A transdiagnostic pattern of psychiatric symptoms in autoimmune encephalitis
Authors: Carsten Finke
Journal: The Lancet Psychiatry (2019)

N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis is a neuropsychiatric disorder1Dalmau J Lancaster E Martinez-Hernandez E Rosenfeld MR Balice-Gordon R Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis.Lancet Neurol. 2011; 10: 63-74Summary Full Text Full Text PDF PubMed Scopus (1758) Google Scholar, 2Irani SR Bera K Waters P et al.N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes.Brain. 2010; 133: 1655-1667Crossref PubMed Scopus (807) Google Scholar that is caused by antibodies against the NR1 subunit of the NMDA receptor. Many patients with NMDAR-antibody encephalitis are first seen by psychiatrists because of the frequent onset of the disease with psychiatric symptoms such as agitation, hallucinations, delusions, or depressed mood. Once the disease progresses, patients typically develop additional neurological symptoms, such as movement disorders, epileptic seizures, autonomic dysfunction, and cognitive deficits. Diagnosis is established by detection of autoantibodies in serum and CSF, and treatment with first-line (eg, intravenous steroids, plasma exchange) and second-line immunotherapy (eg, rituximab) is usually very effective.3Graus F Titulaer MJ Balu R et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Summary Full Text Full Text PDF PubMed Scopus (1936) Google Scholar Accumulating evidence highlights the need for an early diagnosis to achieve a good outcome,4Titulaer MJ McCracken L Gabilondo I et al.Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study.Lancet Neurol. 2013; 12: 157-165Summary Full Text Full Text PDF PubMed Scopus (1914) Google Scholar but antibody testing is often considered only when neurological symptoms begin.5Herken J Prüss H Red flags: clinical signs for identifying autoimmune encephalitis in psychiatric patients.Front Psychiatry. 2017; 8: 25Crossref PubMed Scopus (121) Google Scholar To facilitate early treatment, patients with potential NMDAR-antibody encephalitis and psychiatric symptom onset must be identified rapidly to initiate antibody testing of both serum and CSF. In their systematic review in The Lancet Psychiatry, Al-Diwani and colleagues6Al-Diwani A Handel A Townsend L et al.The psychopathology of anti-NMDA receptor encephalitis in adults: a systematic review and phenotypic analysis of individual patient data.Lancet Psychiatry. 2019; (published online Feb 11.)http://dx.doi.org/10.1016/S2215-0366(19)30001-XSummary Full Text Full Text PDF PubMed Scopus (106) Google Scholar analysed psychiatric symptoms in patients with NMDAR-antibody encephalitis and compared the psychopathological profile to common psychiatric syndromes. Of 1096 records identified in PubMed, 330 satisfied inclusion criteria and described 1100 patients with NMDAR-antibody encephalitis. 464 adult patients with definite NMDAR-antibody encephalitis according to consensus criteria3Graus F Titulaer MJ Balu R et al.A clinical approach to diagnosis of autoimmune encephalitis.Lancet Neurol. 2016; 15: 391-404Summary Full Text Full Text PDF PubMed Scopus (1936) Google Scholar were from papers that reported patient data individually. The authors extracted 50 lower-level psychiatric features reported in these 464 patients, defined their frequency, and grouped them into eight higher-level features. The psychopathological profile of each individual patient was then compared with 14 psychiatric comparator diagnoses using a principal component analysis and a constrained combination model. The authors also assessed whether individual patients were best described by one or by several psychiatric diagnoses. The authors observed that patients had up to 20 lower-level psychiatric features (median three, IQR 2–5). More specifically, a transdiagnostic cluster of seven clinical features (agitation, aggression, hallucinations, delusions, mutism, irritability or mood instability, and depressed mood) explained 77% of the variance in the data. The most common higher-level features were behaviour (316 [68%]), psychosis (310 [67%]), mood (219 [47%]), catatonia (137 [30%]), and sleep disturbance (97 [21%]), and these features frequently coexisted in individual patients. Modelling these results showed that NMDAR-antibody encephalitis psychopathology is best described as a mixed mood-psychosis syndrome rather than by any single diagnosis alone. A network analysis confirmed the strong interconnection between psychiatric features within individual patients. This study used advanced statistical analyses to provide an unprecedented depth and detail to