Pathologic Findings of Chronic PML-IRIS in a Patient with Prolonged PML Survival Following Natalizumab Treatment.

Mai Himedan,Avneesh Gupta,Elizabeth A Mills,Yang Mao-Draayer,Sandra Camelo-Piragua,Rany Aburashed

doi:10.1177/2324709617734248

Abstract

Immune reconstitution inflammatory syndrome (IRIS) is a common complication during treatment for natalizumab-associated progressive multifocal leukoencephalopathy (PML). Although severe IRIS can result in acute worsening of disability and is associated with poor prognosis, effective immune reconstitution may account for the high survival rate of this cohort of PML patients. We present pathological evidence of chronic IRIS 3.5 years after diagnosis with natalizumab-associated PML. Our case showed that the IRIS initially developed after plasma exchange therapy and resolved clinically and radiologically following a combination treatment with corticosteroids, maraviroc, and cidofovir. Autopsy 3.5 years later revealed evidence of grey-white matter junction demyelinating lesions characteristic of PML and perivascular leukocyte infiltrates predominated by CD8+ T-lymphocytes, and polymerase chain reaction analysis demonstrated the presence of JC viral DNA in this tissue, indicative of persistent PML-IRIS. While clinical symptoms of PML-IRIS typically stabilize within 6 months, our case report suggests that prolonged low-grade inflammation may persist in some patients. Better assays are needed to determine the prevalence of prolonged low-grade IRIS among PML survivors.

Highlights

Progressive multifocal leukoencephalopathy (PML) is a rare progressive demyelinating disease caused by a mutated form of the John Cunningham virus (JCV) that often results in severe debilitation or death
All sections containing demyelinating plaques were stained with anti-SV40 (Cell MarqueSigma-Aldrich, Clone MRQ4, pre-diluted, Rocklin, CA), but there was no evidence of active polyomavirus infection by this immunohistochemical stain
The imaging details the progression from PML to Immune reconstitution inflammatory syndrome (IRIS) and eventually radiologic stabilization with extensive tissue destruction

Summary

Introduction

Progressive multifocal leukoencephalopathy (PML) is a rare progressive demyelinating disease caused by a mutated form of the John Cunningham virus (JCV) that often results in severe debilitation or death. IRIS on biopsy has been 9 months, which occurred in a patient with a fatal outcome.[17] Here we present the clinical, radiological, and pathological features of a case of PML occurring during natalizumab use and subsequent IRIS treated with maraviroc that led to prolonged survival with later autopsy findings indicating active IRIS associated inflammation 3.5 years after initial diagnosis. Serum JCV antibodies were detected in September 2011, but the patient elected to continue treatment with natalizumab He subsequently tested negative for JCV DNA in cerebrospinal fluid (CSF) using polymerase chain reaction (PCR) in November 2011. In July 2013, a repeat CSF JCV PCR test was ordered and showed a value down below the level of detection He continued outpatient treatment with cidofovir and maraviroc. Fourteen months after PML diagnosis, MRI showed decreased FLAIR hyperintensity and apparent brain atrophy

Brain Autopsy Findings

Discussion

Declaration of Conflicting Interests