Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease of the central nervous system caused by a reactivation of the JC virus that occurs almost exclusively in immunosuppressed individuals.
PML is a major opportunistic infection associated with HIV infection and AIDS, with a prevalence of about 5 percent. Outside of HIV infection, PML occurs rarely in patients with lymphoproliferative and myeloproliferative diseases, solid organ malignancies, granulomatous and inflammatory diseases, and organ transplant recipients. Rare cases of PML have been reported in patients treated with the immunomodulatory medication natalizumab.
PML typically presents with subacute neurologic deficits including altered mental status, visual symptoms such as hemianopia and diplopia, hemiparesis or monoparesis, and diplopia, hemiparesis or monoparesis, and appendicular or gait ataxia. Seizures occur in up to 18 percent of patients.
New onset or clinical worsening of PML may occur shortly after the initiation of combined antiretroviral therapy (ART) due to the immune reconstitution inflammatory syndrome (IRIS).
JC virus granule cell neuronopathy presents with ataxia and cerebellar atrophy in patients with HIV infection who do not have obvious PML lesions in the cerebellum.
Unusual manifestations of JC virus include infection of cortical neurons causing encephalopathy and infection of leptomeningeal cells causing meningitis.
Clinical suspicion for PML should be heightened if neuroimaging reveals a multifocal process limited to the white matter that does not conform to vascular territories and exhibits neither mass effect nor contrast enhancement. In patients with HIV infection, the differential diagnosis of PML includes HIV encephalopathy and primary central nervous system lymphoma.
Brain biopsy is the gold standard for diagnosis of PML but is associated with clinically significant morbidity and mortality. In patients with appropriate neurologic and neuroradiologic features, the diagnosis of PML can usually be established by polymerase chain reaction detection of JC virus DNA in the cerebrospinal fluid if brain biopsy is not desired. However, the sensitivity of polymerase chain reaction for the diagnosis of PML in patients with HIV infection appears to be declining since the advent of combined ART therapy.
The differential diagnosis of PML includes HIV encephalopathy, primary central nervous system lymphoma, primary angiitis of the central nervous system, reversible posterior leukoencephalopathy, varicella-zoster virus encephalopathy, and new or recurrent attacks of multiple sclerosis.