PML is Not MS

Wüthrich C, Popescu BF, Gheuens S, Marvi M, Ziman R, Denq SP, Tham M, Norton E, Parisi JE, Dang X, Lucchinetti CF, Koralnik IJ. Natalizumab-Associated Progressive Multifocal Leukoencephalopathy in a Patient With Multiple Sclerosis: A Postmortem Study. J Neuropathol Exp Neurol. 2013. [Epub ahead of print]

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, they received plasma exchange, mefloquine, and mirtazapine but died soon thereafter. Post-mortem 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.

So MS may not be caused by JC virus that causes PML

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  • I just hope that the presence of Natalizumab doesn't turn the JC into some kind of super virus, coming back with a vengeance.

  • It seems logical that PML is targeting area with intact myelin (oligodendrocytes). MS plaques with gliosis and denuded of myelin would not be affected. Without immune surveillance JCV becomes activated and once immune reconstitution occurs inflammation ramps up resulting in PML. Seems to reinforce that JCV targets oligos. PML is not chronic inactive MS but does PML tell us about acute MS lesions?

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