N-Methyl-D-Aspartate Receptor-Antibody Encephalitis Impairs Maintenance of Attention to Items in Working Memory.

NMDA receptors (NMDARs) may be crucial to working memory (WM). Computational models predict that they sustain neural firing and produce associative memory, which may underpin maintaining and binding information, respectively. We test this in patients with antibodies to NMDAR (n = 10, female) and compare them with healthy control participants (n = 55, 20 male, 35 female). Patients were tested after recovery with a task that separates two aspects of WM: sustaining attention and feature binding. Participants had to remember two colored arrows. Then attention was directed to one of them. After a variable delay, they reported the direction of either the same arrow (congruent cue) or of the other arrow (incongruent cue). We asked how congruency affected recall precision and measured types of error. Patients had difficulty in both sustaining attention to an item over time and feature binding. Controls were less precise after longer delays and incongruent cues. In contrast, patients did not benefit from congruent cues at longer delays [group × congruency (long condition); p = 0.041], indicating they could not sustain attention. Additionally, patients reported the wrong item (misbinding errors) more than controls after congruent cues [group × delay (congruent condition), main effect of group; p ≤ 0.001]. Our results suggest NMDARs are critical for both maintaining attention and feature binding.

Aberrant Brain Networks and Relative Band Power in Patients with Acute Anti-NMDA Receptor Encephalitis: A Study of Resting-State EEG.

OBJECTIVE: The alterations of the functional network (FN) in anti-N-methyl-Daspartate receptor (NMDAR) encephalitis have been recognized by functional magnetic resonance imaging studies. However, few studies using the electroencephalogram (EEG) have been performed to explore the possible FN changes in anti-NMDAR encephalitis. In this study, the aim was to explore any FN changes in patients with anti-NMDAR encephalitis. METHODS: Twenty-nine anti-NMDAR encephalitis patients and 29 age- and gender-matched healthy controls (HC) were assessed using 19-channel EEG examination. For each participant, five 10-second epochs of resting state EEG with eyes closed were extracted. The cortical source signals of 84 Brodmann areas were calculated using the exact low resolution brain electromagnetic tomography (eLORETA) inverse solution by LORETA-KEY. Phase Lag Index (PLI) matrices were then obtained and graph and relative band power (RBP) analyses were performed. RESULTS: Compared with healthy controls, functional connectivity (FC) in the delta, theta, beta 1 and beta 2 bands significantly increased within the 84 cortical source signals of anti-NMDAR encephalitis patients (p < 0.05) and scalp FC in the alpha band decreased within the 19 electrodes. Additionally, the anti-NMDAR encephalitis group exhibited higher local efficiency and clustering coefficient compared to the healthy control group in the four bands. The slowing band RBP increased while the fast band RBP decreased in multiple-lobes and some of these changes in RBP were correlated with the modified Rankin Scale (mRS) and Mini-mental State Examination (MMSE) in anti-NMDAR encephalitis patients. CONCLUSIONS: This study further deepens the understanding of related changes in the abnormal brain network and power spectrum of anti-NMDA receptor encephalitis. The decreased scalp alpha FC may indicate brain dysfunction, while the increased source beta FC may indicate a compensatory mechanism for brain function in anti-NMDAR encephalitis patients. These findings extend understanding of how the brain FN changes from a cortical source perspective. Further studies are needed to detect correlations between altered FNs and clinical features and characterize their potential value for the management of anti-NMDAR encephalitis.

The relevance of anti-N-methyl-D-aspartate receptor encephalitis for psychiatrists.

