Prevalence of N-Methyl-d-Aspartate Receptor antibody (NMDAR-Ab) encephalitis in patients with first episode psychosis and treatment resistant schizophrenia on clozapine, a population based study
Introduction
N-methyl-d-aspartate receptor antibody (anti-NMDA or NMDAR-Ab) encephalitis has ignited efforts into whether specific autoantibody syndromes might explain a subset of patients with psychotic illnesses. NMDAR-Ab encephalitis is a multistage encephalitis caused by antibodies to the GluN1 (NR1) subunit of the NMDA receptor.
Patients with NMDAR-Ab encephalitis typically present with psychiatric symptoms, usually psychosis, to psychiatric services in approximately 75% of cases, before the emergence of neurological symptoms within one month (Dalmau et al., 2007; Titulaer et al., 2013). These features include cognitive deficits, seizures, autonomic instability, catatonia and movement disorders (Dalmau et al., 2007; Titulaer et al., 2013; Irani et al., 2010). Electroencephalogram (EEG) is abnormal in approximately 90% of patients, usually showing diffuse slow or disorganised activity, epileptic activity or an extreme delta brush sign (Dalmau et al., 2011; Graus et al., 2016; Schmitt et al., 2012). Brain Magnetic Resonance Imaging (MRI) is abnormal in 33-55% of patients and may show increased signal on MRI fluid-attenuated inversion recovery or T2 sequences in the medial temporal lobes, cerebral cortex and cerebellum (Dalmau et al., 2008; Titulaer et al., 2013). Cerebrospinal fluid (CSF) analysis is abnormal in about 80% of patients, demonstrating lymphocytic pleocytosis (Dalmau et al., 2008; Irani et al., 2010). Other findings include normal or mildly increased protein concentration and, in 60% of patients, CSF-specific oligoclonal bands (Dalmau et al., 2011). Identification of NMDAR-Ab should lead to exploration for an underlying malignancy which if present, is almost always an ovarian teratoma (Titulaer et al., 2013).
Rarely cases of anti-NMDA encephalitis can occur with isolated psychiatric features and may respond to immuno-modulatory therapy, suggesting that there are cases who do not have the full spectrum of disease (Zandi et al., 2014; Kayser et al., 2013; Kuppuswamy et al., 2014). Early immunotherapy treatment of NMDAR-Ab encephalitis has demonstrated improved functional and cognitive outcomes (Titulaer et al., 2013; Finke et al., 2012) and screening the serum of patients with first episode psychosis (FEP) for NMDAR-Ab has been recommended (Lennox et al., 2017).
There has been much debate about the methodology for identifying NMDAR-Ab. Live, non-permeabilized cell-based assays (L-CBAs) largely find higher prevalence of NMDAR-Ab in serum of patients compared to fixed permeabilized (F-CBAs) (Zandi et al., 2011; Pathmanandavel et al., 2015; Dahm et al., 2014; Hammer et al., 2014). Other studies that have utilised a CBA as well as immunohistochemistry (IHC) have not identified any seropositive cases in cohorts of first episode psychosis but have done so in post-partum psychosis in one study (de Witte et al., 2015; Bergink et al., 2015).
In 2016, consensus guidelines were published on the diagnostic criteria of NMDAR-Ab encephalitis (Graus et al., 2016). Probable or definite NMDAR-Ab encephalitis is more likely with multiple symptoms, both neurological and psychiatric as well as supportive imaging, electroencephalogram supportive imaging, electroencephalogram and CSF changes Definite NMDAR-Ab encephalitis as defined by the guidelines, is made in the presence of at least one of the major groups of neuro-psychiatric symptoms and IgG anti-GluN1 antibodies in CSF. CSF however can be challenging to obtain from psychiatric cohorts (Lennox et al., 2017). If only serum is available, confirmatory tests should include a cell-based assay as well as tissue immunohistochemistry (Graus et al., 2016).
