This Is MS Multiple Sclerosis Knowledge & Support Community

I know the idea of MRI isn't very attractive, on account of the known side-effects (which are probably permanent), caused by gadolinium injections. These injections are the 'contrast' used to 'enhance' brain lesions. I would not like to be mistaken as encouraging people to have this done. I don't remember how many injections of gadolinium I have had, but I do not like the idea of having more.

In all of the scientific tests, trials, etc. that I have seen which are attempting to reproduce the work of Paulo Zamboni, I have not seen mention of gadolinium-enhancing lesions.

These are 'MS' lesions which light up, or 'enhance' on MRI. The reason for this enhancement on the image is the interesting thing. It happens because there is a blood leakage at the centre of the lesion. Now why would that be?

I read this fact in the earlier work of the scientist Ashton Embry. He said, then, that the reason they 'enhance' is because of blood. You inject it into the vein of someone in the MRI chamber, and the venous blood crosses the so-called 'blood/brain barrier' in the centre of the lesion.

Right at the centre of the 'MS' venous lesion. This fact has been known since MRI has been used for brain imaging. A vein is at the centre of every gadolinium-enhancing lesion. It is at this vein that blood crosses the 'blood/brain barrier'.

What is the 'BBB'? Well BBB is just another TLA (three-letter acronym), and it means 'blood/brain barrier'. The BBB is just a characteristic of blood vessels in the brain, or more generally, the central nervous system. The so-called barrier is just the fact that these vessels have finer filtering ability than others, and so it is more difficult for large items to 'cross' it, or get missed, and allowed by this brain vessel to pass through the blood vessel wall, into the brain tissue. This 'filtering' is at a microscopic level, but gadolinium, a metal in solution injected into veins, will cross at 'weaker' spots, i.e., at the centre of lesions.

In other words, gadolinium atoms or molecules of solution (I don't know which) are so large that they do not normally cross into the brain or spine. But at the specific point where the vein wall is weak, or more largely perforated, i.e., at the centres of lesions, gadolinium passes through, and the lesion is brighter on the image.

I do not know if the only type of vessel where gadolinium passes through a 'weak spot' is a vein (never an artery), but for all I know that is the case, and only veins ever cause this 'enhancement'.

What causes this perforation increase? I suggest it is the blood itself, in a stagnant state, which attacks the vessel wall, and the lesion then ensues.

What does this have to do with Paulo Zamboni? According to what is on the web-site http://angioplastyforall.com, he measured a decrease in gadolinium-enhancing lesions from 50% pre-Liberation to 12% post-liberation, or 38% due to Liberation.

Why is this result, surely a direct measurement of the result on 'MS' of the Liberation procedure, not mentioned alongside the accusation of 'placebo effect'? Maybe the reason this procedure has been marginalized so much is to avoid this issue. Certainly the people who have had this procedure have not had before/after gadolinium-enhancing MRIs, because they have had no cooperation from the medical or insurance contingents. This absence of responsible scientific participation in this work, is notable for having been led by the neurology profession, who have published only papers deliberately and categorically stating their disbelief.

What is wrong with this negative science? There is a plainly stated disbelief in the work of Dr. Zamboni. Even with cold fusion, the attempts were sincere, and worked to try to accurately reproduce what was said to have been achieved. Here, has anyone used what has long been a standard measure of 'MS' activity, the gadolinium-enhancing lesion? As http://angioplastyforall.com states, one cannot attribute a reduction in a crowd of patients' number of gadolinium-enhancing lesions to placebo. It can't be done. Let us sincerely hope the ongoing Liberation trials include this measurement, and get us back into the twenty-first century.

I never saw it that way before. Kinda makes me mad, if they were measuring this all along, and yet not open to incorporating the knowledge of vascular experts into the research.

Is this common knowledge?? edited to say....I'm thinking that this way too deep for me.....

angioplastyforall.com references Dr. Zamboni's paper.

Worsenings have been directly attributed to re-stenosis and clots. I think people should remember: the danger from clots can be likened to what happened to Radek: there is a direct path for clots, or pieces of them, to the heart, and from there to the lungs. Blood thinning seems to be beneficial for multiple reasons, but clots are to be assiduously avoided. That is true whether you are talking about neck veins, arteries, or jugular ports used for plasma exchanges. To me this is a reason to use IVUS, and avoid stents where possible (I have 3 arterial ones). It is much more risky than ballooning, but even there blood thinners are still used.

I know I'm posting on my own thread, but I have not seen much of the vaunted skepticism on this topic, so I thought, well, maybe it's uncontested. I wonder if this metric can be used to help prove that the procedure saves lives, and why it saved them?

Gadolinium crosses the blood brain barrier (BBB) at the site of an active lesion because the white blood cells are crossing the BBB at that point due to active inflammation and have made the BBB permeable.

