Acta Neuropathologica

, Volume 122, Issue 2, pp 155–170 | Cite as

The neuropathological basis of clinical progression in multiple sclerosis

  • Richard ReynoldsEmail author
  • Federico Roncaroli
  • Richard Nicholas
  • Bishan Radotra
  • Djordje Gveric
  • Owain Howell


Multiple sclerosis is the major inflammatory condition affecting the central nervous system (CNS) and is characterised by disseminated focal immune-mediated demyelination. Demyelination is accompanied by variable axonal damage and loss and reactive gliosis. It is this pathology that is thought to be responsible for the clinical relapses that often respond well to immunomodulatory therapy. However, the later secondary progressive stage of MS remains largely refractory to treatment and it is widely suggested that accumulating axon loss is responsible for clinical progression. Although initially thought to be a white matter (WM) disease, it is increasingly apparent that extensive pathology is also seen in the grey matter (GM) throughout the CNS. GM pathology is characterised by demyelination in the relative absence of an immune cell infiltrate. Neuronal loss is also seen both in the GM lesions and in unaffected areas of the GM. The slow progressive nature of this later stage combined with the presence of extensive grey matter pathology has led to the suggestion that neurodegeneration might play an increasing role with increasing disease duration. However, there is a paucity of studies that have correlated the pathological features with clinical milestones during secondary progressive MS. Here, we review the contributions that the various types of pathology are likely to make to the increasing neurological deficit in MS.


Demyelination Remyelination Axon loss Neurodegeneration Inflammation Clinical progression 



Work described in this review was funded by the Multiple Sclerosis Society (Grant No. 747/02 to RR, FR and RN) and the Medical Research Council (Grant No. G0700356 to RR and OH).

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Allen IV, McKeown SR (1979) A histological, histochemical and biochemical study of the macroscopically normal white matter in multiple sclerosis. J Neurol Sci 41:81–91PubMedCrossRefGoogle Scholar
  2. 2.
    Babbe H, Roers A, Waisman A et al (2000) Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 192:393–404PubMedCrossRefGoogle Scholar
  3. 3.
    Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of a newly forming lesion. Ann Neurol 55:458–468PubMedCrossRefGoogle Scholar
  4. 4.
    Bjartmar C, Kidd G, Mörk S et al (2000) Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 48:893–901PubMedCrossRefGoogle Scholar
  5. 5.
    Bö L, Vedeler CA, Nyland H, Trapp BD, Mörk SJ (2003) Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Multiple Scler 4:323–331CrossRefGoogle Scholar
  6. 6.
    Bö L, Geurts JJ, Ravid R, Barkhof F (2004) Magnetic resonance imaging as a tool to examine the neuropathology of multiple sclerosis. Neuropathol Appl Neurobiol 30:106–117PubMedCrossRefGoogle Scholar
  7. 7.
    Bö L, Geurts JJ, Mork SJ, van der Valk P (2006) Grey matter pathology in multiple sclerosis. Acta Neurol Scand Suppl 183:48–50PubMedCrossRefGoogle Scholar
  8. 8.
    Bö L, Geurts J, Van der Valk P, Polman C, Barkhof F (2007) Lack of correlation between cortical demyelination and white matter pathologic changes in multiple sclerosis. Arch Neurol 64:74–80CrossRefGoogle Scholar
  9. 9.
    Bonati U, Fisniku LK, Altmann DR et al (2011) Cervical cord and brain grey matter atrophy independently associate with long term MS disability. J Neurol Neurosurg Psychiatry 82:471–472PubMedCrossRefGoogle Scholar
  10. 10.
    Booss J, Esiri MM, Tourtellotte WW, Mason DY (1983) Immunohistological analysis of T lymphocyte subsets in the central nervous system in chronic progressive multiple sclerosis. J Neurol Sci 62:219–232PubMedCrossRefGoogle Scholar
  11. 11.
    Bramow S, Frischer JM, Lassmann H et al (2010) Demyelination versus remyelination in progressive multiple sclerosis. Brain 133:2983–2998PubMedCrossRefGoogle Scholar
  12. 12.
