Practical Management of Progressive Multifocal Leukoencephalopathy and Immune Reconstitution Inflammatory Syndrome

Purpose of Review: The aim of this narrative review was to provide treating physicians with practical guidance on the management of progressive multifocal leukoencephalopathy (PML), offering a rational, evidence-informed approach to diagnosis and treatment based on published literature and the authors' collective clinical experience. Recent Findings: The management of PML requires precise characterization of disease status at presentation and throughout follow-up. We begin by outlining the clinical scenarios in which PML should be suspected, emphasizing that disease presentation is shaped by the strength and quality of the host's antiviral immune response. We then detail the evaluation of patients at the time of diagnosis and during follow-up, with particular attention to defining whether PML is presenting in its classic form, with inflammatory features, or in the context of immune reconstitution inflammatory syndrome. This assessment should incorporate prognostic markers to evaluate the potential for immune recovery and virologic control. We further summarize the current standard of care and identify clinical contexts in which experimental immunotherapeutic interventions to facilitate restoration of JC virus-specific immune functions may be considered, emphasizing the importance of individualized, risk-benefit-based decision making. Notably, such experimental immunotherapies are likely unnecessary and may even be harmful, once immune reconstitution has already been achieved and virologic control is evident. Finally, we address the management of inflammation in PML, underscoring that not all inflammatory presentations warrant corticosteroid therapy. Summary: The management of PML remains a significant clinical challenge. Standardizing assessment protocols across centers may enhance data quality and comparability and facilitate future collaborative and data-sharing efforts.