Articles of Interest (15): remyelination in progressive MS

#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.”
Myelin is stained dark blue. Punched-out demyelinated plaques (green arrows) look pale or white and remyelinated shadow plaques look pale blue (red arrows).

Prineas & Connell. Remyelination in multiple sclerosis. Ann Neurol. 1979 Jan;5(1):22-31.

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.

Prineas et al. Continual breakdown and regeneration of myelin in progressive multiple sclerosis plaques. Ann N Y Acad Sci. 1984;436:11-32.

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.

Prineas et al. Multiple sclerosis. Pathology of recurrent lesions. Brain. 1993 Jun;116 ( Pt 3):681-93.

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.

14 thoughts on “Articles of Interest (15): remyelination in progressive MS”

  1. Do we know if degeneration stops after remyelination? Is it possible nerves continue to degenerate even if remyelinated?

    1. That's possible (due to activated microglia releasing toxic factors) but must be less likely than demyelinated nerves dying. we need to save as many of these as possible so that remyelination can occur.

  2. Remyelination Junkie goes on like a stuck record (REMYELINATION OR NOTHING! Everything else is dangerous and useless! Stop wasting my tax money on DMTs!)Hope we get less of that now

  3. I have written a very strongly worded letter to the All-Party Parliamentary Group for Multiple Sclerosis and my local MP asking them to restrict the availability of current and future DMTs on the basis that such drugs do not clinically stop brain atrophy and, therefore, have almost no bearing on long-term disability outcomes. These drugs are also highly expensive and toxic in terms of the lack of benefits delivered. Judging by the finite resources available to public health services, one senses NICE will never sanction new DMTs for all MSers, which is actually a good thing as far as I’m concerned. I just feel it’s important to remind them that not everyone with MS is in favour of such medicines. I also highlighted the dangerous nuisance that is CCSVI, demanding that government implement a strategy to sideline their vocal activities in Britain.To be honest, after the debacle that was the CUPID trials, nothing the scientists say on this blog about the nature of MS actually convinces me. CUPID was an embarrassing professional failure, where £8 million was basically thrown down the toilet. After Prof G’s grandstanding about 2012 being a ‘momentous year’ in MS treatment outcomes, I have further cause to be suspicious about your views regarding things such as remyelination. I fear that your opinions may encourage individuals not to donate to Franklin et al pursuit to fund remyelination trials for stem cell therapies. Remyelination, according to those working in the field, will not simply occur by stopping inflammation. It will require intervention, the kind of intervention being tweaked as we speak.I’m sick of my taxes funding pointless DMTs that are lining the pockets of greedy and sociopathic pharmaceutical men. I’m sick to the bottom of my stomach that the Canadian MS society spent millions of its donations into investigating CCSVI when we all knew it was snake oil.In some ways I hope that I’m proven wrong and Team G’s sentiments about remyelination are correct. I f you guys are right then you’ll have forwarded progress by decades, brining about an essential end to MS. However, your odds are bad, and if I was a betting man, I’d bet against you because of how many times you’ve been wrong. In the meantime I pledge my support to the Franklin camp. They are the only ones the media is interested in right now because they’re the only people wanting to revolutionise MS treatments.

    1. There is nothing I like more than a lively and healthy debate; I beg to differ with you. Prof. Franklin will the first to admit that remyelination strategies in MS will have to be added onto drugs that address the inflammation / autoimmunity. Ms is complex disease and requires a complex solution. Your are wrong about atrophy; several of the new and emerging DMTs have a positive impact on brain atrophy. Should we be using these? Should the NHS be paying for these?

    2. I also disagree with you about Pharma people. I know a lot of people who work in the industry; they are normal people who do a good job. They have husbands, wives, partners and children. Most of them are passionate about what they do and care about people who are sick. You need to step back and ask yourself what would we do without pharma? For example, Prof. Franklin is not going to be able to translate his remyelination work into a drug without them. It is just too expensive or risky for academia or the non-profit sector to take this on. In fact, he is working with Pharma right now to test drugs that target remyelination. It is very short-sighted to have, and promote, a them-and-us attitude. We the MS community and Pharma are partners, we share a single vision to make the lives of MSers better. I suggest you reflect on where we are now with regard to MS, its treatment and its future treatment. In a parallel universe without Pharma to do you think they would be in the same situation?

    3. For a start Prof Franklin's studies need to be repeated in an inflammatory model rather than just chemically induced demyelination that has no inflammatory component. Only once this has been done can we say that this work is definitively on the right track.We'd love to collaborate on this!

    4. Another question is also are the factors that make rat/mouse cells remyelinate the same to make human cells remyelinate?. If it was so easily translatable we would have an endless sources of human oligodendrocytes…….we do not. I am sure Robin will be happy to receive your donations and nothing we say should detract you from doing that.

  4. When I read things like this, I think maybe we're closer to stopping and even some repair in MS than I tell myself on my darker days. I've seen Howard Weiner say that the cure for MS will come not all at once, but a few people at a time. In fact, he says, we may have cured it in some people already.I assume he means in people who are doing very well on their DMDs. Maybe in a person on Alemtuzumab who isn't going SPMS. I don't know. What do you think of that? Might some of us get on stronger therapies, stop the inflammation, remyelinate on our own, and live happily ever after?

  5. If remyelination is not a problem, Can't stem cell scientists try to grow new axons to replace dead/damaged axons?

  6. Remyelination is a problem, but it is only part of the problem and only part of the solutionStem cell scientists are trying and can grow nerves, but we need to ask the question why the nervous system has evolved a system of non replacement. Do you need to ensure that you get the right connections?

    1. I thought the non-replacement idea was overturned several years ago? "For over a century, scientists had agreed that in adult mammals, if nerve cells in the brain were damaged or died, unlike other cells in the body, they were not replaced. In other words, it was taken as an article of faith that new neurons never developed in the adult human brain. Each of us was born with as many neurons in our brains as we would ever have, and for the rest of our lives, the number of these neurons decreased continuously, though they could continue making new connections with one another until the day we died. But for the past decade or so, this formerly unquestioned assumption has been gradually undermined, and recent studies indicate that certain parts of the brains of primates, including humans, may maintain their ability to produce new neurons throughout adult life."

    2. The situation still holds apart from a few small areas of the brain such as the hippocampus, nerve cells are not replaced and probably for very good reasons.

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