Neurosyphilis is a slow progressive, destructive infection of the brain and spinal cord caused by the spirochete T. pallidum. Its incidence has declined markedly since the introduction of penicillin therapy. It can occur at any stage of syphilis, although symptomatic early neurosyphilis is a rare manifestation.

Clinical Manifestations

Early diagnosis of neurosyphilis and appropriate antibiotic treatment make notable clinical improvement. However, the clinical diagnosis of neurosyphilis is often difficult because most patients are asymptomatic or present with non-specific symptoms such as memory disturbance or seizures.

Presentations range from asymptomatic neurosyphilis to meningitis and general paresis. Acute syphilitic meningitis (6% of syphilis patients) is typically the earliest manifestation of neurosyphilis. It is often associated with cranial nerve palsies, fever, headache, meningismus, and may even have signs of cortical involvement. Meningovascular syphilis (up to 12% of patients) can present at endarteritis, causing infarction clinically similar to a stroke. Tabes dorsalis, the disease of the posterior columns of spinal cord occurs more than 20 years after initial infection. Now exceedingly rare, it often coexists with general paresis. This typically manifests as an abnormal gait, paresthesias, lightning pains of extremities, loss of proprioception on exam, and a positive Romberg. The famous Argyll-Robertson pupils may be seen with Tabes Dorsalis or with general paresis. Notably, the psychiatric manifestations of neurosyphilis have garnered significant interest, historically. Syphilitic infection of the meninges and cortex causes personality changes, paranoia, emotional lability, eventually progressing to memory loss and dementia.


CSF examination is recommended in all patients with untreated syphilis of unknown duration or of duration greater than one year. The diagnosis of neurosyphilis is based on a CSF WBC count of 20 cells/μL or greater, and/or a reactive CSF Venereal Disease Research Laboratory (VDRL) test, and/or a positive CSF intra-thecal T. pallidum antibody index. Other CSF abnormalities include elevated protein levels and pleocytosis, which are found in up to 70 percent of patients. In addition, the CSF VDRL result is reactive. Some experts advise lumbar puncture in patients with secondary and early latent syphilis. This is because standard penicillin G benzathine therapy for early syphilis does not achieve treponemicidal levels in the CSF.


The recommended regimen is 14 days of aqueous benzylpenicillin IV, administered daily in doses of 2–4 million IU, every 4 hours. If IV therapy is unavailable or not well suited to the individual situation, an alternative regimen is to use procaine benzylpenicillin, 1.2 million IU by IM injection, once daily, and probenecid, 500 mg orally, 4 times daily, both for 10–14 days. Outpatient compliance must be certain (i.e. consider OPAT clinic!).

For penicillin-allergic, non-pregnant patients, we can use doxycycline 200 mg PO twice daily for 30 days, OR tetracycline 500 mg PO 4x daily for 30 days. These alternatives to penicillin have not been evaluated in systematic studies.

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