Objectives/Aims NMDAR-antibody encephalitis frequently presents with psychiatric symptoms. However, new-onset mental illness does not usually receive detailed biomedical investigations. Yet, early diagnosis and treatment correlates with improved outcomes. Here we used detailed psychiatric phenotyping to explore the nature of mental state abnormalities in this immunologically-defined illness.

Methods Prospective and retrospective semi-structured interviews with patients, carers, and clinicians in five consecutive cases of definite NMDAR-antibody encephalitis (all female, median age=20 years, range=16–30, ovarian teratoma in 4). Weekly multi-disciplinary assessment using the Neuropsychiatric Inventory Nursing Home version (NPI-NH) in 2/5. Network analysis was used to evaluate connectedness of psychopathologic features and a qualitative synthesis distilled recurrent psychopathologic features. Finally, each time point was compared with operationalised diagnoses using an automated classifier and plotted with corresponding symptom complexes over time.

Results All had psychiatric features at onset and were seen first by general practitioners or emergency departments. All received an incorrect initial diagnosis (1 neurological, 4 primary psychiatric). Two patients were referred to mental health services and detained while three were admitted to a general hospital. Psychiatric diagnoses spanned psychotic, mood, and stress categories. None had a personal or family history of serious mental illness or substance misuse. Despite the atypicality all were ascribed to non-specific psycho-social aetiologies. Autoimmune encephalitis was then first suspected between 4–28 days from onset (median=21 days) because of the psychopathology (n=2) or development of clear-cut seizures or movement disorder (n=3). 10 consistently reported features were identified: sleep disturbance, nightmares, mixed unstable mood, perplexity, incoherent repetitive speech, musical ±visual hallucinosis, catatonic facies, possession-like/drugged, dissociative-disorganised, and regressed behaviour.

The symptom complex peaked rapidly (within 3 weeks). The peak burden was large and crossed multiple psychopathologic domains. Overall the syndrome is poorly-described by any single primary disorder; mixtures of mixed mood-psychotic-catatonic disorders performed best. Furthermore, it showed clear qualitative and hence diagnostic shifts between onset, peak, and resolution.

Conclusions The psychopathology of NMDAR-antibody encephalitis is complex and dynamic, likely contributing to diagnostic difficulties. However, it appears stereotyped between individuals, hence sensitive features can be derived. Inconsistency with psychosis and/or mood disorder constructs and better approximation with ‘mixtures of mixtures’ suggests specificity is possible but similar studies with primary disorder comparators are needed. As the disease can only be ruled out with cerebrospinal fluid antibody testing the practical implication is that the mental health system needs to embrace lumbar puncture as a routine part of practice in high risk groups.