Inflammation vs. neurodegeneration

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Inflammation vs. neurodegeneration

Postby finn » Sat Mar 03, 2007 5:21 am

Hi,

as some of you might remember, after a serious disagreement on this board eighteen months ago, I got angry and removed all my messages. After reposting one of them few days ago, I checked them all to see if there was something else worth reposting. IMO, there was. As a member of "MS is not an autoimmune disease -camp" I'd like to share following two posts with you again.

The first post underlines the issues and questions related to MS research that I still find important. The second post contains selected quotes of a hypothesis published two and a half years ago. In it Maggs and Palace challenge the theory of inflammation as a cause of demyelination and axonal injury. They state that "suppressing inflammation does not appear to significantly slow disability – inflammation may even be protective for nerves."

This is how I summarized my own opinion then, and I still think the same way:

"What if axonal damage causes demyelination and inflammation, not vice versa, and inflammation occurs only when the system is still able to protect itself? In the light of my current knowledge it seems to me that the less inflammation in lesions, the more progression of disability. So the amount of possible protective elements such as hormones, endorphin, unsaturated fatty acids, and vitamin D in the system at the disease onset - and maybe sometimes also during the disease course - together with the level of genetic susceptibility to MS might have a crucial effect on disease severity.

I tend to believe in the Occam's razor, and think that usually "one should not make more assumptions than the minimum needed". So my guess about the pathology of MS is this: One cause, one trigger, but multiple factors that have an effect on disease progression and severity. I am just glad I don't have to try to prove it ;-)"


be well.

-finn
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Postby finn » Sat Mar 03, 2007 5:22 am

What we know almost for sure at the moment:
  • Inflammation, abnormal T-cell activity, demyelination and axonal degeneration are all present in the pathogenesis of MS.
  • Clinical relapses and reverseable disability are caused by demyelination.
  • Active lesions shown in MRI are caused by inflammation, but removing MRI-activity with anti-inflammatory drugs doesn't necessarily prevent clinical relapses and the progression of disability.
  • Most of the permanent disability is probably caused by axonal degenaration. Normally our system doesn't allow axons to regenarate.
  • (Fortunately) the progression of permanent disability in MS may be much slower process than earlier thought.
Recent findings:
  • Imaging studies done with MTR show that there are changes in MS patients' normally appearing gray matter already after the first clinically isolated syndroms.
  • In a large pathological study researchers found out that individual lesions played a minor role in local spinal cord atrophy in MS. Similar axonal degeneration had taken place also outside lesions.
  • There may be similarities in neurobiological processes between MS and some rare neurodegenerative disorders.
  • Some researchers suggest that inflammation can also promote regeneration and repair in the brain.
Questions to be answered:
  • Is demyelination caused by inflammation the primary process of MS that leads to axonal degeneration and permanent disability? Does preventing inflammation as early as possible halt the disease "in its tracks"?
  • Is neurodegeneration the primary process? Does the inflammation occur only due to the existing damage like in some other CNS-injuries (stroke, spinal cord injury, etc.)? Does preventing neurodegeneration remove inflammation?
  • Are demyelination and axonal degeneration totally separate processes?
  • What causes this disease in the first place?

Finally, a comment by dr Coles: "The key question that remains to be answered is this: if we stop the inflammation of multiple sclerosis as early as possible, as powerfully as possible, will that stop the disease progressing 10-15 years down the line? If the answer is yes, then I believe we have the drugs available now that will help people significantly in the next 10 years. If the answer is no, then we all have a lot more work to do."

(Originally posted may 2005)
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Postby finn » Sat Mar 03, 2007 5:25 am

What if there is no direct correlation between demyelination and axonal loss? Two British researchers questioned that hypothesis in an article published last summer. A couple of selected quotes:

About the relationship between demyelination and axonal loss:
Maggs & Palace wrote:Trapp et al., who also used autopsy tissue from MS patients, examined tissue for axonal transection, identified by the presence of terminal axonal ovoids. Not only did they demonstrate that axonal transection appeared early during lesion evolution, but occasionally, terminal axonal ovoids were surrounded by myelin which appeared normal. More recently, brain biopsy specimens from living MS patients have been studied histologically. One study found that axonal damage did not appear to be related to demyelinating activity and thus concluded that axonal injury is an independent process.

