Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating disease of the central nervous system caused by reactivation of latent JC polyomavirus in oligodendrocytes, leading to multifocal lytic infection and white matter destruction. Up to 80% of adults harbor latent JC virus, but disease only emerges in profound cellular immunosuppression. Risk groups include HIV/AIDS with CD4 counts under 200, multiple sclerosis patients on natalizumab (especially after 24 months therapy with prior immunosuppression and JCV antibody positivity), solid organ and hematopoietic stem cell transplant recipients, and patients on rituximab, fingolimod, mycophenolate, or other immunomodulators.
Clinical presentation evolves over weeks to months with subcortical cognitive decline, hemiparesis, visual field defects, ataxia, aphasia, and behavioral changes reflecting multifocal supratentorial and cerebellar lesions. MRI shows asymmetric, confluent T2/FLAIR hyperintense subcortical white matter lesions without mass effect or significant contrast enhancement, often involving U-fibers; lesions are bilateral but asymmetric and progress over weeks. Diagnosis is supported by detection of JC virus DNA in cerebrospinal fluid by quantitative PCR (sensitivity 70-90% with specialized assays) or by brain biopsy showing demyelination, bizarre astrocytes, and intranuclear inclusion bodies in oligodendrocytes.
There is no specific antiviral therapy. Treatment focuses on rapid restoration of immune function: combination antiretroviral therapy (cART) for HIV/AIDS, plasma exchange or immunoadsorption to remove natalizumab, and reduction or discontinuation of immunosuppressants in transplant recipients. Immune reconstitution inflammatory syndrome (PML-IRIS) may complicate recovery, presenting with paradoxical worsening, contrast enhancement on MRI, and edema requiring corticosteroids. Mortality remains 30-50%, and survivors often have significant residual neurologic deficits. Newer experimental approaches include pembrolizumab and adoptive T-cell therapy targeting JC virus.