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I finally finished my post on progressive MS, covering the research that suggests a rogue immune system develops within the CNS once the disease goes progressive. This has profound implications regardless of treatment modality (CCSVI included).

http://www.wheelchairkamikaze.com/2011/ ... nning.html

Very informative; thank you Marc.

Ditto to what Algis said.

There was quite the demand for this post when you mentioned it in passing. Hope the pressure was not too much.

His previous post has some striking images. Toy camera lens? I like the first three the best, as the out-of-focus look really captures something with the children and the colors.

Marc, excellent writeup. MS research seems to be snowballing at this point. N-Acetyl Glucosamine may prove interesting since I believe it crosses the BBB, and suppresses T & B cells.

I'm sorry, but I don't buy the whole shebang about a "rogue" immune system separate and apart from the principle immune system, in any kind of "MS". A problem in so-called "MS": the immune cells can cross the Blood-Brain-Barrier. It does not function properly in "MS", whatever you say about progression.

A drug whose principle mechanism of action is to defeat the leakage of immune cells, is so effective that the ordinary immune system is rendered unable to fight PML. Immune cells are barred from entering the site of the infection. If there were an immune system of any kind, operating behind the BBB, why would it not be just as effective as the "other" immune system, at fighting PML? Why would a drug designed to prevent leuokocytes, need to cross the BBB itself anyway, to be effective?

Immune cells normally have no problem crossing the BBB. They do it all the time, otherwise we could never fight any infection in the brain, let alone PML. Tysabri is so effective at making it difficult (it prevents adhesion), that the large numbers needed to keep PML in check, are kept out. That problem will occur in any "MS" patient. It is a problem that affects all immune cells.

Natalizumab would be just as effective with "progressive" as with "relapsing" patients. I have not seen any big trials that show it is ineffective. pw"SPMS" were excluded from the trials. About all that can be said, is said: it has not been shown to be effective. That is because money was never found to do these trials.

Why would making it difficult for immune cells to get out of the blood be any less effective for "progressive" MS? It is not the drug that is prevented from entering the CNS. All the DMDs share that attribute: they can all cross the BBB. It may or may not help the patient that they do: I think about all we can say is, we are even less sure that the interferons do any good for progressive patients, which isn't saying much. Have you got the money to run a trial? The only thing that is different about the "progressive" BBB is that it may be more leaky, and a bit harder to plug with Tysabri.

The existence of a separate immune system is pure speculation. Why, indeed, would it be separate? The BBB is compromised from both sides. These "rogue" immune cells will not stay in the CNS just because the BBB used to exist. The BBB is leaky.

It seems that your thoughts relate to statements like "Lymphoid follicle-like structures containing B-cells, T-cells and plasma cells, and a network of follicular dendritic cells producing CXCL13 were observed in the cerebral meninges of 2 out of 3 patients with secondary progressive MS, but not in relapsing remitting and primary progressive MS." This is difficult to swallow to a person who does not even believe in the "phenotype" distinction. If these immune cells are supposed to stay in the CNS, where is the evidence that they do? These studies only claim to have found them there, that the ones they saw originate there: maybe they also originate outside the CNS.

You seem to be saying that once these leukocytes start being born in the CNS because of a surfeit of CXCL13, they will be different: they will already have the propensity to attack myelin and destroy cortex. We will then graduate from RR to SP. That sounds a bit pessimistic.

What if there is no difference between these and the garden-variety immune cells? Maybe they hang around too long in the CNS because the blood is moving too slow? What if axons and myelin are vulnerable because things are entirely different when the blood is slow-moving, has too little oxygen, too many free radicals, not enough glucose ? I just think the circulation has to be working correctly to expect the immune system to also be working correctly. The same is true for all "MS" patients.

Great write up, Marc. I hope there are more answers for those with PPMS. Thank you for taking the time I know it took to compile this clearly written explanation.
One Eye, the debate over the concept of the CNS having its own distinct, immune-privileged organ system has been waging for awhile...in all honesty, I hope the scenario Marc describes turns out to be true, because it would mean hope and help for those with PPMS. But the verdict isn't out yet...for those who want to read more.

CNS immune privilege: hiding in plain sight
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633103/

Galea I, Beckmann I, Perry V.H. (2007). What is Immune Privilege (not)?. Trends in Immunology. 28(1): 12-18
http://www.cell.com/trends/immunology/a ... 06)00326-7

Wenkel, H. et al. (2000). Systemic immune deviation in the CNS does not necessarily depend on the integrity of the blood–brain barrier. Journal of Immunology. 164: 5125–5131
http://www.jimmunol.org/content/164/10/5125.full.pdf

cheer

I thought it sounded rather sci-fi, but then looked in google scholar for tertiary immune system. Yup. In other organs of the body, where there is chronic inflammation, the body reorganizes so that there is this tertiary immune system there in the inflamed organ. If it happens in other organs, I cannot think of a reason it would not happen in the brain.

I posed the Tysabri question too! If there is a tertiary immune system in the brain, you should expect to see PML in RR patients but not in SP or PP patients. You would also expect Tysabri to be less effective against MS in SP or PP than in RR. As there has been very little or no Tysabri research on progressive patients, we do not know if these are true.