    Breij ECW, Brink BP, Veerhuis R, van den Berg C et al (2008) Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol 63:16–25PubMedCrossRefGoogle Scholar
  13. 13.
    Brex PA, Ciccarelli O, O’Riordan JI et al (2002) A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 346:158–164PubMedCrossRefGoogle Scholar
  14. 14.
    Brück W, Porada P, Poser S et al (1995) Monocyte/macrophage differentiation in early multiple sclerosis lesions. Ann Neurol 38:788–796PubMedCrossRefGoogle Scholar
  15. 15.
    Calabrese M, de Stefano N, Atzori M et al (2007) Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis. Arch Neurol 64:1416–1422PubMedCrossRefGoogle Scholar
  16. 16.
    Calabrese M, de Stefano N, Atzori M et al (2008) Extensive cortical inflammation is associated with epilepsy in multiple sclerosis. J Neurol 255:581–586PubMedCrossRefGoogle Scholar
  17. 17.
    Calabrese M, Rocca MA, Atzori M et al (2010) A 3-year magnetic resonance imaging study of cortical lesions in relapse-onset multiple sclerosis. Ann Neurol 67:376–383PubMedGoogle Scholar
  18. 18.
    Calabrese M, Filippi M, Gallo P (2010) Cortical lesions in multiple sclerosis. Nat Rev Neurol 6:438–444PubMedCrossRefGoogle Scholar
  19. 19.
    Campbell GR, Ziabreva I, Reeve AK et al (2011) Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol 69:481–492PubMedCrossRefGoogle Scholar
  20. 20.
    Cifelli A, Arridge M, Jezzard P, Esiri MM, Palace J, Matthews PM (2002) Thalamic neurodegeneration in multiple sclerosis. Ann Neurol 52:650–653PubMedCrossRefGoogle Scholar
  21. 21.
    Clements RJ, McDonough J, Freeman EJ (2008) Distribution of parvalbumin and calretinin immunoreactive interneurons in motor cortex from multiple sclerosis post-mortem tissue. Exp Brain Res 187:459–465PubMedCrossRefGoogle Scholar
  22. 22.
    Compston A, Coles A (2008) Multiple sclerosis. Lancet 372:1502–1517PubMedCrossRefGoogle Scholar
  23. 23.
    Confavreux C, Vukusic S (2006) Age at disability milestones in multiple sclerosis. Brain 129:595–605PubMedCrossRefGoogle Scholar
  24. 24.
    Confavreux C, Vukusic S, Moreau T, Adeleine P (2000) Relapses and progression of disability in multiple sclerosis. N Engl J Med 343:1430–1438PubMedCrossRefGoogle Scholar
  25. 25.
    Dal Bianco A, Bradl M, Frischer J, Kutzelnigg A, Jellinger K, Lassmann H (2008) Multiple sclerosis and Alzheimer’s disease. Ann Neurol 63:174–183PubMedCrossRefGoogle Scholar
  26. 26.
    de Groot CJ, Bergers E, Kamphorst W et al (2001) Post-mortem MRI-guided sampling of multiple sclerosis brain lesions: increased yield of active demyelinating and (p)reactive lesions. Brain 124:1635–1645PubMedCrossRefGoogle Scholar
  27. 27.
    De Stefano N, Matthews PM, Fu L et al (1998) Axonal damage correlates with disability in patients with relapsing–remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 121:1469–1477PubMedCrossRefGoogle Scholar
  28. 28.
    de Stefano N, Matthews PM, Filippi M et al (2003) Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology 60:1157–1162PubMedGoogle Scholar
  29. 29.
    Deloire MS, Ruet A, Hamel D, Bonnet M, Dousset V, Brochet B (2011) MRI predictors of cognitive outcome in early multiple sclerosis. Neurology 76:1161–1167PubMedCrossRefGoogle Scholar
  30. 30.
    Dutta R, McDonough J, Yin X et al (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59:478–489PubMedCrossRefGoogle Scholar
  31. 31.
