title: Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy.
abstract: Natalizumab is an approved medication for highly active multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) may occur as a severe side effect of this drug. Here, we describe pathological and radiological characteristics of immune reconstitution inflammatory syndrome (IRIS), which occurs in natalizumab-associated PML after the cessation of therapy, and we differentiate it from ongoing PML. Brain biopsy tissue and MRI scans from five MS patients with natalizumab-associated PML were analyzed and their histology compared with non-MS PML. Histology showed an extensive CD8-dominated T cell infiltrate and numerous macrophages within lesions, and in nondemyelinated white and grey matter, in four out of five cases. Few or no virally infected cells were found. This was indicative of IRIS as known from HIV patients with PML. Outstandingly high numbers of plasma cells were present as compared to non-MS PML and typical MS lesions. MRI was compatible with IRIS, revealing enlarging lesions with a band-like or speckled contrast enhancement either at the lesion edge or within lesions. Only the fifth patient showed typical PML pathology, with low inflammation and high numbers of virally infected cells. This patient showed a similar interval between drug withdrawal and biopsy (3.5 months) to the rest of the cohort (range 2.5-4 months). MRI could not differentiate between PML-associated IRIS and ongoing PML. We describe in detail the histopathology of IRIS in natalizumab-associated PML. PML-IRIS, ongoing PML infection, and MS exacerbation may be impossible to discern clinically alone. MRI may provide some clues for distinguishing different pathologies that can be differentiated histologically. In our individual cases, biopsy helped to clarify diagnoses in natalizumab-associated PML.
authors: Department of Neuropathology, University Medical Center, Georg August University Göttingen, Germany. imetz@gwdg.de
authors: Imke
authors: I
authors: Metz
authors: Ernst-Wilhelm
authors: EW
authors: Radue
authors: Agustin
authors: A
authors: Oterino
authors: Tania
authors: T
authors: Kümpfel
authors: Heinz
authors: H
authors: Wiendl
authors: Sven
authors: S
authors: Schippling
authors: Jens
authors: J
authors: Kuhle
authors: Mohammad Ali
authors: MA
authors: Sahraian
authors: Francoise
authors: F
authors: Gray
authors: Veronika
authors: V
authors: Jakl
authors: Darius
authors: D
authors: Häusler
authors: Wolfgang
authors: W
authors: Brück
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D005260:Female; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology*; D007968:Leukoencephalopathy, Progressive Multifocal / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D000069442:Natalizumab; D013577:Syndrome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab