#MSBlog: Remyelination junkies; where did you get the idea that MS was a disease of failed remyelination? Another false hope?
"The series of articles below from John Prineas document that remyelination is very common in MS, in both early and late disease. The latter includes progressive disease. John Prineas called remyelinated plaques shadow plaques because they don't show up as brightly as normal when myelin is stained (figure below). What is interesting is that he also showed that remyelination tended to be a delayed phenomenon occurring weeks to months after demyelination. Interestingly in some MS lesions that were remyelinating fresh demyelination was also noted; presumably due to recurrent autoimmune attack. In these studies demyelinating lesions were all inflamed This is why we believe it is important to switch off the inflammation to prevent remyelinated lesions being demyelinated again."
"It is clear from these series of studies that spontaneous remyelination occurs in MS; in fact it appears to be the norm. MSers don't seem to have a problem with remyelination. Therefore if we switch off what is causing the demyelination, remyelination should occur spontaneously. That's assuming the axon has survived so that it can be remyelinated."
"Our treatment mantra is therefore anti-inflammatory, neuroprotection, remyelination; in that order. If you try and reverse the order you are unlikely to make an impact on the course of MS."
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| Myelin is stained dark blue. Punched-out demyelinated plaques (green arrows) look pale or white and remyelinated shadow plaques look pale blue (red arrows). |
Chronic plaques in central nervous system tissue fixed by in situ perfusion for electron microscopy were examined for evidence of remyelination in 2 MSers. Fibers with abnormal central myelin sheaths of several types were found at the margins of most of the plaques studied. The most common of these were: (1) the presence of bare stretches of axon between contiguous internodes, (2) the presence of thin paranodes, (3) internodes which changed markedly in thickness along their length due to premature termination of superficial or deep myelin lamellae that ended as hypertrophic lateral loops, and (4) abnormally thin internodes which were of uniform thickness along their length, which were shorter than normal, and which terminated in the form of normal nodal complexes. The finding of internodes of the last type at the edges of many plaques indicates that remyelination by oligodendrocytes can occur in the adult human CNS and that it is common in some cases of MS, although limited in its extent.
Plaques with lipid macrophages and macrophages containing undigested myelin fragments from five MSers were studied by light microscopy of epoxy-embedded tissue (five cases) and electron microscopy (one case). Cell counts determined electron microscopically revealed that oligodendrocytes were reduced in number in areas of commencing myelin breakdown. The major mechanism of myelin destruction was phagocytosis by macrophages of intact myelin sheaths in the presence of very small numbers of lymphocytes and plasma cells. When plaques were orientated to allow examination of whole myelin internodes, it was found that most lesions, including lesions known to have been present for less than ten months, contained remyelinating internodes, sometimes in numbers large enough to form shadow plaques. It is concluded that the two processes of sometimes massive remyelination and active demyelination frequently coexist in "fatty" subacute plaques filled with lipid-containing macrophages, and that myelin breakdown at the edges of progressive lesions includes destruction of remyelinating internodes.
Prineas et al. Multiple sclerosis: remyelination of nascent lesions. Ann Neurol. 1993 Feb;33(2):137-51.
The relationship between plaque pathology and disease duration was examined in 15 MSers who died early in the course of their illness. Myelin-stained sections revealed that most plaques examined in MSers who died during the first month of their illness showed evidence of ongoing myelin destruction accompanied by a loss of oligodendrocytes. Plaques containing large numbers of oligodendrocytes were not observed in these patients, but were relatively common in patients who died more than 1 month after clinical onset. Remyelination affecting more than 10% of the plaque area was observed in 3 of 82 plaques in 5 patients who died within 10 weeks of clinical onset, in 38 of 105 plaques in 5 patients who died 3 to 10 months after clinical onset, and in 19 of 92 plaques in 5 patients who died 18 months or longer after clinical onset. The study provides new evidence that both oligodendrocytes and myelin are destroyed in new lesions, that this activity ceases completely in many lesions within a few weeks, and that remyelination frequently ensues following repopulation of the plaque by oligodendrocytes. The findings suggest that new lesions normally remyelinate unless interrupted by recurrent activity and that remyelinated shadow plaques are the outcome of a single previous episode of focal demyelination.
Recent autopsy studies suggest that remyelinated shadow plaques located in otherwise intact white matter are the outcome of a previous single episode of acute demyelination. In the present study, of 98 remyelinated plaques examined in 15 MSers who died between 27 days and 5 years after clinical onset, 15 showed evidence of a superimposed new demyelinating lesion. Inspection of old shadow plaques in a separate series of MSers with subacute and long-standing multiple sclerosis revealed that such lesions sometimes exhibit punched-out areas of demyelination and gliosis similar in size and shape to fresh lesions located within or overlapping remyelinated shadow plaques. The findings support magnetic resonance imaging evidence that local recurrence may be as important or more important than progressive edge activity in determining plaque growth and the conversion of nascent lesions into classical demyelinated plaques. The findings also support experimental evidence that recurrent demyelination of the same area of white matter may be one of the factors underlying failed remyelination in multiple sclerosis.
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