This Is MS Multiple Sclerosis Knowledge & Support Community

Bob,

Lyon wrote:Not to disagree finn but in my view to possibly expand on what you are saying...

thanks for giving me the opportunity to quote myself. I have always dreamed about it.

finn wrote:There are several (more or less likely) ways to see the pathological process:

• Inflammation causes demyelination, and eventually demyelination leads to axonal degeneration (traditional hypothesis).
• MS starts as an inflammatory disease with a neurodegenerative component, but can change into a primary neurodegenerative disease (two stage model)
• Neurodegeneration is the primary process from the onset of the disease, and inflammation is a reaction to it (my favourite theory).
• Inflammation and neurodegeneration are seperate and independent processes.
• etc?

-finn

finn wrote: thanks for giving me the opportunity to quote myself. I have always dreamed about it.

Hi finn,
Not that your comment was in the least bit offensive but that was the PERFECT opportunity to use a smiley face.

You only get so many opportunities in life

So.....you are going to add another diamond and

“simultaneous two-component”

to your list?

Bob

My favorite way to think of the pathological process is two concentric overlapping circles, one labeled inflammatory, the other degenerative, the overlapped area being a transitional phase. I think the literature clearly shows axonal and neuronal injury occurs early in MS and gets greater as more time is spent in the degenerative process. I guess that is why I came up with maybe in PPMS the time spent in the inflammatory phase is just really short bursts of inflammation then followed by a more obvious degenerative phase. This model would fit the disease process in me anyway ...I don't know about the rest of you!

Hi Smilingface,
Seems like as good a way as any of viewing it when considering that researchers and laypeople alike are just giving it our best guesses!

I think plasticity isn't given nearly enough credit in explaining the relapsing/remitting phase, "silent" lesions and why, upon initial diagnosis, gm, wm damage and atrophy seems to already be present.

I submit the possibility that the symptoms leading to the diagnosis of MS is invariably synonymous with reaching the limits of plasticity to continue masking the underlying damage, either due to accrued damage reaching a point beyond the ability of plasticity or rate of disability out pacing the ability of plasticity to mask.

If we can finally determine ONE THING with certainty about MS, the rest is a lot more likely to become sensible and I think closer scrutiny of plasticity is the most likely vehicle to get us there.
Bob

Lyon, the more I think about it the more I like your plasticity concept. I think the concept works for PPMS very well. My diagnosis goes back six months, my neurological symptoms go back 5 years, my unususal sensitivity to heat and stiff walking goes back even farther. I was once told by an neurologist that my symptoms were too slow for MS and I had age related cervical radiculopathy. I think his thinking was flawed in more than one way!

Smilingface wrote:but I wanted to throw out an idea. What do you think of the possibility that in PPMS the inflammatory episodes are so quick, they are not detectable?

Hi Smilingface,
At this point I want to go back to one of your recent posts because a similar situation, my wife's, is what caused me to so seriously consider the role of plasticity.

Consider that the different phases of MS (RRMS, SPMS, PPMS, PRMS, Benign and CIS) are man-made definitions and the reason for originally coining those phases was so that researchers have names to refer to situations they've noticed. We put too much emphasis on those definitions of the MS "phases". These phases don't really even exist except by human definition. The course of your disease is going to do whatever it feels like despite the phase that your neuro feels that it seems to fit.

What do you think of the possibility that in PPMS the inflammatory episodes are so quick, they are not detectable?

Alternatively, maybe exacerbations appeared at a rate plasticity is able to match and mask so that you went through the entire RRMS phase without even knowing it, until plasticity reached one of it's limits (in what really should be considered the SPMS "phase") causing you to notice symptoms, or odd things you'd noticed earlier got to the point that you sought diagnosis?

By definition, PPMS is nothing more than SPMS which isn't preceded by RRMS. Is it possible, maybe even likely, that PPMS is nothing more than people who've experienced a "silent" RRMS phase?

I also think there is good reason to believe that, CIS and PRMS are so rare and are so similar to RRMS and SPMS that they should also be explained away as quirky cases of either RRMS or SPMS.

Smilingface wrote:I have to confess, I sometimes lie awake at night trying to figure out how PPMS fits in the picture......

I'm sorry to hear that someone else has to endure this lost sleep obsession but I'm glad to be in such good company Keep up the interesting thought processes!

Bob

Bob,

Lyon wrote:Now to inject some logic to the situation...85% of people with MS are diagnosed with RRMS. 85% is such a high percentage that it's most logical to think of RRMS is the epitome of MS and what we consider the other phases are actually variants of RRMS.

Well, maybe it's time for me to do some quoting again. Dr. Giovannoni has stated that "RRMS and PPMS are the same disease" and "inflammation defines the clinical course of MS". Dr. Behan wrote in his well known paper five years ago that "PPMS is the prototype disease".

I'd suggest that our disease could always be called "progressive MS", a slowly progressive neurodegenerative process followed by demyelination. When there is inflammation present in our CNS, the progression of neurodegeneration (and permanent disability) is slower, and the disease can be called RRMS (or SPMS).

Lyon wrote:So.....you are going to add another diamond and “simultaneous two-component” to your list?

Most likely there is an unknown relationship between the two of them, but I'd say the option is more or less covered when stated that "Inflammation and neurodegeneration are seperate and independent processes".

