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Acta Neuropathologica

, Volume 133, Issue 1, pp 13–24 | Cite as

An updated histological classification system for multiple sclerosis lesions

  • Tanja Kuhlmann
  • Samuel Ludwin
  • Alexandre Prat
  • Jack Antel
  • Wolfgang Brück
  • Hans Lassmann
Consensus Paper

Abstract

Multiple sclerosis is a complex and heterogeneous, most likely autoimmune, demyelinating disease of the central nervous system (CNS). Although a number of histological classification systems for CNS lesions have been used by different groups in recent years, no uniform classification exists. In this paper, we propose a simple and unifying classification of MS lesions incorporating many elements of earlier histological systems that aims to provide guidelines for neuropathologists and researchers studying MS lesions to allow for better comparison of different studies performed with MS tissue, and to aid in understanding the pathogenesis of the disease. Based on the presence/absence and distribution of macrophages/microglia (inflammatory activity) and the presence/absence of ongoing demyelination (demyelinating activity), we suggest differentiating between active, mixed active/inactive, and inactive lesions with or without ongoing demyelination. Active lesions are characterized by macrophages/microglia throughout the lesion area, whereas mixed active/inactive lesions have a hypocellular lesion center with macrophages/microglia limited to the lesion border. Inactive lesions are almost completely lacking macrophages/microglia. Active and mixed active/inactive lesions can be further subdivided into lesions with ongoing myelin destruction (demyelinating lesions) and lesions in which the destruction of myelin has ceased, but macrophages are still present (post-demyelinating lesions). This distinction is based on the presence or absence of myelin degradation products within the cytoplasm of macrophages/microglia. For this classification of MS lesions, identification of myelin with histological stains [such as luxol fast blue-PAS] or by immunohistochemistry using antibodies against myelin basic-protein (MBP) or proteolipid-protein (PLP), as well as, detection of macrophages/microglia by, e.g., anti-CD68 is sufficient. Active and demyelinating lesions may be further subdivided into the early and late demyelinating lesions. The former is defined by the presence in macrophages of major and small molecular weight myelin proteins, such as cyclic nucleotide diphosphoesterase (CNP), myelin oligodendrocyte glycoprotein (MOG), or myelin-associated protein (MAG), whereas macrophages in the latter demonstrate merely the presence of the major myelin proteins MBP or PLP. We discuss the histological features and staining techniques required to classify MS lesions, and, in addition, describe the histological hallmarks of cortical pathology and diffuse white matter changes, as well as of remyelination.

Keywords

Myelin Protein Active Lesion Wallerian Degeneration Myelin Oligodendrocyte Glycoprotein Normal Appear White Matter 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This study was supported by Grants from the German Research Foundation (SFB-TR128-B7; Ku1477/6-1), the Interdisciplinary Clinical Research Center, Münster (IZKF; KuT3/012/15) to TK, the German Ministry for Education and Research (BMBF, ‘‘German Competence Network Multiple Sclerosis’’ (KKNMS) to WB, and the ERA-Net Neuron project MELTRA funded by the Austrian Science Fund (FWF, Project I 2114—B27) and CIHR, Quebec, FRQS to AP, and HL.

References

  1. 1.
    Absinta M, Nair G, Sati P, Cortese IC, Filippi M, Reich DS (2015) Direct MRI detection of impending plaque development in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2:e145CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Albert M, Antel J, Bruck W, Stadelmann C (2007) Extensive cortical remyelination in patients with chronic multiple sclerosis. Brain Pathol 17:129–138CrossRefPubMedGoogle Scholar
  3. 3.
    Alvarez JI, Saint-Laurent O, Godschalk A, Terouz S, Briels C, Larouche S, Bourbonniere L, Larochelle C, Prat A (2015) Focal disturbances in the blood-brain barrier are associated with formation of neuroinflammatory lesions. Neurobiol Dis 74:14–24CrossRefPubMedGoogle Scholar
  4. 4.
    Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55:458–468CrossRefPubMedGoogle Scholar
  5. 5.
    Bo L, Mork S, Kong PA, Nyland H, Pardo CA, Trapp BD (1994) Detection of MHC class II-antigens on macrophages and microglia, but not on astrocytes and endothelia in active multiple sclerosis lesions. J Neuroimmunol 51:135–146CrossRefPubMedGoogle Scholar
  6. 6.
    Bo L, Vedeler CA, Nyland H, Trapp BD, Mork SJ (2003) Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler 9:323–331CrossRefPubMedGoogle Scholar
  7. 7.
    Bo L, Vedeler CA, Nyland HI, Trapp BD, Mork SJ (2003) Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 62:723–732CrossRefPubMedGoogle Scholar
  8. 8.
    Bogie JF, Stinissen P, Hendriks JJ (2014) Macrophage subsets and microglia in multiple sclerosis. Acta Neuropathol 128:191–213CrossRefPubMedGoogle Scholar
  9. 9.
    Bramow S, Frischer JM, Lassmann H, Koch-Henriksen N, Lucchinetti CF, Sorensen PS, Laursen H (2010) Demyelination versus remyelination in progressive multiple sclerosis. Brain 133:2983–2998CrossRefPubMedGoogle Scholar
  10. 10.
    Brink BP, Veerhuis R, Breij EC, van der Valk P, Dijkstra CD, Bö L (2005) The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions. J Neuropathol Exp Neurol 64: 147–155CrossRefPubMedGoogle Scholar
  11. 11.
    Brück W, Porada P, Poser S, Rieckmann P, Hanefeld F, Kretzschmar HA, Lassmann H (1995) Monocyte/macrophage differentiation in early multiple sclerosis lesions. Ann Neurol 38:788–796CrossRefPubMedGoogle Scholar
  12. 12.
    Buss A, Brook GA, Kakulas B, Martin D, Franzen R, Schoenen J, Noth J, Schmitt AB (2004) Gradual loss of myelin and formation of an astrocytic scar during Wallerian degeneration in the human spinal cord. Brain 127:34–44CrossRefPubMedGoogle Scholar
  13. 13.
    Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE et al (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–143CrossRefPubMedGoogle Scholar
  14. 14.
    Calabrese M, Magliozzi R, Ciccarelli O, Geurts JJ, Reynolds R, Martin R (2015) Exploring the origins of grey matter damage in multiple sclerosis. Nat Rev Neurosci 16:147–158. doi: 10.1038/nrn3900 CrossRefPubMedGoogle Scholar
  15. 15.
    Campbell Z, Sahm D, Donohue K, Jamison J, Davis M, Pellicano C, Auh S, Ohayon J, Frank JA, Richert N et al (2012) Characterizing contrast-enhancing and re-enhancing lesions in multiple sclerosis. Neurology 78:1493–1499CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Davie CA, Hawkins CP, Barker GJ, Brennan A, Tofts PS, Miller DH, McDonald WI (1994) Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions. Brain 117:49–58CrossRefPubMedGoogle Scholar
  17. 17.
    De Groot CJA, Bergers E, Kamphorst W, Ravid R, Polman CH, Barkhof F, van der Valk P (2001) Post-mortem MRI-guided sampling of multiple sclerosis brain lesions. Increased yield of active demyelinating and (p)reactive lesions. Brain 124:1635–1645CrossRefPubMedGoogle Scholar
  18. 18.
    Dendrou CA, Fugger L, Friese MA (2015) Immunopathology of multiple sclerosis. Nat Rev Immunol 15:545–558. doi: 10.1038/nri3871 CrossRefPubMedGoogle Scholar
  19. 19.
    Dziedzic T, Metz I, Dallenga T, Konig FB, Muller S, Stadelmann C, Bruck W (2010) Wallerian degeneration: a major component of early axonal pathology in multiple sclerosis. Brain Pathol 20:976–985PubMedGoogle Scholar
  20. 20.
    Filippi M, Rocca MA, Martino G, Horsfield MA, Comi G (1998) Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis. Ann Neurol 43:809–814CrossRefPubMedGoogle Scholar
  21. 21.
