Syphilis management for neurosyphilis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]; Nate Michalak, B.A.


CNS involvement can occur during any stage of syphilis. However, CSF laboratory abnormalities are common in persons with early syphilis, even in the absence of clinical neurological findings. No evidence exists to support variation from recommended treatment for early syphilis for patients found to have such abnormalities. If clinical evidence of neurologic involvement is observed (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis), a CSF examination should be performed. Syphilitic uveitis or other ocular manifestations frequently are associated with neurosyphilis and should be managed according to the treatment recommendations for neurosyphilis. Patients who have neurosyphilis or syphilitic eye disease (e.g., uveitis, neuroretinitis, and optic neuritis) should be treated with the recommended regimen for neurosyphilis; those with eye disease should be managed in collaboration with an ophthalmologist. A CSF examination should be performed for all patients with syphilitic eye disease to identify those with abnormalities; patients found to have abnormal CSF test results should be provided follow-up CSF examinations to assess treatment response.

Management of Neurosyphilis

  • The recommended regimen is intravenous treatment every 4 hours or continuously for 10-14 days.
  • If intravenous administration is not possible, then procaine penicillin is an alternative (administered daily with probenecid for two weeks).
  • Procaine injections are painful, however, and patient compliance may be difficult to ensure.
  • To approximate the 21-day course of therapy for late latent disease and to address concerns about slowly dividing treponemes, most experts now recommend 3 weekly doses of benzathine penicillin G after the completion of a 14-day course of aqueous crystalline or aqueous procaine penicillin G for neurosyphilis.
  • No oral antibiotic alternatives are recommended for the treatment of neurosyphilis. The only alternative that has been studied and shown to be effective is intramuscular ceftriaxone daily for 14 days.

CDC Recommendations: Pharmacotherapy [2]

Recommended Regimen:

Alternative regimen:

If compliance with therapy can be ensured, the following alternative regimen might be considered.

  • The duration of the recommended and alternative regimens for neurosyphilis are shorter than the duration of the regimen used for late syphilis in the absence of neurosyphilis. Therefore, benzathine penicillin, 2.4 million units IM once per week for up to 3 weeks, can be considered after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy.

Other Management Considerations

  • Other considerations in the management of patients who have neurosyphilis are as follows:
  • All persons who have syphilis should be tested for HIV.
  • Although systemic steroids are used frequently as adjunctive therapy for otologic syphilis, such drugs have not been proven to be beneficial.

Special Considerations

Penicillin Allergy: Alternative Regimen

  • Limited data suggest that ceftriaxone 2 g daily either IM or IV for 10-14 days can be used as an alternative treatment for patients with neurosyphilis.[3][4]
  • Other regimens have not been adequately evaluated for treatment of neurosyphilis. Therefore, if concern exists regarding the safety of ceftriaxone for a patient with neurosyphilis, skin testing should be performed (if available) to confirm penicillin allergy and, if necessary, desensitize the patient.


Neurosyphilis Among HIV-Infected Persons:

  • HIV-infected patients with neurosyphilis should be treated according to the recommendations for HIV-negative patients with neurosyphilis.
  • HIV-infected, penicillin-allergic patients who have neurosyphilis should be managed according to the recommendations for penicillin-allergic, HIV-negative patients with neurosyphilis.
  • Several small observational studies conducted in HIV-infected patients with neurosyphilis suggest that ceftriaxone 1-2 g IV daily for 10-14 days might be effective as an alternate agent.[5][6][7]


  • Follow-up CSF examinations also can be used to evaluate changes in the CSF-VDRL or CSF protein after therapy; however, changes in these two parameters occur more slowly than cell counts, and persistent abnormalities might be less important.[8][9]
  • The leukocyte count is a sensitive measure of the effectiveness of therapy. If the cell count has not decreased after 6 months or if the CSF cell count or protein is not normal after 2 years, re-treatment should be considered.
  • Follow-up for neurosyphilis Among HIV-Infected Persons
  • Follow-up CSF examinations also can be used to gauge response after therapy.
  • Limited data suggest that changes in CSF parameters may occur more slowly in HIV-infected patients, especially those with more advanced immunosuppression.[8][10]
  • If the cell count has not decreased after 6 months or if the CSF is not normal after 2 years, re-treatment should be considered.


  1. Accessed on September 27, 2016
  2. "Sexually Transmitted Diseases Treatment Guidelines, 2010". Retrieved 2012-12-19.
  3. Hook EW, Baker-Zander SA, Moskovitz BL, Lukehart SA, Handsfield HH (1986) Ceftriaxone therapy for asymptomatic neurosyphilis. Case report and Western blot analysis of serum and cerebrospinal fluid IgG response to therapy. Sex Transm Dis 13 (3 Suppl):185-8. PMID: 3764632
  4. Shann S, Wilson J (2003) Treatment of neurosyphilis with ceftriaxone. Sex Transm Infect 79 (5):415-6. PMID: 14573840
  5. Dowell ME, Ross PG, Musher DM, Cate TR, Baughn RE (1992) Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus. Am J Med 93 (5):481-8. PMID: 1442850
  6. Smith NH, Musher DM, Huang DB, Rodriguez PS, Dowell ME, Ace W et al. (2004) Response of HIV-infected patients with asymptomatic syphilis to intensive intramuscular therapy with ceftriaxone or procaine penicillin. Int J STD AIDS 15 (5):328-32. DOI:10.1258/095646204323012823 PMID: 15117503
  7. Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ, Zenilman JM, Gebo KA (2008) Antiretroviral therapy is associated with reduced serologic failure rates for syphilis among HIV-infected patients. Clin Infect Dis 47 (2):258-65. DOI:10.1086/589295 PMID: 18532887
  8. 8.0 8.1 Marra CM, Maxwell CL, Tantalo L, Eaton M, Rompalo AM, Raines C et al. (2004) Normalization of cerebrospinal fluid abnormalities after neurosyphilis therapy: does HIV status matter? Clin Infect Dis 38 (7):1001-6. DOI:10.1086/382532 PMID: 15034833
  9. 9.0 9.1 Marra CM, Maxwell CL, Tantalo LC, Sahi SK, Lukehart SA (2008) Normalization of serum rapid plasma reagin titer predicts normalization of cerebrospinal fluid and clinical abnormalities after treatment of neurosyphilis. Clin Infect Dis 47 (7):893-9. DOI:10.1086/591534 PMID: 18715154
  10. Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ, Zenilman JM, Gebo KA (2008) Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS 22 (10):1145-51. DOI:10.1097/QAD.0b013e32830184df PMID: 18525260

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