What investigations should be done to exclude neurosyphilis?

Investigations to Exclude Neurosyphilis

To exclude neurosyphilis, perform a lumbar puncture with CSF examination including CSF-VDRL, white blood cell count with differential, and protein level—a nonreactive CSF treponemal test (such as FTA-ABS) effectively rules out neurosyphilis. 1, 2

When to Perform CSF Examination

The CDC recommends lumbar puncture in the following clinical scenarios: 3, 1

• Neurologic or ocular symptoms/signs (headache, visual disturbances, altered mental status, cranial nerve deficits)
• Active tertiary syphilis (aortitis, gumma, iritis)
• Treatment failure for non-neurologic syphilis
• HIV-infected patients with late-latent syphilis or syphilis of unknown duration
• Some specialists recommend CSF examination for all HIV-infected patients with syphilis, particularly if serum RPR ≥1:32 or CD4+ count <350 cells/µL 3, 4

Essential CSF Tests

CSF-VDRL (Primary Diagnostic Test)

• Highly specific (99-100%) but insensitive (49-87%) for neurosyphilis 5, 6
• A reactive CSF-VDRL is diagnostic of neurosyphilis (assuming no significant blood contamination) 3, 1, 5
• A nonreactive CSF-VDRL does NOT exclude neurosyphilis due to limited sensitivity 3, 5

CSF White Blood Cell Count

• CSF WBC >10 cells/µL combined with reactive CSF-VDRL strongly supports neurosyphilis 3, 1, 2
• Typical range in neurosyphilis: 10-200 cells/µL with mononuclear predominance 3, 2
• Critical caveat: HIV infection itself can cause mild pleocytosis (5-15 cells/µL), particularly with CD4+ counts >500 cells/µL, complicating interpretation 3, 2

CSF Protein

• Usually normal or mildly elevated in neurosyphilis 3, 1, 2
• Never base diagnosis solely on elevated CSF protein without reactive VDRL or elevated WBC 3, 2

CSF Treponemal Tests (FTA-ABS or TPPA)

• Highly sensitive (100%) but not specific (12-13% specificity) 3, 4
• A nonreactive CSF treponemal test excludes neurosyphilis 3, 1
• A reactive test does NOT confirm neurosyphilis 3, 1

Diagnostic Algorithm

Step 1: Perform CSF-VDRL, WBC count, protein, and consider CSF treponemal test 1, 5, 2

Step 2: Interpret results:

• Reactive CSF-VDRL + CSF WBC >10 cells/µL = Neurosyphilis confirmed 3, 1, 2
• Nonreactive CSF treponemal test = Neurosyphilis excluded 3, 1
• Nonreactive CSF-VDRL but elevated WBC or protein = Cannot exclude neurosyphilis; consider treatment if clinical suspicion high 3

Step 3: If neurosyphilis cannot be excluded by nonreactive treponemal test, treat empirically for neurosyphilis 3

Serum Testing Limitations

• Serum RPR/VDRL titers do NOT diagnose or exclude neurosyphilis 5, 4
• Serum RPR titers were not associated with early neurosyphilis in HIV-infected patients 4
• However, serum RPR >1:32 may increase suspicion and warrant CSF examination 3, 7

Critical Pitfalls to Avoid

• Blood contamination during lumbar puncture can cause false-positive CSF-VDRL results 5, 2
• Do not rely on CSF protein elevation alone without other CSF abnormalities 3, 2
• In HIV-infected patients, adjust interpretation for baseline HIV-related pleocytosis; some use >20 cells/µL as the threshold rather than >10 cells/µL 4
• PCR-based methods are NOT recommended for neurosyphilis diagnosis 3
• Calculated indices (TPHA-index) have limited value and should not guide diagnosis 3

Additional Considerations

• False-negative serologic tests can occur in HIV-infected patients; if clinical suspicion is high despite negative serology, pursue other diagnostic procedures 1
• Neuroimaging (MRI or CT) may show abnormalities but is not diagnostic; imaging is essential to demonstrate structural findings and aid in differential diagnosis 8