Given the above, what is the proposed role of CCSVI in the increased permeability of the BBB? As previously discussed, Dr. Simka has stated that the loss of sheer stress due to reflux makes the BBB more permeable by weakening the tight junctions between the endothelial cells lining the blood vessels and also by upregulating the protein ICAM-1 which is used by the immune cells as a binding point to cross the BBB. It is interesting to note that the role of Tysabri is to block the adhesion of the immune cells to ICAM-1. A better approach might be to address the increased prevalence of ICAM-1 first by eliminating the reflux.

http://www.thisisms.com/ftopicp-138243.html#138243

NHE

NHE wrote:Gadolinium crosses the blood brain barrier (BBB) at the site of an active lesion because the white blood cells are crossing the BBB at that point due to active inflammation and have made the BBB permeable.

http://www.thisisms.com/ftopicp-138243.html#138243

NHE

I quote from the original discussion:

NHE wrote:

MegansMom wrote:Then you have the actual lesions- these lesions are from damage from shear stress on the epithelium of the venules (vein walls are designed for flow going one way -"OUT") -inflammation occurs, iron is left (the iron is from Red Blood Cells) and and consequently demyelination. The role of the immune system is not clearly understood at this point.

Simka has discussed that it is the loss of shear stress during reflux that increases blood brain barrier permeability.

Here is a link to the Brenner and Simka letters to JNNP regarding Zamboni's paper. http://jnnp.bmj.com/content/80/4/392/reply#jnnp_el_4236

In addition, this abstract reviews similar material.

My interpretation of Simka's letter to JNNP...

[color=blue]NHE[/color] wrote:Simka's letter in a nutshell... Endothelial cells are the cells that line the blood vessels. In the brain, the endothelial cells make up the blood brain barrier. When blood flows past the endothelial cells, the cells experience shear stress. In response to this stress, the cells upregulate the proteins that make the connections between them stronger, i.e., the statement about tight junctions. Stronger tight junctions help the blood brain barrier limit what can pass between the endothelial cells from the blood to the brain, e.g., the white blood cells of the immune system. Simka's point appeared to be that with reduced blood flow seen in CCSVI in MS patients, the endothelial cells will not experience as much shear stress and will therefore have weaker tight junctions between them leading to increased permeability of the blood brain barrier and that this change in the blood brain barrier may be a contributing factor to the development of MS. In addition, Simka noted that low shear stress upregulates the protein, ICAM-1, that's used by leukocytes to cross the blood brain barrier. This is like a double edged sword against the blood brain barrier, i.e., not only is it more permeable but the adhesion molecules needed by the immune system cells to cross the blood brain barrier are more abundant (that's like opening all the windows in your house just a bit and then putting signs out for the burglars). Simka also proposed that he thought that surgical intervention was a good idea.

NHE

I don't see any argument for immune cells increasing permeability. The comment that the reduced shear stress both upregulates ICAM-1 *and* causes the reduced permeability of the BBB makes sense, however immune cells exist throughout the bloodstream, and both of these actions can take place at other sites just as easily.

Simka argues reduced shear stress causes increased permeability. If this is the case, looking at it the other way up, it is the normal shear stress caused by the normal (higher) flow that *causes* the normal impermeability of the BBB. But we still have no explanation for the BBB being especially compromised at the centre of a lesion, such that gadolinium will cross there and only there. Iron may be causing this, or (less likely IMO) larger scavenger-type immune cells. Or the reduced shear stress happens to be especially prevalent at that point. Or some other component of blood is responsible.

The fact remains (and I don't think we know for sure why), that the gadolinium agent passes out of the vein at the centre of the lesion, which is the vein at the weakest point in the BBB. Nowhere else.

The existence of these gadolinium-enhancing lesions, and their documented reduction in number by the Liberation procedure, indicates it is an effective treatment, independent of the placebo effect, which cannot explain this reduction.

Hi 1eye,
I picture the sequence like this, reflux weakens the tight junctions of the BBB by loss of shear stress which downregulates proteins such as occludin and ZO-1. In addition, the loss of shear stress upregulates ICAM-1 which is the protein to which white blood cells bind to in order to cross the blood brain barrier. Taken together, reflux has both made it easier for the white blood cells to cross the BBB by loosening up the tight junctions and has also installed more "doorways" for them, ICAM-1, in order for them to cross. When the white blood cells cross the BBB, it becomes leaky. The gadolinium flows through this leaky area created by the white blood cells thereby indicating sites of active inflammation (the active lesions). What hasn't been addressed here, and what you allude to, is why are the white blood cells crossing the BBB in the first place? Are they doing it just because there is more ICAM-1 present? Possibly. Or, are they doing it because they recognize cellular distress and degeneration, particularly in the oligodendrocytes, which could be due to iron or other factors including hypoxic stress from a loss of blood flow. These questions, and others we haven't thought of yet, will likely be answered by research to come. In addition, one question that I have which I think is of particular importance is this. If MS is not an autoimmune disease, but one of chronic immune activation, how could we tell the difference?

NHE

The fundamental mechanism is still unclear. How does a series of immune cells perforate the vein wall? You are possibly right that reflux, like slow flow, is another pathological case of shear stress. But it may be *the* cause of damage, if there is a variable called shear stress. If it is proportional to flow (like resistance in electrical circuits is proportional to current). Now, along with slow flow in the right direction, we have reflux; it has the same or even greater shear stress, but 180 degrees opposite in direction. It may be that this varying combination is directly damaging to the BBB. These are also cells, and can show distress chemically as well as any other cell. I am still skeptical (oh, oh ) that immune cells do any damage when they cross the BBB. I have seen film of this, and it does not look as if any 'holes' are being created. I speculate that the effect of combined slow flow, and reflux, in the same vessel may be the actual origin of a lesion.

