Abstract
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is one of the most frequently encountered autoimmune encephalitis. The pathogenesis of both anti-NMDAR encephalitis and schizophrenia involve down-regulation of NMDA receptors. Whether autoantibody-mediated destruction of neuronal NMDA receptors is associated with schizophrenia or first-episode psychosis (FEP) remains unclear, as the current findings from different groups are inconsistent. The main culprits are likely due to heterogeneity of autoantibodies (autoAbs) in a patient's blood or cerebrospinal fluid (CSF), as well as due to limitation of the current detection methods for anti-NMDAR autoAbs. Here, we optimized the current diagnostic method based on the only commercially-available anti-NMDAR test kit. We first increased detection sensitivity by replacing reporter fluorophore fluorescein isothiocyanate (FITC) in the kit with Alexa Fluor 488, which is superior in resisting photobleaching. We also found that using an advanced imaging system could increase the detection limit, compared to using a simple fluorescence microscope. To improve test accuracy, we implemented secondary labeling with a well-characterized mouse anti-NR1 monoclonal antibody (mAb) after immunostaining with a patient's sample. The degree of colocalization between mouse and human antisera in NMDAR-expressing cells served to validate test results to be truly anti-NMDAR positive or false-positive. We also incorporated DNA-specific DAPI to simultaneously differentiate autoAbs targeting the plasma membrane from those targeting cell nuclei or perinuclear compartments. All the technical implementation could be integrated in a general hospital laboratory setting, without the need of specialized expertise or equipment. By sharing our experience, we hope this may help improve sensitivity and accuracy of the mainstream method for anti-NMDAR detection.
Highlights
Diagnosis of anti-NMDAR autoimmune encephalitis requires identification of pathogenic anti-NMDAR autoAbs in a clinical sample [1]
It has been an intriguing research topic to determine whether autoantibodies against NMDA receptor might contribute to the pathogenesis of a subset of schizophrenia through autoimmune-mediated neuroinflammation
As many patients with anti-NMDAR encephalitis are first seen by psychiatrists for their initial prominent psychiatric symptoms, these 4% of the anti-NMDAR-positive patients with only psychiatric symptoms conceivably might be diagnosed as psychosis or even schizophrenia in psychiatric clinics
Summary
Diagnosis of anti-NMDAR autoimmune encephalitis requires identification of pathogenic anti-NMDAR autoAbs in a clinical sample [1]. Because anti-NMDAR autoAbs could target neuronal receptor and impair glutamatergic transmission, psychotic and cognitive disturbing symptoms are prominent in anti-NMDAR encephalitis [2,3,4,5]. Early presentation of antiNMDAR encephalitis shares symptoms of schizophrenia. In an early study of 571 patients diagnosed with antiNMDAR autoAbs, 23 of them (4%) presented no neurological symptoms but isolated psychiatric episodes [6]. As many patients with anti-NMDAR encephalitis are first seen by psychiatrists for their initial prominent psychiatric symptoms, these 4% of the anti-NMDAR-positive patients with only psychiatric symptoms conceivably might be diagnosed as psychosis or even schizophrenia in psychiatric clinics. Their psychiatric symptoms were eventually cured by immunosuppressive treatments, emphasizing the extreme importance of correctly sorting out these patients [7, 8]
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