The Neurological Renaissance: Elucidating the Complex Relationship between Syphilis and Neurodegenerative Disorders in the Contemporary Era

Abstract

The global resurgence of syphilis has coincided with increasing evidence of complex interactions between Treponema pallidum infection and neurological disorders, extending beyond classical neurosyphilis manifestations. This perspective article synthesizes recent clinical and translational evidence on syphilis-associated neurological complications, focusing on (i) putative mechanisms linking infection to neurodegenerative trajectories (molecular mimicry and persistent neuroinflammation), (ii) clinical phenotypes that mimic autoimmune disease, and (iii) diagnostic challenges arising from atypical presentations and evolving biomarker strategies. Recent studies indicate that spirochetal infections may contribute to neuroinflammatory cascades associated with dementia, movement disorders, and psychiatric manifestations through molecular mimicry and persistent neuroinflammation. The increase in syphilis incidence, from 39.6 to 62.5 per 100,000 in the United States between 2019 and 2023, necessitates urgent reconsideration of screening protocols, particularly for populations presenting with unexplained neurological symptoms. We advocate for a paradigm shift toward comprehensive neurological evaluation in syphilis cases, enhanced surveillance for atypical presentations, and integration of advanced diagnostic biomarkers, including Cerebrospinal Fluid (CSF) CXCL13 and other emerging neuroinflammatory markers, with explicit attention to implementation barriers that limit global adoption.