Abstract
BACKGROUND: N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis is a life-threatening neuropsychiatric disorder requiring prompt immunotherapy. The earliest features are mental-state changes, often mistaken for primary psychosis. Improved clinical differentiation could assist rational diagnostic investigation and expedite immunotherapy. Inspired by patients' and relatives' lived experience, we aimed to explore the psychiatric phenotype of NMDAR-antibody encephalitis and the features common to and distinct from real-world episodes of psychosis. METHODS: In this international, multicentre, retrospective phenotypic analysis we collected data on episodes of NMDAR-antibody encephalitis from specialised neurology services in Europe (UK, Germany, and Sweden) and the USA. For comparison, we collected similar data from de-identified accepted referrals to a UK early intervention in psychosis service, including consecutively presenting cases (unselected psychosis) and a group defined by having been assessed and admitted to hospital under the Mental Health Act (selected psychosis). Additionally, we included episodes of postpartum psychosis from a mother and baby unit in the Netherlands. In our mental-state inventory we included core features from ICD-11, the Bush-Francis catatonia score, and the Neuropsychiatric Inventory encompassing anxiety, depression, mania, schizophrenia, catatonia, and also more granular transdiagnostic behavioural features including those common to neuropsychiatric and neurobehavioural syndromes, such as delirium and dementia. Ethnicity data were not available. We compared and visualised the neuropsychiatric phenotype of these cohorts. FINDINGS: We collected data from 100 episodes of NMDAR-antibody encephalitis from 96 patients between 2010 and 2022 (median age 22 years, female:male ratio 3·80), 135 episodes of psychosis from 135 patients between 2018 and 2019 (median age 27 years, female:male ratio 0·75), and ten episodes of postpartum psychosis from ten patients between 2005 and 2012 (median age 30 years, all female sex). Psychopathology in NMDAR-antibody encephalitis was abundant (92 [92%] of 100 episodes) and ultra-rapid in onset (median 1 day [95% CI 1-1; IQR 1-7]) versus unselected primary psychoses (median 180 days [120-210; 91-365]; p<0·0001). 21 (36%) of 58 mental-state features, including catatonic and visual hallucinations, were over-represented in NMDAR-antibody encephalitis and 12 (21%) were under-represented, including features typical of affective (eg, elated mood, flight of ideas, grandiose delusions) and non-affective psychoses (eg, thought broadcasting, thought withdrawal, paranoid delusions; false discovery rate threshold <0·05). Typically, in NMDAR-antibody encephalitis, the complexity sequentially evolved from mood to psychotic to catatonic predominance within 2 weeks. INTERPRETATION: NMDAR-antibody encephalitis has a rapid-onset, complex, and dynamic neuropsychiatric phenotype, sufficiently distinctive to drive a clinical approach to differentiation. FUNDING: UK NIHR, Wellcome, and UK Medical Research Council (MRC)/UK Research and Innovation.