    Fischer MT, Wimmer I, Hoftberger R, Gerlach S, Haider L, Zrzavy T, Hametner S, Mahad D, Binder CJ, Krumbholz M et al (2013) Disease-specific molecular events in cortical multiple sclerosis lesions. Brain 136:1799–1815. doi: 10.1093/brain/awt110 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H (2009) The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132:1175–1189CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Frischer JM, Weigand SD, Guo Y, Kale N, Parisi JE, Pirko I, Mandrekar J, Bramow S, Metz I, Bruck W et al (2015) Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol. 78:710–721CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Goldschmidt T, Antel J, Konig FB, Brück W, Kuhlmann T (2009) Remyelination capacity of the MS brain decreases with disease chronicity. Neurology 72:1914–1921CrossRefPubMedGoogle Scholar
  25. 25.
    Hametner S, Wimmer I, Haider L, Pfeifenbring S, Bruck W, Lassmann H (2013) Iron and neurodegeneration in the multiple sclerosis brain. Ann Neurol 74:848–861. doi: 10.1002/ana.23974 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Harris JO, Frank JA, Patronas N, McFarlin DE, McFarland HF (1991) Serial gadolinium-enhancing magnetic resonance imaging scans in patients with early, relapsing-remitting multiple sclerosis: implications for clinical trials and natural history. Ann Neurol 29:548–555CrossRefPubMedGoogle Scholar
  27. 27.
    Hoftberger R, Fink S, Aboul-Enein F, Botond G, Olah J, Berki T, Ovadi J, Lassmann H, Budka H, Kovacs GG (2010) Tubulin polymerization promoting protein (TPPP/p25) as a marker for oligodendroglial changes in multiple sclerosis. Glia 58:1847–1857. doi: 10.1002/glia.21054 CrossRefPubMedGoogle Scholar
  28. 28.
    Kuhlmann T, Miron V, Cui 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 131:1749–1758CrossRefPubMedGoogle Scholar
  29. 29.
    Kuhlmann T, Remington L, Maruschak B, Owens T, Bruck W (2007) Nogo-A is a reliable oligodendroglial marker in adult human and mouse CNS and in demyelinated lesions. J Neuropathol Exp Neurol 66:238–246CrossRefPubMedGoogle Scholar
  30. 30.
    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 128:2705–2712CrossRefPubMedGoogle Scholar
  31. 31.
    Lassmann H, Bruck W, Lucchinetti CF (2007) The immunopathology of multiple sclerosis: an overview. Brain Pathol 17:210–218. doi: 10.1111/j.1750-3639.2007.00064.x CrossRefPubMedGoogle Scholar
  32. 32.
    Lassmann H, Raine CS, Antel J, Prineas JW (1998) Immunopathology of multiple sclerosis: report on an international meeting held at the Institute of Neurology of the University of Vienna. J Neuroimmunol 86:213–217CrossRefPubMedGoogle Scholar
  33. 33.
    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 47:707–717CrossRefPubMedGoogle Scholar
  34. 34.
    Ludwin SK (2000) The neuropathology of multiple sclerosis. Neuroimaging Clin N Am 10:625–648PubMedGoogle Scholar
  35. 35.
    Ludwin SK (2006) The pathogenesis of multiple sclerosis: relating human pathology to experimental studies. J Neuropathol Exp Neurol 65:305–318CrossRefPubMedGoogle Scholar
  36. 36.
    Maggi P, Macri SM, Gaitan MI, Leibovitch E, Wholer JE, Knight HL, Ellis M, Wu T, Silva AC, Massacesi L et al (2014) The formation of inflammatory demyelinated lesions in cerebral white matter. Ann Neurol 76:594–608CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Mahad DH, Trapp BD, Lassmann H (2015) Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 14:183–193CrossRefPubMedGoogle Scholar
  38. 38.
    Manrique-Hoyos N, Jurgens T, Gronborg M, Kreutzfeldt M, Schedensack M, Kuhlmann T, Schrick C, Bruck W, Urlaub H, Simons M et al (2012) Late motor decline after accomplished remyelination: impact for progressive multiple sclerosis. Ann Neurol 71:227–244CrossRefPubMedGoogle Scholar
  39. 39.
    Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ (2007) Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130:2800–2815. doi: 10.1093/brain/awm236 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Mews I, Bergmann M, Bunkowski S, Gullotta F, Brück W (1998) Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions. Mult Scler 4:55–62CrossRefPubMedGoogle Scholar
  41. 41.
    Moll NM, Rietsch AM, Ransohoff AJ, Cossoy MB, Huang D, Eichler FS, Trapp BD, Ransohoff RM (2008) Cortical demyelination in PML and MS: similarities and differences. Neurology 70:336–343. doi: 10.1212/01.WNL.0000284601.54436.e4 CrossRefPubMedGoogle Scholar
  42. 42.
    Moore CS, Ase AR, Kinsara A, Rao VT, Michell-Robinson M, Leong SY, Butovsky O, Ludwin SK, Seguela P, Bar-Or A et al (2015) P2Y12 expression and function in alternatively activated human microglia. Neurol Neuroimmunol Neuroinflamm 2:e80CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Patani R, Balaratnam M, Vora A, Reynolds R (2007) Remyelination can be extensive in multiple sclerosis despite a long disease course. Neuropathol Appl Neurobiol 33:277–287CrossRefPubMedGoogle Scholar
  44. 44.
    Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidtbauer M, Laursen H, Sorensen P, Brück W, Lucchinetti C, Lassmann H (2006) Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129:3165–3172CrossRefPubMedGoogle Scholar
  45. 45.
    Peterson JW, Bö L, Mörk S, Chang A, Trapp BD (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50:389–400CrossRefPubMedGoogle Scholar
  46. 46.
    Prineas JW (1985) The neuropathology of multiple sclerosis. In: Koetsier JC (ed) Demyelinating Diseases. Elsevier Science Publishers, Amsterdam, pp 213–257Google Scholar
  47. 47.
    Prineas JW, Barnard RO, Kwon EE, Sharer LR, Cho ES (1993) Multiple Sclerosis: remyelination of nascent lesions. Ann Neurol 33:137–151CrossRefPubMedGoogle Scholar
  48. 48.
    Prineas JW, Connell F (1979) Remyelination in multiple sclerosis. Ann Neurol 5:22–31CrossRefPubMedGoogle Scholar
  49. 49.
    Prineas JW, Kwon EE, Cho E-S, Sharer LR, Barnett MH, Oleszak EL, Hoffman B, Morgan BP (2001) Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol 50:646–657CrossRefPubMedGoogle Scholar
  50. 50.
    Prineas JW, Kwon EE, Cho ES, Sharer LR (1984) Continual breakdown and regeneration of myelin in progressive multiple sclerosis plaques. Ann N Y Acad Sci 436:11–32CrossRefPubMedGoogle Scholar
  51. 51.
    Prineas JW, McDonald I, Franklin RJM (2002) Demyelinating diseases. In: Graham D, Lantos PL (eds) Greenfield’s Neuropathology, 7th edn. Arnold, London, p 527–528Google Scholar
  52. 52.
    Reynolds R, Roncaroli F, Nicholas R, Radotra B, Gveric D, Howell O (2011) The neuropathological basis of clinical progression in multiple sclerosis. Acta Neuropathol 122:155–170. doi: 10.1007/s00401-011-0840-0 CrossRefPubMedGoogle Scholar
  53. 53.
    Singh S, Metz I, Amor S, van der Valk P, Stadelmann C, Brück W (2013) Microglial nodules in early multiple sclerosis white matter are associated with degenerating axons. Acta Neuropathol 125:595–608CrossRefGoogle Scholar
  54. 54.
    Thompson AJ, Kermode AG, Wicks D, MacManus DG, Kendall BE, Kingsley DP, McDonald WI (1991) Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann Neurol 29:53–62CrossRefPubMedGoogle Scholar
  55. 55.
    Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. New Engl J Med 338:278–285CrossRefPubMedGoogle Scholar
  56. 56.
    van der Goes A, Boorsma W, Hoekstra K, Montagne L, De Groot CJ, Dijkstra CD (2005) Determination of the sequential degradation of myelin proteins by macrophages. J Neuroimmunol 161:12–20CrossRefPubMedGoogle Scholar
  57. 57.
    van der Valk P, De Groot CJA (2000) Review. Staging of multiple sclerosis (MS) lesions: pathology of the time frame of MS. Neuropathol Appl Neurobiol 26:2–10CrossRefPubMedGoogle Scholar
  58. 58.
    van Horssen J, Singh S, van der Pol S, Kipp M, Lim JL, Peferoen L, Gerritsen W, Kooi EJ, Witte ME, Geurts JJ et al (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 PubMedPubMedCentralGoogle Scholar
  59. 59.
    van Waesberghe JHTM, Kamphorst W, De Groot CJA, van Walderveen MAA, Castelijns JA, Ravid R, van der Valk P, Polman CH, Thompson AJ, Barkhof F (1999) Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann Neurol 46:747–754CrossRefPubMedGoogle Scholar
  60. 60.
    Yamasaki R, Lu H, Butovsky O, Ohno N, Rietsch AM, Cialic R, Wu PM, Doykan CE, Lin J, Cotleur AC et al (2014) Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med 211:1533–1549CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Institute of NeuropathologyUniversity Hospital MünsterMünsterGermany
  2. 2.Department of Pathology and Molecular MedicineQueen’s UniversityKingstonCanada
  3. 3.Neuroimmunology Research LaboratoryCentre de Recherche DU Centre Hospitalier de l’Université de Montréal (CRCHUM)MontrealCanada
  4. 4.Neuroimmunology Unit, Montréal Neurological InstituteMcGill UniversityMontrealCanada
  5. 5.Department of NeuropathologyUniversity Medical Center, Georg August UniversityGöttingenGermany
  6. 6.Center for Brain ResearchMedical University of ViennaViennaAustria

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