Relapsing/Remitting, what the?

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Relapsing/Remitting, what the?

Postby Lyon » Wed Feb 07, 2007 7:48 pm

Last weekend during a search of the internet I came across something that someone named "MSWillow" had written on "thisisms" a couple of years ago and it referred to relapsing being due to damage to the myelin and remitting being due to repair efforts of the body.

Today while looking through the thread "Stem Cells" I looked into a link dignan had provided and I find that a researcher evidently makes the same assumption regarding what is responsible for the relapsing/remitting phase
Spontaneous repair of brain damage also occurs and is the reason that many
patients recover partially or completely from their first MS attacks.
On the long run however,
spontaneous recovery and pharmacological treatment cannot prevent the disease from progressing.
I'm beginning to believe that the commonly held assumption of what is going on "behind the scenes" in the relapsing/remitting phase isn't in alignment with my assumption which, until tonight, I thought would have been the obvious assumption most anyone would make.

This "other" assumption seems obviously faulty because it relies on every relapse doing enough damage to the myelin to impair function of the axon, yet we are to believe that the body repairs that myelin in what sometimes is a very short timespan between relapse and remission and repairs it so completely that sometimes what had seemed to be severe damage sometimes returns to normal function? It does NOTHING to console the fact that steroid administration during relapse can quickly provide positive results by doing nothing more than reducing inflammation. It's illogical and beyond the realm of possibility.

My belief? Remember the comparison the researchers long ago provided as a simple way to make us ignorant laypeople understand a complex situation? You know, the axon is the electric wire and the myelin is the insulating sheath? I'm convinced that we need to take that comparison absolutely literally. ABSOLUTELY LITERALLY.

Anyone familiar with electricity knows that you avoid sharp corners and bends when running electrical wiring. Sharp corners and bends create resistance which impedes function, despite the fact that the insulation is present.

Now imagine on a tiny scale what is going on inside the brain during a relapse. Those long strands of myelin wrapped axons find themselves running through a twisting inflamed, irritated and swollen pathway. At this point we need to remember that we aren't really considering metal wiring and insulation and instead are talking about biological wiring in which the extra moisture involved in swelling and the inflammation itself has additional negative effect on transferring impulses.

This very handily explains how damage can seem so severe during relapse and dissapear to such a great extent during relief of inflammation, irritation and swelling...otherwise known as remission.

Even with my theory some damage to the myelin is done during a relapse which of course is dependant on the severity of the attack. Sometimes nothing more than some minor cracking (for lack of a better term) which the body is capable of repairing and no damage to the axon. Sometimes in a severe relapse the damage is so bad that enough axons are beyond recovery as to show remaining disability even after the relapse ends.

As with any blatant speculation not supported by fact, there are different directions this theory could have headed which are too numerous to mention. Even stating it as simply as I have I think it is hands-down more believable than relapse=damage...remission=the body healed itself.

As I mentioned earlier, otherwise how can it be explained that steroid treatment quickly provides relief? Steroids speed up the body's myelin repair process? I don't think so.

OK, it's your turn. Shred my theory.

Bob
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Re: Relapsing/Remitting, what the?

Postby CureOrBust » Thu Feb 08, 2007 12:21 am

Ok, why did you quote yourself??? entirely?

Lyon wrote:It does NOTHING to console the fact that steroid administration during relapse can quickly provide positive results by doing nothing more than reducing inflammation. It's illogical and beyond the realm of possibility.
Lyon wrote:As I mentioned earlier, otherwise how can it be explained that steroid treatment quickly provides relief? Steroids speed up the body's myelin repair process? I don't think so.
I think it is accepted and proved by the medical fraternity that its the BBB being closed down by the steroids that stops a relapse, not the inflamation reductions; although i am sure it helps. There are many other anti-inflamatories that just dont work for a relapse.

