Clinical Information

Neurosyphilis (NS) caused by the spirochete Treponema pallidum can occur at any stage of syphilis. Currently the Centers for Disease Control and Prevention estimates that approximately 2% of patients with syphilis will develop neuroinvasive syphilis if untreated. Early stages of NS may be asymptomatic or symptomatic, with patients typically exhibiting classic meningitis symptoms. Patients with late-stage NS may present with dementia paralytica or tabes dorsalis. Other manifestations of neuroinvasive syphilis include ocular or otologic syphilis, which can occur at any stage, however are more common during early NS.

The diagnosis of NS is challenging due to a number of factors, including the lack of consensus on the relevance of abnormal cerebrospinal fluid (CSF) findings in patients who are seropositive for syphilis but neurologically asymptomatic. With respect to diagnostic testing, numerous treponemal and non-treponemal (lipoidal) assays have been evaluated, alongside CSF protein and pleocytosis findings, however direct comparisons of these assays are limited. The Venereal Diseases Research Laboratory (VDRL) assay is currently the only assay with US Food and Drug Administration (FDA) clearance as an aid in the diagnosis of NS, however the sensitivity and specificity of this non-treponemal (lipoidal) assay is highly variable, ranging from 66.7% to 85.7% and 78.2% to 86.7%, respectively. Although no treponemal assay has FDA clearance as an aid for diagnosis of NS, studies evaluating the fluorescent treponemal antibody absorption (FTA-ABS) assay performed in CSF from patients with definitive NS was associated with a sensitivity of 90.9% to 100%. Specificity of this approach ranged from 55% to 100% however, primarily due to the issue of passive diffusion of serum antibodies across the blood-brain barrier.

The NS antibody index assay corrects for passive diffusion across an inflamed blood-brain barrier by measuring quantitative levels of anti-T pallidum antibodies in serum and CSF and normalizing those to total IgG and albumin in both specimen sources. A positive NS antibody index indicates true intrathecal antibody synthesis of antibodies to T pallidum, which alongside clinical and exposure history can be used to establish a diagnosis of NS. All NS antibody index positive samples are also reflexed for testing by the VDRL assay to acquire a semi-quantitative titer. The NS antibody index should only be ordered in patients who are seropositive for antibodies to T pallidum in blood, who also present with neurologic manifestations suspicious for NS or who are at risk for asymptomatic NS.