-finn

Btw, I have decided to quit using smileys and give people an opportunity to interpret my posts just the way they want. I'd like to serve my humour dry.

Hi finn,

finn wrote:Btw, I have decided to quit using smileys and give people an opportunity to interpret my posts just the way they want. I'd like to serve my humour dry.

Fine...I'm an old man whose time and smileys are short. I'm going to use the heck out of them until Arron prys them from my cold, dead fingers

finn wrote: I'd suggest that our disease could always be called "progressive MS", a slowly progressive neurodegenerative process followed by demyelination. (thought you snuck that one by me eh?) When there is inflammation present in our CNS, the progression of neurodegeneration (and permanent disability) is slower, and the disease can be called RRMS (or SPMS).

I agree that MS in any stage or phase (even "CIS" and "benign") can be considered progressive but the existance of the separate definitions of PPMS and SPMS implies that some people don't go through the RRMS phase and instead collect $50 and go straight to PPMS.

I think it's a LOT more sensible to consider that EVERYONE goes through RRMS but around 10% (the 10% now diagnosed as PPMS) don't experience symptoms until the limits of plasticity are reached and symptoms become evident in the SPMS phase, rather than the "normal" RRMS phase.

Not a big deal in itself but the existance of the PPMS phase is just another misconception to needlessly complicate things.

Lyon wrote:So.....you are going to add another diamond and “simultaneous two-component” to your list?

Most likely there is an unknown relationship between the two of them, but I'd say the option is more or less covered when stated that "Inflammation and neurodegeneration are seperate and independent processes".[/quote]I somewhat agree finn but the "simultaneous" describes the fact that, whether separate or not, the inflammation and neurodegeneration are acting at the same time. On the other hand the "simultaneous" might hint that neurodegeneration and inflammation start at the same time and I don't want to touch that one because the information doesn't yet exist to prove either way.

Bob

Bob,

in the light of current knowledge it should be quite certain that if there was inflammation, there is also neurodegeneration present at the same time in the pathology of MS (not necessary vice versa, though).

-finn

finn wrote:in the light of current knowledge it should be quite certain that if there was inflammation, there is also neurodegeneration present at the same time in the pathology of MS (not necessary vice versa, though).

Hi finn,
Your English is fine and I'm not trying to purposely frustrate you but to my understanding

(not necessary vice versa, though)

means that there might not necessarily be neurodegeneration without inflammation.

Is that what you mean to imply? Unless I'm not understanding properly that seems contrary to everything the old finn has ever stood for.

Bob

Bob,

Since I got you confused, I must have used the phrase the wrong way. What I meant was that

• when there is inflammation, there is also neurodegeneration.
• there can be neurodegeneration without inflammation.

I hope this clarifies the way I see it.

-finn

Thanks for clarifying finn and I don't disagree.
Bob

Always looking for a chance to kickstart this thread...the abstract below includes information on the role of inflammation in the brain.



Innate immunity and protective neuroinflammation: new emphasis on the role of neuroimmune regulatory proteins.

Int Rev Neurobiol. 2007;82:29-55
Griffiths M, Neal JW, Gasque P.
Brain Inflammation and Immunity Group (BIIG), Department of Medical Biochemistry, School of Medicine, Cardiff University, CF144XN Cardiff, United Kingdom.

Brain inflammation due to infection, hemorrhage, and aging is associated with activation of the local innate immune system as expressed by infiltrating cells, resident glial cells, and neurons. The innate immune response relies on the detection of "nonself" and "danger-self" ligands behaving as "eat me signals" by a plethora of pattern recognition receptors (PRRs) expressed by professional and amateur phagocytes to promote the clearance of pathogens, toxic cell debris (amyloid fibrils, aggregated synucleins, prions), and apoptotic cells accumulating within the brain parenchyma and the cerebrospinal fluid (CSF). These PRRs (e.g., complement, TLR, CD14, scavenger receptors) are highly conserved between vertebrates and invertebrates and may represent the most ancestral innate scavenging system involved in tissue homeostasis. However, in some diseases, these protective mechanisms lead to neurodegeneration on the ground that several innate immune molecules have neurocytotoxic activities. The response is a "double-edged sword" representing a fine balance between protective and detrimental effects. Several key regulatory mechanisms have now been evidenced in the control of CNS innate immunity, and these could be harnessed to explore novel therapeutic avenues. We will herein provide new emphasis on the role of neuroimmune regulatory proteins (NIRegs), such as CD95L, TNF, CD200, CD47, sialic acids, CD55, CD46, fH, C3a, HMGB1, which are involved in silencing innate immunity at the cellular and molecular levels and suppression of inflammation. For instance, NIRegs may play an important role in controlling lymphocyte/macrophage/microglia hyperinflammatory responses, while sparing host defense and repair mechanisms. Moreover, NIRegs have direct beneficial effects on neurogenesis and contributing to brain tissue remodeling.

Pubmed link

Thanks for the attention to this topic! It's my favorite topic to ponder. I interpret this article as support for a dual mechanism in MS which fits in nicely with my current theory, of course.

How Green Tea's EGCG helps the MS situation has recently been published. It is in my web storage area shown below.

It also has good material related to this topic.

jackD


http://home.ix.netcom.com/~jdalton/egcg-neorond-ms.pdf
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