Lyon wrote:OK, it's your turn. Shred my theory.
I am not quite sure how your "theory" is any different to what is commonly "thought". ie a relapse strips myelin, a remission is where the body tries to repair it, but sometimes the damage is too great or repair takes too long and nueronal loss occurs and brain shrinkage.

Lets not also forget that the common belief is that with myelin repair, there is also scar tissue, which is not as good an insulator as myelin. And from this, the more relapses you have, the more scar tissue you have as opposed to nice clean myelin. Just try using partially insulated wires, the whole signal wont make it down the whole path. And the spine is a long path.
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Postby Manchester » Thu Feb 08, 2007 6:44 am

Cureorbust you write
"I think it is accepted and proved by the medical fraternity that its the BBB being closed down by the steroids that stops a relapse, not the inflamation reductions; although i am sure it helps. There are many other anti-inflamatories that just dont work for a relapse."

Can you point me in the right direction for this information about it being proved that steroids stop relapses by closing the BBB more than by reducing inflammation.

I always thought it was more the other way around or much more balanced combination of both-1)they 'help' reduce permeability of the BBB and 2)they 'help' reduce inflammation.

Also as inflammation is causing the damage, steroids are not directly speeding up the repair, rather halting/reducing the process causing the damage by decreasing the inflammation.

Cortisone, for example, has an immunosuppressive effect by deactivating white blood cells -specifically T-cells by inhibiting the release of cytokines and may also kill white blood cells to a degree. Research I have found highlights this role more than its role in helping to modulate the BBB, though it is accepted that it

Also remember the brain has remarkable plasticity which means, at least, in the early stages of MS it can compensate for the damage caused by rerouting connections. This means it not always brain repair of the affected area that is causing the improvement but cortical reorganisation.

There has been some research done in to training-dependent plasticity in MS with mixed results, however, I personally think this can work, again, at least in early stages of the disease. Haven't got time now to go in to details but will later if this is of interest.

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Re: Relapsing/Remitting, what the?

Postby Lyon » Thu Feb 08, 2007 7:31 am

CureOrBust wrote:Ok, why did you quote yourself??? entirely?
Hi Cure,
I thought you had known me long enough to be aware that as a self-professed authority I have the luxury of saying something and then quote myself in order to bolster my subsequent arguments!

Seriously? I have no idea how I manage to do some of the things I do. Thankfully most of them are not life threatening.

I can't respond to your post right now because my break is about over but we've GOT to talk about this idea you have that steroids primarily or even to some large degree control the permiability of the bbb. I'm not aware that that is generally accepted...at all!
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Re: Relapsing/Remitting, what the?

Postby Lyon » Thu Feb 08, 2007 3:10 pm

CureOrBust wrote:I think it is accepted and proved by the medical fraternity that its the BBB being closed down by the steroids that stops a relapse, not the inflamation reductions; although i am sure it helps.
Hi Cure,
I've looked and looked and I can't find anything which would lead one to believe that. I have seen recent speculation about the effect steroids have on the bbb though. Maybe that's what you're thinking of?
CureOrBust wrote:I am not quite sure how your "theory" is any different to what is commonly "thought". ie a relapse strips myelin, a remission is where the body tries to repair it, but sometimes the damage is too great or repair takes too long and nueronal loss occurs and brain shrinkage.
To put it in a nutshell the heart of the difference between my theory and the "faulty" one is that there is no or little real damage during relapse. Although it sometimes can be a preview of what might eventually become permenant disability with subsequent relapses affecting the same area, I feel the temporary disability during a relapse is mechanically caused by the faulty transmission through the axons due to the inflammation, swelling and irritation in the affected areas. If the relapse is deep and devastating, of course there will be permenant damage and even that isn't inconsistant with my theory and that isn't the normal relapsing/remitting scenario.
Lets not also forget that the common belief is that with myelin repair, there is also scar tissue, which is not as good an insulator as myelin. And from this, the more relapses you have, the more scar tissue you have as opposed to nice clean myelin. Just try using partially insulated wires, the whole signal wont make it down the whole path. And the spine is a long path.
Not to be contrary but don't you think it's more accurate to say that with injury there is scar tissue? This conversation has made me remember something that I wanted to do earlier and that is to research the mechanisms of scarring. I also wanted to try to ascertain the depth of MS "lesions" or scar tissue.