About the relationship between axonal damage and inflammation:
Maggs & Palace wrote:Recent studies suggest that this axonal damage is actually detectable at onset: patients with clinically isolated syndromes (CIS) who go on to develop MS already have grey matter and spinal cord atrophy at the time of presentation, and show a significant increase in ventricular volume even over the first year. This atrophy is not significantly correlated with gadolinium-enhancing MRI lesions, suggesting that the majority of atrophy is attributable to alternative mechanisms. Additionally, patients with CIS show decreased whole brain NAA at presentation. So it seems that axonal injury does occur from onset in MS, and so is a candidate for the primary pathological process. Can axonal loss cause inflammation?
-------- clip -------
Suppression of neuronal activity in vitro allows induction, by IFNg, of MHC expression on the neurons themselves as well as neighbouring glial cells. Transection of axons induces an immune response with MHC expression, T-cell infiltration and proinflammatory cytokines in regions distant from the lesion. Thus 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 degree depending on the underlying aetiology of the disease.
-------- clip -------
Not only can axonal damage lead to inflammation, but studies suggest that this inflammation may actually be protective. Data from an experimental model of a partial lesion of optic nerves of rats have shown that T cells show neuroprotective effects, with significantly less secondary degeneration when anti-MBP T cells are injected.

About the clinical course of the disease:
Maggs & Palace wrote:Studies have noted that there is not a simple relationship between inflammatory activity measures (such as the number of relapses in RRMS or MRI activity) and either time to progression of disability or the severity ofirreversible disability. In fact disability may be accruing earlier than clinically detected: studies show similar rates of disability progression from Expanded Disability Status Scale (EDSS) 4.0 and 2.0 in the relapsing/remitting phase when compared to progressive phases. The longer time from onset to disability in RRMS compared to the primary progressive (PP) form may in fact reflect a protective effect of the early inflammatory phase of the disease: among patients with secondaryprogressive (SP)MS the rate of progression appears slower among patients who have superimposed relapses than among those who do not.

The suggestion that inflammation may be secondary could explain the PP phenotype: it has been suggested that the presence of an early relapsing/remitting phase depends on the individual’s innate immune response being more reactive than that in patients with PPMS. Less inflammatory activity is seen in PPMS compared to the relapsing/remitting/secondary progressive cohort in MRI studies. The relatives of patients with PPMS have lower markers of inflammation (higher IL-10 and lower TNF) than those of relapsing/remitting patients. Thus if PPMS is the same disease pattern as SPMS only without the initial inflammatory phase, this would explain the observation that SPMS and PPMS become clinically apparent at the same age, and progress at the same rate.

About drug therapies:
Maggs & Palace wrote:The disease modifying therapies recombinant betainterferons and glatiramer acetate are now widely used in the treatment of RRMS, but questions remain concerning their efficacy in preventing long term disability. The reduction in relapses of around 30% is undoubted as it was seen in all trials, both those studying RRMS and those with SPMS. However, the effect on disability is less clear, as a small effect was seen in only half the trials. In fact, even when an effect on permanent disability was reported, this assumed relapses last less than three or six months. As subsequent analysis showed, many patients took longer to recover. It has been suggested that the treatments only reduced reversible disability.
-------- clip --------
MRI measures of inflammation and lesion load are often dramatically reduced in treated patients. In contrast, the effect on cerebral atrophy is unconvincing: in the European Study Group interferon beta-1b trial33and in the glatiramer study34 a treatment effect was not seen. Only post-hoc analysis of one study showed an effect of interferon beta-1a on brain atrophy progression during the second year of the trial.
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Campath 1H (a humanized monoclonal antibody which targets the CD52) is a powerful immunosuppressive agent leading to prolonged lymphocyte depletion. Studies have shown that a single pulse of Campath 1H suppressed disease activity, as measured by MRI, for six months. However, whereas radiological markers of cerebral inflammation and relapses are profoundly suppressed, brain and spinal cord atrophy, and progressive disability, continue.
------- clip --------
Thus, evidence from clinical trials suggests that immunosuppressants, while being effective in suppressing inflammatory activity, may not reduce progressive axonal damage. It is possible, but as yet purely hypothetical, that a reduction in inflammation could lead to a similar effect on progression after a lag period. Indeed this hope fuels the present practice by many neurologists of treating early to prevent longer-term disability. Nevertheless, as already discussed, the very early appearance of atrophy is against such a lag, and the 12-year cohort data also dispute this hypothesis.

