Multiple sclerosis pathophysiology: Difference between revisions

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__NOTOC__
__NOTOC__
{{Template:Multiple sclerosis}}
{{Template:Multiple sclerosis}}
{{CMG}}
{{CMG}}; {{AE}} {{Fs}},


==Overview==
==Overview==
Multiple sclerosis is a [[disease]] of the [[central nervous system]] and it’s known to be multi factorial. Whatever the [[trigger]] is, it will lead to an acquired [[immune response]] followed by [[Inflammation|inflammatory]] reactions. These reactions lead to secretion of [[cytokines]] in the [[CNS]] [[parenchyma]] and activation of resident [[microglia]]. [[Microglia]] cells activate [[astrocytes]] to release more [[Inflammation|inflammatory]] [[cytokines]], leading to recruitment and [[Infiltration (medical)|infiltration]] of circulatory [[leukocytes]]. This burst events cause destruction of [[myelin sheath]] and forms focal sclerotic [[white matter]] plaques, which are characteristic of multiple sclerotic disease. There is some evidence proving [[genetic]] involvement in onset of [[MS]] so that it increases the risk of developing [[MS]] from 0.1% in general population to 3% in those who have siblings with [[MS]] and 25% in those with a monozygote [[twin]] affected. Based on studies performed on [[post mortem]] [[brain tissue]] of patients with multiple sclerosis, there are four types of [[white matter]] [[lesion]] [[pathology]]. Damage to [[myelin sheath]] is prominent in type 1 and 2 while type 3 and 4 characteristic is dying [[Oligodendrocyte|oligodendrocytes]]. the [[etiology]] of [[Oligodendrocyte|oligodendrocytes]] death known to be multifactorial or followed by [[hypoxia]], [[mitochondrial]] dysfunction and [[Macrophage|macrophages]].


== Pathophysiology ==
== Pathophysiology ==
Multiple sclerosis is a [[disease]] of [[central nervous system]] and it’s known to be multifactorial. There are both [[inflammation]] and [[degeneration]] in the course of the [[disease]] but as it progress, [[degeneration]] becomes more prominent.<ref name="pmid23762311">{{cite journal |vauthors=Fiorini A, Koudriavtseva T, Bucaj E, Coccia R, Foppoli C, Giorgi A, Schininà ME, Di Domenico F, De Marco F, Perluigi M |title=Involvement of oxidative stress in occurrence of relapses in multiple sclerosis: the spectrum of oxidatively modified serum proteins detected by proteomics and redox proteomics analysis |journal=PLoS ONE |volume=8 |issue=6 |pages=e65184 |year=2013 |pmid=23762311 |pmc=3676399 |doi=10.1371/journal.pone.0065184 |url=}}</ref> There are variety of different [[cell]]<nowiki/>s participating in [[MS]] [[pathophysiology]]. Whatever the trigger is, it will lead to acquired [[immune response]] followed by [[Inflammation|inflammatory]] reactions. This reactions lead to secretion of [[cytokines]] in [[CNS]] [[parenchyma]] and activation of resident [[microglia]]. [[Microglia]] cells activate [[astrocytes]] to release more [[Inflammation|inflammatory]] [[cytokines]] leading to recruitment and [[Infiltration (medical)|infiltration]] of circulatory [[leukocytes]].<ref name="pmid15472994">{{cite journal |vauthors=John GR, Lee SC, Song X, Rivieccio M, Brosnan CF |title=IL-1-regulated responses in astrocytes: relevance to injury and recovery |journal=Glia |volume=49 |issue=2 |pages=161–76 |year=2005 |pmid=15472994 |doi=10.1002/glia.20109 |url=}}</ref><ref name="pmid15939794">{{cite journal |vauthors=Kawakami N, Nägerl UV, Odoardi F, Bonhoeffer T, Wekerle H, Flügel A |title=Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion |journal=J. Exp. Med. |volume=201 |issue=11 |pages=1805–14 |year=2005 |pmid=15939794 |pmc=2213265 |doi=10.1084/jem.20050011 |url=}}</ref><ref name="pmid25891508">{{cite journal |vauthors=Sofroniew MV |title=Astrocyte barriers to neurotoxic inflammation |journal=Nat. Rev. Neurosci. |volume=16 |issue=5 |pages=249–63 |year=2015 |pmid=25891508 |pmc=5253239 |doi=10.1038/nrn3898 |url=}}</ref> This burst events cause destruction of [[myelin sheath]] and [[CNS]] tissue and releasing more auto antigens including [[myelin oligodendrocyte glycoprotein]] (MOG), [[myelin basic protein]] (MBP), [[proteolipid protein]] (PLP).<ref name="pmid22933080">{{cite journal |vauthors=McCarthy DP, Richards MH, Miller SD |title=Mouse models of multiple sclerosis: experimental autoimmune encephalomyelitis and Theiler's virus-induced demyelinating disease |journal=Methods Mol. Biol. |volume=900 |issue= |pages=381–401 |year=2012 |pmid=22933080 |pmc=3583382 |doi=10.1007/978-1-60761-720-4_19 |url=}}</ref>