I've always only considered the single axons and their myelin and I've never considered that scar tissue replaces the myelin, so that is a new concept to me. I'm going to look into it, but at this point I'm at a loss :oops:

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Postby Manchester » Thu Feb 08, 2007 5:08 pm

Just adding my two penny's worth.

I would disagree with you Bob that no or little damage is caused during a relapse, in some cases, as I said in my earlier post, cortical reorganisation takes place that can sometimes mask the damage.

I agree that there is huge variations in relapses and some cause less damage than other but axons are damaged netherless even in the very early stages of MS-long before diagnosis, however these are the ones where the brain has a better chance to repair itself but damage is still occuring. All the time, even outside of relapses.

Relapses are for many people with MS far from a temporary disability and more often than not residual damage remains- hence when many people with MS are tired or ill the symptoms may come back as they are still there. In many cases whether this damage to the axons or myelin has any effect depends on what area of the brain it is affecting- i.e neurological loss of function depends on the area of the brain affected so you may think no damage has been caused but it has, it is just chance it is not in area where functional loss will result.

This is why MRIs only tell part of the story- you could be lucky and have a brain like a swiss cheese but no neurological deficits purely because of a)the damage is in an area that does not disrupt function/lead to disabilty or/and b)your brain is simply rerouting the messages through a non damage part. And of course c the myelin is repaired.

Add to this the belief/understanding now that it also affects grey matter much more than thought even 5 years ago and that the constant dengerative process goes on with MS outside of relapses, suggests there are more than one mechanism for damage- not just inflammation and this is where the underlying causes of MS come in ie that it far from being an autoimmune condition- again a fact now recognise by most MS researches and neurologists. It is of course the damage to grey matter that should be more worrying- it is far me- as unlike white matter, grey matter is responsible for information processing

Scar tissue does in some cases replace the sheath as Cureorbust has correctly stated and indeed steroids are thought to modulate the BBB, it is just not thought to be the primary way that steroids are effective. At least not that I know but I am happy to be corrected.

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Postby Lyon » Thu Feb 08, 2007 6:04 pm

Manchester wrote: I agree that there is huge variations in relapses and some cause less damage than other but axons are damaged netherless even in the very early stages of MS-long before diagnosis, however these are the ones where the brain has a better chance to repair itself but damage is still occuring. All the time, even outside of relapses.
I appreciate the fact that you mention "long before diagnosis" because I think that's a very valid point. A lot of people seem to think that MS is like a head cold...that you know almost the moment you come down with it ie..onset and diagnosis (which REALLY means symptoms leading to diagnosis) are synonymous. That doesn't seem valid with MS.

I agree that damage is done and I agree that rerouting plays a part in the favorable results seen during remission. My theory isn't intended to do away with the other things we know, rather think we know but ONLY seeks to explain the amazing difference between disability during relapse and remission. Damage and healing of damage alone isn't logical.

Put MS out of your mind for a minute and consider neurological damage in ANY other situation. Yes, the brain is resiliant but there is no other situation in which people fairly consistantly come "back" to that degree from such "damage" and surely not in this kind of time frame. My wife couldn't talk right, they gave her prednisolone and the next day she was talking fine. That isn't repair, that's reduction of inflammation. Sealing the bbb wouldn't provide results that quickly. It seems obvious that the "temporary damage" during the relapsing/remitting stage of MS isn't ALL damage and in fact is primarily due to inflammation.

