Progression

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Progression

Postby bromley » Tue Jan 17, 2006 4:35 am

We start a discussion on MS being possibly a collection of different diseases and then researchers publish an article suggesting that progression in the various sub-types has common features etc. It also suggests (from my understanding) that there is an underlying mechanism distinct from the immune sytem involvement / damage. As usual no insights into how this underlying mechanism could be halted.

It does pander to my real fear that even if you stopped the inflammatory immune response this disease just keeps on going! (as is the case with SP and PP). This is pretty distressing reading and could demonstrate that measuring relapses, lesions etc etc in a waste of time.

http://www.msif.org/go.rm?id=13166
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Postby gibbledygook » Wed Jan 18, 2006 10:40 am

That article confirms my suspicion that MS is just one disease and that the four or five sub-types are simply labels describing how different immune cells/genes/hormones/enzymes cope with whatever horror is occurring in the CNS.

I wonder if Tovaxin works in the progressive phases of the disease. That's where the pharma companies should put their research efforts. If they could solve primary progressive disease then I reckon we'd all be helped.
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Postby bromley » Wed Jan 18, 2006 12:20 pm

G,

I shift on this everyday - one disease or many? Perhaps it is one disease which is progressive (underlying) and the difference relates to the speed of the progression and / or the response of the individual. Whatever, as they peel away the layers of this bad onion, it always seems to be worse than first thought. More worrying, is that Robin (Raven) and I have, between us, seen three of the top MS docs in the UK. And I don't think any of them really has an idea of what is happening with this disease.

I totally agree with the comment you made about walking earlier on. My daily commute to London is a concentrated effort on not falling over - everyone seems to pass you by. The real killer is when you are overtaken by someone 75+ or someone morbidly obese with a cigarette hanging out of their mouths.

Good luck on the abx regime, perhaps we might cross paths down Victoria street - I'll look out for another slow walker.

Ian
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MS "One Disease" Concepts

Postby Shayk » Wed Jan 18, 2006 8:20 pm

Hi Bromley

It's a new day :) , so today the idea is that MS is one disease.

I discovered a bit more research on the topic of progression that seems to reinforce the idea that MS is one complex rather than several different diseases.
Age at Disability Milestones in MS
Therefore, prognosis in multiple sclerosis appears, at least to some extent, as age-dependent and not substantially affected by the initial course, be it exacerbating-remitting or progressive. Aside acute focal recurrent inflammation and diffuse chronic neurodegeneration, accelerated ageing-related mechanisms may operate in the central nervous system of multiple sclerosis patients.

My hormone soapbox observation (again) is that several hormone levels (DHEA, estrogen, progesterone and testosterone) decline with age in men and women. IMH non-scientific opinion many of the hormones display significant neuroprotective properties (at least in pre-clinical research), so, I have to ask again, is the transition from RRMS to SPMS in part dependent on declining hormone levels? This research makes me wonder even more.

Another abstract by the same authors on basically the same topic, Natural History of MS: A Unifying Concept.
Relapsing-remitting disease can be regarded as multiple sclerosis in which insufficient time has elapsed for the conversion to secondary progression; secondary progressive forms as relapsing-remitting multiple sclerosis that has 'grown older'; and progressive from onset cases as multiple sclerosis 'amputated' from the usual preceding relapsing-remitting phase. Times to reach disability milestones, and ages at which these landmarks are reached, follow a predefined schedule not obviously influenced by relapses, whenever they may occur, or by the initial course of the disease, whatever its phenotype. This leads to a unifying concept of the disease in which primary and secondary progression might be regarded as essentially similar. From the clinical and statistical positions, multiple sclerosis might be considered as one disease with different clinical phenotypes rather than an entity encompassing several distinct diseases--the position of complexity rather than true heterogeneity.


Yet more by the same authors, Accumulation of Irreversible Disability in MS: from Epidemiology to Treatment
There is convincing evidence that neurological relapses in multiple sclerosis (MS) are the clinical counterpart of acute focal inflammation of the central nervous system (CNS) whereas neurological progression is that of chronic diffuse neurodegeneration….

All these observations give support to the fact that relapses do not essentially influence irreversible disability in the long term in MS….

They suggest that MS is as much neurodegenerative as inflammatory, and should cause the modification of disease-modifying therapeutic strategies by focussing on the protection and repair of the nervous system and not only on the control of inflammation.


It’s probably fair to say that these particular researchers see MS as a single disease with neurodegenerative features and that neuroprotection, as you’ve said so often Bromley, should be the focus of new drug development until the cause/cure are identified.