Conclusion:
Maggs & Palace wrote: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 (Figure 1B). Clearly some types of inflammation may lead to damage, seen as the residual deficit from a relapse, but this is unlikely to be a major contributor to overall disability. It is possible that the cryptic aetiological agent may both cause axonal damage and demyelination, as well as inducing an inflammatory response, which plays a minor role only. Of course, much of the data is group data and the pathological basis of MS is likely to be heterogeneous between patients. Nevertheless, what is clear is that we should consider designing a different therapeutic profile for MS drugs, aimed at targeting primarily the process of axonal loss i.e., ‘neuroprotection’, rather than inflammation.

Source:
"The pathogenesis of multiple sclerosis: is it really a primary inflammatory process?" by FG Maggs and J Palace
Multiple Slerosis 2004; 10: 326-329

I have a feeling that the article was not sponsored by drug companies ;-)

(Originally posted may 2005)
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Postby Frank » Sat Mar 03, 2007 7:01 am

Hello Finn,

Thank you for your great roundup! :).
While I basicly agree that inflamation will not turn out to be the only point about MS, I'd like to add two points which seem to support the immune-hypothesis:

1. As TYSABRI showed in its Phase-III study, it is able to slow down
time to disability progression by 42%.

I'd like to point out that this result just tells the time to progression, it does not say a thing about the state that your in after, lets say, 2 years (which was the duration of the study).
So it could be possible, that it takes you longer to get worse, but then you decrease more drastic.
(http://www.thisisms.com/modules.php?nam ... le&sid=255)


2. A parasite infection was found to virtually stop disability progression,
the discussed mechasim of action was a rebalancing of the
immuneresponse.
(http://www.thisisms.com/ftopict-3511.html)

--Frank
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
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Postby bromley » Sat Mar 03, 2007 7:02 am

Finn,

Welcome back.

This, of course, is THE question for the researchers to bottom out.

Recent research has recognised that MS is a global disease of the CNS (I posted a presentation recently by Professor Thompson of the UK).

My recent posting about the 8 Tesla scanner showed that there were many more lesions than could be seen with a conventional MRI scanner.


There was also some research about patients with progressive MS who were treated with very powerful immuno-suppressants. These patients still experienced atrophy / more disability despite the treatment (this outcome was also seen by SP patients treated with Campath). I contacted one of my neuros (not Dr Coles) following the publication of the research and asked if this meant that very powerful immuno-suppressants were a waste of time in treating MS. His response was:

Not necessarily – it means that we have to treat MS early and not after too much damage has happened. It takes a long time for damage axons and neurons to die, probably months to years. This study just confirms our clinical observation that treating progressive MS aggressively, simply stops the relapses and not the progression. Good thing that you have had your Campath early.


So I and people like Robin, who have had treatment early in the disease course with a powerful immuno-suppressant (Campath) may well end up helping to answer the question about neuro-degeneration v inflammation. All I know from my experience to date (I have my 3 month check-up following the infusion on Tuesday) is that I have not expereinced a hint of a relapse and I am gradually getting much of what I had previously lost back . My walking is normalish and I am using the tube again with confidence. Will I run again - I'll wait and see, but it's early day. Following my relapse in early October 2006, I was assessed as 7 on the EDSS score. I will be interested to see my score on Tuesday.

So in my case, a powerful immuno-suppressant has been good news. Dr Coles told me last year that none of the RR patients given Campath have moved into the progressive phase. Only time will tell if this holds good for the long term.

But I totally agree with you about neuro-protective agents, which should benefit us all, whatever stage we are in. And fingers crossed that some bright spark works out how to encourage axonal / neuronal growth.


All the best

Ian
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Postby finn » Sat Mar 03, 2007 8:21 am

Frank,
thanks for your comment. Actually, according to the results of AFFIRM trial Tysabri wasn't able to slow down time to disability progression, but reduce the relative risk of disability progression by 42%. I bet you can see the difference between the nature of those statements. Anyway, I personally wouldn't put too much weight on that conclusion because the trial was done with patients in such a good shape. Over 71% of the placebo group (and 82% of the treated group) remained without any disease progression during the whole 2-year study.

Ian,
thanks for your thorough reply, too. I agree with you (to some extend, anyway). Powerful immunomodulators may produce positive short term results in some cases. It is easy to understand that lessening inflammation may halt (or even reverse) reverseable disability caused by demyelination.

IMO, these are the big questions: Is demyelination caused by inflammation really the primary reason for neurodegeneration (and permanent disability)? Or can neurodegeneration be the primary process and cause secondary inflammation and demyelination (and reverseable disability)?

Be well.

-finn
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Postby Frank » Sat Mar 03, 2007 8:48 am

Could someone tell me where I can find an online source, that states that there is no or only slightest effect on disability progression, using interferons and maybe copaxone?

