progressive multifocal leukoencephalopathy (PML)

Introduction

An opportunistic infection of the brain in an immunocompromised host, 1st described by Astome, Mancall & Richardson in 1958

The causative agent was isolated from the post mortem brain of a patient JC, by using cultures of human fetal glial cells.

Etiology

• polyomavirus: JC virus (majority) & SV40 (2 cases)
• risk factors
  • immunodeficiency, especially AIDS
  • myeloproliferative disorders
  • chronic infections
• a small number of patients do not have any underlying disease or recognized immunodeficiency

Epidemiology

• patients are generally middle-aged
• antibodies to JC virus in 80% of adults

Pathology

• focal demyelination resulting from failure of infected oligodendrocytes to maintain myelination
  • sparing of axons is relative
  • central part of larger lesions may exhibit frank necrosis with phagocytic reaction (microglia & macrophages) indistinguishable from an infarct
• gross pathology
  • brain may appear grossly normal at autopsy
  • may be some cortical atrophy
  • multiple grey foci distributed throughout centrum semiovale &, to a lesser extent cerebellum & brainstem
  • may be large & confluent, even cystic changes in white matter
• histopathology:
  • multiple foci of demyelination, sometimes confluent
  • large, abnormal astrocytes
    • often multinucleate
    • numerous, large processes
  • a few chronic inflammatory cells, mostly lymphocytes
  • intranuclear inclusions, basophilic or eosinophilic, within large swollen oligodendrocyte nuclei
    • numerous at periphery of demyelinated foci
  • granule cell loss & foci of demyelination may be seen in the cerebellum

Clinical manifestations

• insidious onset
• dementia is often presenting symptom
• confusion
• personality change
• hemianopsia, diplopia or other visual field disturbance
• motor weakness, hemiparesis (focal or asymmetric)

Laboratory

• cerebrospinal fluid:
  • cell count, protein, glucose is normal
  • PCR for JC virus from CSF
  • serology: antibodies to JC virus (high titer)
• brain biopsy:
  • detection of viral particles (EM)
    • 30 nm viral particles
    • found profusely in oligodendrocytes
    • rarely found in astrocytes
    • never found in neurons
  • antigen by immunocytochemistry
  • viral genome by in situ hybridization or PCR
  • viral cultures generally not done (see above)
  • diagnostic
• see ARUP consult

Radiology

• CT or MRI shows white matter demyelination
• hypodense, non-enhancing lesions more prominently visualized on T2-weighted MRI scans
  • hyperintense (white) areas on T2-weighted images
  • fluid-attenuated inversion recovery sequences
• hypointense (dark) areas on T1-weighted images
• usually no mass effect.

Differential diagnosis

• AIDS dementia complex
• toxoplasmosis (mass effect, enhancing lesions)
• primary CNS lymphoma (mass effect, enhancing lesions)

Management

• initiation of antiretroviral therapy to reverse the immunosuppression that interferes with the normal host response to JCV.
• prior to effective antiretroviral therapy prognosis was poor
  • death generally occurs within 1-6 months
  • a few patients appear to have remissions & survive for years

More general terms

• leukoencephalopathy
• viral encephalitis
• demyelinating disease

Patient information

progressive multifocal leukoencephalopathy patient information