You also said and it sometimes seems to me as well that the research within the last couple of years has left them “without a clue”. They just now seem to be coming to grips with the idea that neurodegeneration may be an integral part of MS and a major contributor to the irreversible disability that may accumulate. I’m still optimistic though since I think physiologically balanced hormone levels may have something to offer vis a vis neuroprotection in the interim. Obviously, that’s just my personal take on it.

I did post info about the development of 17 alpha estradiol (a form of estrogen) for neuroprotection in a number of neurodegenerative diseases that affect men as well as women. Even though MS was not listed, there is one of those terrific EAE studies to suggest it is the 17 alpha receptor that mediates estrogen's neuroprotection in MS as well.

I’m still optimistic for everyone, men and women alike, when it comes to the potential of hormones in the management of MS. I just wish more researchers would take it seriously.

Sharon
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Postby OddDuck » Thu Jan 19, 2006 5:45 am

Hi, Sharon!

Hey, did you see this abstract (pasted below)? For all I know, it's been discussed previously here and it's not "new", but your post just brought it to mind that I had run across it the other day.

I'm not sure if what they are saying would really hold true in the end, but for some reason, I found it intriguing:

J Immunol. 2005 Sep 15;175(6):4119-26. Related Articles, Links


Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice.

Spach KM, Hayes CE.

Department of Nutritional Sciences, College of Agricultural and Life Sciences, University of Wisconsin, Madison, WI 53706, USA.

The prevalence of multiple sclerosis (MS) increases significantly with decreasing UV B light exposure, possibly reflecting a protective effect of vitamin D(3). Consistent with this theory, previous research has shown a strong protective effect 1,25-dihydroxyvitamin D(3) in experimental autoimmune encephalomyelitis (EAE), an MS model. However, it is not known whether the hormone precursor, vitamin D(3), has protective effects in EAE. To address this question, B10.PL mice were fed a diet with or without vitamin D(3), immunized with myelin basic protein, and studied for signs of EAE and for metabolites and transcripts of the vitamin D(3) endocrine system. The intact, vitamin D(3)-fed female mice had significantly less clinical, histopathological, and immunological signs of EAE than ovariectomized females or intact or castrated males. Correlating with reduced EAE, the intact, vitamin D(3)-fed female mice had significantly more 1,25-dihydroxyvitamin D(3) and fewer CYP24A1 transcripts, encoding the 1,25-dihydroxyvitamin D(3)-inactivating enzyme, in the spinal cord than the other groups of mice. Thus, there was an unexpected synergy between vitamin D(3) and ovarian tissue with regard to EAE inhibition. We hypothesize that an ovarian hormone inhibited CYP24A1 gene expression in the spinal cord, so the locally-produced 1,25-dihydroxyvitamin D(3) accumulated and resolved the inflammation before severe EAE developed. If humans have a similar gender difference in vitamin D(3) metabolism in the CNS, then sunlight deprivation would increase the MS risk more significantly in women than in men, which may contribute to the unexplained higher MS incidence in women than in men.
PMID: 16148162 [PubMed - indexed for MEDLINE]
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Re: Progression

Postby HarryZ » Thu Jan 19, 2006 8:01 am

Ian,

It does pander to my real fear that even if you stopped the inflammatory immune response this disease just keeps on going! (as is the case with SP and PP). This is pretty distressing reading and could demonstrate that measuring relapses, lesions etc etc in a waste of time.


My exact sentiments!! It's been over 10 years since the interferon drugs plus Copaxone have been in use and what have they given us other than minimal relief of disease progression by reducing some of the inflammatory immune response. Yet the companies who make these drugs spend millions by continuing to run head-to-head trials, trying to prove that their drug is better than the next guy's!! Their major end points measure relapses and lesions which look good on paper but do nothing to stop the progression of the disease.

These researchers have to spend their efforts on what is causing the initial attack on the myelin and the resulting inflammation which gets the immune system involved. But unfortunately, I don't see much happening in this area at all :(

Harry
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Postby mrhodes40 » Thu Jan 19, 2006 10:00 am

To me it's clear something is degenerating the nerves first and eventually you stop even responding with inflammation to it. Inflammation is a requirement to healing.

<shortened url>

it's been known for years that in rheumatoid the stopping of the inflammation literally stops the healing as well, but that has been considered the price you had to pay to get free of the disabling pain.
the above abstract which is not the first on this subject in MS indicating inflammation is beneficial to the nerves regenerating and remyalinating,
supports your point of view.

It's not the inflammation, it never was, and stopping it or hampering it will not help us. People progress though they have nice MRI's on immunosuppression.

I am personally very jaded after 15 years of doing the conventional and the alternative. In my mind it simply is not autoimmune, it can't be or steroids would work amd it would be self limiting. I'm with you guys, the real question is what is degenerating the nerves and how can they stimulate repair.
marie
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Postby bromley » Thu Jan 19, 2006 3:26 pm

Marie,

I am in total agreement with you on this (although knowing me I'll change my mind tomorrow).