Thanks!

--Frank
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
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Postby Frank » Sat Mar 03, 2007 9:07 am

Thanks for your response on Tysabri. I'd like to get back to the disablity progression.

The studyresults say:
RESULTS: Over 2 years of treatment in AFFIRM, natalizumab delayed the onset of sustained disability progression by 42% compared with placebo...In addition, natalizumab reduced disability progression as measured by change from baseline in MSFC...the percentage of patients who reached an EDSS of 4.0 (5% vs. 13%...) or an EDSS of 6.0 (2% vs. 6%...), and mean (standard deviation) change in EDSS (0.04 0.86 vs. 0.41 1.09...)


... as english is not my native language I'm not absolutly sure, but I do think the passage below states, that when using Tysabri it takes 42% more time do develop disability progression, doesn't it?

natalizumab delayed the onset of sustained disability progression by 42% compared with placebo


----

but reduce the relative risk of disability progression by 42%.


As far as I understand, it says, that for example in placebo group 100 people had progression, while in verum group only 58 people got worse.
Is that right?

Thanks
--Frank
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
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Postby Lyon » Sat Mar 03, 2007 11:08 am

bromley wrote: So in my case, a powerful immuno-suppressant has been good news. Dr Coles told me last year that none of the RR patients given Campath have moved into the progressive phase. Only time will tell if this holds good for the long term.
Hi Ian,
We talked earlier and I am overjoyed with what you are experiencing.

I think it's also very beneficial to all of us that you are a long time member of thisisms. If you popped in as a newbie even I might have to wonder if you were the likes of a mangostein salesman. The knowledge that Robin/raven, also a longtime thisisms member, is experiencing the same things adds to what you're saying.

I personally find no reason to be greatly concerned about your future unless it's found that the treatment isn't complete enough.....that it didn't kill every last MRTC and memory cell and that they might eventually replicate to the point to again cause problems.

I don't know how big a concern that should be, but who knows how long it would take? I think that at the very least you've bought yourself many years without MS progression being a concern. At this moment, that is good enough.

Am I on the list for chocolates now?

:lol: Bob
Last edited by Lyon on Sun Mar 11, 2007 4:47 pm, edited 1 time in total.
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Postby finn » Sat Mar 03, 2007 11:40 am

Frank,

Frank wrote:As far as I understand, it says, that for example in placebo group 100 people had progression, while in verum group only 58 people got worse.
Is that right?

No, I'm afraid that's not the case. English is not my native language either, but I try to explain it anyway :-) You referred to absolute change, but in clinical trials positive results are usually given as relative changes between treated and placebo group. In the Tysabri trial 18% of treated patients and 29% of the placebo group experienced progression of disability. The relative difference between 29% and 18% is 42%. In absolute numbers it would be only 11%.

BTW, there's an excellent article on understanding clinical trials in Accelerated Cure's newsletter (page 4).

-finn
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member of "MS is not an autoimmune disease -camp"

Postby Lyon » Sat Mar 03, 2007 2:23 pm

Hi Finn,
Welcome back! I joined thisisms well after you'd left but I've seen your name around during searches and wondered what had become of you.

Not to single you due to the fact that you're an admitted member the "MS is not an autoimmune disease -camp", in fact I myself am not convinced either way, but I've always felt that, in order to be given serious consideration, the anti-autoimmune faction needs to come up with a satisfactory explanation for the reasons that these diseases which are considered autoimmune share so much in common.

Geographic gradient, time of drastically increased incidence, clustering in families and clustering in a victim who has already been diagnosed with one "autoimmune" disease.

What commonality do you feel they share if it's not autoimmunity?

It's not really fair to single Finn out for this one so input from anyone who is convinced that MS isn't autoimmune will be appreciated.

Bob
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Postby Frank » Sat Mar 03, 2007 2:24 pm

Thanks you for the explanation, Finn :) .
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
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Postby finn » Sat Mar 03, 2007 3:59 pm

Lyon,
I'd say that reading and understanding the third post in this thread alone could give you at least some kind of idea why MS can also be concidered as "not autoimmune". The key question is: is demyelinating immunoreaction really the central driving force of the pathogenesis of MS? I'd say probably not.

Now, perhaps you could tell me the way you see the primary disease process of MS and its similarities with other "autoimmune" diseases?

Frank,
you're welcome :-)

-finn
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Postby Lyon » Sat Mar 03, 2007 6:35 pm

finn wrote: Now, perhaps you could tell me the way you see the primary disease process of MS and its similarities with other "autoimmune" diseases?
Hi Finn,
It's obvious from the few posts of yours I've read that you have good access to information and that you have used it to educate yourself very well.

