in a much larger cohort of multiple sclerosis patients. Second, if these refluxes only bypass an occlusion and affect exclusively large cerebral and spinal veins, or they extend also into smaller veins (probable, damage of the blood-brain barrier can occur on condition that a decreased shear stress influence the cerebrovascular endothelium in the postcapillary venules). Third, mechanistic links between venous refluxes and cellular and molecular pathways that are responsible for autoimmune reaction should be determined, since such a discovery could result in the development of novel effective pharmacologic agents.

Regarding these mechanisms, it should be suspected that the low shear-induced expression of ICAM-1 (adhesion molecule, which is responsible for the firm adhesion of leukocytes to endothelia) by cerebrovascular endothelium, could be a critical point in the initiation of multiple sclerosis plaque, since the crosslinking of ICAM-1 with integrins expressed on the leukocytic surfaces leads to a weakening of the blood-brain barrier and facilitates the transendothelial leukocyte migration (5).

Furthermore, consequently to Zamboni’s findings it may be speculated that at least for some anatomical variants of pathological venous outflow, surgical correction of steno-occlusions can be a therapeutic option in addition to or instead of pharmacotherapy.

In conclusion, investigations of the extra- and intracranial hemodynamic disturbances in multiple sclerosis patients appear to be a challenging avenue and may open a new chapter of therapeutic approach to this debilitating disease.


1. Schelling F.
Damaging venous reflux into the skull or spine: relevance to multiple sclerosis.
Med Hypothes 1986;21:141-8.

2. Simka M.
Evidence against the role for dural arteriovenous fistulas in the pathogenesis of multiple sclerosis.
Med Hypothes 2008;71:619.

3. Colgan OC, Ferguson G, Collins NT, et al.
Regulation of bovine brain microvascular endothelial tight junction assembly and barrier function by laminar shear stress.
Am J Physiol Heart Circ Physiol 2007;292:H3190-7.

4. Krizanac-Bengez L, Mayberg MR, Cunningham E, et al.
Loss of shear stress induces leukocyte-mediated cytokine release and blood-brain barrier failure in dynamic in vitro blood-brain barrier model.
J Cell Physiol 2006;206:68-77.

5. Lyck R, Reiss Y, Gerwin N, Greenwood J, Adamson P, Engelhardt B.
T-cell interaction with ICAM-1/ICAM-2 double-deficient brain endothelium in vitro: the cytoplasmic tail of endothelial ICAM-1 is necessary for transendothelial migration of T cells.
Blood 2003;102:3675-83.

There is no conflict of interest regarding this letter.

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Postby javaneen » Sat Jul 11, 2009 8:03 am

Hello and welcome! I think you are gonna fit in just fine around here :!: Great first post! I am still sorting through it...I'm not quite as fast as Marie and Cheer with understanding all this stuff :?

Good luck getting testing. Keep us all updated on what they find and what you decide to do. Do you have the tests scheduled already? I would love to here more about you and your condition.

Thanks for adding to this fantastic forum.
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Postby mrhodes40 » Sat Jul 11, 2009 8:44 am

Welcome HP! Nice first contribution, we do have the letters on the Research sticky thread.....they are fabulous as you obviously perceived! It means that peers are evaluating this idea and seeing the value in it. J's right you fit right in!

Dr Simka is doing some of his own research and his understanding has grown and evolved by this point in time as more recent papers show. I believe he is starting a study that includes treatment and is recruiting now.

The Brenner paper is kind of tossing out some other ideas that should be elucidated with time. The idea of retained metabolites in the CSF because the venous pressure is not allowing proper elimination is probably true, and autoimmunity as the result of this anomaly is being investigated and we will see some material on this soon I think--because once CCSVI is shown as the possible cause of MS, it is not necessary for autoimmunity to be part of that picture; though it MAY be--no one knows for sure yet.

welcome to the party
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Postby HappyPoet » Sat Jul 11, 2009 6:11 pm

Thank you both very much for your very thoughtful replies -- TIMS has the classiest people on the Internet!

It seems I'm having a hard time keeping up with all the threads/posts and remembering which ones I've already read, what they said and where they were posted. But I will certainly endeavor to keep trying.

I recently read an interview Prof. Zamboni gave saying he didn't know if CCSVI is the cause of MS or happens because of it -- either way, though, I believe significant occlusions cannot be good for one's brain.

I've had the MRIs with the venography study in two weeks; thank you for asking. If all goes well (insurance-wise, especially), September will be the month for any intervention needed.

TIMS, so full of hope, is definitely the place for me. Again, you're all the best!

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Postby mrhodes40 » Sat Jul 11, 2009 6:23 pm

hard time keeping up

NO problem!! it is good to revisit these I am glad we discussed them because we all forget what we read already and where it is this is a reminder of that great work!

I do not think any of the medical researchers have published anything saying that they have determined that CCSVI happens first because there is nothing proving it yet..... The bar is high for "proof".

While other people--like me for example --may speculate about physiological principles and say this is probably CCSVI then MS lesions, it takes some deep evaluation of the literature to come to such a conclusion from a research perspective that holds water. It will be a little bit before that happens, but this is the best fun I have had in years of looking at MS research developing. This is going a new direction and it feel really hopeful to me
glad you are here
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Postby Sharon » Sat Jul 11, 2009 6:37 pm

HP wrote
It seems I'm having a hard time keeping up with all the threads/posts and remembering which ones I've already read, what they said and where they were posted.

Wait till you go on vacation and can't get to a computer -- it took me a few days to catch up. Just as a reminder --there is a search function on TIMS which will help you locate posts.

Welcome - glad to have you here.
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Postby HappyPoet » Sat Jul 11, 2009 7:32 pm

Saying, "Thanks for your replies!" has a rather nice ring to it :)

Yes, this is such fun, made so in great part thanks to such welcoming, smart, determined, compassionate and hopeful people like yourselves!

Once the terminology and general principal sunk in, it all suddenly seemed so intuitive as to be common sense . . . and I love adding to my knowledge base and reading everyone's ideas regarding all facets of CCSVI.

Thanks again for everything you say, kindest folks :)

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