Serum Borrelia IgG as a rule-out test in suspected lyme neuroborreliosis: a large retrospective cohort study

Abstract Objectives In Europe, the diagnosis of Lyme neuroborreliosis (NB) relies on intrathecal Borrelia burgdorferi sensu lato ( Bb sl) antibody production, but this test has limited sensitivity in early disease and requires lumbar puncture (LP). We therefore evaluated the diagnostic performance of the quantitative LIAISON ® serum Bb sl IgG assay across clinically relevant subgroups and its potential to guide LP decisions in patients with suspected NB. Methods We retrospectively analyzed 3,841 patients who underwent intrathecal Bb sl antibody testing in the Capital Region of Denmark (2016–2024). NB cases were defined by European criteria and matched to non-NB controls. We assessed sensitivity, specificity, predictive values, area under the curve (AUC), and accuracy of Bb sl IgG across age groups, symptom durations, and clinical scenarios, and used logistic regression to model NB probability from serum IgG titers. Results We included 392 NB patients and 2,681 non-NB controls, all with available serum Bb sl IgG LIAISON ® results. Overall sensitivity and specificity were both 88%. Accuracy was highest in children (0.90), while AUC peaked in patients with symptom duration > 4 weeks (0.96). Among patients with symptoms ≥ 2 weeks, sensitivity was 98% and negative predictive value 99%. For those with > 4 weeks symptom duration, both reached 100%. Predicted NB probability increased progressively with higher serum Bb sl titers. Interpretation Taken together, our findings support a re-evaluation of the diagnostic sequence in suspected NB, although prospective external validation is required. A negative quantitative VlsE-based serum Bb sl IgG result after ≥ 2 weeks of symptoms was associated with a very low probability of NB in this selected cohort, supporting its potential use as a rule-out tool to guide LP decisions.