What is the recommended test for diagnosing neurosyphilis?

Diagnostic Testing for Neurosyphilis

The cornerstone of neurosyphilis diagnosis is CSF examination with CSF-VDRL (or CSF-RPR) combined with CSF white blood cell count, where a reactive CSF-VDRL plus CSF WBC >10 cells/µL strongly supports the diagnosis. 1, 2

When to Perform CSF Examination

CSF examination should be performed in the following clinical scenarios:

• Patients with neurologic or ocular symptoms/signs 3, 1
• Active tertiary syphilis 3, 1
• Treatment failure for non-neurologic syphilis 3, 1
• HIV-infected patients with late-latent syphilis or syphilis of unknown duration 3, 1
• Some specialists recommend CSF examination for all HIV-infected patients with syphilis if serum RPR ≥1:32 or CD4+ count <350 cells/µL 3

Diagnostic Algorithm for Interpreting CSF Results

Primary Diagnostic Criteria

A reactive CSF-VDRL combined with CSF WBC >10 cells/µL provides the strongest diagnostic support for neurosyphilis. 3, 1, 2

CSF-VDRL Performance Characteristics

• Sensitivity: 49-87.5% (meaning it misses 13-51% of neurosyphilis cases) 3
• Specificity: 74-100% (highly specific when positive) 3
• A reactive CSF-VDRL establishes the diagnosis, but a nonreactive test does NOT exclude neurosyphilis 3, 1

CSF-RPR Performance Characteristics

• Sensitivity: 51.5-81.8% (appears slightly less sensitive than CSF-VDRL) 3
• Specificity: 81.8-100% 3
• Limited data suggest CSF-RPR may be less sensitive than CSF-VDRL 3

Supporting CSF Findings

• CSF WBC count: Typically 10-200 cells/µL with mononuclear predominance 3, 2
• CSF protein: Normal or mildly elevated 3, 2
• Critical caveat: Never base diagnosis solely on elevated CSF protein without reactive VDRL or elevated WBC 3, 2

Role of CSF Treponemal Tests

CSF treponemal tests (e.g., CSF FTA-ABS, CSF-TPPA) are sensitive but NOT specific:

• A nonreactive CSF treponemal test excludes neurosyphilis 3, 1
• A reactive CSF treponemal test does NOT confirm neurosyphilis (too many false positives) 3, 1
• These tests are useful for ruling out disease when negative, not for ruling in disease when positive 3

Critical Pitfalls to Avoid

Blood Contamination

Traumatic lumbar puncture can cause false-positive CSF-VDRL results, particularly in patients with high serum VDRL titers. 3, 2 Blood contamination must be assessed and considered when interpreting results.

HIV-Related Confounders

HIV infection itself causes mild mononuclear CSF pleocytosis (5-15 cells/µL), particularly in patients with CD4+ counts >500 cells/µL. 3, 2 This complicates interpretation of the CSF WBC threshold of >10 cells/µL in HIV-infected patients.

False Negatives

CSF-VDRL has limited sensitivity (49-87%), so a negative result does not exclude neurosyphilis. 3, 1 If clinical suspicion remains high despite negative CSF-VDRL, treatment for neurosyphilis should be considered, especially if CSF treponemal tests are reactive. 3

False Positives

Rare false-positive CSF-VDRL results can occur with CNS malignancies. 3, 2

Serum Testing as Predictor

Serum RPR titer ≥1:32 significantly increases the likelihood of neurosyphilis:

• In HIV-uninfected patients: 10.85-fold increased odds 4
• In HIV-infected patients: 5.98-fold increased odds 4
• Among patients with asymptomatic late syphilis and RPR ≥1:128,38% had neurosyphilis 5

Summary of Testing Strategy

1. Perform lumbar puncture in patients meeting clinical indications above 3, 1
2. Order CSF-VDRL (preferred) or CSF-RPR as the primary diagnostic test 3, 1
3. Obtain CSF WBC count and protein 3, 2
4. Interpret results algorithmically:
   • Reactive CSF-VDRL + WBC >10 cells/µL = Neurosyphilis confirmed 1, 2
   • Nonreactive CSF-VDRL but high clinical suspicion = Consider CSF treponemal test; if reactive, treat as neurosyphilis 3
   • Elevated protein alone without reactive VDRL or elevated WBC = Insufficient for diagnosis 3, 2