Immune cells probably follow the chemical signals (ICAM-1 and the rest) and go wherever they want to go. Shear stresses may be the direct cause of the initial cellular distress which causes immune response (among other effects, like lesion formation). But this is again speculation.

One thing we know is that if ICAM-1 is suppressed, some protection (against PML) is lost, because the normal crossing of the BBB by immune cells (which can happen anywhere along any vessel) is made impossible. I think it normally does happen whenever there is a signal, anywhere throughout the brain, of cellular distress.

We can tell the difference when we can see that the cellular distress is causing the influx of immune cells. I hate to say it, but find a way to give an experimental animal a case of slow flow combined with reflux, and you will see if this is enough to break down myelin, cause lesions, etc. It may be necessary to choose an animal with a long enough life-span.

I do not believe movement of immune cells, of any kind, is itself damaging, or the cause of lesions. I get colds, I cut myself, my immune responses are pretty normal. The fact that it is the movements of blood causing the inflammation may mean that although there is a response, there is nothing immune cells can do to fix it. Collateral damage is a result, perhaps, of a lot of signaling and no pathogen.

1eye wrote:=
We can tell the difference when we can see that the cellular distress is causing the influx of immune cells. I hate to say it, but find a way to give an experimental animal a case of slow flow combined with reflux, and you will see if this is enough to break down myelin, cause lesions, etc. It may be necessary to choose an animal with a long enough life-span.

Actually, wasn't this already done with dogs?

Bump,
Request For Comments

My take on

Auto Immune vs Normal Immune which escalates over time and demand


I have been less convinced of "Auto" Immune causes of BBB breaching for 3 reasons- mind you there is an Immune response but it is NOT an attack on "self", which is the definition of Autoimmune.

I believe its a normal response at first attempt to try to stop damage, fix the breach and remove the damaged part and build the wall back.......albeit now scarred.

In very early MS or CIS patients during their first few event there are NO T and /or B cell lymphocytes ( major components in all of the "auto"immune response diseases) And that the test ANA is negative in Multiple sclerosis. ANA test is the hallmark for AUTO Immune diseases.

We know that the normal immune system is activated during any damage......and remember this condition has existed from birth and its slow. The body tries to respond and protect- it produces Endothelin in response to shear stress and hypoxia, endothelin makes the vessel more fibrous( stiffer), it can cause hypertrophy ( a thickening of the vein lining and malformed flap, valve web etc) and vasoconstricts ( makes smaller) the vessel lumen.

pwMS have very high endothelin levels. Then add the iron, perhaps over time and with turbulance of reflux, red blood cells are fractured ( this would be not be acute but slow and insidious)and iron is deposited in thru the breaches. Iron out of RBCs is extremely inflammatory and it oxidizes.

The blood uses blood and many of its components to "plug the dike" (tiny openings) and fix the harmed cells, remove the iron and remove dead cells and cell parts. Also Macrophages (the chief garbage men WBCs) ladened with iron are seen in MS. Then it builds a "better dam"(scar) This is a MS lesion.

This fibrin cuff is sort of a reinforcement against further breaching. It is this change- damaged myelin and replacement with scar that are MS lesions.

Gadolinium is used to identify new lesions because at this point the inflammation is new and blood will make the damage "light up".

Also B and T cells are seen later in MS because the Immune system is on chronic over drive and calls in the "Big Guns".

Please note that the location of all MS lesions is "counter current" and around the small veins (venules)........ sort of sandbagging the walls to prevent further breaching.

I honestly believe that all of the actions and reactions the body has in CCSVI/MS seem to be in line with attempts ( albeit feeble and harmful in some cases)to "fix" itself . Unfortunately CCSVI and reflux cause many chain reactions and damage as a consequence.

As you may know , I am new to MS but I have been a nurse for a great many years and although there are rare diseases where the Immune system goes "rogue" I do not believe that MS is one of them. This is completely opposite than all of the medical/nursing text books teach currently, but if you read closely they all say "theorized" or "it is believed".

But with CCSVI it explains it all.........cause and effect, cause and effect. And I am confident that it will all be proved out in the next few years.

that it will all be proved out in the next few years.

That is just what we (I) don't have... But hopefully no much more people will have to suffer in a near future

1eye wrote:

1eye wrote:=
We can tell the difference when we can see that the cellular distress is causing the influx of immune cells. I hate to say it, but find a way to give an experimental animal a case of slow flow combined with reflux, and you will see if this is enough to break down myelin, cause lesions, etc. It may be necessary to choose an animal with a long enough life-span.

Actually, wasn't this already done with dogs?

I believe that Putnam tried something like this around 1930...
but was injecting various things into their veins, not crimping the veins and causing reflux.....

And if you're going to set this type of trial up, don't let PETA know.....