JC Virus - PML

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Demyelinating central nervous system (CNS) lesions in an immunocompromised patient

Laboratory Testing

  • Cerebrospinal fluid (CSF) testing – useful to exclude other more common diagnoses (eg, meningitis, encephalitis)
    • Should include cell count with differential, protein, glucose, and culture
      • Culture for JC virus (JCV) is not performed out of a research setting (too slow of growth)
    • PCR testing – positive test with appropriate clinical symptoms strongly supports diagnosis (high sensitivity)
      • May obviate need for brain biopsy (Berger, 2013)
      • Negative test does not rule out PML

Histology

  • Brain biopsy – gold standard and usually diagnostic
    • Most useful if JCV not detected in CSF
    • May not be able to perform biopsy on debilitated patients
    • Key histologic features
      • Multifocal demyelination
      • Enlarged oligodendrocytes with nuclear inclusions
      • Large, bizarre astrocytes, reactive gliosis
        • Unusual astrocytes may cause confusion with glioma on biopsy
      • Minimal inflammation
  • Immunohistochemistry – JCV staining in oligodendrial cells and astrocytes

Imaging Studies

  • CT – patchy or confluent hypodense white matter lesions
    • Lesions do not conform to cerebrovascular territories 
  • MRI – more sensitive than CT
    • Recommended initial scan if suspicion for PML 
    • Hyperintense subcortical white matter lesions on T2-weighted images
  • Lesions do not have an anatomic predisposition

Differential Diagnosis

JC virus (JCV) is a human neurotropic polyomavirus that is the etiologic agent of progressive multifocal leukoencephalopathy (PML). PML is a rare, fatal, demyelinating disease of the central nervous system which almost always occurs in an immune-compromised setting.

Epidemiology

  • Incidence 
    • ≥50% of population is JC virus infected – typically by late childhood 
    • PML presentation of the infection is rare
  • Age – all ages
  • Sex – M>F

Organism

  • JCV is a nonenveloped double-stranded DNA virus of the Polyomaviridae (formerly Papovaviridae) family, which also includes BK virus (BKV) and SV40
    • JCV infects only humans
    • JCV and BKV – named using the initials of the first patients identified with these diseases

Risk Factors

  • HIV infection
  • Use of immunomodulation therapy
    • Monoclonal antibodies (eg. natalizumab, efalizumab, alemtuzumab, rituximab, brentuximab)
    • Mycophenolate mofetil
    • Malignancy (eg, leukemia, lymphoma)

Pathophysiology

  • Multifocal demyelination caused by lytic infection of the oligodendrocytes
    • Lesions range in size from 1 mm to several centimeters
    • Lesions may coalesce
    • Myelin loss may be extensive
    • Atrophy may occur

Clinical Presentation

  • Clinical presentation is diverse
  • PML
    • Hemiplegia, visual disturbances, and subcortical dementia
      • Progressive – fatal within 3-6 months
    • Other symptoms – motor weakness, incoordination, gait abnormalities
    • Found almost exclusively in patients with severe immune compromise
      • Considered an AIDS-defining illness – 85% of cases occur in this group
        • Usually occurs when CD4 count <200 cells/mm3
      • Also associated with lymphoproliferative disease, natalizumab therapy (Tysabri), rituximab, hematologic malignancies
  • Inflammatory PML
    • Usually occurs during immune reconstitution in HIV patients
    • More favorable outcome than PML
  • JCV cerebellar granule cell neuronopathy
    • Ataxia, cerebellar atrophy
  • JCV encephalopathy
    • Aphasia, cognitive decline
    • Rapidly fatal in case reports
  • JCV meningitis
    • Presents as chronic meningitis signs and symptoms
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

JC Virus by PCR 0099169
Method: Qualitative Polymerase Chain Reaction

Recommended Use 

Use to diagnose PML when there is a suspicion based on imaging and clinical presentation

Specimen should be cerebrospinal fluid

Limitations 

Negative test does not rule out PML

Guidelines

Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, Bartt R, Major EO, Nath A. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology. 2013; 80(15): 1430-8. PubMed

General References

Berger JR. Progressive multifocal leukoencephalopathy. Handb Clin Neurol. 2014; 123: 357-76. PubMed

Jiang M, Abend JR, Johnson SF, Imperiale MJ. The role of polyomaviruses in human disease. Virology. 2009; 384(2): 266-73. PubMed

Morrison BJ, Labo N, Miley WJ, Whitby D. Serodiagnosis for tumor viruses Semin Oncol. 2015; 42(2): 191-206. PubMed

Pinto M, Dobson S. BK and JC virus: a review. J Infect. 2014; 68 Suppl 1: S2-8. PubMed

Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol. 2010; 9(4): 425-37. PubMed

Tyler KL. Emerging viral infections of the central nervous system: part 2. Arch Neurol. 2009; 66(9): 1065-74. PubMed

Wang Y, Kirby JE, Qian Q. Effective use of JC virus PCR for diagnosis of progressive multifocal leukoencephalopathy. J Med Microbiol. 2009; 58(Pt 2): 253-5. PubMed

Medical Reviewers

Hillyard, David R., MD, Medical Director, Molecular Infectious Diseases at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Professor of Biology, University of Utah

Salama, Mohamed E., MD, Medical Director, Hematopathology and Immunohistochemistry Staining at ARUP Laboratories; Associate Professor of Clinical Pathology, Director of Hematopathology Fellowship Program, University of Utah

Last Update: August 2016

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