JC Virus - Progressive Multifocal Leukoencephalopathy

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 (CNS) which almost always occurs in an immunocompromised patient.

Diagnosis

Indications for Testing

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

Laboratory Testing

  • Polymerase chain reaction (PCR) – cerebrospinal fluid (CSF)
    • Positive CSF test with appropriate clinical symptoms strongly supports diagnosis (high sensitivity)
    • May obviate need for brain biopsy (Berger, 2013)
    • Negative test does not rule out progressive multifocal leukoencephalopathy (PML)
    • Blood and urine tests available but do not correlate with active CNS infection
  • Other CSF testing
    • Use to exclude other, more common diagnoses (eg, bacterial or viral meningitis, encephalitis)
    • Should include cell count with differential, protein, glucose, and bacterial culture
    • Culture for JC virus (JCV) should not be performed outside of a research setting (growth is too slow)
  • JCV antibodies (test not available at ARUP Laboratories)
    • Use to stratify risk for PML prior to high-risk treatments (eg, natalizumab)
    • Not useful for diagnosis – >50-86% of people have been exposed to JCV and have positivity

Histology

  • Brain biopsy – gold standard and usually diagnostic
    • Most useful if JCV is not detected in CSF
    • May not be feasible to perform 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 oligodendroglial cells and astrocytes

Imaging Studies

  • Computed tomography (CT) – patchy or confluent hypodense white matter lesions
  • Magnetic resonance imaging (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 or conform to cerebrovascular territories

Differential Diagnosis

Background

Epidemiology

  • Incidence 
    •  >50-86% of population is JC virus (JCV) infected, typically by late childhood
    • Progressive multifocal leukoencephalopathy (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 simian virus 40 (SV40)
    • JCV infects only humans
    • JCV and BKV – names were derived from initials of first patients identified with these diseases

Risk Factors

  • HIV infection
  • Malignancy (eg, leukemia, lymphoma)
  • Medications – benefits of treatment must be weighed against known risk of PML
    • Dimethyl fumarate (Tecfidera) – multiple sclerosis (MS)
    • Natalizumab (Tysabri) – MS, Crohn disease
    • Rituximab – psoriasis, systemic lupus erythematosus (SLE)
    • Efalizumab – psoriasis treatment (withdrawn from market due to PML risk)
    • Ocrelizumab – multiple sclerosis (suspected risk due to medication class)
    • Alemtuzumab – select lymphomas, relapsing MS
    • Brentuximab – select lymphomas
    • Mycophenolate mofetil – immunosuppression following organ transplantation

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
  • Subtypes
    • PML
      • Characterized by multiple focal lesions that gradually increase in size
        • Typical presentation involves distinct focal symptoms, followed by progression (vs. global presentation of more diffuse encephalopathy)
      • Presentation reflects location of lesion(s) – demyelinating regions can occur anywhere in the brain
      • Found almost exclusively in severely immunocompromised patients
      • Considered an AIDS-defining illness – 85% of cases occur in this group
      • Usually occurs when CD4 count <200 cells/mm3
    • 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 with signs and symptoms of chronic meningitis

ARUP Lab Tests

Detect JC virus in cerebrospinal fluid (CSF), serum, or urine specimens

Related Tests

Identify bacteria in CSF

Molecular testing is preferred for patients presenting with meningitis/encephalitis; refer to meningitis/encephalitis panel by PCR

Panel includes measles (rubeola) antibody, IgG, CSF; measles (rubeola) antibody, IgM, CSF; mumps virus antibody, IgG, CSF; mumps virus antibody, IgM, CSF; varicella-zoster virus antibody, IgG, CSF; varicella-zoster virus antibody, IgM by ELISA (CSF); herpes simplex virus type 1 and/or 2 antibodies, IgM by ELISA, CSF; herpes simplex virus type 1 and/or 2 antibodies, IgG, CSF; herpes simplex virus type 1 glycoprotein G-specific antibody, IgG by ELISA, CSF; herpes simplex virus type 2 glycoprotein G-specific antibody, IgG by ELISA, CSF; West Nile virus antibody, IgG by ELISA, CSF; West Nile virus antibody, IgM by ELISA, CSF

Reflex: if HSV 1 and/or 2 IgG, CSF is 1.10 IV or greater, then HSV 1 G-specific IgG, CSF and HSV 2 G-specific IgG, CSF will be added

Use to diagnose and manage diabetes mellitus and other carbohydrate metabolism disorders

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References

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