Treponema pallidum, the bacterium that causes syphilis, invades the central nervous system in about 40% of patients with syphilis. This happens early after infection. Patients with neuroinvasion are at risk of developing serious neurological complications, including vision or hearing loss, stroke and dementia. Because neuroinvasion can happen without symptoms, the only way to identify it is by performing a lumbar puncture (LP) to examine cerebrospinal fluid (CSF).The overall hypothesis to be tested in this study is that a strategy of immediate LP, followed by therapy based on CSF evaluation, results in better serological and functional outcomes in patients with syphilis who are at high risk for neuroinvasion.

Inclusion Criteria:

1. Males and females age 18 years or older
2. Current syphilis
3. Primary language is English or English is a second language but patient self-describes as fluent in English
4. Able to provide informed consent
5. If treated with benzathine penicillin G (BPG), it must have occurred less than 14 days before the entry visit (before the first visit if there is more than one entry visit)

Exclusion Criteria:

1. Provider plans neurosyphilis (NS) treatment regardless of whether the patient has an lumbar puncture (LP)
2. Receipt of antibiotic treatment that would be effective for NS (for example, IV or intramuscular (IM) beta-lactam antibiotics [other than BPG]) within one month before study entry; single dose of IM ceftriaxone in the last month is not exclusionary
3. Allergy to penicillin or lidocaine
4. Contraindication to LP, including untreatable coagulation disorder, use of anticoagulants that cannot be temporarily discontinued, thrombocytopenia, focal neurological examination
5. Other known cause of central nervous system (CNS) infection in the last year, including that due to bacterial, fungal, protozoal or viral agents, such as tuberculosis, Cryptococcus, toxoplasmosis or herpes zoster that could confound interpretation of CSF results
6. Unlikely to be able to comply with study requirements or complete the study, for example, planning to leave the area < 6 months after enrollment
7. Subjects will not be allowed to re-enroll in this study with a new episode of syphilis

Individuals who are unwilling to be randomized can choose LP or no LP. Eligibility criteria for these individuals are:

1. 18 years of age or older
2. Current syphilis infection
3. Primary language is English or fluent in English
4. No contraindications to LP
5. Have not received antibiotics within one month that would treat neurosyphilis

One year

No difference

Inclusion of a non-randomized group introduces risk of bias; however, the groups were comparable with regard to neurosyphilis risk factors.