    Dutta R, Chang A, Doud MK et al (2011) Demyelination causes synaptic alterations in hippocampi from multiple sclerosis patients. Ann Neurol 69:445–454PubMedCrossRefGoogle Scholar
  32. 32.
    Evangelou N, Esiri MM, Smith S et al (2000) Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol 47:391–395PubMedCrossRefGoogle Scholar
  33. 33.
    Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120:393–399PubMedCrossRefGoogle Scholar
  34. 34.
    Filippi M, Paty DW, Kappos L et al (1995) Correlations between changes in disability and T2-weighted brain MRI activity in multiple sclerosis: a follow-up study. Neurology 45:255–260PubMedGoogle Scholar
  35. 35.
    Fisher E, Lee JC, Nakamura K, Rudick RA (2008) Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 64:255–265PubMedCrossRefGoogle Scholar
  36. 36.
    Fisniku LK, Chard DT, Jackson JS et al (2008) Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 64:247–254PubMedCrossRefGoogle Scholar
  37. 37.
    Friese MA, Fugger L (2009) Pathogenic CD8+ T cells in multiple sclerosis. Ann Neurol 66:132–141PubMedCrossRefGoogle Scholar
  38. 38.
    Frischer JM, Bramow S, Dal-Bianco A et al (2009) The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132:1175–1189PubMedCrossRefGoogle Scholar
  39. 39.
    Fu L, Matthews PM, De Stefano N (1998) Imaging axonal damage of normal-appearing white matter in multiple sclerosis. Brain 121:103–113PubMedCrossRefGoogle Scholar
  40. 40.
    Geurts JJ, Pouwels PJ, Uitdehaag BM et al (2005) Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging. Radiology 236:254–260PubMedCrossRefGoogle Scholar
  41. 41.
    Geurts JJ, Bo L, Roosendaal SD et al (2007) Extensive hippocampal demyelination in multiple sclerosis. J Neuropathol Exp Neurol 66:819–827PubMedCrossRefGoogle Scholar
  42. 42.
    Geurts JJ, Barkhof F (2008) Grey matter pathology in multiple sclerosis. Lancet Neurol 7:841–851PubMedCrossRefGoogle Scholar
  43. 43.
    Gilmore CP, Donaldson I, Bo L, Owens T, Lowe J, Evangelou N (2009) Regional variations in the extent and pattern of grey matter demyelination in multiple sclerosis: a comparison between the cerebral cortex, cerebellar cortex, deep grey matter nuclei and the spinal cord. J Neurol Neurosurg Psychiatry 80:182–187PubMedCrossRefGoogle Scholar
  44. 44.
    Giorgio A, de Stefano N (2010) Cognition in multiple sclerosis: relevance of lesions, brain atrophy and proton MR spectroscopy. Neurol Sci 31(Suppl 2):S245–S248PubMedCrossRefGoogle Scholar
  45. 45.
    Glad SB, Aarseth JH, Nyland H, Riise T, Myhr KM (2010) Benign multiple sclerosis: a need for a consensus. Acta Neurol Scand Suppl 190:44–50PubMedCrossRefGoogle Scholar
  46. 46.
    Guseo A, Jellinger K (1975) The significance of perivascular infiltrations in multiple sclerosis. J Neurol 211:51–60PubMedCrossRefGoogle Scholar
  47. 47.
    Hochmeister S, Grundtner R, Bauer J et al (2006) Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis. J Neuropathol Exp Neurol 65:855–865PubMedCrossRefGoogle Scholar
  48. 48.
    Howell OW, Palser A, Polito A et al (2006) Disruption of neurofascin localisation reveals early changes preceding demyelination and remyelination in multiple sclerosis. Brain 129:3173–3185PubMedCrossRefGoogle Scholar
  49. 49.
    Howell OW, Rundle JL, Garg A, Komada M, Brophy PJ, Reynolds R (2010) Activated microglia mediate axoglial disruption that contributes to axonal injury in multiple sclerosis. J Neuropathol Exp Neurol 69:1017–1033PubMedCrossRefGoogle Scholar
  50. 50.
    Kornek B, Lassmann H (1999) Axonal pathology in multiple sclerosis: a historical note. Brain Pathol 9:651–656PubMedCrossRefGoogle Scholar
  51. 51.
