Predictors of Immune Checkpoint Inhibitor-associated Encephalitis Diagnosis and Recovery Trajectories: A Multi-center Retrospective Case-control Study

Objective To identify clinical features that distinguish immune-related encephalitis (irE) from alternative causes of encephalopathy in immune checkpoint inhibitor (ICI) exposed patients, and to characterize predictors of recovery among irE cases. Background ICIs can cause serious immune-related adverse events (irAEs) including irE. Diagnosis of irE is difficult because of a wide range of mimics and lack of diagnostic biomarkers. Existing diagnostic criteria for autoimmune encephalitis were not empirically derived or validated in ICI-exposed patients. Design/Methods Multicenter retrospective case-control study of ICI-exposed patients who developed encephalopathy and diagnosed with either irE (cases) or alternate cause (controls). We reviewed clinical presentations, diagnostics, treatments, and recovery. Graus autoimmune encephalitis criteria and APE2 score were systemically assessed for all patients. Firth penalized logistic regression was used for case-control discrimination and recovery prediction. Results We analyzed 69 irE cases and 72 controls (median age 71 years; 40% female; most common cancers melanoma and lung adenocarcinoma; most common ICIs were pembrolizumab and nivolumab). 74% cases and 15% controls met Graus criteria (p<0.001). Median APE2 scores for cases and controls were 5 (IQR 3-5) and 3 (2-4) respectively (p<0.001). An APE2 score of ≥4 had 67% sensitivity and 72% specificity for irE. Each tier increase in Graus autoimmune encephalitis criteria strongly predicted irE diagnosis (adjusted OR 10.4, 95% CI 4.7–24.9, p<0.001). Augmenting Graus criteria with systemic irAE status and periodic discharges on EEG improved diagnostic discrimination (AUC 0.88 vs. 0.79). Among irE cases, prior CNS radiation (aOR 10.8, 95% CI 1.9–112.3, p=0.005) and each one-point rise in APE2 score (aOR 2.1, 95% CI 1.2–4.1, p=0.003) were both associated with higher odds of incomplete neurologic recovery. Conclusions Empirically derived predictors such as EEG patterns and presence of systemic irAEs enhance existing autoimmune encephalitis diagnostic criteria. Prior CNS radiation and higher APE2 scores are associated with higher odds of incomplete recovery.