Progressive multifocal leukoencephalopathy

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Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the CNS caused by the reactivation of the JC virus. It occurs mainly in patients with severe immunosuppression (e.g., AIDS) and clinical manifestations include focal neurological deficits, seizures, and vision changes. The diagnosis is usually made based on typical imaging findings, but brain biopsy is the gold standard for diagnosis. Treatment is primarily supportive, and in patients with HIV, ART should be started immediately.

See also “HIV-associated conditions.”

A demyelinating disease of the central nervous system caused by the JC virus

• Mainly in patients with severe immunosuppression (e.g., patients with lymphoma/leukemia, patients that received organ transplantation)
• In patients with HIV ^[2]
  • Affects ∼ 5% of AIDS patients (typically at CD4 count < 200)
  • Can also occur after initiation of ART secondary to immune reconstitution inflammatory syndrome (IRIS)
  • Can also occur in patients with HIV well-controlled on ART

Epidemiological data refers to the US, unless otherwise specified.

• Reactivation of JC virus in the setting of immunosuppression due to: ^[2]
  • HIV infection (AIDS-defining opportunistic infection)
  • Hematological and solid cancers
  • Inflammatory diseases
  • Treatment with immunosuppressants or immunomodulators: e.g., natalizumab, rituximab

Reactivation of a past subclinical infection with JC virus is triggered (e.g., by immunosuppression) → oligodendrocyte infection → viral DNA mutation; → aggressive replication within brain tissue → demyelination, destruction of infected oligodendrocytes ^[3]

Symptoms due to PML are insidious in onset and can progress over several weeks. ^[2]

• Focal neurologic deficits: e.g., hemiplegia, aphasia, ataxia
• Seizures
• Impaired attention
• Vision alterations, most commonly hemianopsia
• Isolated encephalopathy, dementia, altered mental state, and behavioral changes are uncommon but may occur alongside focal neurological deficits.

Approach

• A presumptive diagnosis of PML can be made based on the clinical presentation (e.g., progressive onset of focal neurological deficits) and neuroimaging findings.
• Confirmatory testing with CSF analysis (or rarely, brain biopsy) can be considered as needed; for example
  • Inconclusive neuroimaging findings and/or atypical clinical features
  • Before initiating ART in patients with PML as the initial manifestation of HIV infection
  • For prognostication

Neuroimaging findings ^[2][4]

• MRI brain without and with gadolinium contrast (preferred)
  • Multifocal, bilateral, asymmetric white matter lesions (hypointense on T1, hyperintense on T2) without mass effect
  • Frontal, parietal and occipital lobes are mostly commonly involved.
  • Lesions may exhibit faint contrast enhancement
• CT brain with contrast ^[5]
  • Focal, asymmetric hypodense white matter lesions without mass effect
  • Contrast enhancement in the periventricular and subcortical white matter seen in rare cases

Laboratory studies ^[4]

• Screen for HIV if HIV status is unknown.
• CD4 count: for patients with HIV: typically < 200 ^[4]
• CSF analysis
  • Cell count < 20/mm³, elevated protein, occasionally low glucose
  • CSF PCR; for detection of JC virus DNA

Brain biopsy and histology ^[4]

Brain biopsy and histology is the gold standard test for PML but is not routinely performed as it is associated with a significant risk of complications.

• Indications: Consider when there is incongruence between clinical findings, imaging, and/or CSF.
• Findings: The classic triad consists of
  • Demyelination of axons
  • Enlarged oligodendrocyte nuclei with intranuclear inclusions
  • Bizarre astrocytes

• Treatment is mainly supportive (e.g., treatment of seizures).
• Patients with HIV
  • Start ART immediately.
  • For those already taking ART, optimize regimes to improve immune status.
• Monitor for IRIS, which may cause a paradoxical worsening of PML.

References: ^[2]

PML typically progresses rapidly and is associated with high mortality.

• Patients without HIV: Median survival is 3 months. ^[6]
• Patients with HIV: One-year survival is ≥ 50% (with antiretroviral therapy). ^[6]