Focal sclerotic white matter plaques which are characteristic of multiple sclerotic disease, are mostly located in the [[optic nerve]], periventricular white matter, juxtacortical border, [[cerebellum]], [[brain stem]] and [[cervical spine]].<ref name="pmid25802011">{{cite journal |vauthors=Mallucci G, Peruzzotti-Jametti L, Bernstock JD, Pluchino S |title=The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis |journal=Prog. Neurobiol. |volume=127-128 |issue= |pages=1–22 |year=2015 |pmid=25802011 |pmc=4578232 |doi=10.1016/j.pneurobio.2015.02.003 |url=}}</ref> This pattern of [[lesion]] formation is specific for [[MS]].<ref name="pmid25887774">{{cite journal |vauthors=Katz Sand I |title=Classification, diagnosis, and differential diagnosis of multiple sclerosis |journal=Curr. Opin. Neurol. |volume=28 |issue=3 |pages=193–205 |year=2015 |pmid=25887774 |doi=10.1097/WCO.0000000000000206 |url=}}</ref> Appearing of new [[white matter]] lesions is a way to estimate the efficacy of our therapy since it is an indicator of continued [[inflammation]].<ref name="pmid25665031" /> In the [[acute]] phase of the [[disease]] there is several evidence of [[blood brain barrier]] disruption.<ref name="pmid11424635">{{cite journal |vauthors=Silver NC, Tofts PS, Symms MR, Barker GJ, Thompson AJ, Miller DH |title=Quantitative contrast-enhanced magnetic resonance imaging to evaluate blood-brain barrier integrity in multiple sclerosis: a preliminary study |journal=Mult. Scler. |volume=7 |issue=2 |pages=75–82 |year=2001 |pmid=11424635 |doi=10.1177/135245850100700201 |url=}}</ref> Formation of [[white matter]] [[lesions]] is started by [[CD8+ T cells]] and then, [[CD4+ T cells]], [[B cells]], [[plasma cells]] and [[macrophages]] but the most common cells in [[lesions]] are [[macrophages]] and [[Microglial cell|microglial]] cells.<ref name="pmid22747960">{{cite journal |vauthors=van Horssen J, Singh S, van der Pol S, Kipp M, Lim JL, Peferoen L, Gerritsen W, Kooi EJ, Witte ME, Geurts JJ, de Vries HE, Peferoen-Baert R, van den Elsen PJ, van der Valk P, Amor S |title=Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation |journal=J Neuroinflammation |volume=9 |issue= |pages=156 |year=2012 |pmid=22747960 |pmc=3411485 |doi=10.1186/1742-2094-9-156 |url=}}</ref><ref name="pmid17531838">{{cite journal |vauthors=Johnson AJ, Suidan GL, McDole J, Pirko I |title=The CD8 T cell in multiple sclerosis: suppressor cell or mediator of neuropathology? |journal=Int. Rev. Neurobiol. |volume=79 |issue= |pages=73–97 |year=2007 |pmid=17531838 |doi=10.1016/S0074-7742(07)79004-9 |url=}}</ref><ref name="pmid18272891">{{cite journal |vauthors=Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH |title=B-cell depletion with rituximab in relapsing-remitting multiple sclerosis |journal=N. Engl. J. Med. |volume=358 |issue=7 |pages=676–88 |year=2008 |pmid=18272891 |doi=10.1056/NEJMoa0706383 |url=}}</ref>
=== Physiology ===
* [[Soma]] is the [[Neuron|neuronal]] [[cell body]] which is a closed area with [[cell membrane]].<ref name=":0">{{cite book | last = Mattle | first = Heinrich | title = Fundamentals of neurology : an illustrated guide | publisher = Thieme | location = Stuttgart New York | year = 2017 | isbn = 9783131364524 }}</ref>


Based on studies performed on [[post mortem]] brain tissue of patients with multiple sclerosis, there are four types of [[white matter]] [[Lesions|lesion]] [[pathology]]:<ref name="pmid24507512">{{cite journal |vauthors=Kutzelnigg A, Lassmann H |title=Pathology of multiple sclerosis and related inflammatory demyelinating diseases |journal=Handb Clin Neurol |volume=122 |issue= |pages=15–58 |year=2014 |pmid=24507512 |doi=10.1016/B978-0-444-52001-2.00002-9 |url=}}</ref><ref name="pmid25802011">{{cite journal |vauthors=Mallucci G, Peruzzotti-Jametti L, Bernstock JD, Pluchino S |title=The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis |journal=Prog. Neurobiol. |volume=127-128 |issue= |pages=1–22 |year=2015 |pmid=25802011 |pmc=4578232 |doi=10.1016/j.pneurobio.2015.02.003 |url=}}</ref>
* [[Dendrite|Dendrites]] are branched processes which lead the impulse into the [[neuronal]] [[cell body]].


==== Pattern 1: ====
* [[Axon|Axons]] in a single process which lead the impulse away from the [[neuronal]] [[cell body]].
Found in 10% of [[patients]] especially those with less than 1 year of [[disease]] history. In this type, the [[lesions]] have sharp borders and perivascular [[T cell]] infiltration. [[Demyelination]] process is still active and [[Microglial cell|microglia]] cells and [[macrophages]] are full of [[myelin]].


==== Pattern 2: ====
* [[Myelin sheath]] is the [[oligodendrocyte]] membrane which wraps around the [[Axon|axons]].
Found in 55% of [[patients]]. [[IgG]] and [[complement]] (C9neo) deposition with sever [[macrophage]] and [[T cell]] infiltration.  
* [[Myelin sheath]] is insulated against electrical impulses and is separated by [[nodes of Ranvier]] which can transfer the electrical impulse.


==== Pattern 3: ====
* This structure leads to fast traveling of electrical impulses.  
Found in 30% of [[patients]]. The borders of [[Lesions|lesion]] in this type are not sharply defined. There are evidences of [[vessel]] [[inflammation]] and dying [[oligodendrocyte]]<nowiki/>s.


==== Pattern 4: ====
=== Pathogenesis ===
Found in 5% of [[patients]] with PPMS. Degeneration of [[oligodendrocyte]]<nowiki/>s and infiltration of [[T cells]] and [[macrophages]] are seen in this type of [[lesions]].<ref name="pmid21626034">{{cite journal |vauthors=Reynolds R, Roncaroli F, Nicholas R, Radotra B, Gveric D, Howell O |title=The neuropathological basis of clinical progression in multiple sclerosis |journal=Acta Neuropathol. |volume=122 |issue=2 |pages=155–70 |year=2011 |pmid=21626034 |doi=10.1007/s00401-011-0840-0 |url=}}</ref>
* Multiple sclerosis is a [[disease]] of the [[central nervous system]] and it’s known to be multi factorial.<ref name="pmid23762311">{{cite journal |vauthors=Fiorini A, Koudriavtseva T, Bucaj E, Coccia R, Foppoli C, Giorgi A, Schininà ME, Di Domenico F, De Marco F, Perluigi M |title=Involvement of oxidative stress in occurrence of relapses in multiple sclerosis: the spectrum of oxidatively modified serum proteins detected by proteomics and redox proteomics analysis |journal=PLoS ONE |volume=8 |issue=6 |pages=e65184 |year=2013 |pmid=23762311 |pmc=3676399 |doi=10.1371/journal.pone.0065184 |url=}}</ref> 
* There are both [[inflammation]] and [[degeneration]] in the course of the [[disease]], but as it progress, [[degeneration]] becomes more prominent.
* There are variety of different [[cell]]<nowiki/>s participating in [[MS]] [[pathophysiology]]. Whatever the [[trigger]] is, it will lead to an acquired [[immune response]] followed by [[Inflammation|inflammatory]] reactions.
* These reactions lead to secretion o<nowiki/>f [[cytokines]] in [[CNS]] [[parenchyma]] and activation of resident [[microglia]]. [[Microglia]] cells activate [[astrocytes]] to release more [[Inflammation|inflammatory]] [[cytokines]] leading to recruitment and [[Infiltration (medical)|infiltration]] of circulatory [[leukocytes]].<ref name="pmid15472994">{{cite journal |vauthors=John GR, Lee SC, Song X, Rivieccio M, Brosnan CF |title=IL-1-regulated responses in astrocytes: relevance to injury and recovery |journal=Glia |volume=49 |issue=2 |pages=161–76 |year=2005 |pmid=15472994 |doi=10.1002/glia.20109 |url=}}</ref><ref name="pmid15939794">{{cite journal |vauthors=Kawakami N, Nägerl UV, Odoardi F, Bonhoeffer T, Wekerle H, Flügel A |title=Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion |journal=J. Exp. Med. |volume=201 |issue=11 |pages=1805–14 |year=2005 |pmid=15939794 |pmc=2213265 |doi=10.1084/jem.20050011 |url=}}</ref><ref name="pmid25891508">{{cite journal |vauthors=Sofroniew MV |title=Astrocyte barriers to neurotoxic inflammation |journal=Nat. Rev. Neurosci. |volume=16 |issue=5 |pages=249–63 |year=2015 |pmid=25891508 |pmc=5253239 |doi=10.1038/nrn3898 |url=}}</ref>
* This burst events cause destruction<nowiki/> of [[myelin sheath]] and [[CNS]] tissue and releasing more auto antigens including [[myelin oligodendrocyte glycoprotein]] (MOG), [[myelin basic protein]] (MBP), [[proteolipid protein]] (PLP).<ref name="pmid22933080">{{cite journal |vauthors=McCarthy DP, Richards MH, Miller SD |title=Mouse models of multiple sclerosis: experimental autoimmune encephalomyelitis and Theiler's virus-induced demyelinating disease |journal=Methods Mol. Biol. |volume=900 |issue= |pages=381–401 |year=2012 |pmid=22933080 |pmc=3583382 |doi=10.1007/978-1-60761-720-4_19 |url=}}</ref><ref name="pmid18219821">{{cite journal |vauthors=Pirko I, Johnson AJ |title=Neuroimaging of demyelination and remyelination models |journal=Curr. Top. Microbiol. Immunol. |volume=318 |issue= |pages=241–66 |year=2008 |pmid=18219821 |doi= |url=}}</ref>
* Focal sclerotic [[white matter]] plaque<nowiki/>s, which are characteristic of multiple sclerotic disease, are mostly located in the [[optic nerve]], periventricular [[white matter]], juxtacortical border, [[cerebellum]], [[brain stem]], and [[cervical spine]].<ref name="pmid25802011">{{cite journal |vauthors=Mallucci G, Peruzzotti-Jametti L, Bernstock JD, Pluchino S |title=The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis |journal=Prog. Neurobiol. |volume=127-128 |issue= |pages=1–22 |year=2015 |pmid=25802011 |pmc=4578232 |doi=10.1016/j.pneurobio.2015.02.003 |url=}}</ref> This pattern of [[lesion]] formation is specific for [[MS]].<ref name="pmid25887774">{{cite journal |vauthors=Katz Sand I |title=Classification, diagnosis, and differential diagnosis of multiple sclerosis |journal=Curr. Opin. Neurol. |volume=28 |issue=3 |pages=193–205 |year=2015 |pmid=25887774 |doi=10.1097/WCO.0000000000000206 |url=}}</ref>
* Appearing of new [[white matter]] lesio<nowiki/>ns is a way to estimate the efficacy of our therapy since it is an indicator of continued [[inflammation]].<ref name="pmid25665031" />
* In the [[acute]] phase of the [[disease]] t<nowiki/>here is several evidence of [[blood brain barrier]] disruption.<ref name="pmid11424635">{{cite journal |vauthors=Silver NC, Tofts PS, Symms MR, Barker GJ, Thompson AJ, Miller DH |title=Quantitative contrast-enhanced magnetic resonance imaging to evaluate blood-brain barrier integrity in multiple sclerosis: a preliminary study |journal=Mult. Scler. |volume=7 |issue=2 |pages=75–82 |year=2001 |pmid=11424635 |doi=10.1177/135245850100700201 |url=}}</ref>
* Formation of [[white matter]] [[lesions]] i<nowiki/>s started by [[CD8+ T cells]] and then, [[CD4+ T cells]], [[B cells]], [[plasma cells]] and [[macrophages]] but the most common cells in [[lesions]] are [[macrophages]] and [[Microglial cell|microglial]] cells.<ref name="pmid22747960">{{cite journal |vauthors=van Horssen J, Singh S, van der Pol S, Kipp M, Lim JL, Peferoen L, Gerritsen W, Kooi EJ, Witte ME, Geurts JJ, de Vries HE, Peferoen-Baert R, van den Elsen PJ, van der Valk P, Amor S |title=Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation |journal=J Neuroinflammation |volume=9 |issue= |pages=156 |year=2012 |pmid=22747960 |pmc=3411485 |doi=10.1186/1742-2094-9-156 |url=}}</ref><ref name="pmid17531838">{{cite journal |vauthors=Johnson AJ, Suidan GL, McDole J, Pirko I |title=The CD8 T cell in multiple sclerosis: suppressor cell or mediator of neuropathology? |journal=Int. Rev. Neurobiol. |volume=79 |issue= |pages=73–97 |year=2007 |pmid=17531838 |doi=10.1016/S0074-7742(07)79004-9 |url=}}</ref><ref name="pmid18272891">{{cite journal |vauthors=Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH |title=B-cell depletion with rituximab in relapsing-remitting multiple sclerosis |journal=N. Engl. J. Med. |volume=358 |issue=7 |pages=676–88 |year=2008 |pmid=18272891 |doi=10.1056/NEJMoa0706383 |url=}}</ref>
*There is some evidence of cortical ([[gray matter]]) [[demyelination]] in [[MS]] [[patients]].<ref name="pmid16230320">{{cite journal |vauthors=Kutzelnigg A, Lucchinetti CF, Stadelmann C, Brück W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H |title=Cortical demyelination and diffuse white matter injury in multiple sclerosis |journal=Brain |volume=128 |issue=Pt 11 |pages=2705–12 |year=2005 |pmid=16230320 |doi=10.1093/brain/awh641 |url=}}</ref><ref name="pmid12682324">{{cite journal |vauthors=De Stefano N, Matthews PM, Filippi M, Agosta F, De Luca M, Bartolozzi ML, Guidi L, Ghezzi A, Montanari E, Cifelli A, Federico A, Smith SM |title=Evidence of early cortical atrophy in MS: relevance to white matter changes and disability |journal=Neurology |volume=60 |issue=7 |pages=1157–62 |year=2003 |pmid=12682324 |doi= |url=}}</ref> It correlates with [[cognitive]] deficits and [[seizures]] in [[patients]].<ref name="pmid12527995">{{cite journal |vauthors=Dehmeshki J, Chard DT, Leary SM, Watt HC, Silver NC, Tofts PS, Thompson AJ, Miller DH |title=The normal appearing grey matter in primary progressive multiple sclerosis: a magnetisation transfer imaging study |journal=J. Neurol. |volume=250 |issue=1 |pages=67–74 |year=2003 |pmid=12527995 |doi=10.1007/s00415-003-0955-x |url=}}</ref><ref name="pmid23289848">{{cite journal |vauthors=Martínez-Lapiscina EH, Ayuso T, Lacruz F, Gurtubay IG, Soriano G, Otano M, Bujanda M, Bacaicoa MC |title=Cortico-juxtacortical involvement increases risk of epileptic seizures in multiple sclerosis |journal=Acta Neurol. Scand. |volume=128 |issue=1 |pages=24–31 |year=2013 |pmid=23289848 |doi=10.1111/ane.12064 |url=}}</ref> It is not clear yet that whether the pathphysiology of cortical [[demyelination]] is similar to [[white matter]] [[demyelination]] and is a consequence of it or it is a completely different phenomenon.
*Cortical [[demyelination]] tends to be global in contrast with focal [[white matter]] [[lesions]].<ref name="pmid24899728">{{cite journal |vauthors=Haider L, Simeonidou C, Steinberger G, Hametner S, Grigoriadis N, Deretzi G, Kovacs GG, Kutzelnigg A, Lassmann H, Frischer JM |title=Multiple sclerosis deep grey matter: the relation between demyelination, neurodegeneration, inflammation and iron |journal=J. Neurol. Neurosurg. Psychiatry |volume=85 |issue=12 |pages=1386–95 |year=2014 |pmid=24899728 |pmc=4251183 |doi=10.1136/jnnp-2014-307712 |url=}}</ref>
*In [[post mortem]] [[brain tissue]] of patients with [[MS]], [[gray matter]] [[lesions]] show [[blood brain barrier]] dysfunction, [[macrophages]] filled with [[myelin]], [[T cells]], [[B cells]] and [[Meninges|meningeal]] [[inflammation]]. These findings are suggestive of [[inflammation]] as an underlying cause of these [[lesions]].<ref name="pmid22150037">{{cite journal |vauthors=Lucchinetti CF, Popescu BF, Bunyan RF, Moll NM, Roemer SF, Lassmann H, Brück W, Parisi JE, Scheithauer BW, Giannini C, Weigand SD, Mandrekar J, Ransohoff RM |title=Inflammatory cortical demyelination in early multiple sclerosis |journal=N. Engl. J. Med. |volume=365 |issue=23 |pages=2188–97 |year=2011 |pmid=22150037 |pmc=3282172 |doi=10.1056/NEJMoa1100648 |url=}}</ref>
*Cortical [[demyelination]] is more prominent in PPMS and SPMS but it can also be seen in RRMS.<ref name="pmid16230320" />


