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Does myelin fully regenerate after a demyelization disease as ADEM (Acute Disseminated Encephalomyelitis)? Does myelin always get damaged after an ADEM?

  • Are you asking about ADEM in children or in adults? Recently a study suggested that outcomes differ between children and adults (Mult Scler. 2011 Apr;17(4):441-8. doi: 10.1177/1352458510390068. Epub 2010 Dec 8.). Knowing this might help providing a more accurate answer to your question. BR. M. Arrowsmith – M. Arrowsmith Aug 2 '16 at 10:58
  • @M.Arrowsmith Children, 7 years old. – vicaba Aug 2 '16 at 11:10
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Acute disseminated encephalomyelitis (ADEM) is an inflammatory disorder, which often follows an infection or a vaccination. It is the most frequent demyelinating disorder of the CNS in children.

In case of an infectious aetiology, some epidemiological studies suggest that ADEM is more frequently associated with upper respiratory tract infections in countries with significant advances in infectious disease control, whereas in poor or developed countries, ADEM often occurs after childhood infections such as measles. Below a table with a list of the possible aetiologies for ADEM (from Garg et al).

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Current evidence suggest that ADEM results from a transient autoimmune reaction against myelin or other autoantigens which occur through a phenomenon of molecular mimicry or activation of autoreactive T cells.

Your question

Does myelin fully regenerate after a demyelization disease such as ADEM (Acute Disseminated Encephalomyelitis)? Does myelin always get damaged after an ADEM?

I have found two studies focusing on clinical outcome in children with ADEM:

1. According to this study 1 conducted among 39 patients with median age at onset of 8 years:

Of 39 children with 12 months' follow-up, 71 % recovered completely. Thirteen (33 %) children had relapses. Patients who had more than one relapse (n = 4) presented with new symptoms at each attack. Treatment with high-dose methylprednisolone was associated with complete recovery, and tapering over more than 3 weeks, with a lower rate of relapses. MRI lesions could persist even in asymptomatic patients; in particular, periventricular lesions tended to disappear later than others.

2. According to this study 2 including 14 children with a follow up of one and a half year:

10(71%) children had total remission of symptoms within one week of starting steroids. 4(29%) children had residual symptoms at the end of steroid therapy. The children were followed up for a variable period from two months to three and a half years. Most of the cases made uneventful recovery.

You can find additional information in the complete report for each of the study.

Sources:

  • Garg RK et al. Acute disseminated encephalomyelitis. Postgrad Med J 2003;79:11-17 doi:10.1136/pmj.79.927.11
  • Jayakrishnan MP, Krishnakumar P. Clinical profile of acute disseminated encephalomyelitis in children. Journal of Pediatric Neurosciences. 2010;5(2):111-114.
  • Anlar B et al. Acute disseminated encephalomyelitis in children: outcome and prognosis. Neuropediatrics. 2003 Aug;34(4):194-9.

Edit (after additional information was submitted by the OP)

Probably yes, or at least that full remyelination has not completely finished. Concerning your question about the potential of remyelination: There isn't much information available on ADEM and remyelination, but at it shares some common features in terms of pathogenesis with multiple sclerosis (MS), let's take some evidence concerning remyelination in MS:

We know that the treatment of MS aims at two things (1,2):

  • Prevent further damages by modulating the inflammatory processes. This is normally achieved with immunomodulatory therapies.
  • Repair the demyelination which resulted from the pathological inflammatory process by stimulation remyelination, ie the regeneration of new myelin sheats.

While the first has showed some interesting results thanks to growing number of immunomodulatory therapies on the market (among which glucocorticoids, which are also used in ADEM treatment), the second has still to be proven.

Although some immunomodulatory therapies might indirectly stimulate remyelination, current therapies directly targeting regeneration of myelin sheats have yet to be proven. Furthermore, the presence of axon degeneration despite immunomodulatory therapies, suggest that axon integrity and protection may occur through mechanisms independent of inflammation (3,4).

Huang et al provide a good summary of current approach for remyelination (5):

The principal source of new remyelinating cells is an abundant and widely distributed population of cells in the adult CNS traditionally called oligodendrocyte precursor cells (OPCs). In the adult CNS, these cells are both self-renewing and multipotent, having been observed to give rise to certain neurons, astrocytes (albeit rarely), and Schwann cells, as well as oligodendrocytes in vivo, and so can reasonably be regarded as a type of adult neural stem cell. The response to demyelination causes OPCs to become activated, a morphological change accompanied by upregulation of genes not normally expressed in the resting state. Activated OPCs proliferate, migrate and rapidly fill up the demyelinated lesions at a density that far exceeds that in normal tissue. To complete the remyelination process, the cells exit the cell cycle and differentiate into myelin sheath-forming oligodendrocytes, which is a complex process involving axon engagement, ensheathment and formation of compacted myelin.

The article by Huang et al also provides a good review (it is open access) on the current pharmacological targets for remyelination as well as the barriers of remyelination (among which age, probably explaining while cases of ADEM in the adults show a worse outcome that cases in children).

Hope this brings some clarification!

Sources:

  1. Martino G, Franklin RJM, Baron van Evercooren A, Kerr D, Group SC.
    Stem cell transplantation in multiple sclerosis: current status and future prospects. Nat Rev Neurol. 2010;6:247–255.doi:10.1038/nrneurol.2010.35.
  2. Franklin RJM, ffrench-Constant C. Stem cell treatments and multiple sclerosis. BMJ. 2010;340:986–985. doi: 10.1136/bmj.c1387
  3. Coles AJ, Wing MG, Molyneux P, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol. 1999;46:296–304. doi: 10.1002/1531-8249(199909)46:3<296::AID-ANA4>3.0.CO;2-#.
  4. Dutta R, Trapp BD. Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology.2007;68(22 suppl 3):S22–S31. doi: 10.1212/01.wnl.0000275229.13012.32.
  5. Huang JK, Fancy SPJ, Zhao C, Rowitch DH, ffrench-Constant C, Franklin RJM. Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells. Neurotherapeutics. 2011;8(4):650-658. doi:10.1007/s13311-011-0065-x.
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    So, the answer is most of the times yes. But I'm sorry I did not clarify the question. I'm actually the patient (I don't have 7 years old anymore) but I still have motor symptoms, also the MRI showed damaged areas after two years of the monophasic attack. Is that an indicator that my myelin is still not fully recovered? – vicaba Aug 3 '16 at 9:42
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    Hi vicaba. Sorry for my late reply. I had a quick talk with a colleague of mine who is neurologist about the remyelination potential in ADEM. Hope this brings some clarifications. Good luck. Best regards. M. Arrowsmith – M. Arrowsmith Aug 11 '16 at 12:45
  • Thank you for your interest. The resources you provide have a lot of relevant information to me. I've found several studies targeting remyelination but they have to be tested in humans. Just for the record I'll write them down. * An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination * Anti-muscarinic adjunct therapy accelerates functional human oligodendrocyte repair * Vitamin D receptor–retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation – vicaba Aug 16 '16 at 15:04
  • Interesting. Thank you. Considering that demyelinating diseases are associated with a significant burden, those remyelinating therapies are really promising. However, as you noted, evidence from trials conducted in humans are still missing but let's hope that this will come soon! Good luck. Best regards. M. Arrowsmith – M. Arrowsmith Aug 17 '16 at 8:30

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