To compare clinical and paraclinical features between hospitalized adults with expert-confirmed autoimmune encephalitis (AE) and those with suspected AE, but alternative final diagnoses, to identify predictors of AE.

AE commonly presents with subacute neuropsychiatric symptoms, but remains challenging to diagnose. Neural autoantibodies can support the diagnosis, yet their importance depends on clinical context and they may require expert interpretation.

We conducted a retrospective cohort study at Mass General Brigham, including consecutive adult inpatients for whom a serum autoimmune encephalopathy panel was ordered, either directly or on recommendation by neurology (November 2020–March 2022). Expert reviewers adjudicated final diagnoses. Among patients with any positive autoantibody result, positive predictive values (PPVs) for serum and CSF neural autoantibody panels were estimated for expert-confirmed AE. Group comparisons between AE and non-AE were performed, and predictors of AE were assessed using Firth’s penalized logistic regression.

Among 269 patients included in the study, 20 (7.4%) had expert-confirmed AE and 249 had alternative final diagnoses. Compared with non-AE, AE cases more often had subacute cognitive decline (85% vs 48.6%, p<0.01), new onset seizure (55% vs 12.4%, p<0.01), malignancy within 5 years (40% vs 20.5%, p=0.05), inflammatory CSF (61.1% vs 32.1%, p=0.02), and an abnormal brain MRI (30% vs 5.6%, p<0.01). Among seropositive patients, the PPV for expert-confirmed AE was 10.3% for serum and 80% for CSF. In multivariable models, cognitive decline, seizures, malignancy, inflammatory CSF, and CSF autoantibody positivity independently predicted AE, whereas abnormal brain MRI and serum autoantibody positivity did not.

In hospitalized adults evaluated for suspected AE, expert-confirmed AE was uncommon, yet exhibited a coherent clinical/paraclinical profile. Subacute cognitive decline, new onset seizures, malignancy within 5 years, and inflammatory CSF support an AE diagnosis. Serum autoantibody results merit cautious interpretation; CSF autoantibody testing should be pursued in clinically suspicious cases.