Relapses are for many people with MS far from a temporary disability and more often than not residual damage remains- hence when many people with MS are tired or ill the symptoms may come back as they are still there.
Absolutely, in those cases "milder" disability in previously affected areas reappear and those cases it might very well be due to damage. I'm not saying that NO damage happens and I'm not saying that no re-routing happens. [/quote]This is why MRIs only tell part of the story- you could be lucky and have a brain like a swiss cheese but no neurological deficits purely because of a)the damage is in an area that does not disrupt function/lead to disabilty or/and b)your brain is simply rerouting the messages through a non damage part. And of course c the myelin is repaired.[/quote] In this case WHERE the damage happens seems to be the most important aspect. My wife has eight lesions on MRI, the eighth just noticed a couple of weeks ago. So far slurred speech is the only "funny" thing she has experienced.
Add to this the belief/understanding now that it also affects grey matter much more than thought even 5 years ago and that the constant dengerative process goes on with MS outside of relapses, suggests there are more than one mechanism for damage
True, we know so little and there is so much to learn! I mentioned that so far my wife has only noticed slurred speech but her EDSS is 4.0 so obviously damage has been going on behind the scenes.

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Postby Manchester » Thu Feb 08, 2007 7:42 pm

I think we may be talking at cross purposes and I am not sure where you are going with this as it is generally accepted that during a relapse inflammation causes the damage, that Steroids halt the inflammation and that halting the inflammation halts/lessens the relapse so the extent of the damage is lessened - though this is a very simple explanation. I don't think you can compare other neurological conditions with MS in this way - it is a bit like comparing apples to pears.

Just because the steroids have ended the attack early by dampening the inflammation doesn't mean lasting damage has not been caused, only that MAYBE less damage has been caused. Yes, this can lead to what seems like immediate spontaneous recovery but the reality is that it is unlikely that no damage has been caused at all and with repeated attacks this damage will then be built on and worsen.

And that this is indeed separate from repair. This is also the basis on which the DMD work to a lesser or greater extent depending on which camp you are in.

I believe they can be effective to some degree in dampening the immune system which dampens the inflammation and can be used more effectively in doing so than steroids etc etc as the underlying process of damage appears to be still continuing outside of a 'relapse'. So the process of inflammation is continuing but below the radar and the relapse is just tip of the iceberg.

Also consider that inflammation may only be part of the issue, take PPMS where brain atrophy occurs but does not appear to be caused by inflammation. Does this make PPMS a different disease? Definitely a case for it. At the least it can be said that in RRMS inflammation appears to dominate the process and not in the progressive forms and until we fully understand the underlying mechanisms it is better to treat RRMS as soon as possible.

I don't think that halting the inflammation means that the inflammation only causes 'temporary' damage and as soon as you decrease the inflammation everything is hunkydory (or indeed that steroids work in every case) only that in some cases the steroids kick in before what seems to be the more destructive damage (i.e damage to the actual axon not just the sheath etc etc) is done but not in every case.

Some relapses are mild anyway and do not require steroids but does this mean they do not cause lasting damage? I would say not, only it lessens the degree of lasting damage that can be measured and again that is why symptoms that seem to have vanished litterally overnight will come back when a person is tired or ill.

Also MS lesions do not always correlate to the functions that are affected just as this means you can have many lesions and no disability it also means you can have no lesions and much disability.

Does this mean inflammation is going on all time but it just never or only sometimes reaches a critical point where a relapse takes place but all the same the damage is occuring? I think so.

This is a completely different matter to steroids modulating the BBB. It is fact that the primary way they work by decreasing inflammation. Bringing the BBB in may be confusing the issue. But it does play a role in relapses and disease progression outside of relapses.

Blimey, it's 2.40 am in the UK and I have to be up at 7 so I as fascinating as this discussion is I must go to sleep. Thanks Bob for raising these issues, it is real food for thought and I look forward to your next post.

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Postby Lyon » Thu Feb 08, 2007 8:22 pm

Hi Manchester,
Rather than responding to everything point for point I just want to reiterate that in this theory EVERY commonly accepted assumption about MS still holds true EXCEPT that I think the facts show that inflammation rather than actual physical damage are responsible for what later prove to be temporary symptoms in the RRMS phase.

I can't stress enough that I'm only referring to RRMS, I'm not saying that there is no permenant damage, I'm not saying that there isn't damage happening even when there is no obvious inflammation or symptoms......let's see, I'm not saying that steroids lessen damage because I've read two reports tonight that they don't. Steroids evidently just end the relapse sooner. I'm not saying that steroids have no effect on the bbb and I'm not saying that brain circuits don't rewire themselves to some degree eventually.

What I am saying, and all that I'm saying is that the inflammation, irritation and swelling are capable of producing the "disability" noticed during relapse. Additionally, ONLY receding inflammation is capable of explaining symptoms receding in this kind of time frame. Repair, rewiring and tighter bbb are not capable of meeting the time frame and are not capable of producing such a complete transformation in ANY amount of time. It's not even a close race :o

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Postby Manchester » Fri Feb 09, 2007 4:53 am

Hi Bob,

Yes, it is accepted fact that MS symptoms can and do disappear or diminish once the inflammation subsides (whether through steroidal intervention or natural disease course) and that in some cases it is the actual inflammation by and in of itself causing some function loss, this is not new but nor is it by any means the whole picture.

Inflammation doesn't just sit there innocently blocking pathways/aggravating nerves but having no other lasting effect. Yes, it is long accepted fact (at least with the neurologists I have spoken with) that this physical inflammation causes temporary loss of function by and in of itself just by being there but this is only one of its many effects not all. Inflammation is much more than swelling or fluid accumulation causing purely an actual but temporary physical blockage or presence resulting in temporary 'damage' i.e. when the physical blockage/presence is removed the 'damage' also completely goes. If this is what you are saying.

Inflammation is composed of various cellular components –macrophages, mast cells, T/B lymphocytes etc. This means damage is caused by different mechanisms, so far identified ways include primary damage of the oligodendrocytes, T-cell/macrophage mediated demyelination, antibody/complement-mediated demyelination. This damage is going on as long as the inflammation lasts and in most cases does cause permanent damage.

A good example of this is with the role of Nitric Oxide (NO), which is produced at the site of inflammation. NO can bring about a complete sudden, loss of conduction/loss of function and when you remove NO the function may sometimes be completely restored- quite dramatically and quickly but this does not mean other processes are not also causing more subtle/less apparent damage at the same time or that it was merely inflammation in itself causing this loss of function. Also remove NO and you are less likely to have permanent damage but not completely. This is why I take uric acid precursors (to decrease NO) and keep my serum uric acid levels high.

Indeed NO damage is one area that steroids are thought to act upon. Albeit, indirectly by decreasing the cytotoxic effects of NO and this may explain why some quite dramatic symptoms can improve very quickly after steroids have been used.

Whether NO damage is temporary or permanent is also dependent on how big the area affected is, which axons are effected and how long the inflammation lasts. Not simply that the physical inflammation is causing temporary damage just by being there and once it has gone so has the damage.

Your theory would also seem to negate more current findings that the inflammatory component is not the be all and end of all of MS... The question of whether inflammation is primary or secondary to the process remains open. And I am talking about RRMS not just the progressive forms.

Even in very early RRMS disability progression correlates with axonal damage even when a person appears to have complete spontaneous recovery after inflammation has abated, even when it appears to have abated very quickly. Though there appears to be such a close correlation between initial axonal injury appearing and inflammation (still poorly understood) this is not the complete picture either as further damage may/probably is occurring all the time throughout the nervous system and independent of inflammation.

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Postby Lyon » Fri Feb 09, 2007 7:21 am

Hi Manchester,
You've left me nothing left to respond to. I agree!

There is more to my theory, the earliest stages, but I purposely left that out because I need to learn more about "dormant" viruses and bacteria they find in the brain.
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Postby CureOrBust » Sat Feb 10, 2007 5:22 pm

Manchester wrote:Cureorbust ...Can you point me in the right direction for this information about it being proved that steroids stop relapses by closing the BBB more than by reducing inflammation.