Psychiatrists are often the first to be consulted in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. While this disease is rare, psychiatrists need to be aware of its relevant fundamental, clinical and therapeutic aspects. We begin by reviewing the connection between anti-NMDAR encephalitis and the glutamate hypothesis of schizophrenia. Next, we focus on the profile of the patient typically afflicted with this disease. Then, we tackle the limited utility of current diagnostic criteria during the early stage of the disease. After reviewing the psychiatric features, we debate the quest for finding specific psychiatric phenotypes that could facilitate early-stage diagnosis. We conclude by discussing the treatment of psychiatric symptoms and disease outcomes. As follows, this paper presents the relevance of anti-NMDAR encephalitis for psychiatrists.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an essential differential diagnosis in Psychiatry, particularly when dealing with first-episode psychosis.Psychiatrists are often the first to be consulted in patients with NMDAR encephalitis, so they need to be aware of the relevant fundamental, clinical and therapeutic aspects of this disease.

Regional cerebral blood flow in a patient with asystole episodes associated with anti-NMDA receptor encephalitis.

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a rare and severe autoimmune encephalitis that displays neuropsychiatric symptoms and autonomic instability, e.g., hypoventilation and cardiac arrhythmia. Severe arrhythmia including asystole associated with this encephalitis is rare. Several causes have been suggested. Nevertheless, no report of the literature has described examination by functional brain imaging of a patient with asystole during anti-NMDA receptor encephalitis. This case is that of a 34-year-old woman diagnosed as having anti-NMDA receptor encephalitis. She repeatedly showed 10-20 s asystole episodes necessitating a temporary transvenous pacemaker. After resection of the bilateral ovarian cystic tumor, her symptoms improved. Regional cerebral blood flow (rCBF) was evaluated using single-photon emission computed tomography. The rCBF was increased in the amygdala, hypothalamus, anterior cingulate, hippocampus, and anterior temporal lobes, but decreased in the dorsolateral frontal lobes, parietal lobes, and occipital lobes. Findings in this case suggest that altered rCBF in the patient with asystole episodes associated with anti-NMDA receptor encephalitis was observed in several brain lesions. The rCBF increases in the central autonomic networks, i.e., the amygdala, hypothalamus, and anterior cingulate, might be associated with dysregulation of sympathetic and parasympathetic nervous systems leading to asystole.

Altered EEG markers of synaptic plasticity in a human model of NMDA receptor deficiency: Anti-NMDA receptor encephalitis.

Plasticity of synaptic strength and density is a vital mechanism enabling memory consolidation, learning, and neurodevelopment. It is strongly dependent on the intact function of N-Methyl-d-Aspartate Receptors (NMDAR). The importance of NMDAR is further evident as their dysfunction is involved in many diseases such as schizophrenia, Alzheimer's disease, neurodevelopmental disorders, and epilepsies. Synaptic plasticity is thought to be reflected by changes of sleep slow wave slopes across the night, namely higher slopes after wakefulness at the beginning of sleep than after a night of sleep. Hence, a functional NMDAR deficiency should theoretically lead to altered overnight changes of slow wave slopes. Here we investigated whether pediatric patients with anti-NMDAR encephalitis, being a very rare but unique human model of NMDAR deficiency due to autoantibodies against receptor subunits, indeed show alterations in this sleep EEG marker for synaptic plasticity. We retrospectively analyzed 12 whole-night EEGs of 9 patients (age 4.3-20.8 years, 7 females) and compared them to a control group of 45 healthy individuals with the same age distribution. Slow wave slopes were calculated for the first and last hour of Non-Rapid Eye Movement (NREM) sleep (factor 'hour') for patients and controls (factor 'group'). There was a significant interaction between 'hour' and 'group' (p = 0.013), with patients showing a smaller overnight decrease of slow wave slopes than controls. Moreover, we found smaller slopes during the first hour in patients (p = 0.022), whereas there was no group difference during the last hour of NREM sleep (p = 0.980). Importantly, the distribution of sleep stages was not different between the groups, and in our main analyses of patients without severe disturbance of sleep architecture, neither was the incidence of slow waves. These possible confounders could therefore not account for the differences in the slow wave slope values, which we also saw in the analysis of the whole sample of EEGs. These results suggest that quantitative EEG analysis of slow wave characteristics may reveal impaired synaptic plasticity in patients with anti-NMDAR encephalitis, a human model of functional NMDAR deficiency. Thus, in the future, the changes of sleep slow wave slopes may contribute to the development of electrophysiological biomarkers of functional NMDAR deficiency and synaptic plasticity in general.