I have come across a number of research papers that refer to the inflammation as a 'side-show' and some which claim that inflammation can be neuro-protective.

Of course inflammation can cause damage and steroids etc which dampen the inflammation can result in clinical improvement. Some of the heavy drugs - Campath 1-H, Novatrone etc can do this to good effect. But the question is - do they stop the progression of the disease. I keep harpening on about the Campath 1-H trial. Here the drug stopped inflammation and any new lesions but Dr Coles observed for those with SP had 'unrelenting cerbral atrophy'. In Canada, Dr Freedman has been replacing the immune system of MS patients - but I've yet to see any results on whether is has stopped progression (which is what we all want).

Recent research has shown that damage to the nerve fibres take place early on - even the RR phase.

Unfortunately, the vast majority of the drug's on trial (Dignan's list) are for the RR stage and only seek to address inflammation and relapses (easy to measure). Few are targeted at neuro-protection.

My theory is that MS is that it MS is caused by a virus which we pick up when we are young and something reignited it later on (? stress / picking up the virus again etc). The virus slowly detroys the CNS (perhaps faster in some people, may be because they get a worse strain of the virus). The immune system does what it is supposed to but causes damage.

This is an on-going disease - our CNS is under constant attack (shown on MRIs) and only 1 in 10 do we have an attack.

Its time that changed the criteria for judging a drugs effectivess. No more relapse rates or lesion counts. Here are my criteria:

- stops progression
- gives you back walking skills of a normal person
- gives you back vision as before onset of disease
- rids the body on tingling / numbness / pain

These should be the criteria used. Unfortunatley there no drugs on the market which can meet these (or get anywhere near them). YET (note the slight hope injected at the end).

Ian
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Postby Katman » Thu Jan 19, 2006 7:14 pm

Your list of criteria are exactly right. I am an intruder here so I will be short. I am PP and have reversed this in the last 16 mionths. My gait has gone from 2 steps without a cane maximum to the 1/2 to 3/4 mile walk/RUN every day without any support at all. I no longer use Avonex (CRAB), having given it up 6 weeks ago because it no longer had any benefit. My vision had 9 prisms from MS at last refraction so I won't know about that for a while but no brain fog is good. All the sand which filled my right leg is totally gone and I have only residual numbness on my ribcage which is fading. My energy lasts 16 hours instead of 1. I have an MRI Sat Jan 21. If you are interested I will let you know the results. As promised I will stop but this is something that we all should know about and have an opportunity to do.

Rica
2010 5 years 4 months Now on Amoxicillin, Doxy, Rifampin, Azith, and caffeine in addition to  flagyl. 90% normal good days-50% normal bad days. That is a good thing.
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drug criteria

Postby gwa » Thu Jan 19, 2006 7:21 pm

bromley,

Your criteria for a MS drug is right on. It doesn't appear that anything is in the immediate pipeline to include all of the criteria however.

I don't think we are closer to a cure than we were when I was diagnosed when the dinosaurs still roamed the planet. There are a lot of researchers working on a cure or treatment though.

Hang tough, this disease is not for woosies.


gwa
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A Little Bit of This and That

Postby Shayk » Thu Jan 19, 2006 8:16 pm

gwa—I second the vote that Bromley is right on with his criteria. You're right too, MS isn’t for woosies and it isn’t for old age sissies either. :roll:

I’ve had a chance to read the Phase I Clinical Trials for DHEA (which both recommended additional trials) and one of the most amazing things was that in the late 1980’s when those open label trials were done, the expected outcome was a 1 point improvement in EDSS in 14 weeks. That was not the outcome in those trials, but they noted sufficient improvements to recommend additional trials. It’s stunning how the outcomes for clinical trials have changed since then.

Rica—Congratulations on your success and recovery with abx. I agree people should have the opportunity to make an informed choice/decision about whether or not to pursue abx.

Deb--I had read but not posted the study of Vitamin D and EAE. It’s another one of those interesting developments in MS research.

What I wonder is if you’ve seen this case study?
Congenital Adrenal Hyperplasia and MS
Impaired cortisol biosynthesis results in corticotropin hypersecretion, which leads to overproduction of intermediate metabolites and androgens….

CONCLUSIONS: Some clues suggest that the association between CAH and MS could be nonincidental: a possible MS susceptibility locus is on chromosome 6p21, on which the CYP21 gene is located;


I wanted to mention this because you know I seriously question if hypersecretion of the stress hormone cortisol may be a major factor in the MS disease process. Well, as I’m sure you know too they recently found a highly significant linkage in the major histocompatiblity complex (MHC) on chromsome 6p21 in people with MS. The findings were presented by J. Haines of Vandy on behalf of the International MS Genetics Consortium at the ANA meeting last fall in San Diego.