NMDAR-antibody encephalitis psychopathology. Additionally, the results can guide clinical decision making about lumbar punctures for CSF antibody analysis in patients with suggestive psychiatric syndromes. This will most likely lead to more rapid diagnoses and thus better outcomes in patients with NMDAR-antibody encephalitis. The clinical information of this study was derived from individual case reports, which might be biased to highlight unusual features. However, deviations in demographics, aetiology, or neurological profiles were absent in the investigated sample of 464 patients. Furthermore, in a subgroup analysis of patients reported by psychiatrists, the description of psychiatric symptoms was even more detailed, which led to a further increase of symptom overlap in patients and higher coherence of symptoms in the network analysis. The authors suggest that more input by psychiatrists might have accounted for 117 (26%) of 451 patients presenting with only a single higher-level feature (eg, only behavioural abnormalities, or only psychosis). An important next step is assessing the prognostic value of the identified criteria in an independent patient sample, and deriving positive and negative predictive values of the diagnostic features identified in this study to enable even better guidance of clinical decision making, ideally in multicentre studies. The psychiatric features could also be integrated with the profile of cognitive impairment,7Finke C Kopp UA Prüss H Dalmau J Wandinger K-P Ploner CJ Cognitive deficits following anti-NMDA receptor encephalitis.J Neurol Neurosurg Psychiatry. 2012; 83: 195-198Crossref PubMed Scopus (235) Google Scholar functional MRI findings,8Peer M Prüss H Ben-Dayan I Paul F Arzy S Finke C Functional connectivity of large-scale brain networks in patients with anti-NMDA receptor encephalitis: an observational study.Lancet Psychiatry. 2017; 4: 768-774Summary Full Text Full Text PDF PubMed Scopus (83) Google Scholar and serum or CSF biomarkers9Makuch M Wilson R Al-Diwani A et al.N-methyl-D-aspartate receptor antibody production from germinal center reactions: therapeutic implications.Ann Neurol. 2018; 83: 553-561Crossref PubMed Scopus (65) Google Scholar, 10Leypoldt F Höftberger R Titulaer MJ et al.Investigations on CXCL13 in anti-N-methyl-D-aspartate receptor encephalitis: a potential biomarker of treatment response.JAMA Neurol. 2015; 72: 180-186Crossref PubMed Scopus (123) Google Scholar to create scores that predict long-term outcome in patients with NMDAR-antibody encephalitis.11Balu R McCracken L Lancaster E Graus F Dalmau J Titulaer MJ A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis.Neurology. 2018; 92: e244-e252Crossref PubMed Scopus (120) Google Scholar As also noted by the authors, it will be interesting to extend the methods employed here to a paediatric population, since children constitute about one third of patients with NMDAR-antibody encephalitis but present with a different balance of symptoms—for example, more frequent movement disorders and less frequent memory impairments. Indeed, another recent meta-analysis indicates that agitation is more likely and psychosis is less likely in NMDAR encephalitis in children compared with adult patients.12Sarkis RA Coffey MJ Cooper JJ Hassan I Lennox B Anti-N-methyl-D-aspartate receptor encephalitis: a review of psychiatric phenotypes and management considerations: a report of the American Neuropsychiatric Association Committee on Research.J Neuropsychiatry Clin Neurosci. 2018; (published online Dec 18.)DOI:10.1176/appi.neuropsych.18010005Crossref PubMed Scopus (29) Google Scholar In summary, Al-Diwani and colleagues1Dalmau J Lancaster E Martinez-Hernandez E Rosenfeld MR Balice-Gordon R Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis.Lancet Neurol. 2011; 10: 63-74Summary Full Text Full Text PDF PubMed Scopus (1758) Google Scholar identified a psychopathological pattern of NMDAR-antibody encephalitis that could transform the clinical approach to psychiatric patients with suspected autoimmune encephalitis. Future prospective studies should quantify the diagnostic power of the patterns of psychiatric features analysed here, to help identify patients who should undergo a lumbar puncture for CSF antibody testing. Finally, this study emphasises the importance of a close interaction between psychiatrists and neurologists to achieve the best possible outcomes for patients with this neuropsychiatric disorder. I declare no competing interests. The psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient dataThe 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. Full-Text PDF Open Access