A distinct IgM immunoblot signature differentiates neurosyphilis from latent syphilis.

Accurately differentiating neurosyphilis (NS) from latent syphilis (LS) is essential, as it directly guides therapeutic decisions and prevents devastating neurological complications. However, this differentiation remains a significant clinical challenge because it currently relies on cerebrospinal fluid analysis-an invasive and resource-intensive procedure that is not suitable for all patients. To address this, we evaluated whether a detailed IMPORTANCE: This study addresses a fundamental challenge in syphilis management: determining which patients with latent syphilis are at high risk for neurosyphilis without relying on invasive lumbar puncture. By analyzing a simple blood test that profiles the immunoglobulin M antibody response in detail, we discovered that patients with neurosyphilis have a distinctly stronger and broader immune reaction. We further identified key risk factors, including higher antibody levels and reactivity to multiple targets. These findings are significant because they provide doctors with a practical, non-invasive tool to stratify patient risk more accurately. This can help optimize clinical decision-making, ensuring that lumbar punctures are performed on patients who need them most while avoiding unnecessary procedures for others, ultimately leading to better and more personalized patient care.