Inflammation vs. neurodegeneration

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Postby TonyJegs » Mon Apr 09, 2007 12:12 pm

-Sharon

When I said ‘decline of estrogen” I meant that increase of progesterone overlapped increase of estrogen, so technically, when talking about pair ‘progesterone-estrogen’ during pregnancy, there is a relative decrease of estrogen.

All steroid hormones (including sex hormones) participate in inflammatory-immune response for any kind of any tissue damage.

To make it short, estrogen has immunoenhancing effects on antibody production, whereas testosterone has immunosuppressive effects on B and T cell differentiation, as well as macrophage activation. Plus estrogens control salt-water balance and cerebral blow flow in brain.

There is a clue to the main difference in MS in males, prone to be SPMS, and MS in females, prone to be R-R form.
In male MS the tissue response to acute damage is muted (suppressed), therefore there is insufficient ‘clearing out’ in the site of the lesion which will be turn eventually into chronically inflamed plaque and that often lead to development of secondary autoimmune response from the body. The degree of lesion reparation is limited.
In female MS the response to acute lesion is more rapid, but the lesion will be wider because of enhanced edema. The ‘clearing up’ is sufficient, and it would be a perfect situation, but there is an increase of antibody production in females (comparing to males). This feature leads to the secondary autoimmune response, which from one side is more muted/suppressed than in males, from other side triggered much easier than in males. The degree of MS lesion reparation is higher (than in males), but if this particular female has improperly treated acute lesion, she got a chance for an inadequate immune response, which is harmful, and you can foresee the rest.

After menopause the mentioned above increase in antibody production will be less prominent (due lower level of estrogens), the tendency to rapid swell of the brain reduced, and they are reasons (not all of course) why PM women usually have milder course of MS.

This subject is huge and extremely complex; there is a simplified version, as all I say here, adjusted for non-professionals.

I agree only with Voskuhl statement (from articles you posted above) when she said. "Early treatment is crucial to preventing disabling symptoms.”

I have no opposition to any body function or component; I don’t even understand how it could be possible.

Kind regards,
Tony
"All truth passes through three stages.
First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
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Postby Lyon » Mon Apr 09, 2007 12:27 pm

TonyJegs wrote:I agree only with Voskuhl statement (from articles you posted above) when she said. "Early treatment is crucial to preventing disabling symptoms.”

I have no opposition to any body function or component; I don’t even understand how it could be possible.

Hi Tony,

The above text in red....I don't understand your meaning in that statement at all, could you elaborate?

Thanks,
Bob
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Postby TonyJegs » Mon Apr 09, 2007 12:37 pm

Hi,
it was the answer for "why you totally opposed estorgens?"
I am not.

Kind regards,
Tony
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Second it is violently opposed.
Third it is accepted as being self-evident."
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Postby Lyon » Mon Apr 09, 2007 12:43 pm

Makes sense now! Thanks Tony.
Bob
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Postby Shayk » Mon Apr 09, 2007 8:25 pm

Tony

Thanks for your response. I’m sorry I misunderstood and misstated your stance on estrogen. I am definitely a non-professional and mistakenly interpreted your statement:
Practical outcome from this: - MS female patients must not use estrogen based therapy for menopause “flushes” treatment, use something else.

as being in total opposition to estrogen. I do apologize and am glad to learn you’re not opposed to estrogen.

Tony wrote:
why PM women usually have milder course of MS.

That’s really news to me. I’ve had a hard time finding gender specific information about PM women with MS. One of the few things I’ve read is a pilot study from well over 15 years ago:

A pilot study of the effect upon multiple sclerosis of the menopause, hormone replacement therapy and the menstrual cycle
Of the postmenopausal women 54% reported a worsening of symptoms with the menopause, and 75% of those who had tried hormone replacement therapy reported an improvement.

As you said, it is a huge and complex subject that I will never understand. I’ve taken the thread a bit off course here so want to get back to the basics.

Tony wrote:
I agree only with Voskuhl statement (from articles you posted above) when she said. "Early treatment is crucial to preventing disabling symptoms.”

I’m really surprised that you don’t agree with Voskuhl’s interest in neuroprotection. I do believe early neuroprotection is important but I’m not convinced the existing treatment (DMDs) slow disease progression.

Perhaps it’s best to change course and “hormones” here. This abstract about DHEA illustrates the point I was trying to make earlier about the loss of neuroprotection during the aging process. If neurodegeneration is part of the MS disease process, and I personally think it is, then the loss of neuroprotection from lower hormone levels could be a factor in disease progression. Neurosteroids as endogenous inhibitors of neuronal cell apoptosis in aging
The neuroactive steroids dehydroepiandrosterone (DHEA), its sulfate ester DHEAS, and allopregnanolone (Allo) are produced in the adrenals and the brain. Their production rate and levels in serum, brain, and adrenals decrease gradually with advancing age. The decline of their levels was associated with age-related neuronal dysfunction and degeneration, most probably because these steroids protect central nervous system (CNS) neurons against noxious agents.
These findings suggest that neurosteroids may act as endogenous neuroprotective factors. The decline of neurosteroid levels during aging may leave the brain unprotected against neurotoxic challenges.

As I said before, I think DHEA declines most rapidly between the ages of 20-40. It’s at least something to think about as we’re discussing neurodegeneration. Is MS a “neurotoxic” challenge?

Again, thanks Tony and take care all.

Sharon
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Inflammation, Neurodegeneration and Treatment

Postby Shayk » Wed Apr 11, 2007 7:03 pm

Spotted another abstract that seems to belong in this thread.

Inflammation versus neurodegeneration: Consequences for treatment
Inflammation is assumed to be the main driver of neurodegeneration in multiple sclerosis. However there is evidence that questions this hypothesis: Data from pathological studies and from imaging have shown that neuronal/axonal damage occurs early in lesion formation and at the earliest clinical stage of the disease. Additionally axonal damage itself can lead to inflammation and laboratory and clinical observations suggest that inflammation may be neuroprotective. Finally, clinical trials reveal that immunosuppression does not have the predicted effect on axonal damage and disability. Clearly if inflammation is not the primary event but a secondary phenomenon this has important implications in developing treatment regimes.

Finn--are you sure you're not J. Palace? The abstract bears a striking resemblance to much of the information you posted. :roll:

Take care all. I do think progress is being made in understanding MS.

Sharon
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Postby TonyJegs » Wed Apr 11, 2007 9:58 pm

-Sharon

Thanks, I expect that something like this will be published, just wonder why it took so long?
I posted earlier that degree of axonal damage depends on severity and volume of the MS lesion. Also, I have mentioned several times at this forum, that inflammation is secondary to tissue damage. Immunosuppression by its mechanism of action has nothing to do with the damage of axons and therefore with disability.
Please check my post about ‘16 years of betaseron use’ and you will get the picture.

Maybe you have heard that Brits want to change the rules of medical statistics, let’s wait a couple of years, and then, be ready for unpleasant discoveries after recalculation of data in many articles.

Kind regards,
Tony
"All truth passes through three stages.
First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
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Postby finn » Thu Apr 12, 2007 4:24 am

Tony,

I'm sorry, but I found a couple of your recent posts in thist thread quite amusing. IMO, sometimes using phrases like "I'm sorry, I didn't know that" and "I'm sorry, I was wrong" could improve the credibility of a writer.

For example, first you wrote:
TonyJegs wrote:MS female patients must not use estrogen based therapy for menopause “flushes” treatment, use something else.

But few posts later you stated that:
TonyJegs wrote:I have no opposition to any body function or component; I don’t even understand how it could be possible.
Yeah, right :-)

Now you have written that:
TonyJegs wrote:Thanks, I expect that something like this will be published, just wonder why it took so long?
Another possibility might be that you haven't followed contemporary MS-research that much. J. Palace wrote the following statement in a controversial article published almost three years ago:
    "The conventional hypothesis that inflammation is the primary event leading to axonal loss in MS is not supported by the evidence presented here. Axonal loss occurs early, and, disappointingly, recent clinical trials have revealed that immunotherapies do not have the hoped for effect on axonal damage and disability. Axonal damage can lead to inflammation, and inflammation may actually play a protective role."
You can learn more about the article in the first page of this thread. I don't know, maybe sometimes we laypersons just understand you professionals the wrong way, but thank you for the laughs, anyway. I needed it. Do keep on posting!


Sharon,

thank you once again for posting a very interesting abstract. Especially the title was brilliant ;-)

Be well.

-finn
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
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Postby HarryZ » Thu Apr 12, 2007 6:26 am

Tony,

Maybe you have heard that Brits want to change the rules of medical statistics, let’s wait a couple of years, and then, be ready for unpleasant discoveries after recalculation of data in many articles.

Kind regards,
Tony


Are you saying that the numbers used in clinical trials will be changed and reveal some disappointing results?

Harry
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Postby TonyJegs » Thu Apr 12, 2007 7:18 am

-finn

Yeah, I need to make my explanations longer and more chewable.

I didn’t change my position about estrogen use for PM women with MS.
When I said that have no opposition to any body component that was a replay to the question “why I am so opposite to estrogen”, and that was clarified later in my next post below.
Let’s repeat it one more time; I am not opposite to anything in the body per se by default.

Last article mentioned by Sharon about inflammation contained nothing new, this stuff was known for century, but it is very important to have it repeated in current publications, because it could be used for citation now (5 or 10 years rule). There is an urgent need of similar articles on MS (not necessarily about inflammation aspect) based on pathological findings and fundamental biological laws.

Sitting in front of PC and hitting search engines is better use of time, of course, than doing nothing; at least it keeps you busy.
In every MS Society there is a bunch of people who are far from understanding of the problem but they are curious by nature and sometimes they build a pretty impressive database, which could be useful, so, keep digging.

Thank you for critical remarks; I agree that styling could be improved.

Kind regards,
Tony
"All truth passes through three stages.
First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
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Postby TonyJegs » Thu Apr 12, 2007 7:20 am

HarryZ wrote:
Are you saying that the numbers used in clinical trials will be changed and reveal some disappointing results?


You got me right.

Kind regards,
Tony
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First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
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Postby HarryZ » Thu Apr 12, 2007 7:34 am

TonyJegs wrote:
HarryZ wrote:
Are you saying that the numbers used in clinical trials will be changed and reveal some disappointing results?


You got me right.

Kind regards,
Tony


That's what I was afraid of!! I have been told on more than one occasion that the statistics that come out of some clinical drug trials (MS included) have been "tweaked" to look much better than they actually are.

One classical example was the early Copaxone trials whereby the first report showed not enough statistical significance to warrant FDA approval. Supposedly Teva "dredged" the numbers and all of a sudden, they got close enough to finally get FDA approval. Perhaps that is why the Cochrane Group came out with the report that they did about this drug.

Is there any information out there about this new protocol that the UK is exploring? Thanks.

Harry
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Postby TonyJegs » Thu Apr 12, 2007 8:09 am

HarryZ wrote:
That's what I was afraid of!! I have been told on more than one occasion that the statistics that come out of some clinical drug trials (MS included) have been "tweaked" to look much better than they actually are.

One classical example was the early Copaxone trials whereby the first report showed not enough statistical significance to warrant FDA approval. Supposedly Teva "dredged" the numbers and all of a sudden, they got close enough to finally get FDA approval. Perhaps that is why the Cochrane Group came out with the report that they did about this drug.

Is there any information out there about this new protocol that the UK is exploring? Thanks.

Harry


The same story was with Betaseron, they didn't get through at first attempt, but then they changed all statistics of the study and got the approval.

I'll try to locate the source in UK about new proposed rules of medical statistics and post it there.

Kind regards,
Tony
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First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
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Postby finn » Fri Apr 13, 2007 9:00 am

Earlier in this thread Sharon posted a link to a very interesting abstract. Now a dear friend sent me the whole article (thank you!), and I decided to post few selected quotes from it. For those who still have blind faith on autoimmune theory and current drugs, I'd recommend to stop reading now ;-) Following text is by J. Palace, but additional titles between quotes are by me:
    INFLAMMATION VERSUS NEURODEGENERATION: Consequences for treatment

    "Although inflammation, demyelination and axonal injury are all features of MS the primary pathogenesis is unknown. The conventional hypothesis assumes an auto-immune process against myelin, and that the associated inflammation and demyelination lead to subsequent axonal loss and permanent disability. The data supporting inflammation as the primary and early mediator of MS pathology is well rehearsed. However the contra-hypothesis is generated by studies that don't support this assumption and this article aims to review such data."

    Axonal damage

    "Pathological studies suggest axonal damage occurs early in the lesional pathology and can occur in the absence of demyelination."

    "MR surrogates of neurodegeneration demonstrate its occurrence from onset."

    "Progressive irreversible disability occurs early in MS. Patients with relapsing remitting MS deteriorate at the same rate as progressive patients from EDSS 4.0. The same observation has subsequently been demonstrated from an EDSS of 3.0 and EDSS 2.0 (Ebers personal communication). These observations suggest the relentless progression is already occurring early, in the relapsing remitting stage, even though it is not clinically obvious."


    Inflammation and demyelination

    "primary damage to neurons or axons can lead to inflammation. Indeed almost all neurodegenerative diseases (i.e. diseases involving neuronal loss) are associated with inflammation."