Seizures in autoimmune encephalitis-A systematic review and quantitative synthesis.

OBJECTIVE: This study aimed to evaluate the proportion of patients with seizures and electroencephalography (EEG) abnormalities in autoimmune encephalitis (AE) and its most common subtypes. METHODS: This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) standards and was registered with the International Prospective Register of Systematic Reviews (PROSPERO). We searched Medline All, Embase, and PsychINFO in Ovid from inception to June 2019 for articles pertaining to AE and seizure. Included studies reported seizure and/or EEG data in cohorts of ≥10 AE patients. Patient demographics, antibody type, seizure incidence, and EEG findings were extracted. Review of studies and data extraction were performed in duplicate. In addition to descriptive analysis, quantitative synthesis stratified by autoantibody subtype was performed with logistic regression and chi-square analyses. RESULTS: Our search yielded 3856 abstracts: 1616 were selected for full-text review and 118 studies met eligibility criteria. Of 3722 antibody-positive AE patients, 2601 (69.9%) had clinical seizures during the course of their illness. Of the 2025 patients with antibody-positive AE and available EEG data, 1718 (84.8%) had some EEG abnormality (eg, epileptiform discharges, slowing, and so on). Anti- N-methyl-d-aspartate (NMDA) receptor encephalitis (anti-NMDARE) was the most commonly reported type of AE (1985/3722, 53.3%). Of the anti-NMDARE patients with available seizure or EEG data, 71.8% (n = 1425/1985) had clinical seizures during their illness, and 89.7% (n = 1172/1306) had EEG abnormalities. For all AE patients and in the anti-NMDARE subpopulation, seizures were more common in younger patients (p < .05). SIGNIFICANCE: This systematic review provides an estimate of the proportion of AE patients with seizures, confirming the magnitude of seizure burden in this population. Prospective studies are needed to understand population-based prevalence of seizures, identify factors associated with seizures, and evaluate particular EEG findings as biomarkers of seizures and outcomes in AE.

Using EEG and MEG to characterize extreme delta brush in a patient with anti-NMDA receptor encephalitis.

BACKGROUND: Extreme delta brush (EDB) is considered a potential marker for anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. The brain regions involved in EDB are unclear. CASE PRESENTATION: A 16-year-old woman with anti-NMDAR encephalitis who was experiencing psychosis was admitted. Electroencephalography (EEG) and magnetoencephalography (MEG) were used to analyze EDB in the patient. EDB on EEG could be disturbed by opening and closing the eyes, by occipital alpha rhythms and by sleep-wake cycles. The MEG results showed beta activity originating from bilateral superior parietal lobes. However, the delta wave originated from bilateral superior temporal gyri, the right middle temporal gyrus, the right inferior frontal gyrus, and the left inferior parietal lobe. CONCLUSIONS: Delta wave and beta activity might originate from different brain regions. Beta activity might be transmitted forward to the frontotemporal lobe and superimposed with delta activity to form EDB on EEG.

Development of the clinical assessment scale in autoimmune encephalitis.

