Alternative diagnoses in patients referred to neuroimmunology for autoimmune encephalitis evaluation

OBJECTIVE: To evaluate alternative diagnoses in patients referred to neuroimmunology for evaluation of autoimmune encephalitis (AE) and/or positive neural antibodies. BACKGROUND: With increased awareness of AE, AE misdiagnosis has increased-often from improper suspicion of AE or misinterpretation of clinically irrelevant neural antibodies. METHODS: We retrospectively evaluated all cases referred to our center for AE evaluation and/or a positive neural antibody. We evaluated the frequency and characteristics of patients eventually diagnosed with an alternative diagnosis. RESULTS: A total of 119 patients were referred between 2017 and 2024. Twenty-two were referred for a positive neural antibody, and seven for possible antibody-negative AE after testing negative before referral. Eighty-one patients1 were tested by our center after inpatient admission or outpatient referral. Our center deemed antibody testing unnecessary in 9 patients. Overall, 74 patients were antibody-positive (62%). An alternative diagnosis was found in 60 patients (50.4%), including 32 with positive neural antibodies, and 28 antibody-negative patients. Of patients with alternative diagnoses, 22 had low-clinical-relevance antibodies: low-titer GAD65 (12), AchG (6), VGCC (5), and double-seronegative VGKC (4). Conversely, 10 had antibodies classically considered highly clinically relevant: high-titer GAD65 (4), GABA-BR (2), NMDAR (1), LGI-1 (1), CASPR2 (1), and GFAP (1). Of these, two had concurrent low-titer GAD65. The most common alternative diagnoses included other immune-mediated disorders (28.3%), somatic symptom disorder (23.3%), primary psychiatric disorders (11.7%), metabolic encephalopathy/myoclonus (5%), neurodegenerative disorders (5%), and at 3.3% each, Down syndrome regression disorder, genetic disorders, neuromuscular disorders, and posterior reversible encephalopathy syndrome. CONCLUSION: Alternative diagnoses are common in patients referred for AE evaluation and include mostly psychiatric and other autoimmune conditions. Alternative diagnoses are not restricted to patients with low-clinical-relevance neural antibodies-they are also seen in patients with high-clinical-relevance antibodies and antibody-negative patients.