Dr. Zivadinov asks, is it time to redefine MS pathogenesis?

[cheerleader]

Advances in understanding gray matter pathology in multiple sclerosis: Are we ready to redefine disease pathogenesis?
http://www.biomedcentral.com/content/pd ... 7-12-9.pdf

In the last 5 years, numerous cross-sectional and longitudinal studies established that GM damage is a better predictor of physical disability and cognitive impairment than WM damage. [5] Most studies examining this argument used novel imaging techniques that can indirectly assess the extent of GM damage, the most important being a measurement of GM atrophy. [2,5] Therefore, monitoring the evolution of GM damage by various imaging techniques is becoming an important marker in predicting the future disease course and response to therapy in MS patients. A number of current clinical trials examine the effects of immunomodulatory treatments on slowing down GM damage over time.

In conclusion, the review papers by Lucchinetti and Popescu, [4] Walker and colleagues, [3] Hulst and colleagues [2] and Horakova and colleagues [5] represent a comprehensive update on the role and significance of GM damage in MS. They also raise a number of important new questions and outline comprehensive approaches to address those questions in years to come.

[HarryZ]

Cheer,

If the GM appears to be more important than WM in correlating lesions to MS disease activity, then what does this mean to the hundreds of MS drug trials that pinned the vast majority of their results to MRIs of the WM?

Harry

[cheerleader]

Cheer,

If the GM appears to be more important than WM in correlating lesions to MS disease activity, then what does this mean to the hundreds of MS drug trials that pinned the vast majority of their results to MRIs of the WM?

Harry

That's a very good question, Harry. It would appear that gray matter atrophy is looking like the true indicator of disease progression in MS. And the current therapies were not created to address this.

The British Medical Journal had a good review in 2010. There was much debate in the journal--but the final realization was that the current therapies, although mostly effective in decreasing relapses, did not change disability levels in the long run, and were therefore not cost effective. In one study published in the journal, those treated with DMDs fared worse than those never treated at all.

The first report on the scheme was published in late 2009, with details of patients’ outcomes for 2005-7.3 Disease progression was not only worse than predicted by the model used by NICE,1 it was worse than that in the untreated control group. The primary outcome—the difference between actual and expected benefit as a percentage of expected benefit—was 113%, well above the 20% tolerance for price changes (any value above 0 indicates that benefit is less than expected). The report stated "the outcomes so far obtained in the pre-specified primary analysis suggest a lack of delay in disease progression."3

http://www.bmj.com/cgi/content/full/340/jun03_1/c1672

There are new claims being made that the new therapies will address brain atrophy. Indeed, we are going to see a re-working of data to show this, as the reality of the MS disease process becomes clearer.
Here are BNAC's new studies....note most of them now use gray matter atrophy as a biomarker, not white matter lesions. Why is BNAC leading the new research? They have been looking at gray matter atrophy and iron deposition in MS as the biomarker for disease progression for several years now, also in collaboration with Dr. Zamboni.
http://www.bnac.net/?page_id=363
cheer

[HarryZ]

The British Medical Journal had a good review in 2010. There was much debate in the journal--but the final realization was that the current therapies, although mostly effective in decreasing relapses, did not change disability levels in the long run, and were therefore not cost effective. In one study published in the journal, those treated with DMDs fared worse than those never treated at all.

The first report on the scheme was published in late 2009, with details of patients’ outcomes for 2005-7.3 Disease progression was not only worse than predicted by the model used by NICE,1 it was worse than that in the untreated control group. The primary outcome—the difference between actual and expected benefit as a percentage of expected benefit—was 113%, well above the 20% tolerance for price changes (any value above 0 indicates that benefit is less than expected). The report stated "the outcomes so far obtained in the pre-specified primary analysis suggest a lack of delay in disease progression."3

http://www.bmj.com/cgi/content/full/340/jun03_1/c1672

Cheer,

Why am I not surprised by that report?!! For years I have been saying the DMDs are terribly over-priced and not very effective. I won't count the number of times I was accused of being a negative person and having a special agenda against the companies that produce these expensive drugs.

Fortunately, in the past few years research has branched out from the typical immune suppressive therapies and we are now starting to learn information that suggests the limited efficacy and huge cost they have given MS patients.

But the current mainstream group of MS medicine is very powerful and they won't sit by idlely with anything that threatens the cash cow!

Harry

[Leonard]

I think he is looking too far into the disease process here, where things have already gone terribly wrong..
This will never lead to anything...
Neurologists will be inclined to go down this path because they consider this domain to be theirs..
It's neurological and it's neurological treatment..

But many things have gone wrong before you reach this stage, with the veins and the metabolism.
I believe that finding a cure or as a minimum the best way to manage MS should be starting from there, from where it all begins, with a focus on the metabolic processes.
I do not want to sound arrogant or inappropriate push forward my sketch of concept but I seriously believe this is a much more promising way forward.
I invite you to look at pg 1 and the last few pages of http://www.thisisms.com/forum/general-d ... 15188.html

[HarryZ]

I think he is looking too far into the disease process here, where things have already gone terribly wrong..
This will never lead to anything...
Neurologists will be inclined to go down this path because they consider this domain to be theirs..
It's neurological and it's neurological treatment..