Damage to [[myelin sheath]] is prominent in type 1 and 2 while type 3 and 4 characteristic is dying [[Oligodendrocyte|oligodendrocytes]].<ref name="pmid25802011">{{cite journal |vauthors=Mallucci G, Peruzzotti-Jametti L, Bernstock JD, Pluchino S |title=The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis |journal=Prog. Neurobiol. |volume=127-128 |issue= |pages=1–22 |year=2015 |pmid=25802011 |pmc=4578232 |doi=10.1016/j.pneurobio.2015.02.003 |url=}}</ref><ref name="pmid10852536">{{cite journal |vauthors=Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H |title=Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination |journal=Ann. Neurol. |volume=47 |issue=6 |pages=707–17 |year=2000 |pmid=10852536 |doi= |url=}}</ref> the [[etiology]] of [[oligodendrocyte]]<nowiki/>s death known to be multifactorial or followed by [[hypoxia]], [[mitochondrial]] dysfunction and [[macrophages]].<ref name="pmid11286782">{{cite journal |vauthors=Lassmann H, Brück W, Lucchinetti C |title=Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy |journal=Trends Mol Med |volume=7 |issue=3 |pages=115–21 |year=2001 |pmid=11286782 |doi= |url=}}</ref><ref name="pmid20665559">{{cite journal |vauthors=Ziabreva I, Campbell G, Rist J, Zambonin J, Rorbach J, Wydro MM, Lassmann H, Franklin RJ, Mahad D |title=Injury and differentiation following inhibition of mitochondrial respiratory chain complex IV in rat oligodendrocytes |journal=Glia |volume=58 |issue=15 |pages=1827–37 |year=2010 |pmid=20665559 |pmc=3580049 |doi=10.1002/glia.21052 |url=}}</ref>
* There are some [[lesions]] called "shadow plaques". [[Remyelination]] occurs in these [[lesions]] and they have a large number of [[Oligodendrocyte precursor cell|oligodendrocyte precursor cells]] (OPC) and mature [[Oligodendrocyte|oligodendrocytes]].<ref name="pmid20855416">{{cite journal |vauthors=Bramow S, Frischer JM, Lassmann H, Koch-Henriksen N, Lucchinetti CF, Sørensen PS, Laursen H |title=Demyelination versus remyelination in progressive multiple sclerosis |journal=Brain |volume=133 |issue=10 |pages=2983–98 |year=2010 |pmid=20855416 |doi=10.1093/brain/awq250 |url=}}</ref><ref name="pmid18515322">{{cite journal |vauthors=Kuhlmann T, Miron V, Cui Q, Cuo Q, Wegner C, Antel J, Brück W |title=Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis |journal=Brain |volume=131 |issue=Pt 7 |pages=1749–58 |year=2008 |pmid=18515322 |doi=10.1093/brain/awn096 |url=}}</ref>
* It may be because of more permissive environment that this event occurs mostly in cortical [[lesions]] rather than [[white matter]] lesions.<ref name="pmid20855416" />
* [[Remyelination]] occurs equally among patients with RRMS, SPMS and PPMS.<ref name="pmid16921173">{{cite journal |vauthors=Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Brück W, Lucchinetti C, Lassmann H |title=Remyelination is extensive in a subset of multiple sclerosis patients |journal=Brain |volume=129 |issue=Pt 12 |pages=3165–72 |year=2006 |pmid=16921173 |doi=10.1093/brain/awl217 |url=}}</ref>  
* The loss of mature [[oligodendrocyte|oli]]<nowiki/>[[oligodendrocyte|godendrocyte]]<nowiki/>s in [[chronic]] [[MS]] is a [[Sign (medical)|sign]] of [[failure]] in the course of [[maturation]].
* Several [[inhibitory]] mediators have been found to have a role in this and [[Prevention|prevent]] the [[axonal]] attachment and expre<nowiki/>ssing myelin-specific genes.<ref name="pmid23831296">{{cite journal |vauthors=Bin JM, Rajasekharan S, Kuhlmann T, Hanes I, Marcal N, Han D, Rodrigues SP, Leong SY, Newcombe J, Antel JP, Kennedy TE |title=Full-length and fragmented netrin-1 in multiple sclerosis plaques are inhibitors of oligodendrocyte precursor cell migration |journal=Am. J. Pathol. |volume=183 |issue=3 |pages=673–80 |year=2013 |pmid=23831296 |doi=10.1016/j.ajpath.2013.06.004 |url=}}</ref><ref name="pmid24446279">{{cite journal |vauthors=Franklin RJ, Gallo V |title=The translational biology of remyelination: past, present, and future |journal=Glia |volume=62 |issue=11 |pages=1905–15 |year=2014 |pmid=24446279 |doi=10.1002/glia.22622 |url=}}</ref>  
* There are no imaging techniques which can differentiate remyelinated plaques from early [[demyelinating]] <nowiki/>[[lesions]]. It seems that remyelinated plaques are more susceptible to [[demyelination|demyelin]]<nowiki/>[[demyelination|ation]] attacks.


