Cortical Pathology in Multiple Sclerosis – Morphology, Immunopathology and Clinical Context

Authors: J. Piťha 1,2;  M. Vachová 1;  E. Havrdová 2
Authors‘ workplace: MS centrum při neurologickém oddělení, Krajská zdravotní, a. s. – Nemocnice Teplice o. z. 1;  Neurologická klinika 1. LF UK a VFN v Praze 2
Published in: Cesk Slov Neurol N 2012; 75/108(6): 684-688
Category: Review Article


The early pathological changes in multiple sclerosis suggest that the morphological and functional changes in the cerebral cortex and subcortical gray matter may precede pathological changes in the white matter of the brain. Modern investigational methods allow histopathological analysis of the pathological changes that lead to the early demyelination and atrophy. New imaging techniques (T2-weighted turbo spin-echo, double inversion recovery MRI – DIR-MRI) or phase-sensitive inversion recovery (PSIR-MRI) allow more detailed detection of cortical pathology. Cortical and subcortical pathology clinically correlates with cognitive disorders, depression, epilepsy and fatigue, compared to white matter changes that correlate with impaired motor skills. In the future, new techniques may allow MRI to further speed up the diagnosis and early treatment.

Key words:
multiple sclerosis – cortical grey matter – subcortical grey matter – cortical lesion – atrophy – magnetic resonance imaging


1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000; 343(13): 938–952.

2. Moll NM, Rietsch AM, Thomas S, Ransohoff AJ, Lee JC, Fox R et al. Multiple sclerosis normal-appearing white matter: pathology-imaging correlations. Ann Neurol 2011; 70(5): 764–773.

3. Dawson JW. The Histology of Multiple Sclerosis. Trans R Soc Edinburgh 1916; 50: 517–740.

4. Kidd D, Barkhof F, McConnell R, Algra PR, Allen IV, Revesz T. Cortical lesions in multiple sclerosis. Brain 1999; 122 (Pt 1): 17–26.

5. Newcombe J, Hawkins CP, Henderson CL, Patel HA, Woodroofe MN, Hayes GM et al. Histopathology of multiple sclerosis lesions detected by magnetic resonance imaging in unfixed postmortem central nervous system tissue. Brain 1991; 114 (Pt 2): 1013–1023.

6. Boggild MD, Williams R, Haq N, Hawkins C. Cortical plaques visualised by fluid-attenuated inversion recovery imaging in relapsing multiple sclerosis. Neuroradiology 1996; 38 (Suppl 1): S10–S13.

7. Fisniku LK, Chard DT, Jackson JS, Anderson VM, Altmann DR, Miszkiel KA et al. Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 2008; 64(3): 247–254.

8. Fisher E, Lee JC, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008; 64(3): 255–265.

9. Rudick RA, Lee JC, Nakamura K, Fisher E. Gray matter atrophy correlates with MS disability progression measured with MSFC but not EDSS. J Neurol Sci 2009; 282(1–2): 106–111.

10. Papadopoulos D, Dukes S, Patel R, Nicholas R, Vora A, Reynolds R. Substantial archaeocortical atrophy and neuronal loss in multiple sclerosis. Brain Pathol 2009; 19(2): 238–253.

11. Bö L, Geurts JJ, van der Valk P, Polman C, Barkhof F. Lack of correlation between cortical demyelination and white matter pathologic changes in multiple sclerosis. Arch Neurol 2007; 64(1): 76–80.

12. Kutzelnigg A, Lucchinetti CF, Stadelmann C, Brück W, Rauschka H, Bergmann M et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005; 128 (Pt 11): 2705–2712.

13. Bö L, Vedeler CA, Nyland HI, Trapp BD, Mörk SJ. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 2003; 62(7): 723–732.

14. Peterson JW, Bö L, Mörk S, Chang A, Trapp BD. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001; 50(3): 389–400.

15. Calabrese M, Filippi M, Gallo P. Cortical le­sions in multiple sclerosis. Nat Rev Neurol 2010; 6(8): 438–444.

16. van Horssen J, Brink BP, de Vries HE, van der Valk P, Bö L. The blood-brain barrier in cortical multiple sclerosis lesions. J Neuropathol Exp Neurol 2007; 66(4): 321–328.

17. Vercellino M, Masera S, Lorenzatti M, Condello C, Merola A, Mattioda A et al. Demyelination, inflammation, and neurodegeneration in multiple sclerosis deep gray matter. J Neuropathol Exp Neurol 2009; 68(5): 489–502.

18. Torkildsen O, Stansberg C, Angelskår SM, Kooi EJ, Geurts JJ, van der Valk P et al. Upregulation of immunoglobulin-related genes in cortical sections from multiple sclerosis patients. Brain Pathol 2010; 20(4): 720–729.

19. Popescu BF, Bunyan RF, Parisi JE, Ransohoff RM, Lucchinetti CF. A case of multiple sclerosis presenting with inflammatory cortical demyelination. Neurology 2011; 76(20): 1705–1710.

