Despite more than a century of clinical experience diagnosing and managing patients with syphilis, many clinical questions remain unanswered and are explored in a review of the Centers for Disease Control and Prevention (CDC) Syphilis Summit, published in Sexually Transmitted Diseases.

This review focused on several areas of uncertainty for the clinician: (1) the role of serologic tests in diagnosing syphilis and assessing syphilis treatment response, (2) the risk of neurosyphilis and ocular syphilis in patients with syphilis, and (3) the interpretation of serologic test results after syphilis treatment and the impact of lumbar puncture on clinical outcome in individuals co-infected with HIV and Treponema pallidum.

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Confirmation of the diagnosis of syphilis relies largely on serologic tests. There are 2 types of these tests: treponemal and non-treponemal. Treponemal test results are expressed qualitatively (reactive or nonreactive), whereas reactive non-treponemal tests are expressed quantitatively as a titers reported in 2-fold increments. Regardless of the sequence of these tests, individuals without clinical manifestations of syphilis require reactivity of treponemal and/or non-treponemal tests to confirm diagnosis.

When assessing treatment response, cure is described as stabilization or resolution of clinical abnormalities, resolution of infectiousness to others, and absence of relapse. In clinical practice, cure has been defined serologically as an “appropriate” reduction in non-treponemal test titers. The CDC syphilis treatment guidelines define an appropriate reduction as a 4-fold drop in titer after 12 months of treatment of primary, secondary, or early latent syphilis and after 24 months for late latent syphilis. However, other definitions have also been used, adding to the complexity of interpretation.

Studies from the pre-penicillin era showed that the likelihood of developing symptomatic neurosyphilis in patients with asymptomatic neurosyphilis was highest in patients with the most abnormal cerebrospinal fluid (CSF) profiles. Routine lumbar puncture (LP) was largely abandoned once penicillin became widely available and remained uncommon in syphilis until the advent of HIV. In the early 1990s, there were reports of individuals who tested positive for HIV infection and who had been treated appropriately for uncomplicated syphilis but had subsequently developed neurosyphilis. The most recent guidelines do not explicitly recommend LP in neurologically asymptomatic individuals unless they have not responded to therapy for uncomplicated syphilis based on serologic criteria. Therefore, investigation of whether identifying CSF abnormalities in asymptomatic individuals with or without a lack of serologic response improves outcome is unknown and requires further study before informed recommendations for LP can be made.

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Finally, ocular syphilis may occur at any stage of infection and may involve any portion of the eye, and incidence has been increasing since 2015. Most diagnoses of ocular syphilis tend to be presumptive based on ocular signs and symptoms, such as vision loss and flashing lights, and reactive syphilis serologies. Although CDC guidelines recommend the same treatment for ocular syphilis as for neurosyphilis, the syndromes may not always overlap. The question regarding the need for a CSF examination and the best treatment of ocular syphilis hinges on the distinction between ocular and neurosyphilis.

Overall, the study authors concluded that, “The current increases in syphilis rates in the United States and elsewhere underscore our urgent need to definitively address these issues.”


Marra CM, Ghanem KG. Centers for Disease Control and Prevention syphilis summit: difficult clinical and patient management issues. Sex Transm Dis. 2018; 45:S10-S12.