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.

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Clinical Overview

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

Infectious
- Encephalitis
- Meningitis
- Subacute sclerosing panencephalitis
- Bovine spongiform encephalopathy (BSE) (mad cow disease)
- Rabies virus
- Toxoplasma gondii
Vascular
- Cerebral infarction
- Vasculitis
Other neurologic diseases
- Multiple sclerosis (MS)
- Acute demyelinating encephalomyelitis
- Parkinson disease
- Alzheimer disease
- Huntington disease
- Reversible posterior leukoencephalopathy
Tumor
- CNS lymphoma
- Metastatic cancer

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

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

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

Medical Experts

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

References

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
Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H, Centers for Disease Control and Prevention (CDC), National Institutes of Health, HIV Medicine Association of the Infectious Diseases Society of America. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009; 58(RR-4): 1-207; quiz CE1-4. PubMed
European Medicines Agency. Updated recommendations to minimise the risk of the rare brain infection PML with Tecfidera. London, United Kingdom. [Accessed: Dec 2017]
United Kingdom Medicines and Healthcare Products Regulatory Agency. Dimethyl fumarate (Tecfidera): updated advice on risk of progressive multifocal leukoencephalopathy. London, United Kingdom. [Accessed: Dec 2017]

General References

Bartsch T, Rempe T, Wrede A, Leypoldt F, Brück W, Adams O, Rohr A, Jansen O, Wüthrich C, Deuschl G, Koralnik IJ. Progressive neurologic dysfunction in a psoriasis patient treated with dimethyl fumarate. Ann Neurol. 2015; 78(4): 501-14. PubMed

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

McGuigan C, Craner M, Guadagno J, Kapoor R, Mazibrada G, Molyneux P, Nicholas R, Palace J, Pearson OR, Rog D, Young CA. Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. J Neurol Neurosurg Psychiatry. 2016; 87(2): 117-25. PubMed

Miskin DP, Koralnik IJ. Novel syndromes associated with JC virus infection of neurons and meningeal cells: no longer a gray area. Curr Opin Neurol. 2015; 28(3): 288-94. 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

Ryschkewitsch CF, Jensen PN, Monaco MC, Major EO. JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab. Ann Neurol. 2010; 68(3): 384-91. 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

White MK, Sariyer IK, Gordon J, Delbue S, Pietropaolo V, Berger JR, Khalili K. Diagnostic assays for polyomavirus JC and progressive multifocal leukoencephalopathy. Rev Med Virol. 2016; 26(2): 102-14. PubMed

Content Review:

May 2017

Last Update: July 2018