20. Lucchinetti CF, Popescu BF, Bunyan RF, Moll NM, Roemer SF, Lassmann H et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 2011; 365(23): 2188–2197.

21. Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007; 130 (Pt 4): 1089–1104.

22. Howell OW, Reeves CA, Nicholas R, Carassiti D, Radotra B, Gentleman SM et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 2011; 134 (Pt 9): 2755–2771.

23. Le Panse R, Bismuth J, Cizeron-Clairac G, Weiss JM, Cufi P, Dartevelle P et al. Thymic remodeling associated with hyperplasia in myasthenia gravis. Autoimmunity 2010; 43(5–6): 401–412.

24. Weyland CM, Kurtin PJ, Goronzy JJ. Ectopic lymphoid organogenesis: a fast track for autoimmunity. Am J Pathol 2001; 159(3): 787–793.

25. Aloisi F, Pujol-Borrell R. Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 2006; 6(3): 205–217.

26. Magliozzi R, Howell OW, Reeves C, Roncaroli F, Nicholas R, Serafini B et al. A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 2010; 68(4): 477–493.

27. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 2009; 132 (Pt 5): 1175–1189.

28. Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P et al. Dysregulated Epstein--Barr virus infection in the multiple sclerosis brain. J Exp Med 2007; 204(12): 2899–2912.

29. Sargsyan SA, Owens GP, Gilden DH, Bennett JL, Shearer AJ, Ritchie AM et al. Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology 2010; 74(14): 1127–1135.

30. He D, Zhou H, Han W, Zhang S. Rituximab for relapsing-remitting multiple sclerosis. Cochrane Database Syst Rev 2011; 12: CD009130.

31. Miller DH, Barkhof F, Frank JA, Parker GJ, Thompson AJ. Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 2002; 125 (Pt 8): 1676–1695.

32. Calabrese M, Atzori M, Bernardi V, Morra A, Romualdi C, Rinaldi L et al. Cortical atrophy is relevant in multiple sclerosis at clinical onset. J Neurol 2007; 254(9): 1212–1220.

33. Sastre-Garriga J, Ingle GT, Chard DT, Cercignani M, Ramió-Torrentà L, Miller DH et al. Grey and white matter volume changes in early primary progressive multiple sclerosis: a longitudinal study. Brain 2005; 128 (Pt 6): 1454–1460.

34. Roosendaal SD, Bendfeldt K, Vrenken H, Polman CH, Borgwardt S, Radue EW et al. Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability. Mult Scler 2011; 17(9): 1098–1106.

35. Dalton CM, Chard DT, Davies GR, Miszkiel KA, Altmann DR, Fernando K et al. Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain 2004; 127 (Pt 5): 1101–1107.

36. Fisher E, Lee JC, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008; 64(3): 255–265.

37. Frohman EM, Dwyer MG, Frohman T, Cox JL, Salter A, Greenberg BM et al. Relationship of optic nerve and brain conventional and non-conventional MRI measures and retinal nerve fiber layer thickness, as assessed by OCT and GDx: a pilot study. J Neurol Sci 2009; 282(1–2): 96–105.

38. Geurts JJ, Bö L, Pouwels PJ, Castelijns JA, Polman CH, Barkhof F. Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology. AJNR Am J Neuroradiol 2005; 26(3): 572–577.

39. Seewann A, Kooi EJ, Roosendaal SD, Pouwels PJ, Wattjes MP, van der Valk P et al. Postmortem verification of MS cortical lesion detection with 3D DIR. Neurology 2012; 78(5): 302–308.

40. Redpath TW, Smith FW. Technical note: use of a double inversion recovery pulse sequence to image selectively grey or white brain matter. Br J Radiol 1994; 67(804): 1258–1263.

41. Simon B, Schmidt S, Lukas C, Gieseke J, Träber F, Knol DL et al. Improved in vivo detection of cortical lesions in multiple sclerosis using double inversion recovery MR imaging at 3 Tesla. Eur Radiol 2010; 20(7): 1675–1683.

42. Hulst HE, Geurts JJ. Gray matter imaging in multiple sclerosis: what have we learned? BCM Neurol 2011; 11: 153.

43. Calabrese M, Filippi M, Rovaris M, Bernardi V, Atzori M, Mattisi I et al. Evidence for relative cortical sparing in benign multiple sclerosis: a longitudinal magnetic resonance imaging study. Mult Scler 2009; 15(1): 36–41.

44. Calabrese M, Rocca MA, Atzori M, Mattisi I, Favaretto A, Perini P et al. A 3-year magnetic resonance imaging study of cortical lesions in relapse-onset multiple sclerosis. Ann Neurol 2010; 67(3): 376–383.

45. Calabrese M, De Stefano N, Atzori M, Bernardi V, Mattisi I, Barachino L et al. Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis. Arch Neurol 2007; 64(10): 1416–1422.

