"mostly neuron death"

[Wind_and_Water]

In another thread, Quix said her type of MS is "mostly neuron death and not so much immune-inflammatory involvement."

I understand that MS is classified as relapsing-remitting, secondary progressive, primary progressive, and so on.  How does "mostly neuron death" fit in the classification system?

Sorry if this question is unclear.  I don't know enough, to know how to ask what I don't know.  If you know what I mean. :)

Thanks.

(Here is the original thread...
http://www.medhelp.org/posts/Multiple-Sclerosis/Sail-Away--Sail-Away/show/1250255)

[shoshin]

The article I was thinking of is:

Lucchinetti C. et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000 Jun;47(6):707-17

and is available from:

http://marchwellness.net/nod/documents/2007/06-01/Lucchinetti2000.pdf

A couple of alternate views on MS: is it one disease?:

http://www.msforum.net/journal/download/20091639.pdf

http://www.msforum.net/journal/download/20091657.pdf

sho

[Wind_and_Water]

Alex and Jan, thanks for your additional responses.

Sho, thanks for your abundant "odd thoughts."  :)

In particular, you said, "there is some pathology research that has identified four types of MS lesions and the researchers have found that in a given brain, only one type occurs."

Could you please share a link?  This is fascinating.  Thanks.

[BOK2Bjan]

Agreed!  Diseases are FILLED with grey areas!  Unless you're talking about a fracture of a specific type in the exact location as another, etc. - there just isn't anything that's that static.  And RRMS isn't the precursor of PPMS - I believe I said (at least meant) that SOME do and some don't with time get the PPMS diagnosis.  It could be that it was that all along - OR the disease took on its different nature due to any number of factors.  I say God's creation is FAR above what I can understand with certainty or in its entirety.  And sho - love the odd thoughts - they're always worth a lot!

Blessings, Jan

[shoshin]

This is sort of in response to both this post and the one on PPMS.

There is thought to be both inflammation and neuron death in all types of MS. Axon transection (cutting of axons leading to the death of the neurons) begins very early and is probably going on in varying degrees in all people with MS. However, in RRMS, it is the acute inflammation and resolution of that inflammation that predominates. The permanent damage that occurs in MS is thought to be caused by the death of neurons. The relationship between the autoimmune/inflammatory processes and neurodegeneration is unclear. I wrote a health page on this that you might find interesting: http://www.medhelp.org/health_pages/Multiple%20Sclerosis/Neurodegeneration-in-MS/show/716?cid=36 Also, contrary to what I said in that health page, there is some newer research that suggests that the autoimmune response may follow the destruction of the myelin rather than cause it http://www.medhelp.org/posts/Multiple-Sclerosis/Prime-mover-for-MS-lesions-not-autoimmune/show/1161501

An important thing to keep in mind is that these four categories that show up in all the MS new patient literature like they’re biblical truth are really more arbitrary than you would think. They were developed by MS experts through a consensus process (which was not unanimous) based on clinical observation and for the very pragmatic purpose of sorting people with MS into categories for clinical trials. There is no proven biological theory or biomarkers underlying the RRMS, SPMS, PPMS, and PRMS categories.

There are also no sharp boundaries and a nontrivial number of people seem to fall into a gray area. If you look at the health page on the transition from SPMS to RRMS, it starts off by saying that it’s a subjective judgment (http://www.medhelp.org/health_pages/Multiple-Sclerosis/Transitioning-from-RRMS-to-SPMS/show/1105?cid=36) Prior to the introduction of the four types currently used, there were some researchers who used a category called Transitional Progressive MS where people had a single relapse and remission, a gap, and then started on a progressive course. This has always struck me as describing my history better than the existing categories. Anyway, it seems to me that there are a lot of people in the fuzzy spaces between the sharply-defined categories.

If you read some of the natural history studies, these tend to say that the progression of PPMS is highly variable with some people having a benign course for a long time. This is contrary to the widely held impression (even by some neuros) that all people with PPMS deteriorate rapidly. In fact, an early PPMS trial ended up being less conclusive than the researchers had planned because the placebo arm didn’t progress as fast as the scientists had anticipated.