I always thought it was more the other way around or much more balanced combination of both-1)they 'help' reduce permeability of the BBB and 2)they 'help' reduce inflammation.
OK, I admit, I was a little gung-ho with the statement, however, I feel there is some truth in it. I recently started a thread on the BBB and was posting extreme absolutes to illicit responses, maybe i was still in that groove. :roll:

If it were a "balanced" contribution, I would expect to see an equal sharing of BBB improvement and Anti-inflamatory effects. However, steroids are the only substance I have herd of that "close" the BBB, while we have many NSAID's, which are not as effective, to my knowledge in accute MS relapses.

I am NOT saying that the anti-inflamatory effects, have no effect. However, we have numerous antinflamatories that are not steroids (NSAID such as asprin), yet they are not used as commonly as steroids. Ive have never herd of a neurologist saying to a patient in accute MS relapse, "take two asprins and call me in the morning" :)

http://www.nationalmssociety.org/Meds-Methylprednisolone.asp
Methylprednisolone is one of a group of corticosteroids (cortisone-like medications) that are used to relieve inflammation in different parts of the body. Corticosteroids are used in MS for the management of acute exacerbations because they have the capacity to close the damaged blood-brain barrier and reduce inflammation in the central nervous system.
Although it talks of anti-inflamatory properties to start with, I read that sentence as more of a background on steroids

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1619410

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=1866009

Even Statins which I think were originally thought to be anti-inflamatory, are being found to affect the BBB

Statins reduce human blood-brain barrier permeability and restrict leukocyte migration: relevance to multiple sclerosis.
Ann Neurol. 2006 Jul;60(1):45-55.

I guess I am also drawing from my own history. I was originally diagnosed with CIDP (a peripheral neuropathy) for which prednisone is taken 24/7 (20-100mg/day) is the general treatment (I use to pulse as it didnt seem to help except during a relapse... funny that...). Now, with CIDP, I dont remember ever hearing that its effectiveness reduced over time. I am GUESSING that this is because its anti-inflamatory and immune modulation continues over long term use. Meanwhile, in MS, steroids arent a long term option. Also, I have never herd of steroids failing for transplant patients in the long term. Remember, this last paragraph is all from my own history, not from research.

Hopefully I have made it a little clearer where I got that statement from. Although, I can see peoples reason to disagree with it.
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Postby Lyon » Sat Feb 10, 2007 6:42 pm

CureOrBust wrote: I am NOT saying that the anti-inflamatory effects, have no effect. However, we have numerous antinflamatories that are not steroids (NSAID such as asprin), yet they are not used as commonly as steroids. Ive have never herd of a neurologist saying to a patient in accute MS relapse, "take two asprins and call me in the morning" :)
Thanks for going to the effort to find the links Cure, they were good ones and were what seem to be conclusive evidence that steroids do a pretty good job of sealing the bbb. I'd never seen that definitive information before and you've convinced me.

Alas, despite my appreciation, the point remains the same. Even effective and immediate sealing of the bbb doesn't account for the rapid improvement in symptoms experienced (sometimes/most times) after steroid treatment in RRMS, although reduced inflammation does.

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Re: Relapsing/Remitting, what the?

Postby NHE » Sun Feb 11, 2007 4:03 am

CureOrBust wrote:I think it is accepted and proved by the medical fraternity that its the BBB being closed down by the steroids that stops a relapse, not the inflamation reductions; although i am sure it helps. There are many other anti-inflamatories that just dont work for a relapse.

Corticosteroids induce apoptosis in white blood cells. Apoptosis is the process of programmed cell death. If there are less white cells in circulation, then there will be less to cross the blood brain barrier. Here's a link to an introduction on apoptosis from Alberts et al's Molecular Biology of the Cell.

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