What is the recommended treatment for neurosyphilis?

Treatment for Neurosyphilis

The recommended treatment for neurosyphilis is aqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units IV every 4 hours or by continuous infusion, for 10-14 days. 1, 2, 3

Primary Treatment Regimen

Intravenous penicillin G remains the gold standard for neurosyphilis treatment based on CDC guidelines and FDA labeling:

• Aqueous crystalline penicillin G: 18-24 million units/day IV, given as 3-4 million units every 4 hours or continuous infusion for 10-14 days 1, 2, 3
• This high-dose regimen ensures adequate CSF penetration to achieve treponemicidal concentrations continuously throughout treatment 4

Alternative Regimen (If IV Access is Problematic)

If intravenous administration is not feasible, an alternative exists but is less preferred:

• Procaine penicillin: 2.4 million units IM once daily 1, 2
• PLUS Probenecid: 500 mg orally four times daily 1, 2
• Both medications for 10-14 days 1, 2

Completion Therapy Consideration

After completing either the IV or IM regimen, consider adding benzathine penicillin G 2.4 million units IM weekly for 3 weeks to provide a total treatment duration comparable to late syphilis therapy 1, 3. This supplemental therapy addresses the shorter duration of neurosyphilis-specific regimens compared to standard late syphilis treatment.

Management of Penicillin Allergy

Penicillin desensitization is strongly preferred over alternative antibiotics for patients with penicillin allergy, as penicillin remains the only proven effective therapy with adequate evidence 5:

• All patients with neurosyphilis and penicillin allergy should undergo desensitization followed by standard penicillin G treatment 5
• If desensitization is refused or not feasible: Ceftriaxone 2 g daily (IM or IV) for 10-14 days may be considered 1, 2, 5
• Critical caveat: Cross-reactivity between ceftriaxone and penicillin occurs in approximately 10% of penicillin-allergic patients, making this option substantially risky 5
• The efficacy of ceftriaxone is not well-established, with very low-quality evidence showing inconclusive results 6

Special Populations and Considerations

HIV-Positive Patients

HIV co-infection significantly impacts treatment outcomes:

• All patients with neurosyphilis must be tested for HIV 1, 2, 7, 5
• HIV-positive patients have higher risk of neurological complications and treatment failure rates 7, 5, 8
• Standard high-dose penicillin regimens are not consistently effective in HIV-infected patients, with documented treatment failures even after appropriate therapy 8
• HIV-positive patients require closer monitoring and more frequent follow-up 5
• Notably, patients with early syphilis treated with benzathine penicillin G may still develop neurosyphilis if HIV co-infected 8

Ocular Syphilis

Syphilitic eye disease requires neurosyphilis treatment protocols:

• Patients with syphilitic uveitis, neuroretinitis, or optic neuritis should receive the full neurosyphilis regimen 1, 5
• Mandatory ophthalmology consultation for collaborative management 1, 5
• CSF examination should be performed for all patients with ocular manifestations 1

Critical Follow-Up Protocol

CSF monitoring is essential to assess treatment response:

• If initial CSF pleocytosis was present: Repeat CSF examination every 6 months until cell count normalizes 1, 2, 7, 5
• CSF white blood cell count is the most sensitive measure of treatment effectiveness 1, 7, 5
• CSF-VDRL and protein changes occur more slowly than cell counts and may be less important for monitoring 1

Retreatment Indications

Consider retreatment if:

• CSF cell count has not decreased after 6 months 1, 2, 7
• CSF cell count or protein is not normal after 2 years 1, 7
• Use the same aqueous crystalline penicillin G regimen (18-24 million units/day IV for 10-14 days) for retreatment 7

Important Clinical Pitfalls

Avoid these common errors:

• Do not use benzathine penicillin G alone for neurosyphilis—it does not achieve adequate CSF levels 1
• Do not assume CSF abnormalities in early syphilis require neurosyphilis treatment; clinical neurological findings must be present 1
• Do not rely on alternative antibiotics without attempting penicillin desensitization first 5
• Do not assume standard penicillin regimens are adequate in HIV-positive patients without intensive follow-up 8
• Systemic steroids for otologic syphilis have not been proven beneficial 1