Анти-NMDA-рецепторный энцефалит и шизофрения

CONTEXT Evidence for symptomatic convergence of schizophrenia and N -methyl-D-aspartate glutamate receptor (NMDA-R) encephalitis highlights the need for an assessment of antibody prevalence and specificity for distinct disease mechanisms in patients with a diagnosis of schizophrenia among glutamatergic pathophysiologic abnormalities in psychiatric disorders. OBJECTIVES To compare the specificity and prevalence of NMDA-R antibodies in schizophrenia (DSM-IV criteria) with those of other psychiatric diagnoses and to determine whether antibody subtypes characterize overlap with and distinction from those in NMDA-R encephalitis. DESIGN Serum from 459 patients admitted with acute schizophrenia, major depression (MD), and borderline personality disorder (BLPD) or individuals serving as matched controls was obtained from our scientific blood bank. To explore epitope specificity and antibody subtype, IgA/IgG/IgM NMDA-R (NR1a or NR1a/NR2b) and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPA-R) (GluR1/GluR2) serum antibodies were determined. PARTICIPANTS Two hundred thirty matched healthy controls were compared with patients (unmedicated for at least 6 weeks) with schizophrenia (n = 121), MD (n = 70), or BLPD (n = 38). MAIN OUTCOME MEASURES The primary outcome was the overall number of seropositive cases for NMDA-R and AMPA-R antibodies; the secondary outcome was disease specificity of IgA/IgG/IgM antibodies and epitope specificity for clinical subgroups. RESULTS Diverse NMDA-R antibodies were identified in 15 subjects, primarily those with an initial schizophrenia diagnosis (9.9%), opposed to MD (2.8%), BLPD (0), and controls (0.4%). Retrospectively, 2 patients initially classified as having catatonic or disorganized schizophrenia were reclassified as having misdiagnosed NMDA-R encephalitis (presence of specific serum and cerebrospinal fluid IgG NR1a antibodies). In all other seropositive cases, the antibodies consisted of classes IgA and/or IgM or were directed against NR1a/NR2b (not against NR1a alone). None of the patients or controls had antibodies against AMPA-R. CONCLUSIONS Acutely ill patients with an initial schizophrenia diagnosis show an increased prevalence of NMDA-R antibodies. The repertoire of antibody subtypes in schizophrenia and MD is different from that with NMDA-R encephalitis. The latter disorder should be considered as a differential diagnosis, particularly in young females with acute disorganized behavior or catatonia.

Increased Prevalence of Diverse N -Methyl-D-Aspartate Glutamate Receptor Antibodies in Patients With an Initial Diagnosis of Schizophrenia: Specific Relevance of IgG NR1a Antibodies for Distinction From N -Methyl-D-Aspartate Glutamate Receptor Encephalitis.

