Neurosyphilis Treatment
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
The standard approach requires high-dose intravenous penicillin to achieve adequate CSF penetration and treponemicidal concentrations:
- Aqueous crystalline penicillin G: 18-24 million units daily, given as 3-4 million units IV every 4 hours or continuous infusion for 10-14 days 4, 1, 2, 3
- This regimen achieves CSF penicillin concentrations of 0.062-3.0 mg/L, which remain continuously above the minimal treponemicidal concentration needed to kill Treponema pallidum 5
Alternative Regimen (When IV Access is Problematic)
If intravenous administration is not feasible, an alternative intramuscular regimen can be used:
- Procaine penicillin: 2.4 million units IM once daily 4, 1, 2
- PLUS Probenecid: 500 mg orally four times daily 4, 1
- Duration: Both medications for 10-14 days 4, 1
- Research suggests this IM regimen achieves comparable clinical outcomes to IV therapy, though IV remains the guideline-recommended first choice 6
Supplemental Therapy Consideration
After completing either the IV or IM neurosyphilis regimen, consider additional benzathine penicillin:
- Benzathine penicillin G: 2.4 million units IM once weekly for 3 weeks 4, 3
- This provides comparable total treatment duration to late syphilis regimens and may reduce relapse risk 4
Penicillin Allergy Management
For patients with documented penicillin allergy, ceftriaxone 2 g daily IM or IV for 10-14 days is the alternative, though cross-reactivity with penicillin is possible. 1, 7
- Be aware that ceftriaxone has limited evidence supporting its efficacy—only one small trial with 36 HIV-positive patients showed inconclusive results 8
- Desensitization to penicillin should be strongly considered, as penicillin remains the only proven effective treatment 2
Special Populations: HIV-Infected Patients
HIV-positive patients require the same treatment regimen but warrant closer monitoring:
- Use identical dosing: aqueous crystalline penicillin G 18-24 million units daily for 10-14 days 2
- HIV-infected patients may have higher rates of treatment failure and neurological complications 7, 9
- One study found that even high-dose IV penicillin was not consistently effective in HIV-infected patients, with some showing no serological improvement and one experiencing relapse at 6 months 9
- All patients with syphilis must be tested for HIV 4, 7
Ocular Syphilis
Patients with syphilitic eye disease (uveitis, neuroretinitis, optic neuritis) require neurosyphilis treatment:
- Treat with the full neurosyphilis regimen (aqueous crystalline penicillin G 18-24 million units daily for 10-14 days) 4, 7
- Manage in collaboration with an ophthalmologist 4, 7
- Perform CSF examination on all patients with ocular syphilis to identify CSF abnormalities 4
Follow-Up Protocol
If CSF pleocytosis was present initially, repeat CSF examination every 6 months until the cell count normalizes. 4, 1, 7
- The CSF leukocyte count is the most sensitive measure of treatment effectiveness 4, 1
- CSF-VDRL and protein levels change more slowly than cell counts and may remain abnormal longer 4
- Consider retreatment if:
Critical Pitfalls to Avoid
- Do not use benzathine penicillin alone for neurosyphilis—it does not achieve adequate CSF concentrations and may lead to treatment failure, particularly in HIV-infected patients who may develop neurosyphilis despite prior benzathine penicillin treatment for early syphilis 9
- Do not assume CSF abnormalities in early syphilis require neurosyphilis treatment—CSF abnormalities are common in early syphilis without clinical neurological findings and do not warrant deviation from standard early syphilis treatment 4
- Warn patients about Jarisch-Herxheimer reaction—an acute febrile reaction that can occur within 24 hours of initiating any syphilis therapy 2