title: Natalizumab-associated progressive multifocal leukoencephalopathy in a patient with multiple sclerosis: a postmortem study.
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.
authors.affiliation: From the Division of Neurovirology, Department of Neurology (CW, SG, EN, XD, IJK), and Center for Virology and Vaccine Research, Department of Medicine (CW, SG, EN, XD, IJK), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Department of Anatomy and Cell Biology (BFGhP, MT), and Cameco MS Neuroscience Research Center (BFGh.P, MT), University of Saskatchewan, Saskatoon, Saskatchewan, Canada; Providence Saint Joseph Medical Center, The Hycy and Howard Hill Neuroscience Institute, Movement Disorder Center, Burbank (MM); David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (RZ); Department of Medicine, Northridge Hospital Medical Center, Northridge (RZ); and Buddhist Tzu Chi Medical Center, Alhambra, California (SPD); and Department of Laboratory Medicine and Pathology (JEP), and Department of Neurology (CFL), Mayo Clinic, Rochester, Minnesota.
authors.forename: Christian
authors.initials: C
authors.lastname: Wüthrich
authors.forename: Bogdan F Gh
authors.initials: BF
authors.lastname: Popescu
authors.forename: Sarah
authors.initials: S
authors.lastname: Gheuens
authors.forename: Michael
authors.initials: M
authors.lastname: Marvi
authors.forename: Ronald
authors.initials: R
authors.lastname: Ziman
authors.forename: Stephen Pojen
authors.initials: SP
authors.lastname: Denq
authors.forename: Mylyne
authors.initials: M
authors.lastname: Tham
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Norton
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.forename: Xin
authors.initials: X
authors.lastname: Dang
authors.forename: Claudia F
authors.initials: CF
authors.lastname: Lucchinetti
authors.forename: Igor J
authors.initials: IJ
authors.lastname: Koralnik
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects* / Q000627:therapeutic use; D001344:Autopsy; D001921:Brain / Q000473:pathology*; D005260:Female; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal / Q000139:chemically induced* / Q000473:pathology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology; D000069442:Natalizumab; D013116:Spinal Cord / Q000473:pathology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab