Interesting takes on the etiology of MS

[shoshin]

Since scientists don't know what causes MS or exactly how it works its damage, that hampers attempts to cure it. I came across a couple intriguing perspectives on the genesis of MS that I thought other people might be interested in.

First is an article described by MSNews from the Accelerated Cure Project as giving "an interesting alternate theory for MS as a vascular disease (1).

I don’t completely understand this, but apparently the researchers did a procedure called venography on people with and without MS. According to Wikipedia, venography (or phlebography)  is “a procedure in which an x-ray of the veins, a venogram, is taken after a special dye is injected into the bone marrow or veins” (2).

Unlike the controls (normal people or people with other neurological conditions), people with MS had “multiple severe extracranial stenosis, affecting the principal cerebrospinal venous segments” (3), which I think means that they had narrowing of the veins (and I guess the blood flow) outside the cranium but near the brain and spine. The were looking at venous outflow, which presumably would affect the outflow of blood.

Apparently, there were four different patterns of venous problems (which might go with the four clinical types or maybe with the four pathological types of MS?). The patterns generally associated with RRMS/SPMS and PPMS were different.

These patterns of problems are “characterised by multiple substitute circles [alternative pathways or vicarious venous shunts (this second seems to mean that the blood moves through an abnormal passageway) that allow for the piping of blood toward available venous segments outside the CNS], with a very high incidence of reflux in both intracranial and extracranial venous segments, and loss of the postural regulation of cerebral venous outflow.” The researchers think this reflux is likely caused by a “stenosing lesion that cannot be crossed with postural or respiratory mechanisms, thereby becoming a long-lasting reverse flow” (3). (that reflux/reverse flow bit doesn’t sound too good, does it?)

Intriguingly, the authors suggest that “the absence of Doppler and venographic features [whatever those are] of CCSVI [chronic cerebrospinal venous insufficiency] in controls suggests that venous obstructions may be causative of MS rather than a coincidental finding” (3). However, they do also entertain the opposite hypothesis, i.e., that the vascular abnormalities are caused by MS, although they then point out what they see as evidence that this explanation is less likely. In any event, more research is needed.

Secondly, I came across an article that talked about the inadequacy of EAE (experimental allergic encephalomyelitis) as an animal model of MS (4). EAE is induced in mice and causes demyelination, lesions, and relapses and remissions. However, from what I can tell, researchers are pretty good at curing EAE, but obviously this hasn’t carried over to curing MS. This suggests that there are significant differences between EAE and MS. These researchers think that EAE is more similar to ADEM [acute disseminated encephalomyelitis], that “both EAE and ADEM are T-cell-dependent, organ-specific, autoimmune diseases of the central nervous system,” (4) and that EAE should not be used as a justification for an inflammatory, autoimmune theory of MS. They say that MS is different from EAE because MS arises naturally, includes “progressive and global brain and spinal cord atrophy” from an early stage, and involves the normal-appearing white matter, whereas EAE has to be externally induced and does not share these other characteristics. EAE is also more typically monophasic or requires repeat “challenges to some encephalitogenic antigen” to induce relapses, which has not been shown to be necessary in MS.

They list some other differences and then baldly state that “nearly 60 years of EAE-based research yielded not a single MS-halting therapy.” They also point out that it is now believed that it is neurodegeneration rather than demyelination that causes long-term disability. They suggest, among other things, that a new animal model for MS is needed.

Interesting, in a third article, researchers report having found what they hope to be just such a model. Researchers at the Max Planck Institute of Neurobiology have bred mice that “spontaneously develop a disease pattern that is practically identical to the course of the human form of MS most common in our part of the world [RRMS??]. Because the disease also develops spontaneously in humans, the new model is superior to all of the previous models which only develop MS symptoms following injection with brain tissue. Moreover, the research using the new model has already prompted a rather sensational discovery: the emergence of the disease requires significantly more immune cells than previously assumed” (5).