Случай нейропсихиатрической манифестации анти-NMDA-рецепторного энцефалита

A 52-year-old Chinese man was admitted to the inpatient psychiatric unit of an academic teaching hospital with an admitting diagnosis of major depressive disorder (MDD) with psychotic features. His chief complaint was "I do not feel happy." The patient endorsed insomnia, hopelessness, passive suicidal ideation, and increased anxiety, especially at bedtime. He was disheveled, guarded, demonstrated poor eye contact, slurred and decreased speech output, psychomotor retardation, poor cognition, flat affect, and vague auditory and visual hallucinations of seeing and hearing people. The patient had a past psychiatric history of MDD with psychotic features diagnosed when he was in his early 30s, and suicidal gestures. He had two previous inpatient admissions while in China in 2008, for psychotic features described then as robotic speech, flat affect, and minimal verbal responsiveness. At the time of his current admission, he was being followed in the psychiatry outpatient clinic. He denied past or current substance abuse. The patient's past medical history was significant for one observed tonic–clonic seizure in December 2009, which was managed with phenytoin 300 mg daily. At that time, neurologic evaluation was unrevealing, and no etiology of the seizure was identified.
After initial evaluation in the hospital, the patient was started on escitalopram 15 mg daily and paliperidone 3 mg daily, and his phenytoin 300 mg daily was continued. ECT had been considered while he was being followed as an outpatient. Upon admission, he was started on a course of ECT. Despite numerous medication trials including paliperidone, olanzapine, and clozapine, as well as a series of 12 ECT treatments, the patient's condition did not improve, and he began to show signs of cognitive decline. A neurology consult was requested for continued agitated and bizarre behavior. An EEG showed diffuse slowing, and a magnetic resonance (MRI) scan showed only small-vessel ischemic microvascular disease.
After 2 months, while still on the psychiatry inpatient unit, he developed symptoms of extreme agitation, aggressiveness, and unusual behavior, and was verbally unresponsive. His agitation was treated with lorazepam. Vital signs at that time revealed tachycardia to a heart rate of 120 bpm, a blood pressure of 90/50 mmHg, and O2 saturation of 90% at room air. His temperature was 102.3°F. The patient was transferred to the medical intensive care unit (MICU) and intubated for airway protection. Laboratory data at transfer revealed a white cell count of 11.2 K/µl, BUN 32 mg/dl, Cr 1.2 mg/dl, and creatine kinase 2,361 u. Neuroleptic malignant syndrome was suspected but ruled out, as the patient's temperature and creatine kinase trended down in the subsequent days without any active intervention. After 11 days, he was extubated. He displayed echopraxia, but no focal findings were documented.
Because of his unusual course, failure to respond to standard treatments for depression and psychosis, and the presence of a documented seizure 1 month before admission, a work-up for possible anti-NMDA receptor antibody encephalitis was started. Lumbar puncture yielded clear, colorless fluid which was acellular, with a glucose of 76 mg/dl and protein of 21 mg/dl. VDRL and oligoclonal bands were negative. CSF and serum sample was also sent for anti-NMDA receptor antibody testing. The patient had an EEG performed, which revealed bilateral independent temporal lobe discharges more prominent in the left hemisphere than the right, but no active seizures were seen. CSF and serum results confirmed the patient's diagnosis of anti-NMDA antibody encephalitis by the presence of antibodies against NRI-NR2 heteromers of the NMDA receptor. The patient was transferred to another hospital and lost to follow-up.

An Unusual Case of Anti-NMDA-Receptor Encephalitis in the Psychiatry Inpatient Unit

Анти-NMDA-рецепторный энцефалит

Of 100 patients with anti-NMDA-receptor encephalitis, a disorder that associates with antibodies against the NR1 subunit of the receptor, many were initially seen by psychiatrists or admitted to psychiatric centres but subsequently developed seizures, decline of consciousness, and complex symptoms requiring multidisciplinary care. While poorly responsive or in a catatonic-like state, 93 patients developed hypoventilation, autonomic imbalance, or abnormal movements, all overlapping in 52 patients. 59% of patients had a tumour, most commonly ovarian teratoma. Despite the severity of the disorder, 75 patients recovered and 25 had severe deficits or died.
This disorder largely affects young people, and its diagnosis is facilitated by the characteristic clinical picture that develops in association with CSF pleocytosis. By contrast to the consistency of the clinical picture, MRI findings are less predictable; only 55% of patients had increased FLAIR or T2 signal in one or several brain regions, without significant correlation with patients’ symptoms (data not shown). Our study indicates that 41% of patients with anti-NMDA-receptor encephalitis do not have a clinically detectable tumour, and that men and children can also be affected. Therefore, although the presence of a tumour that expresses NMDA receptors likely contributes to breaking immune tolerance, other unknown immunological triggers seem to be involved. This paradigm is similar to the Lambert-Eaton myasthenic syndrome, an antibody-mediated disorder of the neuromuscular junction that can occur with or without tumour association.16 In Lambert-Eaton myasthenic syndrome the presence of a small-cell lung cancer confers a poor neurological prognosis; however, in anti-NMDA-receptor encephalitis, detection of teratoma is a good prognostic factor, probably because this tumour is curable.

Anti-NMDA-receptor encephalitis represents a new category of immune-mediated disorder that is often paraneoplastic, treatable, and can be diagnosed serologically. Future studies should clarify the best type and duration of immunotherapy, the role of prodromal events in triggering the immune response, and the molecular mechanisms involved in decreasing the number of NMDA receptors.

Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies