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I have been reading about this topic
recently and find it fascinating (although I think I’d like it more if it
weren’t happening to me). I thought I’d summarize some of what I’ve read below
in case anyone else is interested. I should also say to take this with a large
grain of salt as I read some what erratically and only on the topics that
interest me and I do not have a scientific or medical background.
I’m sure most of you know this, but I just want to mention at the beginning that axons are long fibers that come off of the cell body of neurons and send signals to other neurons. They are like wires that conduct electricity. Many axons are normally covered with myelin. Myelin, like insulation on a wire, improves conduction and is attacked in MS.
There seem to be two major things that go on in MS:
1. Inflammation. This is thought to be caused by an autoimmune attack on the myelin surrounding the axons in the central nervous system. Acute inflammatory demyelination is what causes relapses where you get suddenly worse. Many of the symptoms of relapses can resolve over time as the attack abates, inflammation goes down, and the body attempts to repair itself and remyelinate the axons. In fact, some inflammation during an attack appears to be good in that it triggers the body’s self-repair mechanisms so it may not be ideal to completely suppress the immune system in MS.
2. Neurodegeneration. This is thought to cause the slow, insidious progression in MS and to be caused by permanent damage to axons. Although neurodegeneration starts early in MS, it usually takes a while to show noticeable effects because the brain is very good at compensating and can work around the damage for some time (yay for neuroplasticity).
**How do axons get damaged in MS?
Axons can be damaged by inflammation in active lesions, due to various substances associated with inflammation that can injure them, and this can be reversible. They are also damaged by transection (which means to cut transversely, which sounds pretty irreversible to me. You can see a picture of transection in the rotating picture, second from top, at http://www.msalliance.com/aboutMS/index.asp?m=1&f=5&s=1&t=3&c=123 or http://tinyurl.com/d8o6hq). It was not clear to me what causes the transection, but it is apparently associated with the level of inflammation in active lesions.
In chronic lesions, the likely cause of damage is lack of trophic support. (I looked this up and it seems to mean something like “nutritive.” Basically it has to do with the things in the surrounding environment that support the growth and health of axons, such as myelin, oligodendrocytes, and glia). In addition, axons probably become less able to recover over time.
There is also known to be axonal damage in normal-appearing areas of the brain.
Wilkins and Scolding list some possibilities for mechanisms of axonal loss in later stages of MS:
(1) previous inflammatory damage to axons
(2) low grade inflammation occurring causing damage to already vulnerable demyelinated axons
(3) loss of trophic environment for axons to survive
(4) alterations in energy requirements of demyelinated axons
(5) as part of a completely independent neurodegenerative process
They conclude that “in all likelihood, the axonopathy of MS is multi-factorial.”
**How do we know there are damaged axons in MS?
One way is though a newer type of imaging called MRS (magnetic resonance spectroscopy), which can measure something called NAA (N-acetylaspartate) which is a marker of axonal density. Loss of axons can be seen in brain biopsies and at autopsy. Axonal loss is also associated with brain atrophy.
**What can be done about neurodegeneration?
Right now, it sounds like not much of anything, but trying to find ways to protect axons from damage is a hot area in MS research. Wilkins and Scolding list three potential strategies: (1) neuroprotective drugs; (2) growth factors; (3) stem-cell based therapies.
At least a couple drugs that are in currently in clinical trials are thought to potentially have neuroprotective effects. One is FTY720 or fingolimod (which I am in a trial for and there’s also a new trial for PPMS) and another is MBP8298, which is being tested in secondary progressive MS.
**What is the relationship between inflammation and neurodegeneration?
Until fairly recently, MS was thought to be the “archetypal inflammatory demyelinating disease of the central nervous system” (Wilkins and Scolding) in which the repeated ravages of inflammation and resultant demyelination caused progression and neurodegeneration. This is now thought to be more complicated.
Epidemiological and natural history studies suggest that, when looking at large groups of people (there’s still a lot of individual variation), progression in MS is related to age and that after a certain point progression occurs at more or less the same rate for all people with MS regardless of prior history of relapses. That is, after a certain point the relapses have no significant influence on how quickly you progress. This break point usually seems to be given as a sustained score of 4 on the EDSS (Expanded Disability Status Scale). EDSS 4 is defined as “Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite relatively severe disability consisting of one FS grade 4 (others 0 or 1), or combination of lesser grades exceeding limits of previous steps; able to walk without aid or rest some 500 meters.” (My EDSS always seems to work out to 3 or 3.5, which I find uncomfortably close to 4). Some have argued that primary progressive MS is just secondary progressive MS with the relapsing-remitting phase cut off. Trapp and Nave conclude that “much of the recent epidemiological data can be interpreted as indicating that all MS patients have a similar rate of primary neurodegeneration with variable secondary inflammatory demyelination.” These studies suggest that inflammation might not be the cause of neurodegeneration.
Peterson and Fujinami list five possible relationships between inflammation and neurodegeneration (which are not mutually exclusive):
(1) inflammation induces neurodegeneration
(2) neurodegeneration causes inflammation
(3) other factors contribute to the development of inflammation and/or neurodegeneration
(4) inflammation and neurodegeneration participate in a cycle or a cascade in which they augment one another
(5) inflammation can protect against neurodegeneration
Wilkins and Scolding say that it would be hard to show whether inflammation or neurodegeneration is primary, but one approach might be to see whether progression is prevented when intense immunosuppression is used very early in MS.
**Related post (lots of good info):
“It’s not the amount of lesions...” http://www.medhelp.org/posts/show/354591, Nov. 20, 2007.
Frohman, E. F. et. al. (2005).“Characterizing the mechanisms of progression in multiple sclerosis.” Archives of Neurology, 62 (9), 1345-1356. Free fulltext at http://archneur.ama-assn.org/cgi/content/full/62/9/1345
Peterson, L. K., & R. S. Fujinami. (2007). “Inflammation, demyelination, neurodegeneration, and neuroprotection in the pathogenesis of multiple sclerosis.” Journal of Neuroimmunology, 184 (1-2), 37-44. Preprint at http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1933528
Trapp, B.D., & K.-A. Nave. (2008). “Multiple sclerosis: An immune or neurodegenerative disorder?” Annual Review of Neuroscience, 31, 247-269.
Wilkins, A., & N. Scolding. (2008). “Protecting axons in multiple sclerosis.” Multiple Sclerosis, 14, 1013-1025.