The common wisdom seems to be that MS is mainly caused by misguided T cells (a type of immune cell). This new model suggests that another type of immune cell, B cells, have an essential role and that if the B cells are not also triggered, the disease will not start. Also, in MS some errant T cells are more aggressive than others and the researchers found that some of these will attack more than one protein (which was apparently unexpected). The researchers think that targeting these super-activated T cells could be a productive treatment strategy.

Sorry, this post got really long, but I hope a few of you find this sort of thing as fascinating as I do.

sho

References:

1. Chronic cerebrospinal venous insufficiency in patients with MS, http://www.acceleratedcure.org:8080/node/3532

2. Venography, http://en.wikipedia.org/wiki/Venography

3. Zamboni, P. et al. “Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis.” J Neurol Neurosurg Psychiatry. 2009 April; 80(4): 392–399. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19060024

4. Chaudhuri, Abhijit and, Peter O Behan. “Multiple sclerosis and EAE - are researchers barking up the wrong tree?” http://www.msrc.co.uk/index.cfm?fuseaction=show&pageid=7

5. Tracking Down The Causes Of Multiple Sclerosis - New Discoveries In Immune Response, http://www.medicalnewstoday.com/articles/153740.php

[wadeheather]

It would explain the tingling and numbness, eh?

[sllowe]

This reminds me of some of the info provided at a presentation this year.

The Neuro talked about a handful of the new meds - one in particular and cell depletion.  The one thing that sticks out in my mind is that they were concerned about that depletion and once they were gone - they could not be regenerated (the particular cell).

I could of sworn it was the B-cell, so I better pull out and dust off my notes!

Thanks Sho, and Doc Q!

[jensequitur]

This is really fascinating reading, even though I didn't understand most of it.  

It reminds me of when I was looking at DH's angioplasty video, years and years ago.  You can see the open veins quite clearly in the control cases, and then WHAM! the MS cases are obviously obstructed.

So I guess that leads to the question of how many of us have circulation problems, like DVT or varicose veins.  Maybe I'll post a question tomorrow...

[AmishErin]

Very very interesting.  I used to read alot about MS but I don't anymore...I don't understand half of what I read anyways, thanks for condensing it a bit... bite sized pieces eh

About 10 years before I was diagnosed with MS I had went to donate plasma.  Of course there are all sorts of medical tests before they want your blood.  I passed all of the first tests and was allowed to donate once.  The next time I came in a Doctor called me out of the waiting room to tell me that they could not take my blood.  She said that I had non ABO antibodies.  She told me that all it meant was that I had gotten sick sometime when I was little and my antibodies were now not the same as the general public.  She said that it wouldn't ever affect anything but that they didn't want my plasma because of it.  

10 years later I was diagnosed and I have been wondering ever since.  I always assumed that any genetic predisposition I had I got from the paternal side as many autoimmune diseases are prevalent, but my maternal side has lots of circulation type disorders....

Anyways thanks for the post and thanks also to the added explanations.

[patientx]

In regard, to the venous insuffiency, I can expound on this a little, as I've been reading quite a bit about it that last few months.  In the original research, Paolo Zamboni, an Italian vascular surgeon, performed venography on MS patients and controls.  In all of the MS patients (I forget the exact number, but it's around 60) he found stenosis in either the jugular veins, azygous vein or both. (Stenosis is a narrowing of the vein, which causes poor drainage and increased pressure and backflow).  None of the controls had these.  Since then, he has scanned more patients, and, so far, all of the MS patients are showing these venous stenosis.  This is an observation, which says nothing about how venous insuffiency might cause the neurological damage of MS. But he has put forth a theory that the increased venous backflow or pressure sets up an inflammatory reaction, recruiting T-cells, MMP-9s and various other immune components to the site.  In time, this leads to the breakdown of the endothelial wall, the immune cells migrate into the brain and spinal cord, and do their damage.

This is just the theory - all of this is very new.  But in the meantime, Zamboni has treated 100 patients to open up the stenosis, and see what happens with their MS.  He did this last fall, and will announce preliminary results in Sept., I believe.  In the U.S., their is a small (but growing) group who are having surgery to do the same thing.  This outside of any trial.  Many have taken the research papers and tried to interest their doctors.  The really sad thing is that many neuros have dismissed this idea out-of-hand.

