Cortical demyelination and diffuse white matter injury in multiple sclerosis

Alexandra Kutzelnigg, Claudia F. Lucchinetti, Christine Stadelmann, Wolfgang Brück, Helmut Rauschka, Markus Bergmann, Manfred Schmidbauer, Joseph E. Parisi, Hans Lassmann

Research output: Contribution to journalArticlepeer-review

1205 Scopus citations


Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient's clinical deficits. We thus analysed global brain pathology in multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination.

Original languageEnglish (US)
Pages (from-to)2705-2712
Number of pages8
Issue number11
StatePublished - Nov 2005


  • Cortical demyelination
  • Multiple sclerosis
  • Normal-appearing white matter
  • PPMS
  • SPMS

ASJC Scopus subject areas

  • Clinical Neurology


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