Natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis: a postmortem study.

Christian Wüthrich, Bogdan F Gh Popescu, Sarah Gheuens, Michael Marvi, Ronald Ziman, Stephen Pojen Denq, Mylyne Tham, Elizabeth Norton, Joseph E Parisi, Xin Dang, Claudia F Lucchinetti, Igor J. Koralnik

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Abstract

Natalizumab, a monoclonal antibody directed against α4 integrins, has, to date, been associated with 399 cases of progressive multifocal leukoencephalopathy (PML) worldwide in patients receiving treatment for multiple sclerosis (MS). Because of the limited number of histologic studies, the possible interplay between MS and PML lesions has not been investigated. We report the clinical, radiologic, and histologic findings of an MS patient who developed PML after 32 months of natalizumab monotherapy. After withdrawal of natalizumab, she received plasma exchange, mefloquine, and mirtazapine but died soon thereafter. Postmortem examination was restricted to examination of the brain and spinal cord. Extensive PML lesions, characterized by the presence of JC virus DNA were found in the cerebral white matter and neocortex. Sharply demarcated areas of active PML lesions contained prominent inflammatory infiltrates composed of approximately equal numbers of CD4-positive and CD8-positive T cells, consistent with an immune reconstitution inflammatory syndrome. Conversely, all MS lesions identified were hypocellular, long-standing inactive plaques characterized by myelin loss, relative axonal preservation, and gliosis and, importantly, were devoid of JC virus DNA and active inflammation. Chronic inactive MS lesions were separate and distinct from nearby PML lesions. This case demonstrates the coexistence and apparent lack of interplay between chronic inactive MS and PML lesions, and that immune reconstitution inflammatory syndrome seems to affect the shape and appearance of PML but not MS lesions.

Original languageEnglish (US)
Pages (from-to)1043-1051
Number of pages9
JournalJournal of Neuropathology and Experimental Neurology
Volume72
Issue number11
StatePublished - Nov 2013

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Progressive Multifocal Leukoencephalopathy
Multiple Sclerosis
Immune Reconstitution Inflammatory Syndrome
JC Virus
Mefloquine
Plasma Exchange
Gliosis
Natalizumab
DNA
Neocortex
Myelin Sheath
Integrins
Autopsy
Spinal Cord
Monoclonal Antibodies
Inflammation
T-Lymphocytes
Brain

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Neurology
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Wüthrich, C., Popescu, B. F. G., Gheuens, S., Marvi, M., Ziman, R., Denq, S. P., ... Koralnik, I. J. (2013). Natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis: a postmortem study. Journal of Neuropathology and Experimental Neurology, 72(11), 1043-1051.

Natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis : a postmortem study. / Wüthrich, Christian; Popescu, Bogdan F Gh; Gheuens, Sarah; Marvi, Michael; Ziman, Ronald; Denq, Stephen Pojen; Tham, Mylyne; Norton, Elizabeth; Parisi, Joseph E; Dang, Xin; Lucchinetti, Claudia F; Koralnik, Igor J.

In: Journal of Neuropathology and Experimental Neurology, Vol. 72, No. 11, 11.2013, p. 1043-1051.

Research output: Contribution to journalArticle

Wüthrich, C, Popescu, BFG, Gheuens, S, Marvi, M, Ziman, R, Denq, SP, Tham, M, Norton, E, Parisi, JE, Dang, X, Lucchinetti, CF & Koralnik, IJ 2013, 'Natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis: a postmortem study.', Journal of Neuropathology and Experimental Neurology, vol. 72, no. 11, pp. 1043-1051.
Wüthrich, Christian ; Popescu, Bogdan F Gh ; Gheuens, Sarah ; Marvi, Michael ; Ziman, Ronald ; Denq, Stephen Pojen ; Tham, Mylyne ; Norton, Elizabeth ; Parisi, Joseph E ; Dang, Xin ; Lucchinetti, Claudia F ; Koralnik, Igor J. / Natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis : a postmortem study. In: Journal of Neuropathology and Experimental Neurology. 2013 ; Vol. 72, No. 11. pp. 1043-1051.
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