Neurosyphilis, Ocular Syphilis, and Otosyphilis


CNS involvement can occur during any stage of syphilis, and CSF laboratory abnormalities are common among persons with early syphilis, even in the absence of clinical neurologic findings. No evidence exists to support variation from recommended diagnosis and treatment for syphilis at any stage for persons without clinical neurologic findings, except tertiary syphilis. If clinical evidence of neurologic involvement is observed (e.g., cognitive dysfunction, motor or sensory deficits, cranial nerve palsies, or symptoms or signs of meningitis or stroke), a CSF examination should be performed before treatment.

Syphilitic uveitis or other ocular syphilis manifestations (e.g., neuroretinitis and optic neuritis) can occur at any stage of syphilis and can be isolated abnormalities or associated with neurosyphilis. All persons with ocular symptoms and reactive syphilis serology need a full ocular examination, including cranial nerve evaluation. If cranial nerve dysfunction is present, a CSF evaluation is needed. Among persons with isolated ocular symptoms (no cranial nerve dysfunction or other neurologic abnormalities), reactive syphilis serology, and confirmed ocular abnormalities on examination, CSF examination is unnecessary before treatment. CSF analysis might be helpful in evaluating persons with ocular symptoms and reactive syphilis serology who do not have ocular findings on examination. If ocular syphilis is suspected, immediate referral to and management in collaboration with an ophthalmologist is crucial. Ocular syphilis should be treated similarly to neurosyphilis, even if a CSF examination is normal.

Hearing loss and other otologic symptoms can occur at any stage of syphilis and can be isolated abnormalities or associated with neurosyphilis, especially of cranial nerve 8. However, among persons with isolated auditory symptoms, normal neurologic examination, and reactive syphilis serology, CSF examination is likely to be normal and is not recommended before treatment. Otosyphilis should be managed in collaboration with an otolaryngologist and treated by using the same regimen as for neurosyphilis.

Recommended Regimen for Neurosyphilis, Ocular Syphilis, or Otosyphilis Among Adults

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

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

Alternative Regimen

Procaine penicillin G 2.4 million units IM once daily


Probenecid 500 mg orally 4 times/day, both for 10–14 days

The durations of the recommended and alternative regimens for neurosyphilis are shorter than the duration of the regimen used for latent syphilis. Therefore, benzathine penicillin, 2.4 million units IM once per week for 1–3 weeks, can be considered after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy.

Other Management Considerations

The following are other considerations in the management of persons who have neurosyphilis:

  • All persons who have neurosyphilis, ocular syphilis, or otosyphilis should be tested for HIV at the time of diagnosis. Those whose HIV test results are negative should be offered HIV PrEP.
  • Although systemic steroids are used frequently as adjunctive therapy for otosyphilis and for ocular syphilis, such drugs have not been proven to be beneficial.


Data from two studies indicate that, among immunocompetent persons and persons with HIV infection who are on effective ART, normalization of the serum RPR titer predicts normalization of abnormal CSF parameters after neurosyphilis treatment (614,615). Therefore, repeated CSF examinations are unnecessary for persons without HIV infection or persons with HIV infection who are on ART and who exhibit serologic and clinical responses after treatment.

Management of Sex Partners

See Syphilis, Management of Sex Partners.

Special Considerations

Penicillin Allergy

Limited data indicate that ceftriaxone 1–2 g daily either IM or IV for 10–14 days can be used as an alternative treatment for persons with neurosyphilis (603,616,617). Cross-sensitivity between ceftriaxone and penicillin can occur; however, the risk for penicillin cross-reactivity between third-generation cephalosporins is negligible (618621) (see Management of Persons Who Have a History of Penicillin Allergy). If concern exists regarding ceftriaxone safety for a patient with neurosyphilis, skin testing should be performed to confirm penicillin allergy and, if necessary, penicillin desensitization in consultation with a specialist is recommended. Other regimens have not been adequately evaluated for treatment of neurosyphilis.


Pregnant women who are allergic to penicillin should be desensitized and treated with penicillin G. Skin testing or oral graded penicillin dose challenge might be helpful in identifying women at risk for acute allergic reactions (see Management of Persons Who Have a History of Penicillin Allergy).

HIV Infection

Persons with HIV infection who have neurosyphilis should be treated as described for persons without HIV (see Syphilis Among Persons with HIV Infection).