The psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data

BACKGROUND: Early immunotherapy administration improves outcomes in patients with N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis. As most patients with NMDAR-antibody encephalitis present to psychiatrists, the psychopathology of NMDAR-antibody encephalitis needs to be clearly defined to encourage accurate clinical identification and prompt treatment. METHODS: For this systematic review, we searched PubMed for all studies published in English between Jan 1, 2005, and Oct 7, 2017, to identify individually reported adult patients (≥18 years) who satisfied consensus criteria for definite NMDAR-antibody encephalitis. After generating a list of 50 fine-grained, lower-level features, we extracted psychopathological data in addition to demographic and aetiological data. The lower-level features were later ordered within higher-level categories. As a means of quality control, we filtered the data according to proxy markers of psychiatric involvement in their description. Subsequently, we compared lower-level features from individual patient data with operationalised psychiatric syndromes using a constrained combination approach and principal component analysis, and did a network analysis to explore the inter-relationships between multiple lower-level features. The review protocol was prospectively registered with PROSPERO, number CRD42017068981. FINDINGS: Of 1096 records identified in PubMed, 333 satisfied inclusion criteria and described 1100 patients in total with NMDAR-antibody encephalitis. The psychopathology of 505 (46%) patients with reported psychiatric symptoms was described in more detailed terms than only psychiatric or behavioural. 464 (91%) of the 505 patients were from papers in which patient data were reported individually. The remainder of the analyses focused exclusively on these 464 patients. Median age was 27 years (IQR 22–34), 368 (79%) of 464 patients were female and in 147 (32%), NMDAR-antibody encephalitis was associated with ovarian teratoma. The five higher-level categories into which the 464 patients most frequently grouped were behaviour (316 [68%]), psychosis (310 [67%]), mood (219 [47%]), catatonia (137 [30%]), and sleep disturbance (97 [21%]). The overall pattern of lower-level features was statistically stable across subgroups classified by age, sex, pregnancy association, presence of ovarian teratoma, prior herpes simplex virus encephalitis, and isolated psychiatric presentations (two-way ANOVA p=0·6–0·9). Constrained combination and principal component analyses found that mixtures of mood and psychosis syndromes fit each patient better than any single diagnosis alone, particularly for the patients in the psychiatric-described subgroup (mean ΔAkaike information criterion −0·04 in non-psychiatric-described subgroup vs 0·61 in psychiatric-described subgroup). The overlapping nature of the higher-level features was also enriched upon analysis of the psychiatric-described data (221 [67%] of 329 overlaps in non-psychiatric-described subgroup vs 96 [81%] of 118 overlaps in psychiatric-described subgroup, p=0·0052). Network analysis confirmed that the features were closely related and consistent between individual patients; the psychiatric-described subgroup had a markedly high and narrow range of closeness centralities (92% above 0·93 in psychiatric-described subgroup vs 51% above 0·93 in the non-psychiatric group). INTERPRETATION: The distinctive aspect of NMDAR-antibody encephalitis psychopathology is complexity; core aspects of mood and psychotic disorders consistently coexist within individual patients. Alongside the predominant young female demographic, these psychopathological features could help psychiatrists identify patients who would benefit from cerebrospinal fluid testing and immunotherapies. Well-controlled prospective studies with bespoke inventories are needed to advance this clinically grounded approach. FUNDING: Wellcome Trust, NIHR Oxford Biomedical Research Centre, NIHR Oxford Health Biomedical Research Centre, British Medical Association Foundation for Medical Research.