What is the recommended treatment for neurosyphilis?

Treatment of 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

• Aqueous crystalline penicillin G remains the gold standard, delivering 18-24 million units daily via IV route for 10-14 days 1, 2
• The medication can be administered either as 3-4 million units IV every 4 hours or as a continuous infusion 1, 3
• This regimen ensures adequate CSF penetration with penicillin concentrations continuously above the minimal treponemicidal level 4

Alternative Regimen (When IV Access is Problematic)

If compliance can be ensured and IV access is difficult:

• Procaine penicillin 2.4 million units IM once daily 1, 2
• PLUS Probenecid 500 mg orally four times daily 1, 2
• Both medications given for 10-14 days 1
• Important caveat: HIV-infected patients allergic to sulfa-containing medications should NOT receive probenecid due to potential allergic reactions 1

Extended Therapy Consideration

Because the neurosyphilis treatment duration (10-14 days) is shorter than late syphilis treatment, benzathine penicillin 2.4 million units IM once weekly for up to 3 weeks can be added after completing the neurosyphilis regimen to provide comparable total treatment duration. 1, 2

Management of Penicillin Allergy

This is a critical clinical scenario requiring careful handling:

• Penicillin desensitization is the strongly preferred approach for penicillin-allergic patients, as penicillin remains the only proven effective treatment 1, 5
• Ceftriaxone 2 g daily (IM or IV) for 10-14 days may be used as an alternative, but with significant caveats 1, 2
• Major limitation: Cross-reactivity between ceftriaxone and penicillin exists, potentially causing allergic reactions 1, 2
• Skin testing to confirm penicillin allergy should be performed when concern exists about ceftriaxone safety 1
• Other alternative regimens have not been adequately evaluated and should be avoided 1

Special Populations

HIV-Infected Patients

• Use the same treatment regimen as HIV-negative patients (aqueous crystalline penicillin G 18-24 million units daily for 10-14 days) 1, 5
• Critical warning: HIV-infected patients with early syphilis have higher risk of neurological complications and higher rates of serological treatment failure 1, 2, 6
• Prior treatment with benzathine penicillin G may fail in HIV-infected patients, leading to neurosyphilis development 7
• High-dose IV penicillin is not consistently effective in all HIV-infected patients with neurosyphilis 7
• Closer follow-up is essential to detect treatment failures or disease progression 5

Ocular Syphilis

• All patients with syphilitic eye disease (uveitis, neuroretinitis, optic neuritis) must be treated with the full neurosyphilis regimen, not early syphilis treatment 1, 2
• Management should occur in collaboration with an ophthalmologist 1, 5
• CSF examination is mandatory for all patients with ocular manifestations to identify abnormalities requiring follow-up 1

Pregnant Patients

• Pregnant patients allergic to penicillin must be desensitized and treated with penicillin - no alternatives are acceptable 1

Mandatory Concurrent Testing

• All patients with neurosyphilis must be tested for HIV 1, 2, 6

Follow-Up Protocol

CSF Monitoring

• If CSF pleocytosis was present initially, repeat CSF examination every 6 months until cell count normalizes 1, 2, 6
• The CSF leukocyte count is the most sensitive measure of treatment effectiveness 1, 2, 6
• CSF-VDRL and protein changes occur more slowly than cell count changes and persistent abnormalities may be less clinically significant 1

Criteria for Retreatment

Retreatment should be considered if: 1, 2, 6

• Cell count has not decreased after 6 months
• CSF cell count or protein is not normal after 2 years

Serologic Monitoring

• Perform quantitative nontreponemal tests at 3,6,9,12, and 24 months after therapy 1, 5
• Expect at least a fourfold decline in serum nontreponemal titers 1
• If titers do not decline fourfold, repeat CSF examination and consider retreatment 1

Common Pitfalls to Avoid

1. Do not treat ocular syphilis as early syphilis - it requires the full neurosyphilis regimen regardless of CSF findings 1
2. Do not use alternative antibiotics without penicillin desensitization in penicillin-allergic patients - the evidence for alternatives is insufficient 1, 5
3. Do not assume benzathine penicillin adequately treats neurosyphilis - it does not achieve adequate CSF levels 7
4. Do not give probenecid to sulfa-allergic patients when using the procaine penicillin alternative regimen 1
5. Do not skip HIV testing - all neurosyphilis patients require HIV screening 1, 2, 6

Evidence Quality Note

While CDC guidelines consistently recommend aqueous crystalline penicillin G across multiple iterations (2002,2010), the actual research evidence supporting this recommendation is limited. A 2019 Cochrane review found only one small trial (36 participants) comparing ceftriaxone to penicillin G, with very low-quality evidence and inconclusive results 8. Despite this limitation, penicillin G remains the standard of care based on decades of clinical experience and the absence of proven superior alternatives.