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Cortical lesions in multiple sclerosis

Abstract

Multiple sclerosis (MS) is typically considered to be a chronic inflammatory–demyelinating disease of CNS white matter. In the past decade, however, pathological and MRI studies have shown that lesions are often located in the gray matter, especially in the cerebral cortex. The histopathological characteristics of these cortical lesions differ substantially from lesions located in the white matter, which suggests location-dependent expression of the MS immunopathological process. Double inversion recovery imaging—an MRI technique that selectively images gray matter and lesions—has enabled researchers to image cortical lesions in vivo. Double inversion recovery studies have shown that cortical lesions can be detected at the earliest clinical stages of MS, and cortical lesion burden positively correlates with the severity of physical and cognitive impairments. These gray matter lesions are also independent predictors of subsequent disease evolution. This Review provides a summary of the main histopathological and MRI findings with regard to cortical lesions in MS, and indicates that increasing our understanding of cortical lesions has increased our knowledge of MS pathobiology.

Key Points

  • Four types of cortical lesion have been identified in multiple sclerosis (MS)

  • Double inversion recovery imaging detects more cortical lesions than conventional MRI

  • Cortical lesions can be identified at early clinical phases of MS, and are evident in 35–40% of patients with clinically isolated syndrome

  • Cortical lesions positively correlate with physical disability and with cognitive impairment in MS

  • Cortical lesions could be one of the pathological factors that lead to cortical atrophy in patients with MS

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Figure 1: The four types of cortical lesion identified by double inversion recovery imaging.
Figure 2: Cortical lesion identified using three-dimensional DIR imaging.

References

  1. Charcot, J. M. Lectures on the Disease of the Nervous System Vol. 1 (The Sydenham Society, London, 1877).

    Google Scholar 

  2. Pirko, I., Lucchinetti, C. F., Sriram, S. & Bakshi, R. Gray matter involvement in multiple sclerosis. Neurology 68, 634–642 (2007).

    Article  PubMed  Google Scholar 

  3. Charil, A. & Filippi, M. Inflammatory demyelination and neurodegeneration in early multiple sclerosis. J. Neurol. Sci. 259, 7–15 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Chard, D. T. et al. Brain metabolite changes in cortical grey and normal-appearing white matter in clinically early relapsing–remitting multiple sclerosis. Brain 125, 2342–2352 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. De Stefano, N. et al. Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology 60, 1157–1162 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Dalton, C. M. et al. Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain 127, 1101–1107 (2004).

    Article  PubMed  Google Scholar 

  7. Filippi, M. et al. Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet 364, 1489–1496 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Chard, D. T. et al. Progressive grey matter atrophy in clinically early relapsing–remitting multiple sclerosis. Mult. Scler. 10, 387–391 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Sailer, M. et al. Focal thinning of the cerebral cortex in multiple sclerosis. Brain 126, 1734–1744 (2003).

    Article  PubMed  Google Scholar 

  10. Sanfilipo, M. P., Benedict, R. H., Sharma, J., Weinstock-Guttman, B. & Bakshi, R. The relationship between whole brain volume and disability in multiple sclerosis: a comparison of normalized gray vs white matter with misclassification correction. Neuroimage 26, 1068–1077 (2005).

    Article  PubMed  Google Scholar 

  11. Sanfilipo, M. P., Benedict, R. H., Weinstock-Guttman, B. & Bakshi, R. Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis. Neurology 66, 685–692 (2006).

    Article  PubMed  Google Scholar 

  12. Tiberio, M. et al. Gray and white matter volume changes in early RRMS: a 2-year longitudinal study. Neurology 64, 1001–1007 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Amato, M. P. et al. Neocortical volume decrease in relapsing–remitting MS patients with mild cognitive impairment. Neurology 63, 89–93 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Magliozzi, R. et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 130, 1089–1104 (2007).

    Article  PubMed  Google Scholar 

  15. Evangelou, N. et al. Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. Brain 123, 1845–1849 (2000).

    Article  PubMed  Google Scholar 

  16. Kidd, D. et al. Cortical lesions in multiple sclerosis. Brain 122, 17–26 (1999).

    Article  PubMed  Google Scholar 

  17. Peterson, J. W., Bö, L., Mörk, S. J., Chang, A. & Trapp, B. D. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann. Neurol. 50, 389–400 (2001).

