How do you diagnose JC virus?

Diagnosis of JC Virus

JC virus infection is most reliably diagnosed through detection of virus-specific antibodies in cerebrospinal fluid (CSF) or serum, as nucleic acid amplification tests lack sensitivity for routine diagnosis. 1

Clinical Presentation

JC virus is associated with Progressive Multifocal Leukoencephalopathy (PML), which typically presents with:

• Neurological symptoms that develop over days to weeks
• Mental status changes
• Focal neurologic deficits
• Movement disorders
• Seizures (especially in children)
• Parkinsonian syndrome with mask-like facies, tremor, and rigidity
• Acute flaccid paralysis in some cases 1

Diagnostic Algorithm

1. Serological Testing (Primary Method)

• First-line test: IgM antibody-capture enzyme-linked immunosorbent assay (MAC ELISA) on CSF and serum
  • JC virus IgM antibodies can be detected in CSF within 4 days after symptom onset
  • Serum antibodies typically detectable by 7-8 days after onset 1
  • Presence of JC virus IgM antibodies in CSF strongly indicates CNS infection 1

2. Confirmatory Testing

• Plaque reduction neutralization tests (PRNT) to:
  • Confirm recent infection
  • Measure virus-specific neutralizing antibodies
  • Discriminate between cross-reacting antibodies from other flavivirus infections
  • A fourfold or greater rise in virus-specific neutralizing antibodies between acute and convalescent-phase serum specimens (collected 2-3 weeks apart) confirms recent infection 1, 2

3. Neuroimaging

• MRI is superior to CT for detecting JC virus-associated abnormalities
• Look for characteristic changes in:
  • Thalamus (most common abnormality)
  • Basal ganglia
  • Midbrain
  • Pons
  • Medulla 1

4. CSF Analysis

• Typically shows:
  • Lymphocytic pleocytosis
  • Moderately elevated protein levels
  • Normal glucose 1

Important Caveats and Pitfalls

• Nucleic acid amplification tests (NAATs) and virus isolation have poor sensitivity and should not be used to rule out JC virus infection

  • Humans have low or undetectable viremia by the time clinical symptoms appear 1, 2
  • In one study, JC virus could not be isolated from plasma or CSF in any of 30 nonfatal cases 1

• Cross-reactivity issues: Antibody tests may cross-react with other flaviviruses

  • Consider vaccination history and exposure to other arboviruses when interpreting results
  • PRNT can help differentiate between cross-reacting antibodies 1

• False-negative PCR results can occur despite clinical and radiological findings suggestive of PML

  • In cases with high clinical suspicion but negative CSF PCR, consider:
    • Repeat testing with ultrasensitive PCR assays
    • Brain biopsy for definitive diagnosis 3, 4

• Brain biopsy may be more reliable than CSF DNA testing in some cases

  • Consider early brain biopsy in cases with high clinical suspicion but negative CSF results 3

Special Considerations

• In immunocompromised patients with suspected PML, higher viral loads in CSF (>4.68 log) have been associated with shorter survival time 5

• Intrathecal JC virus antibody production indicates active CNS infection and has been reported to have 67% sensitivity and 100% specificity for PML diagnosis 6

• The absence of serum JC virus antibody nearly always excludes a diagnosis of PML 6