    Kremenchutzky M, Rice GP, Baskerville J, Wingerchuk DM, Ebers GC (2006) The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain 129:584–594PubMedCrossRefGoogle Scholar
  52. 52.
    Kuhlmann T, Lingfeld G, Bitsch A, Schuchardt J, Bruck W (2002) Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 125:2202–2212PubMedCrossRefGoogle Scholar
  53. 53.
    Kutzelnigg A, Lucchinetti CF, Stadelmann C et al (2005) Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128:2705–2712PubMedCrossRefGoogle Scholar
  54. 54.
    Lassmann H, Wekerle H (2005) The pathology of multiple sclerosis. McAlpine’s multiple sclerosis, vol 4. Churchill Livingstone, London, pp 557–599Google Scholar
  55. 55.
    Leray E, Yaouanq J, Le Page E et al (2010) Evidence for a two-stage disability progression in multiple sclerosis. Brain 133:1900–1913PubMedCrossRefGoogle Scholar
  56. 56.
    Losseff NA, Webb SL, O’Riordan JI et al (1996) Spinal cord atrophy and disability in multiple sclerosis. A new reproducible and sensitive MRI method with potential to monitor disease progression. Brain 119:2009–2019PubMedCrossRefGoogle Scholar
  57. 57.
    Lovas G, Szilagyi N, Majtenyi K et al (2000) Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain 123:308–317PubMedCrossRefGoogle Scholar
  58. 58.
    Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–717PubMedCrossRefGoogle Scholar
  59. 59.
    Magliozzi R, Howell O, Vora A et al (2007) Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130:1089–1104PubMedCrossRefGoogle Scholar
  60. 60.
    Magliozzi R, Howell OW, Reeves C et al (2010) A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 68:477–493PubMedCrossRefGoogle Scholar
  61. 61.
    McAlpine D (1961) The benign form of multiple sclerosis. A study based on 241 cases seen within three years of onset and followed up until the tenth year or more of the disease. Brain 84:186–203PubMedCrossRefGoogle Scholar
  62. 62.
    Meinl E, Krumholtz M, Derfuss T, Junker A, Hohlfeld R (2008) Compartmentalization of inflammation in the CNS: a major mechanism driving progressive multiple sclerosis. J Neurol Sci 274:42–44PubMedCrossRefGoogle Scholar
  63. 63.
    Miller DH (1995) Magnetic resonance imaging and spectroscopy in multiple sclerosis. Curr Opin Neurol 8:210–215PubMedCrossRefGoogle Scholar
  64. 64.
    Molyneux PD, Filippi M, Barkhof F et al (1998) Correlations between monthly enhanced MRI lesion rate and changes in T2 lesion volume in multiple sclerosis. Ann Neurol 43:332–339PubMedCrossRefGoogle Scholar
  65. 65.
    Neumann H, Medana I, Bauer J, Lassmann H (2002) Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trend Neurosci 25:313–319PubMedCrossRefGoogle Scholar
  66. 66.
    Nijeholt GJ, Bergers E, Kamphorst W et al (2001) Post-mortem high-resolution MRI of the spinal cord in multiple sclerosis: a correlative study with conventional MRI, histopathology and clinical phenotype. Brain 124:154–166PubMedCrossRefGoogle Scholar
  67. 67.
    Patani R, Balaratnam M, Vora A, Reynolds R (2007) Remyelination can be extensive in multiple sclerosis despite a long disease course. Neuropath App Neurobiol 33:277–287CrossRefGoogle Scholar
  68. 68.
    Patrikios P, Stadelmann C, Kutzelnigg A et al (2006) Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129:3165–3172PubMedCrossRefGoogle Scholar
  69. 69.
    Peterson JW, Bö L, Mörk S, Chang A, Trapp BD (2001) Transected neuritis, apoptotic neurons and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 50:389–400PubMedCrossRefGoogle Scholar
  70. 70.
    Pirko I, Lucchinetti CF, Sriram S, Bakshi R (2007) Gray matter involvement in multiple sclerosis. Neurology. 68:634–642PubMedCrossRefGoogle Scholar
  71. 71.