But many things have gone wrong before you reach this stage, with the veins and the metabolism.
I believe that finding a cure or as a minimum the best way to manage MS should be starting from there, from where it all begins, with a focus on the metabolic processes.
I do not want to sound arrogant or inappropriate push forward my sketch of concept but I seriously believe this is a much more promising way forward.
I invite you to look at pg 1 and the last few pages of http://www.thisisms.com/forum/general-d ... 15188.html

I tend to agree overall with your opinion on this but unfortunately there aren't a lot of people doing research in this area. Not enough monetary incentive and glory. One can't patent good eating habits!

Harry

[cheerleader]

Actually, loss of gray matter is one of the FIRST things that happens in the MS process, before white matter lesions. It's being noted in children, CIS and early MS. I wasn't discussing Dr. Zamboni's theory, Leonard. Or my own.

Merely sticking to the facts, and actual scientific observation on gray matter:

Thalmic gray matter loss in pediatric MS
http://www.mendeley.com/research/eviden ... sclerosis/

Cognitive impairment linked to reduced brain size in children with MS: York U study
http://news.yorku.ca/2011/06/16/cogniti ... k-u-study/

This study shows that gray matter damage in relapsing–remitting MS evolves markedly over a short period of observation.
http://www.neurology.org/content/65/7/1126.abstract

Atrophy in the deep gray matter in early PPMS
http://archneur.ama-assn.org/cgi/reprint/63/8/1175.pdf

Loss of gray matter is real. It happens in early MS (in all its forms), before lesion accumulation.
And Dr. Zivadinov is suggesting in this is the new bio-marker for MS, and there is an entire BMC issue with other researchers, outlining the importance of gray matter loss. Those who have MS might want to ask their doctors how their gray matter looks. (here comes the anecdotal part of my post...skip if you want.) Jeff did ask. His gray matter was slightly atrophied at his first MRI at Stanford in 2009, prior to his treatment. The atrophy has reversed on MRI, and his gray matter now appears more normal.
cheer

[DougL]

(here comes the anecdotal part of my post...skip if you want.) Jeff did ask. His gray matter was slightly atrophied at his first MRI at Stanford in 2009, prior to his treatment. The atrophy has reversed on MRI, and his gray matter now appears more normal.
cheer

did the doc have any way of explaining this reversal?

[cheerleader]

(here comes the anecdotal part of my post...skip if you want.) Jeff did ask. His gray matter was slightly atrophied at his first MRI at Stanford in 2009, prior to his treatment. The atrophy has reversed on MRI, and his gray matter now appears more normal.
cheer

did the doc have any way of explaining this reversal?

anecdotal caveat---
The only thing that had changed, Doug, was that he had his jugular malformations repaired at Stanford, and he now had blood leaving his brain thru his jugular veins, rather than collaterals. He showed more bloodflow to and from the brain on MRV after this procedure. His diet and copaxone use remained the same from 2 years prior to this procedure, to present day. He remains relapse and progression free, now 3 years later.
cheer

[DougL]

He remains relapse and progression free, now 3 years later.
cheer

one year ago when i first learned about CCSVI and MS, my wildest expectations were to stop progression after treatment.

with posts like these, that is no longer good enough. i now want to stop progression and i want recovery.

[HarryZ]

Cheer,

With GM loss happening early in MS before WM lesions appear, that would mean that drug companies would have to shift their clinical trial data to focus on GM in order to determine the efficacy of their drug. You can imagine that this would be a huge change in process and quite possibly invalidation of their medications. Scary indeed for them when you take into consideration what effect that could have on their bottom line!

Harry

[Leonard]

I tend to agree overall with your opinion on this but unfortunately there aren't a lot of people doing research in this area. Not enough monetary incentive and glory. One can't patent good eating habits!

Harry

good eating habits or... a transplantation of the gut flora. I think it is a real option...

And on the who: I can accept that pharma's won't see many incentives here, that hositals and doctors may only get lukewarm..

but for public health, the issue is there, it is big, and the prospects are huge.
and despite economic crises, a few hundreds of millions to tackle this disease is a drop in the ocean for them..

[Leonard]

to redefine MS pathogenesis is fine, but please please do not do that in a narrow neurological context...

[HarryZ]

to redefine MS pathogenesis is fine, but please please do not do that in a narrow neurological context...

Hasn't big pharma been doing that for years in the development of their immuno-suppressive MS medications?

If the trials show reduced WM lesions as per MRI, then the drug must be working!!

[cheerleader]

I was quoting Dr. Zivadinov in the usage of pathogenesis (literally, the origin of disease)
That was his title for the article in a neurological journal, and he wrote on the importance of gray matter--not me, Leonard.
I wrote the endothelial health program in '08 for Jeff...it contains nutritional and lifestyle measures (including gut flora, inflammation and coagulation), based on the work of Dr. Swank and Dr. John Cooke, to address what I saw as a systemic breakdown in MS. But that's not what I posted about.
http://ccsvi.org/index.php/helping-myse ... ial-health

Dr. Zivadinov (a real neurologist) is asking if it's time to look at MS as a disease of the gray matter.
This is a radical shift, since, as Harry notes---the drugs on the market were not created to address gray matter degradation. It's as if Dr. Zivadinov is saying, we're back to square one...the days before EAE. That's pretty interesting.
cheer