OBJECTIVE: There is no scale for rating the severity of autoimmune encephalitis (AE). In this study, we aimed to develop a novel scale for rating severity in patients with diverse AE syndromes and to verify the reliability and validity of the developed scale. METHODS: The key items were generated by a panel of experts and selected according to content validity ratios. The developed scale was initially applied to 50 patients with AE (development cohort) to evaluate its acceptability, reproducibility, internal consistency, and construct validity. Then, the scale was applied to another independent cohort (validation cohort, n = 38). RESULTS: A new scale consisting of 9 items (seizure, memory dysfunction, psychiatric symptoms, consciousness, language problems, dyskinesia/dystonia, gait instability and ataxia, brainstem dysfunction, and weakness) was developed. Each item was assigned a value of up to 3 points. The total score could therefore range from 0 to 27. We named the scale the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). The new scale showed excellent interobserver (intraclass correlation coefficient [ICC] = 0.97) and intraobserver (ICC = 0.96) reliability for total scores, was highly correlated with modified Rankin scale (r = 0.86, p < 0.001), and had acceptable internal consistency (Cronbach α = 0.88). Additionally, in the validation cohort, the scale showed high interobserver reliability (ICC = 0.99) and internal consistency (Cronbach α = 0.92). INTERPRETATION: CASE is a novel clinical scale for AE with a high level of clinimetric properties. It would be suitable for application in clinical practice and might help overcome the limitations of current outcome scales for AE. ANN NEUROL 2019;85:352-358.

A Metabolic Brain Pattern Associated With Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis causes substantial neurological disability. Autoantibodies causing encephalitis directed against the neuronal cell surface or synapse are of diagnostic importance giving the possibility of successful immunotherapy. OBJECTIVE: In this study, we aim to provide supporting evidence that brain 18F-FDG-PET may be helpful in identifying likely patterns of regional brain glucose metabolism. METHODS: Thirty-three patients (18 men and 15 women; age range of 17-55 y) with positive NMDA receptor antibody encephalitis that underwent an 18F-FDG-PET imaging examination were prospectively selected and compared with a reference group of 14 brain 18F-FDG-PET scans from healthy volunteers using voxel-based statistical analysis. Clusters of hyper- and hypo-metabolism were reported for the whole sample of patients (FWE-corrected P < 0.05), and uncorrected at P < 0.005 for a group of relapsed patients. RESULTS: Mixed metabolic patterns (focal/bilateral hypermetabolism in the temporal lobe, insula, and cerebellum; associated with severe bilateral hypometabolism in the occipital and parietal lobes) were found. CONCLUSIONS: Our findings suggest that 18F-FDG-PET should be included as an imaging tool when assessing affected patients in the clinical workup to rule out anti-NMDA encephalitis and help determine the most effective treatment.

[Research progress on electroencephalogram characteristics of anti-N-methyl-D-aspartate receptor encephalitis].

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a kind of autoimmune disease aiming at NR1 subunit of NMDA receptor. In the early stage, functional damage is the main cause. Electroencephalogram (EEG) can reflect the abnormal brain function by recording the changes of EEG signals. The common EEG patterns of anti NMDA receptor encephalitis are slow wave abnormality, epileptic discharge, a large number of ß activity, extreme delta brush, etc. Here we review the waveform characteristics, origin, pathogenesis and clinical value of EEG in patients with NMDA receptor encephalitis.

Frequency and temporal sequence of clinical features in adults with anti-NMDA receptor encephalitis presenting with psychiatric symptoms.

BACKGROUND: Anti-NMDA receptor (NMDAr) encephalitis is the most common autoimmune encephalitis in adults. It mimics psychiatric disorders so often that most patients are initially referred to a psychiatrist, and many are misdiagnosed. Without prompt and effective treatment, patients are likely to suffer a protracted course with significant residual disability, or death. This study focuses on the frequency and chronology of salient clinical features in adults with anti-NMDAr encephalitis who are likely to be first evaluated by a psychiatrist because their presentation suggests a primary psychiatric disorder. METHODS: A systematic search of PubMed and EMBASE databases identified published reports of anti-NMDAr encephalitis associated with prominent behavioral or psychiatric symptoms. After eliminating redundancies, the frequencies and relative timing of clinical features were tabulated. Signs and symptoms were assigned temporal ranks based on the timing of their first appearance relative to the first appearance of other signs and symptoms in each patient; median ranks were used to compare temporal sequencing of both individual features and major symptom domains. RESULTS: Two hundred thirty unique cases (185 female) met study inclusion criteria. The most common features were seizures (60.4%), disorientation/confusion (42.6%), orofacial dyskinesias (39.1%), and mutism/staring (37.4%). Seizures, fever, and cognitive dysfunction were often the earliest features to emerge, but psychiatric features predominated and sequencing varied greatly between individuals. CONCLUSIONS: Clinicians should consider anti-NMDAr encephalitis when new psychiatric symptoms are accompanied by a recent viral prodrome, seizures or unexplained fever, or when the quality of the psychiatric symptoms is unusual (e.g. non-verbal auditory hallucinations).

