Autoimmune Encephalitis as Treatment-Responsive Cause of Rapidly Progressive Dementia: A Multicenter Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: Early recognition of patients with rapidly progressive dementia (RPD) attributed to autoimmune encephalitis (AE) is important because rapid initiation of immunotherapy improves outcomes. However, ancillary testing is often time-consuming because of the broad differential diagnosis, highlighting the need for accurate patient selection based on early clinical features. We aim to determine the frequency of AE subtypes in patients with RPD (AE-RPD) and characterize presenting subphenotypes (i.e., symptoms in addition to dementia) compared with other diagnoses.

METHODS: This prospective multicenter observational cohort study was conducted from December 2019 to December 2024 across centers in the Netherlands and included adult patients with RPD, defined as dementia beginning within 1 year of symptom onset. Clinical features and ancillary testing data were collected and reviewed by 3 neurologists. Serum and CSF were evaluated for neuronal/glial autoantibodies.

RESULTS: A total of 147 patients were included (46% female; median age 67 years, range 36-86). AE-RPD was the largest diagnostic category (58/147; 39%) and most common treatment-responsive cause of RPD (58/95; 61%). Neurodegenerative diseases (20/147; 14%) and Creutzfeldt-Jakob disease (CJD, 17/147; 12%) accounted for the largest nonresponsive causes of RPD. RPD accompanied by seizures at first presentation was more frequent in AE-RPD compared with other diagnoses (20/58; 34% vs 9/89; 10%; p < 0.001), with anti-LG1 (11/20; 55%) encephalitis representing the most frequent underlying subtype. Seizures manifested as subtle focal events in 9 of 20 patients with AE-RPD (42%), complicating early clinical identification. Movement disorders were observed at presentation in similar proportions of patients with AE-RPD (17%) and CJD (35%; p = 0.11) but were more likely to emerge within 3 months of symptom onset in patients with RPD-AE (80% vs 25%; p = 0.004). In patients with AE-RPD without seizures, autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy was the most common subtype (8/31; 26%), mostly presenting with prominent psychotic features or movement disorders (both 4/8; 50%).

DISCUSSION: In this study, AE was the most common treatment-responsive cause of RPD. Anti-leucine-rich, glioma-inactivated 1 encephalitis and autoimmune GFAP astrocytopathy were the predominant subtypes in AE-RPD.