If you get a chance, maybe you could ask someone at Vandy to be on the lookout for other things on chromsome 6p21 that might be linked to MS, like the CYP21 gene that is associated with impaired cortisol biosynthesis and corticotrophin hypersecretion. :wink: I know it doesn’t fit neatly with the MHC mindset, but hey, people with MS continue to report that stress is bad and many of the putative MS triggers (viral, bacterial, physical or mental trauma) result in a rise in cortisol levels. To the extent that that’s true, “high cortisol levels” may be a common MS trigger. One never knows about these things. :)

That’s it for now. Thanks Deb and take care everyone.

Sharon
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Postby HarryZ » Thu Jan 19, 2006 8:47 pm

Ian,

In Canada, Dr Freedman has been replacing the immune system of MS patients - but I've yet to see any results on whether is has stopped progression (which is what we all want).



Ever since they did a television special in Canada on Dr. Freedman's work several months ago, there hasn't been much said about his experimental procedure. That procedure is very drastic and one of his patients died from it. The liver suffers dramatically and is the main reason the patient can die.

In my non-medical opinion, I think that the patient may initially show signs of improvement after undergoing this procedure but in the long term, that unknown cause of MS is going to come back and again cause more damage to the myelin.

Harry
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Postby Jaded » Fri Jan 20, 2006 6:03 am

Today I am in total confision about this disease. :cry:

Yes Ian I agree with you about the criteria. And I don't think that MS is autoimmune either - having tried the steroids - and not had a bit of improvement. Did you know that there are trials to test whether steroids makes MS better or worse? They don't know!! The Dr who prescribes my LDN advised me not to do the steroids!!


As for stress, I'd say that does make my MS worse - and is probably the only thing that noticeably does. So Sharon, maybe there is something in the study you mention. I'd like to know how all of these different studies "intersect". We seem to see bits of benefits from different drugs/studies. Is there a common denominator?

Rica, yes please - do let us know what happens with your latest MRI.

I don't know where I'd be without this site!

J.
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Postby HarryZ » Fri Jan 20, 2006 6:59 am

J,

The Dr who prescribes my LDN advised me not to do the steroids!!


Likely some very good advice from that doc!

Steroids, being an anti-inflammatory drug, reduce the inflammation that is associated with an MS exacerbation. Often they will reduce the severity and duration of an attack. But they have absolutely no effect on the progression of the disease and each time they are used, their effect on the next usage is reduced. MS docs will use them sparingly and only when necessary and they can have some nasty side-effects, especially when used often and long term.

Harry
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Postby mrhodes40 » Fri Jan 20, 2006 10:03 am

I agree with you Ian about the criteria used for MS drugs. They keep doing it the way they do it because it's easy to impact the inflammation and make a "pretty MRI". I alo agree that inflammation is a double edged sword. in every body system it is both healing and potentially damaging at normal physiological levels. That's why after knee surgery for example a major treatment goal is control of inflammation. We always give people NSAIDS and ice the area aggressively in that case. I have always thought this was why the meds used for MS had some small effect seemingly: because to the extent that the inflammation is in fact harmful, it can be ameliorated by use of suppressive methods. the fact that the disease continues in spite of this is just a repeat of the rheumatoid story: they can get very good reduction of joint inflammation but the joints degenerate anyway.

The HLA story is one i have been interested in. Oddly enough I personally do not have HLA dqbi 1501, the "MS gene" mentioned in the article. I do have 0301, which is mildly associated with gluten issues. but this may not be important at all because the HLA types are in charge of how you respond to foreign proteins in your system. potentially the gene you have simply dictates the kind of response. In this case you may respond to certain bacteria with more vigorous or conversely less effective immune response than the next guy. If you think of the abx approach it is possible that people with certain HLA types are simply more susceptible to certain kinds of bacteria. This would require that the person get the bacteria but also have the genotype that is problematic in order to get sick. you might have heard that in AIDS it turns out that a certain genotype, the same one that resisted the plague, does not convert to AIDs when HIV infected as their cells simply resist the HIV invading the blood cells and subverting the immune system. These folks simply have better response than the next guy to that germ, it means they do not get sick. http://www.pbs.org/wnet/secrets/case_plague/clues.html Also note that in this case it is a viral resistence, but plague is a bacterium. Effectiveness of the system is better for both in this case.

everything that we point to about the immune system is also about our resistence to, or possibly susceptibility to, germs in our environment.
I just wanted to mention it as the research in this arena can seem to be a smoking gun for autoimmunity and it just is not necessarily.
Marie
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