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.

Overview

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

• For patients diagnosed with neurosyphilis including ocular or auditory syphilis with or without positive CSF results, aqueous crystalline penicillin G is the treatment of choice.

• 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

Recommended Regimen:

• 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.

Alternative regimen:

• Procaine penicillin 2.4 million units IM once daily, plus probenecid 500 mg orally four times a day, both for 10-14 days.

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.

• The possibility of cross-reactivity between ceftriaxone and penicillin exists.

• 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.

Pregnancy:

• Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin.

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.

Follow-Up

• If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal.

• 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.

• 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.

• Limited data suggest that in immunocompetent persons and HIV-infected persons on highly active antiretroviral therapy, normalization of the serum RPR titer predicts normalization of CSF parameters.

• Follow-up for neurosyphilis Among HIV-Infected Persons

• If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal.

• 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.

• 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.