    CAS  PubMed  Google Scholar 

  18. Geurts, J. J. et al. Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology. AJNR Am. J. Neuroradiol. 26, 572–577 (2005).

    PubMed  PubMed Central  Google Scholar 

  19. Calabrese, M. et al. Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis. Arch. Neurol. 64, 1416–1422 (2007).

    Article  PubMed  Google Scholar 

  20. Brownell, B. & Hughes, J. T. The distribution of plaques in the cerebrum in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 25, 315–320 (1962).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lumsden, C. E. The neuropathology of multiple sclerosis. In Handbook of Clinical Neurology Vol. 9 (eds Vinken, P. J. & Bruyn, G. W.) 217–309 (Elsevier, Amsterdam, 1970).

    Google Scholar 

  22. Bø, L., Vedeler, C. A., Nyland, H. I., Trapp, B. D. & Mørk, S. J. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J. Neuropathol. Exp. Neurol. 62, 723–732 (2003).

    Article  PubMed  Google Scholar 

  23. Kutzelnigg, A. et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 128, 2705–2712 (2005).

    Article  PubMed  Google Scholar 

  24. Vercellino, M. et al. Grey matter pathology in multiple sclerosis. J. Neuropathol. Exp. Neurol. 64, 1101–1107 (2005).

    Article  PubMed  Google Scholar 

  25. Gilmore, C. P. et al. 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, 182–187 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Albert, M., Antel, J., Brück, W. & Stadelmann, C. Extensive cortical remyelination in patients with chronic multiple sclerosis. Brain Pathol. 17, 129–138 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Geurts, J. J. et al. Extensive hippocampal demyelination in multiple sclerosis. J. Neuropathol. Exp. Neurol. 66, 819–827 (2007).

    Article  PubMed  Google Scholar 

  28. Papadopoulos, D. et al. Substantial archaeocortical atrophy and neuronal loss in multiple sclerosis. Brain Pathol. 19, 238–253 (2009).

    Article  PubMed  Google Scholar 

  29. Wang, Q., Yu, S., Simonyi, A., Sun, G. Y. & Sun, A. Y. Kainic acid-mediated excitotoxicity as a model for neurodegeneration. Mol. Neurobiol. 31, 3–16 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Vallejo-Illarramendi, A., Domercq, M., Pérez-Cerdá, F., Ravid, R. & Matute, C. Increased expression and function of glutamate transporters in multiple sclerosis. Neurobiol. Dis. 21, 154–164 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Simon, J. H., Kinkel, R. P., Jacobs, L., Bub, L. & Simonian N. A Wallerian degeneration pattern in patients at high risk for MS. Neurology 54, 1155–1160 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Fisher, E., Lee, J. C., Nakamura, K. & Rudick, R. A. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann. Neurol. 64, 255–265 (2008).

    Article  PubMed  Google Scholar 

  33. Calabrese, M. & Gallo, P. Magnetic resonance evidence of cortical onset of multiple sclerosis. Mult. Scler. 15, 933–941 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Van Horssen, J., Brink, B. P., De Vries, H. E., van der Valk, P. & Bø, L. The blood–brain barrier in cortical multiple sclerosis lesions. J. Neuropathol. Exp. Neurol. 66, 321–328 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Brink, B. P. et al. The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions. J. Neuropathol. Exp. Neurol. 64, 147–155 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Bø, L., Vedeler, C. A., Nyland, H., Trapp, B. D. & Mørk, S. J. Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult. Scler. 9, 323–331 (2003).

    Article  PubMed  Google Scholar 

  37. Peterson, J. W. et al. VCAM-1-positive microglia target oligodendrocytes at the border of multiple sclerosis lesions. J. Neuropathol. Exp. Neurol. 61, 539–546 (2002).

    Article  PubMed  Google Scholar 

  38. Gray, E., Thomas, T. L., Betmouni, S., Scolding, N. & Love, S. Elevated activity and microglial expression of myeloperoxidase in demyelinated cerebral cortex in multiple sclerosis. Brain Pathol. 18, 86–95 (2008).

    Article  PubMed  Google Scholar 

  39. Dal Bianco, A. et al. Multiple sclerosis and Alzheimer's disease. Ann. Neurol. 63, 174–183 (2008).

    Article  PubMed  Google Scholar 

  40. Serafini, B., Rosicarelli, B., Magliozzi, R., Stigliano, E. & Aloisi, F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 14, 164–174 (2004).