I think the theory may hold merit. It is worth investigating.

I guess to you as well, I am a heretic, for I don't believe PP is any different than SP is, to RR"MS". It's all the same disease, and the right things help everybody: maybe different veins help different things. The brain can recover from stroke at age 20 and 80. I think recovery depends on your health and how you use your body. CCSVI procedures put an end to the continuing damage. It may be up to you to do the rest.

Once you have been abandoned by the medical world as a hopeless case, i.e., "progressive", further attempts to help you are more rare, your appointments become perfunctory, and protection against abuse becomes thinner on the ground.

Cece, I remind you, the distinction in the paper I quoted was between two groups, (RR + PP) and SP. That means the SP "phenotype" was deemed to have the unique and different immune system. The distinction therein, is not so much between "Relapsing" and "Progressive", but between late and early onset of "progression". The implication is that it is this late onset, that creates the "rogue" immune system, which is not immune to the "privileged" one in the CNS. Hogwash. Don't let murine experiments make you lose your grip on homo sapiens reality.

I think "PP" people have been notably included in the ranks of those helped by CCSVI procedures. Maybe that's why some people don't like it: they might lose some of their favorite experimental subjects. My friend was "PP". He was subjected to very painful irrigation surgery, which only made him worse. Maybe because they are animals, the mice are better protected.

your articles are always great. you say that ccsvi treatment did not work and that there is a muscle pressing that won't let the vein stay open . have you read dr. flanagan's book or looked into his thread and considered maybe giveing it a try. if your spine is screwed up it's very possible it may be causing the pressure.

If I read the papers correctly, these follicles are observed in roughly 40-60% of SPMS cases. I think that's also adding new questions, such as

What makes F- (i.e. those who don't have the follicles) SPMS patients get worse?
What's the mechanism of ITMTX in PwPPMS?

I agree that this needs to be investigated further. If at least some SPMS patients can be saved from disability progression by using intrathecal immunosuppressive agents, that's a big leap forward.

Still, we have the other 50% of SPMS and all of PPMS cases... and what's happening to them might also still happen to the F+ SPMS people.

oops, I think I spilled my alphabet soup...

...SPMS cases. I think that's also adding new questions, such as

What makes F- SPMS patients get worse?
What's the mechanism of ITMTX in PwPPMS?

I will not ask about acronyms for stuff I don't believe exists. However, in order to answer the last question, for me, "ITMTX" would have to have more discrete words. I guess maybe my answer could never make sense anyway to someone who believes "RR" patients are not == "PP" or == "SP". I think I read somewhere that there is atrophy and axon loss even as soon as the first clinical indication. The divide and conquer strategy only works if you are fighting patients, not disease. Is there a physical, non-venous indication that a person with "MS" is one "phenotype", and not also the others? Is the presence of these follicles to be the new tatoo, since we have recently become aware of it?

This "SPMS" course of mine seems to have been getting milder lately. Where does that fit in?

The remission is a myth that needs busting. Nobody on earth could convince me I was free from progression, back when I was having "remissions". I claim this is not my imagination or some cognitive problem fooling me. If I have not lost touch with reality completely, "MS" is a continuum, a sentence at first punctuated with attacks. You keep adapting to it, until the body runs out of resources (like room for new collateral drainage).

I put all my remissions down to the growth of new collateral veins. Isn't that really why steroids help, and why they only help once or twice? Do they not induce rapid "remissions", or more accurately, adaptations?

Some people, called "PPMS", are just unable to adapt for physical, spatial, likely congenital, plumbing reasons.

I have "PPMS", and "SPMS", and "RRMS", because it is all just "MS". If you want to call it that.

my guess is intrathecal methotrexate injections

@1eye, sorry for excessive (ab)use of acronyms. ITMTX was supposed to be "intrathecal Methotrexate". I think the rest is obvious, even if one doesn't agree with the concepts.



I do agree that between two distant points in time, MS generally only has one direction, which is downhill. This is widely ignored, possibly because such a picture is in the way of drug marketing.





However, SPMS does not primarily present with CNS inflammation, in that it is different from the initial RRMS people get. Also there's changes in experimental blood biomarkers and in those you can see a clear difference between MS onset and 20 years into SPMS, although in the middle the differences might be less clear. I'll dig out a link if you insist...

SPMS simply is a a later stage of MS. In regard to PPMS, one might argue it could be SPMS with undiscovered previous RRMS, and I guess there are indeed cases where that is happening, however, PPMS appears to have distinct lesion characteristics. The PPMS lesions are never found in RRMS or SPMS.

In regard to PPMS, one might argue it could be SPMS with undiscovered previous RRMS, and I guess there are indeed cases where that is happening, however, PPMS appears to have distinct lesion characteristics.

Sometimes you get a cold with a cough. It is still a cold. I bet PPMS has mostly very familiar lesions. My brother told me he had a teacher once who classified people as 'lumpers' and 'stringers'. I guess that makes me a lumper.

If we were to treat it as one condition, maybe we could find a fix that works for everybody. I think the CCSVI procedure (s?) is such, given a lot of tuning. If we pursue 'MS" as if it were three different diseases, we will never get to a 440 A.