CV2/CRMP5 antibodies are specifically associated with parenchymal neurosyphilis: a retrospective cohort study

BACKGROUND: Neurosyphilis can trigger neuro-specific immune responses, but evidence remains scarce. This study investigates the prevalence and clinical significance of neural antibodies in neurosyphilis, with a focus on CV2/CRMP5 antibodies. METHODS: We retrospectively analyzed 1149 patients with syphilitic neurological symptoms. Of 247 diagnosed with neurosyphilis, 215 met inclusion criteria. Using CBA and line blot, 97 patients suspected of autoimmune encephalitis were tested for neural antibodies, with positives confirmed by in-house CBA. Complete medical records were collected. Homology between CV2/CRMP5 and Treponema pallidum was assessed via BLAST and structural modeling. RESULTS: Twenty neurosyphilis patients were positive for neural antibodies. Antibodies against neuronal intracellular antigens (NIA-abs) predominated (15/20, 75%), with CV2/CRMP5 being the most frequent (73.3% of NIA-abs). Critically, all CV2/CRMP5-positive cases (11/11, 100%) had parenchymal neurosyphilis (p-NS), and none were found in 86 asymptomatic neurosyphilis (a-NS) patients. In the prospective validation cohort of 115 p-NS patients, 8 CV2/CRMP5-positive cases were identified. Combining retrospective and prospective data, the serum positivity rate of CV2/CRMP5 antibodies in p-NS was 9.79%. These patients exhibited significantly higher serum Toluidine Red Unheated Serum Test (TRUST) titers (median 1:64 vs. 1:16, P < 0.001) and elevated cerebrospinal fluid Immunoglobulin G (CSF IgG) indices (median 2.90 vs. 2.06, P = 0.005) compared to CV2/CRMP5-negative p-NS patients. No homology between CV2/CRMP5 and Treponema pallidum proteins was found. CONCLUSION: Our study identifies a strong association between CV2/CRMP5 antibodies and p-NS. Screening for these antibodies is recommended for p-NS patients, especially those with high serum TRUST titers and intrathecal immunoglobulin synthesis, as they may represent a subgroup with distinct immunopathological mechanisms.