How should I evaluate and manage a patient with fever who is suspected of having neurosyphilis?

Evaluation and Management of Fever in Suspected Neurosyphilis

Initial Clinical Assessment

When evaluating a patient with fever and suspected neurosyphilis, immediately perform a comprehensive neurologic examination looking specifically for cognitive dysfunction, motor or sensory deficits, cranial nerve palsies, meningeal signs, ophthalmic symptoms (uveitis, vision changes), and auditory symptoms (hearing loss, tinnitus). 1

Key Clinical Red Flags Requiring CSF Examination

Proceed urgently to lumbar puncture if the patient demonstrates any of the following 2, 1:

• Neurologic signs or symptoms: cognitive dysfunction, motor/sensory deficits, cranial nerve palsies, meningeal signs 1
• Ophthalmic manifestations: uveitis, neuroretinitis, optic neuritis, or any visual complaints 1
• Auditory symptoms: hearing loss or tinnitus 1
• Evidence of tertiary syphilis: aortitis, gumma, iritis 2
• Treatment failure from prior syphilis therapy 2
• HIV infection with late latent syphilis or syphilis of unknown duration 2
• Serum nontreponemal titer ≥1:32 (unless infection duration known to be <1 year) 2, 1

Diagnostic Workup

Serologic Testing

• Obtain both treponemal and non-treponemal serologic tests on serum 1
• Test all patients with syphilis for HIV - this is mandatory, not optional 2, 3, 1

CSF Analysis

When performing lumbar puncture, specifically evaluate for 2, 1:

• CSF pleocytosis (typically mild mononuclear, 10-200 cells/µL) 2
• Elevated protein (normal or mildly elevated) 2
• CSF-VDRL (specific but not sensitive - reactive test establishes diagnosis, but nonreactive does not exclude it) 2
• CSF white blood cell count >10 cells/µL plus reactive CSF-VDRL strongly supports neurosyphilis diagnosis 2

Important caveat: HIV infection itself can cause mild CSF pleocytosis (5-15 cells/µL), particularly with CD4+ counts >500 cells/µL, making diagnosis more challenging 2. HIV-infected patients with CD4 ≤350 cells/µL and/or RPR titer ≥1:32 are more likely to have CSF abnormalities 1.

Treatment

Standard Regimen (First-Line)

Treat immediately with aqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units IV every 4 hours or continuous infusion, for 10-14 days. 3, 1

Alternative Regimen (If IV Access Problematic)

• Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily for 10-14 days 3

Penicillin Allergy Management

For patients with severe penicillin allergy, penicillin desensitization followed by standard penicillin G treatment is the only proven effective therapy and should be performed rather than using alternative antibiotics. 4

If desensitization is refused or not feasible:

• Ceftriaxone 2 grams daily IM or IV for 10-14 days may be considered, but carries substantial risk due to ~10% cross-reactivity with penicillin 3, 4, 1

Special Populations

HIV-infected patients: Use the same treatment regimen but recognize they have increased risk of neurologic complications and higher rates of treatment failure 2, 4, 1. Closer monitoring is essential 2.

Ocular syphilis: Treat with neurosyphilis regimen and manage in collaboration with ophthalmology 3, 4.

Follow-Up Protocol

CSF Monitoring

• Repeat CSF examination every 6 months until cell count normalizes 3, 4, 1
• CSF white blood cell count is the most sensitive measure of treatment effectiveness 3, 4
• If cell count has not decreased after 6 months, or if cell count or protein are not normal after 2 years, consider retreatment 3

Serologic Monitoring

• Repeat quantitative nontreponemal tests at 6,12, and 24 months 4

Critical Pitfalls to Avoid

• Do not miss neurosyphilis in patients with unexplained neurologic deficits or encephalitis-like symptoms - fever with altered mental status should trigger consideration of neurosyphilis 1, 5
• Do not fail to perform CSF examination in patients with any ocular symptoms - syphilitic uveitis is frequently associated with neurosyphilis 2, 1
• Do not use alternative antibiotics without desensitization - no alternative antibiotics have been systematically evaluated or proven effective for neurosyphilis 4
• Do not assume treatment success without CSF follow-up - treatment failure can occur even with appropriate penicillin therapy, requiring repeat courses 6
• Do not forget HIV testing - all patients with syphilis must be tested for HIV 2, 3, 1

Treatment Failure Recognition

Be alert for treatment failure, which may manifest as 6:

• Persistent or worsening neurologic symptoms despite treatment
• Unchanged or rising CSF RPR titers at 2-month follow-up
• Progressive imaging changes

If treatment failure occurs, repeat the full 10-14 day course of IV penicillin G and maintain a lower threshold for repeat CSF examinations 6.