There is some evidence of cortical ([[gray matter]]) demyelination in [[MS]] [[patients]].<ref name="pmid16230320">{{cite journal |vauthors=Kutzelnigg A, Lucchinetti CF, Stadelmann C, Brück W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H |title=Cortical demyelination and diffuse white matter injury in multiple sclerosis |journal=Brain |volume=128 |issue=Pt 11 |pages=2705–12 |year=2005 |pmid=16230320 |doi=10.1093/brain/awh641 |url=}}</ref><ref name="pmid12682324">{{cite journal |vauthors=De Stefano N, Matthews PM, Filippi M, Agosta F, De Luca M, Bartolozzi ML, Guidi L, Ghezzi A, Montanari E, Cifelli A, Federico A, Smith SM |title=Evidence of early cortical atrophy in MS: relevance to white matter changes and disability |journal=Neurology |volume=60 |issue=7 |pages=1157–62 |year=2003 |pmid=12682324 |doi= |url=}}</ref> It correlates with [[cognitive]] deficits and [[seizures]] in [[patients]].<ref name="pmid12527995">{{cite journal |vauthors=Dehmeshki J, Chard DT, Leary SM, Watt HC, Silver NC, Tofts PS, Thompson AJ, Miller DH |title=The normal appearing grey matter in primary progressive multiple sclerosis: a magnetisation transfer imaging study |journal=J. Neurol. |volume=250 |issue=1 |pages=67–74 |year=2003 |pmid=12527995 |doi=10.1007/s00415-003-0955-x |url=}}</ref><ref name="pmid23289848">{{cite journal |vauthors=Martínez-Lapiscina EH, Ayuso T, Lacruz F, Gurtubay IG, Soriano G, Otano M, Bujanda M, Bacaicoa MC |title=Cortico-juxtacortical involvement increases risk of epileptic seizures in multiple sclerosis |journal=Acta Neurol. Scand. |volume=128 |issue=1 |pages=24–31 |year=2013 |pmid=23289848 |doi=10.1111/ane.12064 |url=}}</ref> It is not clear yet that whether the pathphysiology of cortical demyelinetion is similar to [[white matter]] demyelinetion and is a consequence of it or it is a completely different phenomenon. Cortical demyelination tends to be global in contrast with focal [[white matter]] [[lesions]].<ref name="pmid24899728">{{cite journal |vauthors=Haider L, Simeonidou C, Steinberger G, Hametner S, Grigoriadis N, Deretzi G, Kovacs GG, Kutzelnigg A, Lassmann H, Frischer JM |title=Multiple sclerosis deep grey matter: the relation between demyelination, neurodegeneration, inflammation and iron |journal=J. Neurol. Neurosurg. Psychiatry |volume=85 |issue=12 |pages=1386–95 |year=2014 |pmid=24899728 |pmc=4251183 |doi=10.1136/jnnp-2014-307712 |url=}}</ref> In [[post mortem]] brain tissue of patients with [[MS]], [[gray matter]] [[lesions]] show [[blood brain barrier]] dysfunction, [[macrophages]] filled with [[myelin]], [[T cells]], [[B cells]] and [[Meninges|meningeal]] [[inflammation]]. These findings are suggestive of [[inflammation]] as an underlying cause of these [[lesions]].<ref name="pmid22150037">{{cite journal |vauthors=Lucchinetti CF, Popescu BF, Bunyan RF, Moll NM, Roemer SF, Lassmann H, Brück W, Parisi JE, Scheithauer BW, Giannini C, Weigand SD, Mandrekar J, Ransohoff RM |title=Inflammatory cortical demyelination in early multiple sclerosis |journal=N. Engl. J. Med. |volume=365 |issue=23 |pages=2188–97 |year=2011 |pmid=22150037 |pmc=3282172 |doi=10.1056/NEJMoa1100648 |url=}}</ref> Cortical demyelination is more prominent in PPMS and SPMS but it can also be seen in RRMS.<ref name="pmid16230320">{{cite journal |vauthors=Kutzelnigg A, Lucchinetti CF, Stadelmann C, Brück W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H |title=Cortical demyelination and diffuse white matter injury in multiple sclerosis |journal=Brain |volume=128 |issue=Pt 11 |pages=2705–12 |year=2005 |pmid=16230320 |doi=10.1093/brain/awh641 |url=}}</ref>
== Genetics ==
* There is some evidence proving [[genetic]] involvement in onset of [[MS]] so tha<nowiki/>t it increases the risk of developing [[MS]] from 0.1% in general population to 3% in those who have siblings with [[MS]] and 25% in those with a monozygote<nowiki/> [[twin]] affected.<ref name="pmid12127654">{{cite journal |vauthors=Dessa Sadovnick A |title=The genetics of multiple sclerosis |journal=Clin Neurol Neurosurg |volume=104 |issue=3 |pages=199–202 |date=July 2002 |pmid=12127654 |doi= |url=}}</ref>  
* [[HLA]] alleles seems to have a huge relationship with [[MS]] susceptibility.<ref name="pmid21541245">{{cite journal |vauthors=Ramagopalan SV, Dyment DA |title=What is Next for the Genetics of Multiple Sclerosis? |journal=Autoimmune Dis |volume=2011 |issue= |pages=519450 |date=March 2011 |pmid=21541245 |pmc=3085300 |doi=10.4061/2011/519450 |url=}}</ref>