Several epidemiological studies have demonstrated that patients with schizophrenia had a higher prevalence of autoimmune diseases (Cullen et al., 2019; Benros et al., 2014; Chen et al., 2012). Recently it has been suggested that in addition to screening all FEP cases, patients with treatment-resistant psychosis patients should be considered for autoantibody screening (Ellul et al., 2017; Jézéquel et al., 2018). Pilot data has identified that NMDAR-Ab may be present in patients with chronic refractory psychosis (7%, 3/43), although none appear to have been diagnosed with encephalitis or treated with immunotherapy (Beck et al., 2015). About 30% of patients with schizophrenia have been found to be treatment resistant (Wimberley et al., 2016) and NMDAR-Ab are associated with neuroleptic intolerance (Lejuste et al., 2016). Potentially, this may have led to patients with NMDAR-Ab encephalitis to be disproportionately diagnosed as treatment resistant.
We aimed to screen all cases with first episode psychosis presenting to psychiatric services for NMDAR-Ab in serum using L-CBA. All seropositive cases would be clinically investigated (neurology review, MRI-brain, EEG, CSF, malignancy screen) for features of encephalitis. We retrospectively applied consensus criteria to any seropositive samples we identified which included using immunohistochemistry. A cohort of patients with treatment resistant schizophrenia (TRS) were also invited to participate.
Section snippets
Patients and clinical data
Patient recruitment was from general adult psychiatry services serving strictly defined catchment areas attached to St James's Hospital and Tallaght University Hospital in Dublin and Newcastle Hospital in Wicklow (total population ~264,000). For recruitment of FEP cases, community mental health teams who cover both inpatient and outpatient services were educated about the research study and asked to refer those meeting inclusion criteria who were willing to participate.
Inclusion criteria for
Demographic information
215 individuals were recruited to this study. The final FEP cohort comprised of 115 patients. Following recruitment, two patients were withdrawn from the study- one as they were found to have a history of epilepsy and another as they became medically unwell from a pre-existing illness. A further patient requested to withdraw from the study. Therefore the final FEP cohort amounted to 112 individuals, the majority of whom were male (N = 74, 66%) with a mean (SD) age of 33 (12) years and were
Discussion
In this real-word clinical study, we identified an NMDAR-Ab seroprevalence rate in first episode psychosis of 4/112 (3.5%) using a live cell based assay, which corroborates previous seroprevalence studies, varying between ~1% (N = 1/98) and 3.5% (N = 7/228) (Gaughran et al., 2017; Lennox et al., 2017). This study reports the clinical evidence for encephalitis in the identified cases, which has been cited as a limitation in previous studies (Schou and Saether, 2018) and formally utilises recent
Contributors
EK and AC contributed to the initial study design. EK, PM, CM, DH, BF, PW, MG and AC contributed to patient data collection. EH contributed to statistics. JD, NC and AV were responsible for the sample management and sample analysis using the live cell based assay. CD and RW were responsible for assessment of seropositive cases. All authors contributed to the manuscript and gave final approval of the version to be published, and agree to be accountable for all aspects of the work in ensuring
Funding
Trinity College Dublin.
Patient consent
Obtained.
Ethics approval
This study was approved by the Adelaide and Meath Ethics committee (ref: 2012/11/28) according to the principles of the Declaration of Helsinki.
Declaration of competing interest
AV and the University of Oxford hold patents for antibody assays, and AV receives a proportion of royalties from Athena Diagnostics and Euroimmun AG. Other authors have no competing interests.
Acknowledgements
We sincerely thank all the patients who participated in this research. We are grateful to our consultant colleagues - Dr Mairead Condron, Dr Niall Crumlish, Dr Yolande Ferguson, Dr Grainne Flynn, Dr Moayyadd Kamali, Dr Eamonn Kenny, Dr Kieran OLoughlin and Dr Paul Scully as well as their teams for their assistance with recruitment. We thank Professor Dalmau and his team for their expertise and the analysis and interpretation of patient samples. We acknowledge the work of laboratory staff across
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Visiting Research Fellow, Department of Psychiatry, Trinity College Dublin, Ireland.