Progressive multifocal leukoencephalopathy — a diagnostic guide for the clinical neurologist

Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal demyelinating disease of the central nervous system caused by reactivation of latent JC virus in immunocompromised individuals. Despite advances in understanding its pathogenesis, PML remains a diagnostic challenge due to its diverse clinical manifestations, radiographic overlap with other disorders, low incidence and subsequent lack of clinical familiarity. Diagnostic delays, often extending months after symptom onset, are common and contribute to poor outcomes. This review outlines the key clinical features, risk factors, diagnostic and neuroradiographic findings of PML to aid practicing neurologists in timely recognition and expedited diagnosis. We review emerging biomarkers and advanced diagnostic tools to identify PML. We also compare PML with its common mimics to underscore diagnostic pitfalls and how to overcome them. Novel and experimental therapies are beyond the scope of this article; instead, we focus on equipping neurologists with a framework grounded in patient data and clinical experience to establish timely diagnoses of PML.