    "The immune system may be involved in reparative responses and its privileged status in the CNS may contribute to restricted post-injury recovery. - - - The observed neuroprotective role of immune cells may be in part mediated by their production of neurotrophic factors such as brain derived neurotrophic factor."

    "In addition to the above observations that axonal damage can occur where myelin appears normal, brain biopsy specimens of living MS patients demonstrated that axonal damage did not appear to be related to demyelinating activity."

    "It is also noteworthy that during the phase of the disease where inflammation predominates, progression is minimal and may in fact suggest a protective effect of the early inflammatory phase of the disease."


    Mismatch of inflammation and neurodegeneration

    "If inflammation is the initiator of subsequent axonal loss it seems reasonable to use drugs that modify this pathological process. In-fact the gold standard for testing this hypothesis is by interventional studies using anti-inflammatory treatments and studying their effects on neurodegeneration. It is the disappointing results of such studies that have led the way for questioning this hypothesis.
    Interferon-beta and glatiramer acetate aim to attenuate the inflammatory response associated with MS. Although theeffect on MRI inflammatory activity can be dramatic and the effect on relapses is a consistent one third reduction, the effect on confirmed disability is less clear with a smaller effect being demonstrated and in less than half of the pivotal studies. All these trials assume relapses last less than 3 or 6 months and subsequent analysis has shown many patients take longer to recover. This has led to the suggestion that the disability effect, when demonstrated, could be due to the treatment effect on reducing long lasting relapses, i.e. a reversible disability effect. Furthermore, a long-term (12 year) follow-up of patients who received β-interferon showed that although the lesion load was decreased from baseline whereas untreated patients showed increases over time, brain atrophy continued to advance equally in both groups of patients."

    "Even powerful immunosuppressive therapies demonstrate the mismatch between the effect on inflammation and neurodegeneration. A single pulse of Campath 1 H (a humanised monoclonal antibody which targets the CD52) profoundly suppressed radiological markers of cerebral inflammation and relapses, but brain and spinal cord atrophy, and progressive disability, continued."

    "The current drive is to propose immune modification early in the disease and using drugs that have more complete suppression of inflammation in order to impact substantially on long-term disability. This assumption is as yet a hope and such a protocol carries a high risk to benefit ratio in the early stages and in benign variants of MS."


    Conclusions

    "Thus powerful immunomodulation at onset is a reasonable aim if an inflammatory autoimmune response is the initiator. However if this hypothesis is not correct such treatment will not only be ineffective but harmful."

    "If neurodegeneration is the primary driver then specific neuroprotective strategies should be employed, although selecting the candidate drugs is a challenge."

    "It seems most likely that the roles played by inflammation, demyelination and axonal loss at onset and later on during the progressive phase will be best answered by treatment trials. Investigating all possible hypotheses in parallel studies is a quicker route to resolving this crucial dilemma."


    -Journal of the Neurological Sciences xx (2007) xxx–xxx

For those of us who have followed MS reseach there was nothing new in the article, but I think it is good to know there are researchers who think differently.

Be well.

-finn
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
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Postby TwistedHelix » Fri Apr 13, 2007 11:24 am

Thanks Finn, that was really interesting. As you said, there were no great surprises, just a very concise explanation of the big question which is at the heart of the MS conundrum and, of course, the title of this thread.

No great surprises except this: I was astounded to read
Patients with relapsing remitting MS deteriorate at the same rate as progressive patients from EDSS 4.0. The same observation has subsequently been demonstrated from an EDSS of 3.0 and EDSS 2.0 (Ebers personal communication).

So in other words: whatever your EDSS score is, it would have been exactly the same no matter what type of MS you've got -- that's a new one on me: I'd always been led to believe that certain forms of MS were "worse" than others, (not counting the rapid, aggressive subtypes). But it sounds as if the speed of deterioration is set within each individual, no matter what form their MS takes.

Tony, I'm sure you didn't intend to, but the following paragraph...
Sitting in front of PC and hitting search engines is better use of time, of course, than doing nothing; at least it keeps you busy.
In every MS Society there is a bunch of people who are far from understanding of the problem but they are curious by nature and sometimes they build a pretty impressive database, which could be useful, so, keep digging.

...came across as quite condescending and insulting. Most of us here are struggling with MS in some way: either as sufferers or those who watch, (and also suffer), their loved ones falter and fail against this relentless onslaught hour after hour, year after year. One of the few things we can do to maintain a sense of control is to try and understand this disease, and also to try and translate the bits of research we hear about and fit the pieces together into a jigsaw that spells out "hope". Still, at least it keeps us busy.

Dom.
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