There are some [[lesions]] called "shadow plaques". [[Remyelination]] occurs in these [[lesions]] and they have a large number of [[Oligodendrocyte precursor cell|oligodendrocyte precursor cells]] (OPC) and mature [[Oligodendrocyte|oligodendrocytes]].<ref name="pmid20855416">{{cite journal |vauthors=Bramow S, Frischer JM, Lassmann H, Koch-Henriksen N, Lucchinetti CF, Sørensen PS, Laursen H |title=Demyelination versus remyelination in progressive multiple sclerosis |journal=Brain |volume=133 |issue=10 |pages=2983–98 |year=2010 |pmid=20855416 |doi=10.1093/brain/awq250 |url=}}</ref><ref name="pmid18515322">{{cite journal |vauthors=Kuhlmann T, Miron V, Cui Q, Cuo Q, Wegner C, Antel J, Brück W |title=Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis |journal=Brain |volume=131 |issue=Pt 7 |pages=1749–58 |year=2008 |pmid=18515322 |doi=10.1093/brain/awn096 |url=}}</ref> It may be because of more permissive environment that this event occurs mostly in cortical lesions rather than [[white matter]] lesions.<ref name="pmid20855416">{{cite journal |vauthors=Bramow S, Frischer JM, Lassmann H, Koch-Henriksen N, Lucchinetti CF, Sørensen PS, Laursen H |title=Demyelination versus remyelination in progressive multiple sclerosis |journal=Brain |volume=133 |issue=10 |pages=2983–98 |year=2010 |pmid=20855416 |doi=10.1093/brain/awq250 |url=}}</ref> [[Remyelination]] occurs equally among patients with RRMS, SPMS and PPMS.<ref name="pmid16921173">{{cite journal |vauthors=Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Brück W, Lucchinetti C, Lassmann H |title=Remyelination is extensive in a subset of multiple sclerosis patients |journal=Brain |volume=129 |issue=Pt 12 |pages=3165–72 |year=2006 |pmid=16921173 |doi=10.1093/brain/awl217 |url=}}</ref> The loss of mature olidodendrocytes in chronic MS is a sign of failure in the course of maturation. Several inhibitory mediators have been found to have a role in this and prevent the axonal attachment and expressing myelin-specific genes.<ref name="pmid23831296">{{cite journal |vauthors=Bin JM, Rajasekharan S, Kuhlmann T, Hanes I, Marcal N, Han D, Rodrigues SP, Leong SY, Newcombe J, Antel JP, Kennedy TE |title=Full-length and fragmented netrin-1 in multiple sclerosis plaques are inhibitors of oligodendrocyte precursor cell migration |journal=Am. J. Pathol. |volume=183 |issue=3 |pages=673–80 |year=2013 |pmid=23831296 |doi=10.1016/j.ajpath.2013.06.004 |url=}}</ref><ref name="pmid24446279">{{cite journal |vauthors=Franklin RJ, Gallo V |title=The translational biology of remyelination: past, present, and future |journal=Glia |volume=62 |issue=11 |pages=1905–15 |year=2014 |pmid=24446279 |doi=10.1002/glia.22622 |url=}}</ref>
== Microscopic Pathology ==


Based on studies performed on [[post mortem]] brain tissue of patients with multiple sclerosis, there are four types of [[white matter]] [[Lesions|lesion]] [[pathology]]:<ref name="pmid24507512">{{cite journal |vauthors=Kutzelnigg A, Lassmann H |title=Pathology of multiple sclerosis and related inflammatory demyelinating diseases |journal=Handb Clin Neurol |volume=122 |issue= |pages=15–58 |year=2014 |pmid=24507512 |doi=10.1016/B978-0-444-52001-2.00002-9 |url=}}</ref><ref name="pmid25802011" />
* '''Microscopic pathology type 1:''' Found in 10% of [[patients]] especially those with less than 1 year of [[disease]] history. In this type, the [[lesions]] have sharp borders and perivascular [[T cell]] infiltration. [[Demyelination]] process is still active and [[Microglial cell|microglia]] cells and [[macrophages]] are full of [[myelin]].
* '''Microscopic pathology type 2:''' Found in 55% of [[patients]]. [[IgG]] and [[complement]] (C9neo) deposition with sever [[macrophage]] and [[T cell]] infiltration.
* '''Microscopic pathology type 3:''' Found in 30% of [[patients]]. The borders of [[Lesions|lesion]] in this type are not sharply defined. There are evidences of [[vessel]] [[inflammation]] and dying [[oligodendrocyte]]<nowiki/>s.
* '''Microscopic pathology type 4:''' Found in 5% of [[patients]] with PPMS. Degeneration of [[oligodendrocyte]]<nowiki/>s and infiltration of [[T cells]] and [[macrophages]] are seen in this type of [[lesions]].<ref name="pmid21626034">{{cite journal |vauthors=Reynolds R, Roncaroli F, Nicholas R, Radotra B, Gveric D, Howell O |title=The neuropathological basis of clinical progression in multiple sclerosis |journal=Acta Neuropathol. |volume=122 |issue=2 |pages=155–70 |year=2011 |pmid=21626034 |doi=10.1007/s00401-011-0840-0 |url=}}</ref> <nowiki/><nowiki/>
'''NOTE:''' Damage to [[myelin sheath]] is prominent in type 1 and 2 while type 3 and 4 characteristic is dying [[Oligodendrocyte|oligodendrocytes]].<ref name="pmid25802011" /><ref name="pmid10852536">{{cite journal |vauthors=Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H |title=Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination |journal=Ann. Neurol. |volume=47 |issue=6 |pages=707–17 |year=2000 |pmid=10852536 |doi= |url=}}</ref> the [[etiology]] of [[oligodendrocyte]]<nowiki/>s death known to be multifactorial or followed by [[hypoxia]], [[mitochondrial]] dysfunction and [[macrophages]].<ref name="pmid11286782">{{cite journal |vauthors=Lassmann H, Brück W, Lucchinetti C |title=Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy |journal=Trends Mol Med |volume=7 |issue=3 |pages=115–21 |year=2001 |pmid=11286782 |doi= |url=}}</ref><ref name="pmid20665559">{{cite journal |vauthors=Ziabreva I, Campbell G, Rist J, Zambonin J, Rorbach J, Wydro MM, Lassmann H, Franklin RJ, Mahad D |title=Injury and differentiation following inhibition of mitochondrial respiratory chain complex IV in rat oligodendrocytes |journal=Glia |volume=58 |issue=15 |pages=1827–37 |year=2010 |pmid=20665559 |pmc=3580049 |doi=10.1002/glia.21052 |url=}}</ref>
<nowiki/><nowiki/>[[File:MS_Demyelinisation_CD68_10xv2.jpg|500px|none|thumb|Photomicrograph of a demyelinating MS-Lesion. Immunohistochemical staining for CD68 highlights numerous macrophages (brown) . Original Magnification 10x [https://librepathology.org/wiki/File:MS_Demyelinisation_CD68_10xv2.jpg Source: Librepathology]]]
[[File:MS_Demyelinisation_KB_10x.jpg|500px|none|thumb|Photomicrograph of a demyelinating MS-Lesion. Klüver-Barerra-Stain. Original Magnification 10x [https://librepathology.org/wiki/File:MS_Demyelinisation_KB_10x.jpg Source: Librepathology]]]
==References==
==References==


