This note was written by Marie Rhodes author of "CCSVI as the Cause of Multiple Sclerosis: The Science behind the Controversial Theory".  

See it at   CCSVIBook.com  Do you have your book yet?

In 2004 Prineas and Barnett authored

"Relapsing remitting multiple sclerosis: pathology of a newly forming lesion."  

It's my favorite MS paper.

link to paper

This paper turned our understanding of MS on its ear by offering solid evidence that the oligodendrocyte dies first which then leads to myelin degeneration and loss (the myelin is an extension of the oligodendrocyte).

It appeared that after the myelin is lost the immune system comes in to clean up the dead myelin as a secondary phenomenon...which is what the immune system is supposed to do to heal an area after tissue has degenerated and died.  

In later work further facts support the first paper.  This paper was called "Multiple sclerosis: Distribution of inflammatory cells in newly forming lesions"

link to paper #2

RESULTS:

Parenchymal T and B cells were largely absent in areas of initial oligodendrocyte loss and in areas of degenerate and dead myelin infiltrated by myelin phagocytes. In contrast, trailing areas of complete demyelination packed with lipid macrophages, and, in some lesions, regenerating oligodendrocytes, showed large numbers of T cells, B cells, and immunoglobulin G (IgG)-positive plasma cells. Lesions in 2 exceptionally early cases contained relatively few T and B cells, and no IgG-positive plasma cells.

To break that down it means that the oligodenrocytes were dead but there were no immune system T-cells or B cells there that could have done it.  In areas where the macrophages were cleaning up the dead myelin, it was the same--no T cells or B cells.  It is normal for phagocytes (macrophages are a phagocyte) to clean up dead tissue; they are the body's scavengers.

This is important because it is a reverse process compared to the autoimmune model, which is supposedly that the immune system accidentally got programmed to attack myelin (genes? viruses? epstein barr?) followed by the programmed T cells and B cells marching in to the brain and destroying perfectly healthy myelin....standard theory holds that only THEN --after the T cells ruin the myelin-- the phagocytes scavenge the leftover debris.  

The second half of that quoted comment says in the areas where all of the myelin was completely gone after the phagocytes were done scavenging and cleaning up there were signs of regeneration--oligodendrocyte recovery and remyelination-- and this healing area is where the T-cells, B-cells and IgG antibodies were found.  Notice, that means the T cells were adjacent to brand new myelin---and NOT attacking it!--but helping recovery as they are supposed to.

The author continues with interpretation of what that means as follows:

INTERPRETATION:

Early loss of oligodendrocytes is a prominent feature in tissue bordering rapidly expanding MS lesions. Macrophage activity is largely an innate scavenging response to the presence of degenerate and dead myelin. Adaptive immune activity involving T and B cells is conspicuous chiefly in recently demyelinated tissue, which may show signs of oligodendrocyte regeneration. The findings suggest that plaque formation has some basis other than destructive cell-mediated immunity directed against a myelin or oligodendrocyte antigen.

This is saying that oligodendrocytes die then macrophages clean up.  The programmed T cells and B cells were found in areas that were healing and this suggests that MS lesions are not initially caused by an attack from the immune system.

In the paper itself it is very important to note the authors feel that the inflammation is "amplified" in this process and this overactive immune response is a significant contributor to the damage.  They suggest this is why therapies that suppress immune function work to reduce lesions.  However they caution that such suppression of immune activity would not alter the changes to the oligodendrocytes which appear to occur first.

In another paper "The macrophage is it MS just a scavenger after all?" they again try to solve the problem of what is hurting the oligodendrocytes  "Ischaemia which can result in the generation of both reactive oxygen species and excitotoxicity has been proposed as one potential mechaism of oligodendrocyte loss in MS"

Ischaemia is the word (with European spelling) for lack of oxygen, so lack of oxygen can cause oxidative damage to the oligodendrocyte.  The paper goes on to evaluate the other possibilities point by point then suggests that in their opinion ischemia (American spelling) is the most likely culprit for oligodendrocyte damage they identified as the first event.

