Abstract
Multiple sclerosis is a disease of the central nervous system that destroys myelin, oligodendrocytes, neurons and axons. Historically considered to be caused by an autoimmune process mainly affecting myelin and oligodendrocytes in the white matter, recent data provide evidence that a generalized, diffuse neurodegenerative process plays an important role in the pathogenesis of MS. There is a high density of axonal transections in active demyelinating lesions, but also persistent low-level axonal damage in inactive plaques and diffuse axonal and neuronal loss throughout the nervous system. Initial axonal injury appears to be closely related to inflammation, but is not restricted to the lesions themselves. Damage may be propagated throughout the nervous system by anterograde Wallerian, retrograde or transynaptic degeneration. Cumulative tissue loss in the grey and white matter, especially of axons, is important and probably the principal determinant of accumulation of irreversible neurological disability and of conversion to a progressive disease course.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Barnett MH, Prineas JW (2004) Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 55:458–468
Bjartmar C, Kinkel RP, Kidd G, Rudick RA, Trapp BD (2001) Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology 57:1248–1252
Bo L, Vedeler CA, Nyland H, Trapp BD, Mork SJ (2003) Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler 9:323–331
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 62:723–732
Brady ST, Witt AS, Kirkpatrick LL, de Waegh SM, Readhead C, Tu PH, Lee VM (1999) Formation of compact myelin is required for maturation of the axonal cytoskeleton. J Neurosci 19:7278–7288
Brownell B, Hughes JT (1962) The distribution of plaques in the cerebrum in multiple sclerosis. J Neurol Neurosurg Psychiatry 25:315–320
Fassas A, Passweg JR, Anagnostopoulos A, Kazis A, Kozak T, Havrdova E, Carreras E, Graus F, Kashyap A, Openshaw H, Schipperus M, Deconinck E, Mancardi G, Marmont A, Hansz J, Rabusin M, Zuazu Nagore FJ, Besalduch J, Dentamaro T, Fouillard L, Hertenstein B, La Nasa G, Musso M, Papineschi F, Rowe JM, Saccardi R, Steck A, Kappos L, Gratwohl A, Tyndall A, Samijn J (2002) Autoimmune Disease Working Party of the EBMT (European Group for Blood and Marrow Transplantation) Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol 249:1088–1097
Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120:393–399
Griffiths I, Klugmann M, Anderson T, Yool D, Thomson C, Schwab MH, Schneider A, Zimmermann F, McCulloch M, Nadon N, Nave KA (1998) Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280:1610–1613
Inglese M, Mancardi GL, Pagani E, Rocca MA, Murialdo A, Saccardi R, Comi G, Filippi M (2004) Italian GITMO-NEURO Group on Autologous Hematopoietic Stem Cell Transplantation. Brain tissue loss occurs after suppression of enhancement in patients with multiple sclerosis treated with autologous hematopoietic stem cell transplantation. J Neurol Neurosurg Psychiatry 75:643–644
Karussis DM, Slavin S, Lehmann D, Mizrachi-Koll R, Abramsky O, Ben-Nun A (1992) Prevention of experimental autoimmune encephalomyelitis and induction of tolerance with acute immunosuppression followed by syngeneic bone marrow transplantation. J Immunol 148:1693–1698
Kidd D, Barkhof F, McConnell R, Algra PR, Allen IV, Revesz T (1999) Cortical lesions in multiple sclerosis. Brain 122:17–26
Kuhlmann T, Lingfield 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 125:2202–2212
Kutzelnigg A, Lassmann H (2005) Cortical lesions and brain atrophy in MSJ Neurol Sci 233:55–59
Kutzelnigg A, Rauschka H, Stadelmann C, Schmidbauer M, Brück W, Lucchinetti C, Lassmann H (2004) The pathology of progressive multiple sclerosis. Multiple Sclerosis 10(Suppl 2):111
Lappe-Siefke C, Goebbels S, Gravel M, Nicksch E, Lee J, Braun PE, Griffiths IR, Nave KA (2003) Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nat Genet 33:366–374
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
Lumsden CE (1970) The neuropathology of multiple sclerosis. In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology, Vol. 9. North-Holland, Amsterdam pp 217–309
Mancardi GL, Saccardi R, Filippi M, Gualandi F, Murialdo A, Inglese M, Marrosu MG, Meucci G, Massacesi L, Lugaresi A, Pagliai F, Sormani MP, Sardanelli F, Marmont A (2001) Italian GITMO-NEURO Intergroup on Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. Autologous hematopoietic stem cell transplantation suppresses Gd-enhanced MRI activity in MS. Neurology 57:62–68
Peterson JW, Bo L, Mork S, Chang A, Trapp BD (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 150:389–400
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285
Uschkureit T, Sporkel O, Stracke J, Bussow H, Stoffel W (2000) Early onset of axonal degeneration in double (plp-/-mag-/-) and hypomyelinosis in triple (plp-/-mbp-/-mag-/-) mutant mice. J Neurosci 20:5225–5233
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Brück, W. Inflammatory demyelination is not central to the pathogenesis of multiple sclerosis. J Neurol 252 (Suppl 5), v10–v15 (2005). https://doi.org/10.1007/s00415-005-5003-6
Issue Date:
DOI: https://doi.org/10.1007/s00415-005-5003-6