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.,

Overview

Multiple sclerosis is a disease of the central nervous system and it’s known to be multi factorial. Whatever the trigger is, it will lead to an acquired immune response followed by inflammatory reactions. These reactions lead to secretion of cytokines in the CNS parenchyma and activation of resident microglia. Microglia cells activate astrocytes to release more inflammatory cytokines, leading to recruitment and infiltration of circulatory leukocytes. This burst events cause destruction of myelin sheath and forms focal sclerotic white matter plaques, which are characteristic of multiple sclerotic disease. There is some evidence proving genetic involvement in onset of MS so that it increases the risk of developing MS from 0.1% in general population to 3% in those who have siblings with MS and 25% in those with a monozygote twin affected. Based on studies performed on post mortem brain tissue of patients with multiple sclerosis, there are four types of white matter lesion pathology. Damage to myelin sheath is prominent in type 1 and 2 while type 3 and 4 characteristic is dying oligodendrocytes. the etiology of oligodendrocytes death known to be multifactorial or followed by hypoxia, mitochondrial dysfunction and macrophages.

Pathophysiology

Physiology

  • This structure leads to fast traveling of electrical impulses.

Pathogenesis

Genetics

  • There is some evidence proving genetic involvement in onset of MS so that it increases the risk of developing MS from 0.1% in general population to 3% in those who have siblings with MS and 25% in those with a monozygote twin affected.[26]
  • HLA alleles seems to have a huge relationship with MS susceptibility.[27]

Microscopic Pathology

Based on studies performed on post mortem brain tissue of patients with multiple sclerosis, there are four types of white matter lesion pathology:[28][8]

NOTE: Damage to myelin sheath is prominent in type 1 and 2 while type 3 and 4 characteristic is dying oligodendrocytes.[8][30] the etiology of oligodendrocytes death known to be multifactorial or followed by hypoxia, mitochondrial dysfunction and macrophages.[31][32]

Photomicrograph of a demyelinating MS-Lesion. Immunohistochemical staining for CD68 highlights numerous macrophages (brown) . Original Magnification 10x Source: Librepathology
Photomicrograph of a demyelinating MS-Lesion. Klüver-Barerra-Stain. Original Magnification 10x Source: Librepathology