But the interesting thing is that this is credible work that suggests the oxidative stress from ischemia kills the oligodendrocyte and because of this the myelin degenerates then scavenging occurs with phagocytes cleaning up the dead tissue finally followed by T-cells and B cells at the healing phase.

And now a new paper by a new team of workers is out titled "Peripheral oxidative stress in relapsing–remitting multiple sclerosis." by Inmaculada Tasset, Eduardo Agüera, Fernando Sánchez-López, Montserrat Feijóo, Ana I. Giraldo, Antonio H. Cruz, Félix Gascón, Isaac Túnez

This one supports the idea that oxidative stress precedes the immune system activity in MS.  These researchers tested the blood of a whole bunch of people with MS and normals for many things related to oxidative damage.

 "In summary, the findings of the present study support the hypothesis that: i) oxidative stress plays a major role in RR-MS, and precedes the inflammatory response; ii) MS patients presented a global oxidation status; and iii)MS patients exhibited an antioxidant global deficiency. This opens up new avenues for a better understanding of the physiopathological events underlying MS, and for the identification of potential new thera- peutic targets. However, further research is required in this area.."(emphasis added MRhodes)

The fact that these people are saying the oxidative stress occurs before the inflammation is important-- inflammation itself causes oxidative damage as well, so having this team say the oxidative damage was first leads to an interpretation that it wasn't autoimmune inflammation that caused the oxidative damage but some other process that is not quite understood.  

They are also making the point that this oxidative issue is global and detected in the blood.  According to them, MS patients also appear to have depleted stores of antioxidants.  The body appears to be in a kind of overall state of oxidative stress.  In other research MS patients are well known to have low uric acid levels--uric acid is used up to counteract something called peroxynitrite which is an oxidative agent.  So, uric acid is used up by the body to counteract the oxidation.

But guess who else has low uric acid levels?  People with venous insufficiency of the legs...their bodies also show a global depletion of antioxidant status and an overall oxidative state.  Venous insufficiency causes a lot of global oxidative stress.

http://www.ncbi.nlm.nih.gov/pubmed/22129904

Taken together this material leads to the suggestion that what is really needed to get at the root of MS is find out what is causing the all this oxidative damage and how this leads to oligodendrocyte damage.  

CCSVI is of course a potential culprit because venous insufficiency of the legs is a well known cause of hypoxia (low oxygenation of the tissue) and inflammation as well as immune system activity all of which cause oxidative damage. As just mentioned, venous insufficiency also leads to a global oxidative state.  If this is in fact the initial stressor that hurts the oligodendrocyte then this could be the first event in an MS lesion.  Of course as the research team noted there seemed to be an overactive, or as they termed it, "amplified" immune system response that was damaging in its own right on top of the already oxidated and degenerated tissue.

Should CCSVI related hypoxia turn out to be the initial step in an MS lesion, the next question would be "How much DMD (if any) is necessary to deal with the "amplified" immune response to the initial oligodendrocyte loss?" and "Can CCSVI treatment restore circulation to a point where oligodendrocytes are safe from oxidative stress?" and "if an old lesion still has old inflammatory cells in it and iron deposits leftover from before CCSVI treatment, do those cells ever go away or do they remain a source of oxidative stress long after treatment?" and "is it possible with good circulation for the area to become truly clean and healthy tissue free of reactive oxygen species and in balance?"

We can speculate about the answers but it'd be a guess.  Guesses, even educated guesses, aren't science.

And thus we see the need for collaboration among the disciiplines.  Neurologists can't treat CCSVI, and vascular docs can't answer that last batch of questions.  We absolutely need them both.

*Note: anti-oxidants are well known to beneficial in MS startiing in research as far back as the 70's.  Clearly there is excessive oxidative damage as well as ongoing triggers for further damage, like inflammation.  

Reducing this with ample antioxidants makes logical sense. Minding My Mitochondria is a newer book that talks about dietary approaches that help in this area.  Joan's Endothelial Health plan is likewise beneficial for this...but that's a topic for another essay by the expert! ~Marie