Neurosyphilis presenting with predominant psychiatric manifestations: diagnostic challenges and clinical implications

Abstract Neurosyphilis represents a persistent diagnostic challenge in modern clinical practice, not because of therapeutic limitations, but due to its remarkable ability to imitate primary psychiatric and neurodegenerative disorders. Caused by Treponema pallidum , neurosyphilis may present predominantly with changes in behavior, mood, personality, or cognition, often long before classical neurological signs become evident. In such cases, patients are frequently managed within psychiatric settings, where the underlying infectious etiology may remain unrecognized. This narrative review synthesizes contemporary clinical literature to explore how neurosyphilis continues to masquerade as mental illnesses, highlighting the mechanisms that drive neuropsychiatric dysfunctions, the variability of clinical presentations, and the limitations of existing diagnostic approaches. The evidence demonstrates that reliance on isolated serological or cerebrospinal fluid tests may lead to false reassurance, particularly given the imperfect sensitivity of CSF-VDRL testing. Neuroimaging findings, while supportive, are often nonspecific, further contributing to diagnostic uncertainty. These challenges are amplified in individuals with HIV co-infection, where disease progression may be accelerated and presentations atypical. To address recurring diagnostic gaps identified in the literature, the manuscript proposes a clinically oriented probability-based framework that integrates psychiatric features, neurological signs, risk factors, laboratory findings, and neuroimaging patterns to support earlier recognition of neurosyphilis. Despite these obstacles, neurosyphilis remains a largely treatable condition. Prompt recognition and appropriate antimicrobial therapy can halt disease progression and, in many cases, result in partial or substantial improvement of neuropsychiatric symptoms. Failure to identify the condition early, however, may lead to irreversible neurological damage. This review underscores the need for sustained diagnostic vigilance and interdisciplinary awareness, reminding clinicians that not all psychiatric illnesses are primary, and some remain manifestations of infection in disguise.