References

  1. ↑ Mattle, Heinrich (2017). Fundamentals of neurology : an illustrated guide. Stuttgart New York: Thieme. ISBN 9783131364524.
  2. ↑ Fiorini A, Koudriavtseva T, Bucaj E, Coccia R, Foppoli C, Giorgi A, Schininà ME, Di Domenico F, De Marco F, Perluigi M (2013). "Involvement of oxidative stress in occurrence of relapses in multiple sclerosis: the spectrum of oxidatively modified serum proteins detected by proteomics and redox proteomics analysis". PLoS ONE. 8 (6): e65184. doi:10.1371/journal.pone.0065184. PMC 3676399. PMID 23762311.
  3. ↑ John GR, Lee SC, Song X, Rivieccio M, Brosnan CF (2005). "IL-1-regulated responses in astrocytes: relevance to injury and recovery". Glia. 49 (2): 161–76. doi:10.1002/glia.20109. PMID 15472994.
  4. ↑ Kawakami N, Nägerl UV, Odoardi F, Bonhoeffer T, Wekerle H, Flügel A (2005). "Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion". J. Exp. Med. 201 (11): 1805–14. doi:10.1084/jem.20050011. PMC 2213265. PMID 15939794.
  5. ↑ Sofroniew MV (2015). "Astrocyte barriers to neurotoxic inflammation". Nat. Rev. Neurosci. 16 (5): 249–63. doi:10.1038/nrn3898. PMC 5253239. PMID 25891508.
  6. ↑ McCarthy DP, Richards MH, Miller SD (2012). "Mouse models of multiple sclerosis: experimental autoimmune encephalomyelitis and Theiler's virus-induced demyelinating disease". Methods Mol. Biol. 900: 381–401. doi:10.1007/978-1-60761-720-4_19. PMC 3583382. PMID 22933080.
  7. ↑ Pirko I, Johnson AJ (2008). "Neuroimaging of demyelination and remyelination models". Curr. Top. Microbiol. Immunol. 318: 241–66. PMID 18219821.
  8. ↑ 8.0 8.1 8.2 Mallucci G, Peruzzotti-Jametti L, Bernstock JD, Pluchino S (2015). "The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis". Prog. Neurobiol. 127-128: 1–22. doi:10.1016/j.pneurobio.2015.02.003. PMC 4578232. PMID 25802011.
  9. ↑ Katz Sand I (2015). "Classification, diagnosis, and differential diagnosis of multiple sclerosis". Curr. Opin. Neurol. 28 (3): 193–205. doi:10.1097/WCO.0000000000000206. PMID 25887774.
  10. ↑
  11. ↑ Silver NC, Tofts PS, Symms MR, Barker GJ, Thompson AJ, Miller DH (2001). "Quantitative contrast-enhanced magnetic resonance imaging to evaluate blood-brain barrier integrity in multiple sclerosis: a preliminary study". Mult. Scler. 7 (2): 75–82. doi:10.1177/135245850100700201. PMID 11424635.
  12. ↑ van Horssen J, Singh S, van der Pol S, Kipp M, Lim JL, Peferoen L, Gerritsen W, Kooi EJ, Witte ME, Geurts JJ, de Vries HE, Peferoen-Baert R, van den Elsen PJ, van der Valk P, Amor S (2012). "Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation". J Neuroinflammation. 9: 156. doi:10.1186/1742-2094-9-156. PMC 3411485. PMID 22747960.
  13. ↑ Johnson AJ, Suidan GL, McDole J, Pirko I (2007). "The CD8 T cell in multiple sclerosis: suppressor cell or mediator of neuropathology?". Int. Rev. Neurobiol. 79: 73–97. doi:10.1016/S0074-7742(07)79004-9. PMID 17531838.
  14. ↑ Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH (2008). "B-cell depletion with rituximab in relapsing-remitting multiple sclerosis". N. Engl. J. Med. 358 (7): 676–88. doi:10.1056/NEJMoa0706383. PMID 18272891.
  15. ↑ 15.0 15.1 Kutzelnigg A, Lucchinetti CF, Stadelmann C, Brück W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H (2005). "Cortical demyelination and diffuse white matter injury in multiple sclerosis". Brain. 128 (Pt 11): 2705–12. doi:10.1093/brain/awh641. PMID 16230320.
  16. ↑ De Stefano N, Matthews PM, Filippi M, Agosta F, De Luca M, Bartolozzi ML, Guidi L, Ghezzi A, Montanari E, Cifelli A, Federico A, Smith SM (2003). "Evidence of early cortical atrophy in MS: relevance to white matter changes and disability". Neurology. 60 (7): 1157–62. PMID 12682324.
  17. ↑ Dehmeshki J, Chard DT, Leary SM, Watt HC, Silver NC, Tofts PS, Thompson AJ, Miller DH (2003). "The normal appearing grey matter in primary progressive multiple sclerosis: a magnetisation transfer imaging study". J. Neurol. 250 (1): 67–74. doi:10.1007/s00415-003-0955-x. PMID 12527995.
  18. ↑ Martínez-Lapiscina EH, Ayuso T, Lacruz F, Gurtubay IG, Soriano G, Otano M, Bujanda M, Bacaicoa MC (2013). "Cortico-juxtacortical involvement increases risk of epileptic seizures in multiple sclerosis". Acta Neurol. Scand. 128 (1): 24–31. doi:10.1111/ane.12064. PMID 23289848.
  19. ↑ Haider L, Simeonidou C, Steinberger G, Hametner S, Grigoriadis N, Deretzi G, Kovacs GG, Kutzelnigg A, Lassmann H, Frischer JM (2014). "Multiple sclerosis deep grey matter: the relation between demyelination, neurodegeneration, inflammation and iron". J. Neurol. Neurosurg. Psychiatry. 85 (12): 1386–95. doi:10.1136/jnnp-2014-307712. PMC 4251183. PMID 24899728.
  20. ↑ Lucchinetti CF, Popescu BF, Bunyan RF, Moll NM, Roemer SF, Lassmann H, Brück W, Parisi JE, Scheithauer BW, Giannini C, Weigand SD, Mandrekar J, Ransohoff RM (2011). "Inflammatory cortical demyelination in early multiple sclerosis". N. Engl. J. Med. 365 (23): 2188–97. doi:10.1056/NEJMoa1100648. PMC 3282172. PMID 22150037.
  21. ↑ 21.0 21.1 Bramow S, Frischer JM, Lassmann H, Koch-Henriksen N, Lucchinetti CF, Sørensen PS, Laursen H (2010). "Demyelination versus remyelination in progressive multiple sclerosis". Brain. 133 (10): 2983–98. doi:10.1093/brain/awq250. PMID 20855416.
  22. ↑ Kuhlmann T, Miron V, Cui Q, Cuo Q, Wegner C, Antel J, Brück W (2008). "Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis". Brain. 131 (Pt 7): 1749–58. doi:10.1093/brain/awn096. PMID 18515322.
  23. ↑ Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Brück W, Lucchinetti C, Lassmann H (2006). "Remyelination is extensive in a subset of multiple sclerosis patients". Brain. 129 (Pt 12): 3165–72. doi:10.1093/brain/awl217. PMID 16921173.
  24. ↑ Bin JM, Rajasekharan S, Kuhlmann T, Hanes I, Marcal N, Han D, Rodrigues SP, Leong SY, Newcombe J, Antel JP, Kennedy TE (2013). "Full-length and fragmented netrin-1 in multiple sclerosis plaques are inhibitors of oligodendrocyte precursor cell migration". Am. J. Pathol. 183 (3): 673–80. doi:10.1016/j.ajpath.2013.06.004. PMID 23831296.
  25. ↑ Franklin RJ, Gallo V (2014). "The translational biology of remyelination: past, present, and future". Glia. 62 (11): 1905–15. doi:10.1002/glia.22622. PMID 24446279.
  26. ↑ Dessa Sadovnick A (July 2002). "The genetics of multiple sclerosis". Clin Neurol Neurosurg. 104 (3): 199–202. PMID 12127654.
  27. ↑ Ramagopalan SV, Dyment DA (March 2011). "What is Next for the Genetics of Multiple Sclerosis?". Autoimmune Dis. 2011: 519450. doi:10.4061/2011/519450. PMC 3085300. PMID 21541245.
  28. ↑ Kutzelnigg A, Lassmann H (2014). "Pathology of multiple sclerosis and related inflammatory demyelinating diseases". Handb Clin Neurol. 122: 15–58. doi:10.1016/B978-0-444-52001-2.00002-9. PMID 24507512.
  29. ↑ Reynolds R, Roncaroli F, Nicholas R, Radotra B, Gveric D, Howell O (2011). "The neuropathological basis of clinical progression in multiple sclerosis". Acta Neuropathol. 122 (2): 155–70. doi:10.1007/s00401-011-0840-0. PMID 21626034.
  30. ↑ Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000). "Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination". Ann. Neurol. 47 (6): 707–17. PMID 10852536.
  31. ↑ Lassmann H, Brück W, Lucchinetti C (2001). "Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy". Trends Mol Med. 7 (3): 115–21. PMID 11286782.
  32. ↑ Ziabreva I, Campbell G, Rist J, Zambonin J, Rorbach J, Wydro MM, Lassmann H, Franklin RJ, Mahad D (2010). "Injury and differentiation following inhibition of mitochondrial respiratory chain complex IV in rat oligodendrocytes". Glia. 58 (15): 1827–37. doi:10.1002/glia.21052. PMC 3580049. PMID 20665559.

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