[shoshin]

Quix: Thank you so much for explaining the main points to much more clearly than I could. Hopefully, some of these researchers who are thinking outside the box will come up with something useful.

Steph: It does seem that there is not a strong correlation between lesion count/volume and disability. Of course, lesion location plays a big part, but there also appear to be other things going on. I just read a blurb today about a study that used a newer MRI technique to show that "the spinal cord of people with MS showed abnormalities even in the absence of lesions, suggesting that these abnormalities could partially explain the accrual of disability in people with MS." (http://www.msif.org/en/research/ms_research_news/adiffusiontensor.html)

I did write a health page on neurodegeneration in MS which you might find interesting. It's at http://www.medhelp.org/health_pages/Multiple%20Sclerosis/Neurodegeneration-in-MS/show/716?cid=36

sho

[Lulu54]

Sho, another piece of great research work.  Thanks - that was interesting to read, even though I struggle mightily with all things scientific.  

at one of the chicken dinner/lunches I have gone to this year I heard a neuro talk about the t-cell, b-cell connection and the research that is being done looking at those links.   In the recesses of my brain I am also thinking he said something about the new oral drugs working on both of those...  

thanks Q for the usual interpretation that we need to fully understand the science.

Lulu

[steph74]

Thanks for collecting all that information and sharing with us.  And thanks to Quix, too, for the interpretation (it's still early and I haven't had all my coffee yet!)

Especially interesting is that the lesions aren't the primary cause of disability.  Did I read that right?

[Quixotic1]

Wow, this was really interesting and thank you for putting it all together.

The first part was somethiong I have never come across - a theory that MS is related to a state of venous insufficiency.  For those who haven't a clue what this means, think of it this way.

The body's circulation is like a river flowing through a valley and nourishing it.  The river entering the valley, rushing out of the mountains, is like are arteries.  The arteries carry oxygen-rich blood to the parts of body (like the brain), then spread out into little, tiny vessels which field the surrounding tissue.  Then the blood re-collects into the drainage system of the veins (the venous system) and collects into ever larger vessels and returns to the heart.  In the analogy the river nourishes the fields of the valley, collects into a drainage system and then makes it's way on out of the valley on it's way to continue the cycle.

In "venous insufficiency" the drainage system is inadequate.  The blood cannot drain off like it needs to and it backs up.  If you prevent a field from drainage the water backs up.  the result is not good.  You get soggy fields, where moss and algae grow.  It may become swampy or form stagnant ponds.  Normal crops can't grow.

So, it sounds like they are suggesting that in MS there is this blockage to the prompt drainage of blood from the brain.  In other parts of the body when there is a problem with good draining blood flow, we see the back up of fluid, like edema.  I wonder if they saw similar things.  I certainly can vouch for the growth of moss and algae in my brain!

I was fascinated to see an argument against EAE being used as the "animal model" of MS.  And they are right.  If EAE was a correct picture of MS in the rat, then we should have seen more effective treatments by now.  This will be great stuff to watch.

The third article talks about how complex the body's immune system is in MS.  What Sho told us is important to read again.  It appears that the both arms of the immune system the T-cells (in which the cells themselves attack invaders) and the B-cells (in which the cells make antibodies to attack invaders) are BOTH haywire in setting off MS.  Usually a single T-cell group is programmed to attack just one single protein and a single B-cell and its clones make just one kind of antibody.

Again, folks, all of these articles point to the need to see MS as FAR MORE than just a disease made up of immune inflammatory lesions.  MS is so much more than a T2 hyperintense lesion, yet some neurologists insist on defining the disease only by how many T2 lesions they see.  B-cell/antibody attacks on the myelin sheath of the nerves is only part of the problem - and not even the part that causes us our ultimate disability!

The Health Page called "Lesions! Lesions! Lesions!" talks about some of the different kinds of damage we suffer with MS, beyond the T2 lesions that can be counted on the MRIs.

Quix (I'm back)