    Article  PubMed  Google Scholar 

  41. Guseo, A. & Jellinger, K. The significance of perivascular infiltrations in multiple sclerosis. J. Neurol. 211, 51–60 (1975).

    Article  CAS  PubMed  Google Scholar 

  42. Kooi, E. J., Geurts, J. J., van Horssen, J., Bø, L. & van der Valk, P. Meningeal inflammation is not associated with cortical demyelination in chronic multiple sclerosis. J. Neuropathol. Exp. Neurol. 68, 1021–1028 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Willis, S. N. et al. Epstein–Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain 132, 3318–3328 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Serafini, B. et al. Dysregulated Epstein–Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 204, 2899–2912 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Torkildsen, Ø. et al. Upregulation of immunoglobulin-related genes in cortical sections from multiple sclerosis patients. Brain Pathol. 20, 720–729 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Geurts, J. J. et al. Does high-field MR imaging improve cortical lesion detection in multiple sclerosis? J. Neurol. 255, 183–191 (2008).

    Article  PubMed  Google Scholar 

  47. Schmierer, K. et al. High field (9.4 Tesla) magnetic resonance imaging of cortical grey matter lesions in multiple sclerosis. Brain 133, 858–867 (2010).

    Article  PubMed  Google Scholar 

  48. Geurts, J. J. et al. Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging. Radiology 236, 254–260 (2005).

    Article  PubMed  Google Scholar 

  49. Bagnato, F. et al. In vivo detection of cortical plaques by MR imaging in patients with multiple sclerosis. AJNR Am. J. Neuroradiol. 27, 2161–2167 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Nelson, F. et al. Improved identification of intracortical lesions in multiple sclerosis with phase-sensitive inversion recovery in combination with fast double inversion recovery MR imaging. AJNR Am. J. Neuroradiol. 28, 1645–1649 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Calabrese, M. et al. A 3-year magnetic resonance imaging study of cortical lesions in relapse-onset multiple sclerosis. Ann. Neurol. 67, 376–383 (2010).

    PubMed  Google Scholar 

  52. Calabrese, M. et al. Cortical lesions in primary progressive multiple sclerosis: a 2-year longitudinal MR study. Neurology 72, 1330–1336 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Calabrese, M. et al. Evidence for relative cortical sparing in benign multiple sclerosis: a longitudinal magnetic resonance imaging study. Mult. Scler. 15, 36–41 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Rocca, M. A. et al. Preserved brain adaptive properties in patients with benign multiple sclerosis. Neurology 74, 142–149 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Calabrese, M. et al. Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. Arch. Neurol. 66, 1144–1150 (2009).

    Article  PubMed  Google Scholar 

  56. Geurts, J. J. & Barkhof, F. Grey matter pathology in multiple sclerosis. Lancet Neurol. 7, 841–851 (2008).

    Article  PubMed  Google Scholar 

  57. Amato, M. P., Zipoli, V. & Portaccio, E. Multiple sclerosis-related cognitive changes: a review of cross-sectional and longitudinal studies. J. Neurol. Sci. 245, 41–46 (2006).

    Article  PubMed  Google Scholar 

  58. Rovaris, M., Comi, G. & Filippi, M. MRI markers of destructive pathology in multiple sclerosis-related cognitive dysfunction. J. Neurol. Sci. 245, 111–116 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Calabrese, M. et al. Extensive cortical inflammation is associated with epilepsy in multiple sclerosis. J. Neurol. 255, 581–586 (2008).

    Article  PubMed  Google Scholar 

  60. The Center for Information Technology. National Institutes of Health [online], (2010).

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Correspondence to Massimiliano Calabrese.

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Competing interests

M. Filippi has received honoraria from BayerScheringPharma, Biogen-Dompé, Genmab, Merck Serano and Teva for lectures and consulting. He has also received research funding from BayerScheringPharma, Biogen-Dompé, Genmab, Merck Serano and Teva. The other authors declare no competing interests.

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Calabrese, M., Filippi, M. & Gallo, P. Cortical lesions in multiple sclerosis. Nat Rev Neurol 6, 438–444 (2010). https://doi.org/10.1038/nrneurol.2010.93

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