What are the recommended tests and treatment for serological diagnosis of neurosyphilis?

Serological Testing for Neurosyphilis

Direct Diagnostic Recommendation

For neurosyphilis diagnosis, perform CSF examination with VDRL-CSF as the standard test, combined with CSF white blood cell count and protein analysis—no single test is sufficient, and diagnosis requires the combination of reactive VDRL-CSF (highly specific when positive) plus elevated CSF WBC >5-10 cells/mm³, along with reactive serum treponemal tests. 1, 2, 3

Diagnostic Algorithm

When to Perform CSF Examination

Obtain CSF in patients with:

• Neurologic or ocular symptoms/signs 3
• Active tertiary syphilis 3
• Treatment failure for non-neurologic syphilis 3
• HIV-infected patients with late-latent syphilis or syphilis of unknown duration 3

CSF Testing Panel

Perform the following tests on cerebrospinal fluid:

1. VDRL-CSF (Standard Test)

• This is the gold standard serologic test for CSF 1, 4, 3
• Reactive VDRL-CSF is diagnostic of neurosyphilis when there is no significant blood contamination 1, 4
• Sensitivity: 49-87% (meaning it can be negative even when neurosyphilis is present) 4
• Specificity: 74-100% (highly specific—false positives are rare) 4
• A negative VDRL-CSF does NOT exclude neurosyphilis 4

2. CSF White Blood Cell Count

• Elevation >5 cells/mm³ (some sources use >10 cells/mm³) is typically present in neurosyphilis 1, 4, 3
• This is the most sensitive measure of disease activity and treatment effectiveness 1, 4
• Reactive VDRL-CSF plus CSF WBC >10 cells/µL strongly supports neurosyphilis diagnosis 3

3. CSF Protein

• Usually elevated or mildly elevated in neurosyphilis 3
• Less specific than WBC count but contributes to overall diagnostic picture 3

4. Optional: CSF Treponemal Tests (FTA-ABS)

• Highly sensitive (95% pooled sensitivity) but less specific than VDRL-CSF 1, 4, 5
• A negative CSF FTA-ABS effectively excludes neurosyphilis according to some experts 1, 3
• A positive result does not confirm neurosyphilis due to lower specificity 3
• Pooled specificity: 85% 5

Serum Testing (Complementary, Not Diagnostic for Neurosyphilis)

Always perform both nontreponemal and treponemal tests on serum:

• Nontreponemal tests (VDRL or RPR): Monitor disease activity quantitatively 1, 2
• Treponemal tests (FTA-ABS or TP-PA): Confirm treponemal infection 2
• Serum tests alone cannot diagnose or exclude neurosyphilis 4

Diagnostic Interpretation

Diagnostic Criteria for Neurosyphilis

Neurosyphilis is diagnosed when you have:

• Reactive VDRL-CSF (without blood contamination) 1, 4, 3
• PLUS elevated CSF WBC >5-10 cells/mm³ 1, 3
• PLUS reactive serum treponemal test 1, 2
• With or without clinical neurologic manifestations 1

Alternative Diagnostic Patterns

If VDRL-CSF is negative but clinical suspicion remains high:

• Elevated CSF WBC >10 cells/mm³ with reactive serum tests suggests possible neurosyphilis 3
• Consider CSF FTA-ABS—if negative, neurosyphilis is unlikely 1, 3
• Elevated CSF protein supports the diagnosis but is not specific 3

Test Performance Comparison

Recent meta-analysis data shows:

• Nontreponemal CSF tests (VDRL, RPR, TRUST): 77% sensitivity, 99% specificity 5
• Treponemal CSF tests: 95% sensitivity, 85% specificity 5
• TRUST may be a satisfactory substitute for VDRL with higher sensitivity (83% vs 77%) 5
• EIA (enzyme immunoassay) shows promising performance: 99% sensitivity, 98% specificity 5

Critical Pitfalls to Avoid

Blood Contamination

• Blood contamination during lumbar puncture can cause false-positive VDRL-CSF results 1, 4
• Ensure proper technique and note any visible blood in CSF 4

Sequential Testing Errors

• Always use the same nontreponemal test method (VDRL or RPR) for serial monitoring, preferably by the same laboratory 1, 2
• VDRL and RPR titers cannot be directly compared—RPR titers are often slightly higher 1, 2

HIV-Infected Patients

• Most HIV-infected patients have accurate and reliable serologic tests 1, 4
• Some may have atypical results (unusually high, low, or fluctuating titers) 1, 2
• If clinical suspicion is high despite negative serology, pursue other diagnostic procedures 3

Relying on Single Tests

• Never diagnose neurosyphilis based on VDRL-CSF alone without considering CSF cell count and clinical context 1, 4
• Never use treponemal test titers to assess treatment response—they remain positive for life in most patients 1, 2

Treatment Monitoring

Follow-Up CSF Examination

• Repeat CSF examination at 6-month intervals until CSF WBC count normalizes 3
• CSF WBC count is the most sensitive measure of treatment effectiveness 1, 4

Serologic Follow-Up

• Repeat serum nontreponemal tests at 3,6,12, and 24 months 3
• A fourfold decline in titer (two dilutions) indicates adequate treatment response 1, 2, 3

Treatment

Penicillin G crystalline aqueous 18-24 million units IV daily (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days is the first-line treatment 3

• Parenteral penicillin G is the only therapy with documented efficacy for neurosyphilis 1
• Penicillin-allergic patients require desensitization—no alternative is proven effective 1, 3
• Jarisch-Herxheimer reaction may occur within 24 hours of treatment initiation 1, 3