    Prineas JW, Barnard RO, Revesz T, Kwon EE, Sharer L, Cho ES (1993) Multiple sclerosis. Pathology of recurrent lesions. Brain 116:681–693PubMedCrossRefGoogle Scholar
  72. 72.
    Rovaris M, Barkhof F, Calabrese M et al (2009) MRI features of benign multiple sclerosis: toward a new definition of this disease phenotype. Neurology 72:1693–1701PubMedCrossRefGoogle Scholar
  73. 73.
    Scalfari A, Neuhaus A, Degenhardt A et al (2010) The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain 133:1914–1929PubMedCrossRefGoogle Scholar
  74. 74.
    Seewann A, Kooi EJ, Roosendaal SD, Barkhof F, van der Valk P, Geurts JJ (2009) Translating pathology in multiple sclerosis: the combination of post-mortem imaging, histopathology and clinical findings. Acta Neurol Scand 119:349–355PubMedCrossRefGoogle Scholar
  75. 75.
    Schmierer K, Scaravilli F, Altmann DR, Barker GJ, Miller DH (2004) Magnetization transfer ratio and myelin in post-mortem multiple sclerosis brain. Ann Neurol 56:407–415PubMedCrossRefGoogle Scholar
  76. 76.
    Schmierer K, Parkes HG, So P-W et al (2010) High field (9.4 Tesla) magnetic resonance imaging of cortical grey matter lesions in multiple sclerosis. Brain 133:858–867PubMedCrossRefGoogle Scholar
  77. 77.
    Siffrin V, Vogt J, Radbruch H, Nitsch R, Zipp F (2010) Multiple sclerosis—candidate mechanisms underlying CNS atrophy. Trends Neurosci 33:202–210PubMedCrossRefGoogle Scholar
  78. 78.
    Smith KJ, Kapoor R, Hall SM, Davies M (2001) Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol 49:470–479PubMedCrossRefGoogle Scholar
  79. 79.
    Stadelmann C (2011) Multiple sclerosis as a neurodegenerative disease: pathology, mechanisms and therapeutic implications. Curr Opin Neurol Adv. Access Mar 31Google Scholar
  80. 80.
    Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, Bö L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285PubMedCrossRefGoogle Scholar
  81. 81.
    Van der Valk P, Amor S (2009) Preactive lesions in multiple sclerosis. Curr Opin Neurol 22:207–213PubMedGoogle Scholar
  82. 82.
    Vellinga MM, Oude Engberink RD, Seewann A et al (2008) Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement. Brain 131:800–807PubMedCrossRefGoogle Scholar
  83. 83.
    Vercellino M, Plano F, Votta B, Mutani R, Giordana MT, Cavalla P (2005) Grey matter pathology in multiple sclerosis. J Neuropathol Exp Neurol 64:1101–1107PubMedCrossRefGoogle Scholar
  84. 84.
    Vuia O (1977) The benign form of multiple sclerosis. Anatomo-clinical aspects. Acta Neurol Scand 55:289–298PubMedCrossRefGoogle Scholar
  85. 85.
    Wegner C, Esiri MM, Chance SA, Palace J, Matthews PM (2006) Neocortical neuronal, synaptic, and glial loss in multiple sclerosis. Neurology 67:960–967PubMedCrossRefGoogle Scholar
  86. 86.
    Wuerfel J, Haertle M, Waiczies H et al (2008) Perivascular spaces—MRI marker of inflammatory activity in the brain? Brain 131:2332–2340PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Richard Reynolds
    • 1
    Email author
  • Federico Roncaroli
    • 1
  • Richard Nicholas
    • 1
  • Bishan Radotra
    • 1
  • Djordje Gveric
    • 1
  • Owain Howell
    • 1
  1. 1.Wolfson Neuroscience Laboratories, Division of Experimental Medicine, UK Multiple Sclerosis Tissue Bank, Centre for NeuroscienceImperial Faculty of Medicine College London, Hammersmith Hospital CampusLondonUK

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