Successful Outpatient Management of Neurosyphilis with Benzathine Penicillin Plus Doxycycline: A Case-Based Review

Background: Neurosyphilis remains a major diagnostic challenge because of its heterogeneous neurological manifestations and the limited evidence supporting alternatives to guideline-recommended intravenous penicillin G. Doxycycline-containing regimens have been reported only sporadically, and their role in neurosyphilis remains poorly defined. We present a successfully treated case of neurosyphilis managed with benzathine penicillin plus doxycycline and performed a case-based review of the published literature. Methods: A retrospective clinical review of the present case was conducted according to the CARE guidelines [10]. In addition, a comprehensive literature review was performed using PubMed/MEDLINE, Embase, Web of Science, Scopus, Cochrane Library, LILACS, SciELO, and Google Scholar from database inception through July 2026 to identify reports describing doxycycline-containing regimens for neurosyphilis. Clinical characteristics, treatment strategies, and outcomes were extracted and qualitatively synthesized. Results: An 81-year-old man presented with a one-month history of progressive dizziness, gait ataxia, pathological nystagmus, and a positive Romberg sign. Brain computed tomography demonstrated a right parietal extra-axial lesion suggestive of a subdural collection. Serum VDRL was reactive (1:64), FTA-ABS was positive, and investigations for HIV and other infectious diseases were negative. After refusing lumbar puncture and hospitalization, he received outpatient treatment with intramuscular benzathine penicillin (2.4 million units weekly for three weeks) plus doxycycline (100 mg twice daily for 28 days), achieving complete neurological recovery, radiological resolution, and progressive VDRL negativization during follow-up. The literature review identified only a limited number of reports, comprising isolated case reports and one retrospective cohort, indicating favorable outcomes with doxycycline-containing regimens in carefully selected patients but no high-quality comparative evidence. Conclusions: Evidence supporting doxycycline for neurosyphilis remains scarce and is limited to low-level observational data. This case, together with the available literature, suggests that doxycycline-containing outpatient regimens may represent a reasonable individualized alternative when standard intravenous therapy cannot be administered. Nevertheless, intravenous penicillin G remains the recommended first-line treatment, and prospective studies are required to define the efficacy and safety of alternative therapeutic strategies.