I imagine you've noticed that researchers are increasingly grouping what are considered the "autoimmune" diseases together into one bundle when they make reference to them in research papers.

That is the result of, what I consider, a positive changing attitude driven by the dawning realization that the fact that these diseases arose in incidence at the same time, share similar geographic incidence, share the fact that most affect women at higher rates than men, share increased familial incidence. In this case that means that one of your close relatives is not only more likely to also be diagnosed with MS but also means that odds are drastically higher that one of your close relatives will be diagnosed with any one of the other diseases which are considered autoimmune. Not to be overlooked is the fact that the odds are greatly higher that someone diagnosed with one autoimmune disease might also be found to suffer from more than one.

I'm not aware of any studies but I'm personally convinced that there is evidence that a great number of people who have been diagnosed with one autoimmune disease experience symptoms of other autoimmune diseases and are accepted as "just another symptom" and don't ever result in additional diagnosis.

I think it's important to realize that the history of MS (and indeed all the other separate diseases which are considered autoimmune) has understandably been a long "comedy" of errors.

From the very beginning people with MS have gone to their doctors for relief of their outward symptoms. Relieving these outward symptoms is what MS doctors and researchers have historically concerned themselves with. To this day most people consider MS to be no more and no less than the outward symptoms, with the understanding that they result from the underlying mechanics that researchers have identified so far.....increased permeability of the blood brain barrier, inflammation, myelin loss, lesions, axon loss and brain atrophy.

Upon asking, any reputable researcher will quickly admit that those things (increased permeability of the blood brain barrier, inflammation, myelin loss, lesions, axon loss and brain atrophy) are only the aspects of the MS process which have been identified to this point and might also point out that those are not necessarily the entirety of the MS process.

Obviously those things are all that has been identified and therefore is all we can aim research and treatments at. Therein lies the long term absolute puzzlement regarding MS and our inability to effectively treat it.

Probably not the best comparison, but what comes to mind is a situation in which a guy goes to the doctor because his fingers are turning blue and losing feeling. The doctor calls in other doctors and researchers and they all focus on the patient's fingers and hand. They do years and years of research with all the newest research methods, focusing only on the fingers, because that's where the problem is. They develop many medicines based on this research and sometimes they even "seem" to provide positive results.

The moral of this story? Despite any amount of years of research and treatment development the researchers are never going to provide this patient satisfactory results by focusing on his fingers because the problem is the result of a restricted blood supply much farther upstream.

The fact is that what we know as the MS disease process (increased permeability of the blood brain barrier, inflammation, myelin loss, lesions, axon loss and brain atrophy) in itself does nothing to console the obvious and very important relationship to these other diseases.

Obviously people are frustrated with the lack of forward motion in MS research. It seems that in this technological age there is no justification for the years of bafflement we've experienced, unless researchers have taken a wrong turn along the way.

In truth we have passed many cross roads along the way which might have been the point of a wrong turn but some people have chosen the autoimmunity road as the wrong turn they have sought.

In fact autoimmunity is the only sensible thing found so far which consoles the obvious and unavoidable (if we ever hope to cure MS) relationship to these other diseases.

In direct response to your question
Now, perhaps you could tell me the way you see the primary disease process of MS and its similarities with other "autoimmune" diseases?
. I admit that there are no similarities to the other "autoimmune" diseases in what you and others consider the "primary MS disease process" (increased permeability of the blood brain barrier, inflammation, myelin loss, lesions, axon loss and brain atrophy) nor should we expect there to be.

Indeed, what likely is responsible for our years and years of frustration is the very fact that we consider MS a disease onto itself has caused us to only focus on the tree directly in front of us which never has and never will allow us to see the forest.

Bob
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Postby ewizabeth » Sat Mar 03, 2007 7:14 pm

You guys are a bit over my head on this, but answer me this if you can:

What if there are not any signs of inflammation, but there is still progression. Is that generally the point which MS turns to a gradual decline even without the inflammation?

I don't think I've ever had inflammation or if I did, not a lot. Steroids did nothing to help me, but made me worse. After interferons and Copaxone, my white blood cell levels are very low. I did have two definite and bad relapses though, in the beginning...?
Take care, Ewizabeth Previously Avonex, Rebif & Copaxone RRMS ~Tysabri, 31 infusions, ended 9/09. Starting Copaxone 12/09, waiting for Cladribine to be approved in 2010.
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