46. Metcalf M, Xu D, Okuda DT, Carvajal L, Srinivasan R, Kelley DA et al. High-resolution phased-array MRI of the human brain at 7 tesla: initial experience in multiple sclerosis patients. J Neuroimaging 2010; 20(2): 141–147.

47. Ciccarelly O, Chen JT. MS cortical lesions on double inversion recovery MRI: few but true. Neurology 2012; 78(5): 296–297.

48. Seewann A, Vrenken H, Kooi EJ, van der Valk P, Knol DL, Polman CH et al. Imaging the tip of the iceberg: visualization of cortical lesions in multiple sclerosis. Mult Scler 2011; 17(10): 1202–1210.

49. Geurts JJ, Roosendaal SD, Calabrese M, Circcarelli O, Agosta F, Chard DT et al. Consensus recommenda­tions for MS cortical lesion scoring using double inversion recovery MRI. Neurology 2011; 76(5): 418–424.

50. Ramasamy DP, Benedict RH, Cox JL, Fritz D, Abdelrahman N, Hussein S et al. Extent of cerebellum, subcortical and cortical atrophy in patients with MS: a case-control study. J Neurol Sci 2009; 282(1–2): 47–54.

51. Rocca MA, Mesaros S, Pagani E, Sormani MP, Comi G, Filippi M. Thalamic damage and long-term progression of disability in multiple sclerosis. Radiology 2010; 257(2): 463–469.

52. Bergsland N, Horakova D, Dwyer MG, Dolezal O, Seidl ZK, Vaneckova M et al. Subcortical and cortical gray matter atrophy in a large sample of patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis. AJNR Am J Neuroradiol 2012; 33(8): 1573–1578.

53. Geurts JJ, Bö L, Roosendaal SD, Hazes T, Daniëls R, Barkhof F et al. Extensive hippocampal demyelination in multiple sclerosis. J Neuropathol Exp Neurol 2007; 66(9): 819–827.

54. Sicotte NL, Kern KC, Giesser BS, Arshanapalli A, Schultz A, Montag M et al. Regional hippocampal atrophy in multiple sclerosis. Brain 2008; 131 (Pt 4): 1134–1141.

55. Roosendaal SD, Hulst HE, Vrenken H, Feenstra HE, Castelijns JA, Pouwels PJ et al. Structural and functional hippocampal changes in multiple sclerosis pa­tients with intact memory function. Radiology 2010; 255(2): 595–604.

56. Patti F. Cognitive impairment in multiple sclerosis. Mult Scler 2009; 15(1): 2–8.

57. Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol 2008; 7(12): 1139–1151.

58. Tedeschi G, Lavorgna L, Russo P, Prinster A, Dinacci D, Savettieri G et al. Brain atrophy and lesion load in a large population of patients with multiple sclerosis. Neurology 2005; 65(2): 280–285.

59. Calabrese M, Rinaldi F, Grossi P, Gallo P. Cortical pathology and cognitive impairment in multiple sclerosis. Expert Rev Neurother 2011; 11(3): 425–432.

60. Calabrese M, Rinaldi F, Mattisi I, Bernardi V, Favaretto A, Perini P et al. The predictive value of gray matter atrophy in clinically isolated syndromes. Neurology 2011; 77(3): 257–263.

61. Feinstein A, Roy P, Lobaugh N, Feinstein K, O’Connor P, Black S. Structural brain abnormalities in multiple sclerosis patients with major depression. Neurology 2004; 62(4): 586–590.

62. Calabrese M, Grossi P, Favaretto A, Romualdi C, Atzori M, Rinaldi F et al. Cortical pathology in multiple sclerosis patients with epilepsy: a 3 year longitudinal study. J Neurol Neurosurg Psychiatry 2012; 83(1): 49–54.

63. Calabrese M, Bernardi V, Atzori M, Mattisi I, Favaretto A, Rinaldi F et al. Effect of disease-modifying drugs on cortical lesions and atrophy in relapsing-remitting multiple sclerosis. Mult Scler 2012; 18(4): 418–424.

64. Houtchens MK, Benedict RH, Killiany R, Sharma J, Jaisani Z, Singh B et al Thalamic atrophy and cognition in multiple sclerosis. Neurology 2007; 69(12): 1213–1223.

65. Calabrese M, Rinaldi F, Grossi P, Mattisi I, Bernardi V, Favaretto A et al. Basal ganglia and frontal/parietal cortical atrophy is associated with fatigue in relapsing-remitting multiple sclerosis. Mult Scler 2010; 16(10): 1220–1228.

66. Kiy G, Lehmann P, Hahn HK, Eling P, Kastrup A, Hildebrandt H. Decreased hippocampal volume, indirectly measured, is associated with depressive symptoms and consolidation deficits in multiple sclerosis. Mult Scler 2011; 17(9): 1088–1097.

Paediatric neurology Neurosurgery Neurology

Article was published in

Czech and Slovak Neurology and Neurosurgery

Issue 6

2012 Issue 6

Most read in this issue

This topic is also in:

Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account