Should the Traditional Algorithm for Syphilis Screening be Abandoned? Neurosyphilis Presenting as Limbic...

Neurosyphilis is a treatable mimic of viral and autoimmune limbic encephalitis. The prozone phenomenon-antibody excess preventing the antigen-antibody lattice-can render an undiluted non-treponemal test such as the rapid plasma reagin (RPR) test falsely negative, with reactivity restored on dilution.

A 37-year-old man presented with seizures and rapidly progressive limbic encephalitis; Brain magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery sequences showed hyperintensities in the amygdalae, periventricular regions, left insula and left putamen. On admission, the possibility of a sexually transmitted infection was considered, but only an RPR was requested, and it was negative. When the encephalitis failed to respond to empirical antiviral, antibacterial and corticosteroid therapy, a Treponema pallidum haemagglutination assay was added; it was positive, and serially diluted serum yielded a reactive RPR (endpoint titre 1:32), revealing a prozone false negative. Cerebrospinal fluid studies confirmed neurosyphilis, and the patient recovered fully after penicillin.

With an RPR-only screen, the non-treponemal/treponemal discordance that typically signals a prozone never arose, so the false negative was accepted at face value; the delay reflected the prozone compounded by the initial testing strategy. Because empirical ceftriaxone active against T. pallidum had been started on admission, effective treatment was not delayed.

When syphilis is suspected, a negative undiluted RPR does not exclude it; pairing a treponemal test with the RPR-or adopting a treponemal-first screening strategy-guards against prozone-related false negatives.

When a sexually transmitted infection is being considered, obtain a careful, respectful sexual history and request non-treponemal and treponemal tests together; a rapid plasma reagin -only screen cannot reveal the non-treponemal/treponemal discordance that signals a prozone false negative. A treponemal-first (reverse-sequence) algorithm avoids this particular pitfall.A negative undiluted RPR does not exclude syphilis: the prozone phenomenon occurs even at low-to-moderate titres and in human immunodeficiency virus-negative patients, so serial dilution should be requested when clinical suspicion is high.Neurosyphilis is a treatable mimic of limbic encephalitis; outcome depends on prompt effective therapy, and including a treponemal-active agent (e.g. ceftriaxone) in empirical meningoencephalitis coverage may limit harm from diagnostic delay.