A mouse model of seizures in anti-N-methyl-d-aspartate receptor encephalitis.

OBJECTIVE: Seizures develop in 80% of patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, and these represent a major cause of morbidity and mortality. Anti-NMDAR antibodies have been linked to memory loss in encephalitis; however, their role in seizures has not been established. We determined whether anti-NMDAR antibodies from autoimmune encephalitis patients are pathogenic for seizures. METHODS: We performed continuous intracerebroventricular infusion of cerebrospinal fluid (CSF) or purified immunoglobulin (IgG) from the CSF of patients with anti-NMDAR encephalitis or polyclonal rabbit anti-NMDAR IgG, in male C57BL/6 mice. Seizure status during a 2-week treatment was assessed with video-electroencephalography. We assessed memory, anxiety-related behavior, and motor function at the end of treatment and assessed the extent of neuronal damage and gliosis in the CA1 region of hippocampus. We also performed whole-cell patch recordings from the CA1 pyramidal neurons in hippocampal slices of mice with seizures. RESULTS: Prolonged exposure to rabbit anti-NMDAR IgG, patient CSF, or human IgG purified from the CSF of patients with encephalitis induced seizures in 33 of 36 mice. The median number of seizures recorded in 2 weeks was 13, 39, and 35 per mouse in these groups, respectively. We observed only 18 brief nonconvulsive seizures in 11 of 29 control mice (median seizure count of 0) infused with vehicle (n = 4), normal CSF obtained from patients with noninflammatory central nervous system (CNS) conditions (n = 12), polyclonal rabbit IgG (n = 7), albumin (n = 3), and normal human IgG (n = 3). We did not observe memory deficits, anxiety-related behavior, or motor impairment measured at 2 weeks in animals treated with CSF from affected patients or rabbit IgG. Furthermore, there was no evidence of hippocampal cell loss or astrocyte proliferation in the same mice. SIGNIFICANCE: Our findings indicate that autoantibodies can induce seizures in anti-NMDAR encephalitis and offer a model for testing novel therapies for refractory autoimmune seizures.

The Psychiatric Phenotype of Anti-NMDA Receptor Encephalitis.

In its early stages, anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is often characterized by prominent psychiatric manifestations that can lead to delays in diagnosis and treatment. The authors aimed to address this problem by providing a detailed description of the psychiatric phenotype and demographic features that may influence presentation. Eighty-six patients with positive serum NMDAR antibodies were identified, 22 of whom met diagnostic criteria for anti-NMDAR encephalitis. Medical notes were reviewed retrospectively to rate psychiatric symptoms using standardized scales. Clinical and demographic characteristics were compared for patients with and without psychosis. Patients with psychosis exhibited severe psychopathology with a characteristic phenotype: severe and disproportionate cognitive disturbance (p<0.005) with high negative symptom scores and excitability. Those presenting with psychotic symptoms were significantly younger than those without (p<0.005). Patients with anti-NMDAR encephalitis present with a somewhat distinct cluster of psychiatric symptoms not commonly seen in functional psychoses. When encountered, this atypical pattern should warrant further investigation and a high index of suspicion for anti-NMDAR encephalitis. The more prominent psychotic features in younger adults may reflect greater susceptibility of the young brain to exogenous psychosis.

Ion channels in EEG: isolating channel dysfunction in NMDA receptor antibody encephalitis.

