JC Virus - Progressive Multifocal Leukoencephalopathy

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
  • 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's 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