The question of whether MS is one disease or many is also a fascinating one and there are a lot of different ideas. Until recently NMO/Devic’s was thought to be an MS variant, but now that there is a blood test for it, opinion has shifted and it is generally thought to be a different disease. Some of the natural history studies argue that not only is MS one disease, but PPMS is essentially the same as SPMS except the initial relapsing phase has been cut off. On the other hand, there is some pathology research that has identified four types of MS lesions and the researchers have found that in a given brain, only one type occurs. There are some criticisms of this, but it it’s true, these lesion might correspond to different disease types.

A few odd thoughts, for what they’re worth.

sho

[HVAC]

Jan

  Primary Progressive MS is not a second stage of RRMS like SPMS or SRMS. Some theorize it may turn out to be another disease all together at some point.

[BOK2Bjan]

I have a hard time keeping up with the forums I enjoy because of having so many diseases that I have to keep up with.  Due to having Medicaid and a neuro who can't figure me out due to the complexity of my case, I basically get NO help with my MS.  That is not to say I get a great deal of help with the other diseases either, but the MS gets the least attention.  Quix, I am sorry to see that you've been having a lot of difficulties - I can relate and greatly empathize.  I have Interstitial Cystitis PLUS bladder issues from the MS - so my bladder talks to me very loudly.  I used to cath myself with medications to try to numb the pain, but it began to cause as many problems.  My symptoms are like a bad UTI, which I have had so many of anyway.  It makes it hard to tell which is which.  Anyway - I know it's really hard.  I have to go b/w 30 - 50 X a day/night.

I wanted to respond to the "black hole" concept, and  to JJ's post as well.  I don't know whether to feel bad about this or not - but I understand where you're coming from JJ.  I think you are merely mixing the concepts and their labels.  The cell death (neuronal and axonal) is not "the black hole".  The radiologist will see an absence of tissue (or as Q said, a loss of density of tissue) that they label a "black hole".  When enough cells die in an area to show up on MRI as "missing", it's seen as a black hole.  So, it's not that you have to have enough black holes to be visible, but rather, when there has been enough cell death, a "black hole" will be seen.  I think you had the idea right. ?  

And Quix, I don't know as I write this, the exact location of your lesions (something I probably knew at one time, lol), but the fact that you have hemiparesis would seem to indicate a spinal lesion.  So I'm defending your thinking JJ.  I think the combining of the two issues got a bit hazy.

Quix - I'm in your camp on this.  I've found, as I've studied my various diseases, that there is no such thing as a pure classification of any of the autoimmune - like diseases.  They are too complex, by their very nature, being an interaction between the genetic predispositions of the patient, what they've been exposed to, how their body reacts to those toxins, medications, or other environmental factors, and the variety of treatments they've been given - even for other disorders.  We know many who start as RRMS turn into PPMS, and to think there aren't millions of varieties in between would be counter-intuitive.  I have seen a fairly consistent agreement with researchers that there is damage going on in the background, "unrelated" to the T2 lesions.  I had quite a bit of brain atrophy at the time of diagnosis (waaa), and my neuro told me at my first appt, that she didn't think many MRIs were useful after diagnosis - that the clinical course told the story of the progression much better.  She does 1 - 2 per year unless there are extenuating circumstances.

I believe that as with so many things past - as imaging gets better and better, we are able to see things - sometimes before we can actually understand the underlying physiology.  Hence the false positive scans and lots of worry and confusion.

Well - I've waxed philosophical as anyone would with brain atrophy such as mine.  I've said very little, but mean well!  But Quix - I do empathize with difficult times, when you aren't up for joining in.  You're loved and thought of, even when not active.

Keep theorizing - Blessings, Jan

[Wind_and_Water]

cali1892, thanks for your answer. I see, it makes sense that different types would do better with different medications.

Alex, thanks also.  I have been following your posts with interest, because I too have experienced an insidious progression of symptoms.  I have not been diagnosed yet.  Nonetheless, even if it is not MS, my situation is quite similar in that, over the years, I have continually adjusted to the new "normal."

Quix, thank you from the very bottom of my heart, for taking the time to thoughtfully answer even in the midst of your own difficulties.  I have read your posts several times, and I have read the health page you cited, and I am mulling over new questions.

[supermum_ms]

LOL!! I have no idea what i was getting at, I know I wrote it but even i can't work it out, lets chalk that one up to verbal diareah! Its been a weird and some what loopy day lol!

Sorry about that!

Cheers......JJ

[Quixotic1]

Actually, JJ, I do not follow what you are asking.  My MRIs have not shown black holes.  As I said, these thoughts are not fully fleshed out, nor have I ever heard them discussed in the literature.  I'm just trying to understand my neuro's comments and opinions.  It would just make sense that some people with RRMS would have a different degree of inflammation versus direct neuronal death than others.

Black holes could certainly be symptomatic as they would be the absence of needed nerves in many cases.

As for atrophy, my OCT showed mild optic nerve atrophy and that has been shown to parallel the atrophy in the brain and spinal cord.

I don't think that I can answer detailed questions on it, because it is a theory and not something I've learned.  It makes sense to me.

Sorry

Quix

[supermum_ms]

Ok, thinking about what you've said Quix, does that mean that if a persons type of MS is forming the black holes due to direct neuronal degeneration, these black holes will not necessarily be seen on MRI as expected because the black holes are pin sized axon deaths and not lesions as such. Substancial increase in black holes will eventualy lead to visible brain atrophy on the MRI. Is that about right?

I've been thinking that its posible that your brain is forming the black holes but the spine is forming the lesions, could that account for the discrepancy of your mobility being one side vs both, if the MS was focused just in the brain and creating the black holes? I'm not sure i've made what i'm thinking clear enough, do get what i'm saying?

Cheers.......JJ

[Quixotic1]

I should say that my esteemed neurologist is the one who told me that I have RRMS and that he believes that the bulk of my damage is in direct neuronal degeneration.

Q

[Quixotic1]

I wondered if people would ask questions about that comment.

A little background on the topic.  First, there is no official "typing" of MS into inflammatory and direct neuronal death.  But, we all get lulled into thinking that our MS is made up of the T2 Hyperintense Lesions and that is as far as it goes.  Still, most of us know that there is more to MS than the lesions we talk about all the time and there is.

In the Health Page "Lesions! Lesions! Lesions!"  we talk about the different types of abnoramlities we see in the MS brain in an MRI.  The most common are the T2 Hyperintense ones, but there are also "T1 Black Holes", there are the abnormalities seen in the Normal-Appearing White Matter (NAWM) and there are lesions in the gray matter, the cortex.  How all of these play together in MS is still largely a mystery, but we do know that the worst of what happens to us is NOT in the common T2 lesions - the ones we talk about all the time.

http://www.medhelp.org/health_pages/Multiple-Sclerosis/Lesions-Lesions-Lesions/show/762?cid=36

The T2 lesions are the ones that are most directly related to the autoimmune inflammatory action of our disease.  Those lesions are where the antibodies directed against myelin play their greatest role.  Those lesions are also most directly correlated with the relapses of Relapsing Remitting form of MS.  It is not a complete correlation, but it is a strong one.  More T2 lesions -> generally more relapses and vice versa.  It's why the neuros often will do an MRI at the sign of a big relapse - so they can find a new and maybe enhancing lesion.  The lesions enhance because the immune attack on the myelin causes inflammation and the inflammation causes a breach in the Blood Brain Barrier.  That breach is what allows the contrast material to appear in the brain matter.

But, we all also know that there is another force at work in MS and that is a steady accumulation of disability.  For some time the experts in MS have been aware that the progression of disability was not particularly linked to the number of relapses nor to the accumulation of new T2 lesions.  So, clearly something else is causing brain damage beyond the antibody attacks on the myelin.  A process called direct neuronal (or axonal) degeneration (or death) happens also.  

Whereas the T2 lesions are known to be able to repair themselves (to an extent), the damage caused by neuron death is not reversible.  The entire nerve cell dies along with the long nerve fiber extending from it, called the axon.  One by one as these nerves die, brain tissue is lost and the end result is a shrinking of the total amount of brain tissue.  This is called brain "atrophy".  Places where there have been a large number of cells that have died can be seen on the MRIs.  They are best seen on the T1-weighted technique.  They are called "Balck Holes."  My understanding is that the black holes are areas of lost brain tissue.  

This is a fuzzy area, because some researchers claim black holes can heal and disappear.  Hmmm.  I don't see how, so I don't totally understand this whole topic.  Some people speak about black holes as areas where the brain has lost tissue density and that is how I understand it.

Now, as the typical person with MS goes through life, they have their relapses now and then.  Symptoms appear, cause problems, and mostly disappear.  But, in the background we see a process of disability occuring - function is lost and not regained.  Statisically they can tell that this disability is happening independently of the relapses.

The disability that a person has is far more closely associated with the Black Holes than with the T2 Lesions.  This makes sense.  On the forum here we have seen many people with tons of T2 lesions, but not much disability.  But then, there are other people (like me) with a piddly amount of small lesions, an a lot of disability.  

Relapses correlate mostly with T2 lesions.

Disability correlates best with Direct Neuronal Death and with brain atrophy.

In the four types of MS, the largest group is RRMS and their course is mapped by the T2 lesions.  The meds for MS target the inflammatory part of the disease course, called the Immuno-Inflammatory lesions which are the T2 lesions we talk about with MRI reports.

The smallest group is PPMS - They have some inflammatory activity, but by far most of their brain damage is in Direct Neuronal Death (Direct Axonal Death).  So, the meds which only target the inflammation don't have much affect on them.  That is why all of the therapies we have to date don't have much affect.  We don't yet know what the "trigger" or cause of this direct tissue death is, so we can't target it yet.

Okay, that part is pretty clear.  What did I mean, then, when I said I have RRMS and my neuro said most of my damage is in direct neuronal death?  I haven't pinned him down yet on this.  I think he is saying that - by all measurements I do not have PPMS.  I don't have the proper type of lesions and my pattern of disability is not characteristic of PPMS.  Specifically I only have a few lesions at all.  And my disability is a persistent and progressive hemiparesis (the right half my body is affected).  My neuro said that almost exclusively, eleven years into the disease course (as I am), a person with PPMS will have BOTH legs involved in a spastic paraparesis. (weak lower half of the body). I have only the right leg involved.

So, what can that mean?  From all my reading and study of MS it is clear that MS has an almost infinite way of presenting.  I think that my picture is one with very few T2 Lesions - and thus little immuno-inflammatory activity.  I would likely be in that group of people who does not respond to a DMD.  Remember - one of the criticisms against the DMD's is that only about 40% of the people will have a good response to them.  They still don't know why the other 60% don't respond.  Perhaps they have - on average - a higher amount of progressive disability than the other group.

What this says is that RRMS is hot really a homogenous group.  Well, if you have read much on the forum, that is pretty obvious.  

This is what I have surmised, and it makes sense to me.  But, I have only figured this out and not read it as science.  Still, my track record on such things, like my statements more than a year ago that MS frequently DOES affect the Autonomic Nervous System, is pretty good.

Secretly I believe that I will eventually be categorized as PPMS, so all of this might be mute.  On the other hand I do have what could be called relapses.

I hope that this clarifies some of the thinking.

Quix

[HVAC]

I have Primary Progressive MS and my MS Specialist have said mine is mostly neuron death. It is not treated with steroids or any of the DMDs which are used for RRMS to slow the progression. I do not have attacks and remissions, just a steady progression. My symptoms are pretty much constant.

Basically the only thing that gets treated for me is symptoms. Some of the new oral drugs are being studied in PPMS. So far there is no FDA treatments.

I have had the disease for over forty years with no treatment. It took them this long to diagnose. Now that I am diagnosed little has changed.

I have double vision, vertigo, balance problems, cognitive issues, left side weakness and, headaches, and it is getting harder to walk over time.

Unlike others on the forum this does not get better and worse it is always there. Since I have always had these things I do better than others. For example I climbed ladders for a living with vertigo and I have always driven with double vision. I am used to headaches because I have always had them.

Others have these symptoms come out of the blue and that must be scary.

I see a MS Specialist twice a year and he basically measures things and lets me know there is nothing to be done.

The bad part in PPMS is sooner or later mobility is an issue.

Alex

[cali1892]

I saw that to, and am wondering the same thing.  ... I think I have read somewhere that the inflammatory kind of ms responds to certain medications differently.  Something about the interferons or something.  And when the disease doesn't respond they switch to the other kind of dmd's.  I know that's clear as mud. Sorry.  That's about how my mind is right now.  I really did read something about it somewhere online.  Hopefully, someone else can chime in and give us better information about this subject.