See Roberts and Breakspear (doi:10.1093/brain/awy136) for a scientific commentary on this article.Neurological and psychiatric practice frequently lack diagnostic probes that can assess mechanisms of neuronal communication non-invasively in humans. In N-methyl-d-aspartate (NMDA) receptor antibody encephalitis, functional molecular assays are particularly important given the presence of NMDA antibodies in healthy populations, the multifarious symptomology and the lack of radiological signs. Recent advances in biophysical modelling techniques suggest that inferring cellular-level properties of neural circuits from macroscopic measures of brain activity is possible. Here, we estimated receptor function from EEG in patients with NMDA receptor antibody encephalitis (n = 29) as well as from encephalopathic and neurological patient controls (n = 36). We show that the autoimmune patients exhibit distinct fronto-parietal network changes from which ion channel estimates can be obtained using a microcircuit model. Specifically, a dynamic causal model of EEG data applied to spontaneous brain responses identifies a selective deficit in signalling at NMDA receptors in patients with NMDA receptor antibody encephalitis but not at other ionotropic receptors. Moreover, though these changes are observed across brain regions, these effects predominate at the NMDA receptors of excitatory neurons rather than at inhibitory interneurons. Given that EEG is a ubiquitously available clinical method, our findings suggest a unique re-purposing of EEG data as an assay of brain network dysfunction at the molecular level.

Recognizing psychiatric presentations of anti-NMDA receptor encephalitis in children and adolescents: A synthesis of published reports.

AIM: The aim of this study was to improve early recognition of anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDArE) in children and adolescents by identifying characteristic temporal patterns of clinical features in patients likely to be referred for psychiatric evaluation. In this form of autoimmune encephalitis, NMDAr hypofunction is caused by autoantibodies to receptor surface components. Clinical outcomes following prompt immunotherapy are usually good, but delayed treatment often results in a protracted course with significant residual disability or death. Anti-NMDArE frequently mimics psychiatric disorders, so most patients are referred initially to a psychiatrist and treated for days or weeks before being correctly diagnosed. METHODS: A systematic search of PubMed and EMBASE electronic databases identified all published reports of antibody-confirmed anti-NMDArE associated with psychiatric symptoms in patients <19 years old. Redundant reports were eliminated manually. For each patient, the order in which each feature was first observed was ranked relative to others. Median temporal ranks were used to compare the sequencing of individual features and major symptom domains. RESULTS: One hundred and sixty seven cases (121 females) met the inclusion criteria. The most common features were dyskinesias (77.8%), seizures (72.5%), mutism or staring (40.7%), insomnia (39.5%), language dysfunction (36.5%), fever (31.1%), disorientation/confusion (28.7%), reduced arousal (28.1%), and memory disturbance (26.9%). The configuration and temporal sequencing of features were highly variable between individuals. CONCLUSION: Clinicians need to suspect this disorder: if new behavioral symptoms arise in the context of a recent viral prodrome; if they are accompanied by dyskinesias, seizures or insomnia; or if psychiatric symptoms are unusual (e.g., non-verbal auditory hallucinations).

Catatonia in patients with anti-NMDA receptor encephalitis.

AIM: There is a lack of studies related to the frequency, phenomenology, and associated features of catatonic syndrome in patients with anti-NMDA receptor encephalitis (ANMDARE). This study aimed to measure the frequency of catatonia in this condition and to delineate its particular symptoms. METHODS: A prospective study was done with all inpatients who fulfilled the criteria of definite ANMDARE admitted to the National Institute of Neurology and Neurosurgery of Mexico from January 2014 to September 2018. The Bush-Francis Catatonia Rating Scale and Braünig Catatonia Rating Scale were administered at admission. RESULTS: Fifty-eight patients were included and catatonia was diagnosed in 41 of these patients (70.6%). Immobility, staring, mutism, and posturing were the most frequent catatonic signs. Catatonia was associated with delirium, hallucinations, psychomotor agitation, generalized electroencephalography dysfunction, and previous use of antipsychotics. Mortality was present in 10% of the total sample; it was associated with status epilepticus, and was less frequent in the catatonia group. After immunotherapy, all cases showed a complete recovery from catatonic signs. CONCLUSION: This systematic assessment of catatonic syndrome shows that it is a frequent feature in patients with ANMDARE as part of a clinical pattern that includes delirium, psychomotor agitation, and hallucinations. The lack of recognition of this pattern may be a source of diagnostic and therapeutic errors, as most physicians associate catatonia with schizophrenia and affective disorders.

