BackgroundDistinguishing between viral encephalitis (VE) and autoimmune limbic encephalitis (ALE) presents a clinical challenge due to the overlap in symptoms. We aimed to develop and validate a diagnostic prediction model to differentiate VE and ALE.MethodsA prospective observational multicentre cohort study, which continuously enrolled patients diagnosed with either ALE or VE from October 2011 to April 2023. The demographic data, clinical features, and laboratory test results were collected and subjected to logistic regression analyses. The model was displayed as a web-based nomogram and then modified into a scored prediction tool. Model performance was assessed in both derivation and external validation cohorts.ResultsA total of 2423 individuals were recruited, and 1001 (496 VE, 505 ALE) patients were included. Based on the derivation cohort (389 VE, 388 ALE), the model was developed with eight variables including age at onset, acuity, fever, headache, nausea/vomiting, psychiatric or memory complaints, status epilepticus, and CSF white blood cell count. The model showed good discrimination and calibration in both derivation (AUC 0.890; 0.868-0.913) and external validation (107 VE, 117 ALE, AUC 0.872; 0.827-0.917) cohorts. The scored prediction tool had a total point that ranged from - 4 to 10 also showing good discrimination and calibration in both derivation (AUC 0.885, 0.863-0.908) and external validation (AUC 0.868, 0.823-0.913) cohorts.ConclusionsThe prediction model provides a reliable and user-friendly tool for differentiating between the VE and ALE, which would benefit early diagnosis and appropriate treatment and alleviate economic burdens on both patients and society.