Neurosyphilis in Non-HIV Patients

Neurosyphilis is a complex and heterogeneous manifestation of Treponema pallidum infection that may occur at any stage of disease and continues to pose significant diagnostic and clinical challenges. Despite the availability of effective antimicrobial therapy, the global resurgence of syphilis has renewed interest in its neurological complications. This narrative review aims to provide an integrated overview of neurosyphilis in non-HIV patients, focusing on its pathophysiology, clinical spectrum, diagnostic strategies, and current management approaches. Neuroinvasion is an early event mediated by multiple mechanisms, including disruption of the blood–brain barrier and transcellular migration, followed by a sustained neuroinflammatory response that contributes to disease progression. Clinically, neurosyphilis encompasses a broad spectrum ranging from asymptomatic involvement to severe manifestations such as meningitis, meningovascular disease, general paresis, and tabes dorsalis. Diagnosis remains challenging due to the absence of a single definitive test and relies on the integration of clinical findings, serologic testing, and cerebrospinal fluid analysis. While CSF-VDRL is highly specific, its limited sensitivity necessitates cautious interpretation. Emerging biomarkers may improve diagnostic accuracy but remain investigational. Penicillin-based regimens remain the cornerstone of treatment and are generally associated with favorable outcomes, particularly in early stages. However, delayed diagnosis may result in irreversible neurological damage. Improved clinical awareness and refined diagnostic approaches are essential to enhance early detection and optimize patient outcomes.