Predictive value of electroencephalography in anti-NMDA receptor encephalitis.

OBJECTIVES: Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is a severe, but treatable disease. This study aims to give a detailed description of electroencephalogram (EEG) results in paediatric and adult patients to improve disease recognition, and analyses the predictive value of the first EEG for the final clinical outcome. METHODS: This nationwide cohort study includes patients with N-methyl-D-aspartate receptor antibodies confirmed with cell-based assay and immunohistochemistry in serum and cerebrospinal fluid. EEG recordings were re-evaluated by two experienced neurophysiologists, mixed with control EEGs for blinding. Initial EEG as well as follow-up registrations were analysed. RESULTS: 35 adults and 18 children were included. Only two patients (4%) had a normal EEG. During the first recording, the majority of the patients had normal posterior rhythm (71%), which was associated with better modified Rankin Scale at final outcome (OR 4.74; 95% CI 1.56 to 14.47; p=0.006). In addition, EEGs showed focal (73%) or diffuse (67%) slowing. The first EEG was severely abnormal in 26%. However, 8 of 14 patients with a severely abnormal first EEG still had a favourable outcome. During the course of the disease, extreme delta brushes (EDBs) were present in 6 of 53(11%)patients. CONCLUSIONS: The first EEG commonly shows normal posterior rhythm with focal or diffuse slowing. Although the sensitivity of an abnormal EEG is high (96%), normal EEG does not exclude anti-NMDARE. EDBs are only present in severely affected patients. The first EEG recording is predictive of the final clinical outcome.

Refining the psychiatric syndrome of anti-N-methyl-d-aspartate receptor encephalitis.

OBJECTIVE: To review the psychiatric symptoms of anti-N-methyl-d-aspartate (NMDA) receptor encephalitis, in an attempt to differentiate the presentation from a primary psychiatric disorder. METHOD: A systematic literature review of PubMed and EMBASE of all published cases of anti-NMDA receptor encephalitis was performed from inception to January 2018. RESULTS: There were 706 cases of anti-NMDA receptor encephalitis identified. Cases were typically young (mean age 22.6 years, SD 14.8), female (F : M ratio 3.5 : 1) and presented with significant behavioural disturbance. Reported behaviour was most commonly severe agitation and aggression, abnormal speech, and catatonia. Psychosis occurred in 45.8% of cases. Investigation results were inconsistent (MRI abnormal in 35.6%, EEG abnormal in 83.0%) and non-specific. Psychiatric treatment often required multiple psychotropics, and there may be increased risk of significant side-effects such as neuroleptic malignant syndrome. Prognosis was usually good; however, cognitive and behavioral symptoms remained prominent during recovery, and psychiatrist involvement was required in this period. CONCLUSION: The presentation of anti-NMDA receptor encephalitis is variable. However, there are often psychiatric features which are atypical to a primary psychiatric illness, such as severe agitation, speech abnormalities, and catatonia, which may help early identification.

Altered perception might be a symptom of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.

Most patients with N-methyl-D-aspartate receptor (NMDAR) encephalitis initially present with psychiatric symptoms. Although a delayed diagnosis may lead to a poor outcome, psychiatric symptoms that could differentiate anti-NMDAR encephalitis from other psychoses have not been fully investigated. We evaluated two patients with anti-NMDAR encephalitis who were observed by psychiatrists from onset throughout the course of disease. Both patients exhibited disorientation, memory deficits, perceptual disturbances, hallucinations, and mood liability. Among those, altered perceptions were most prominent - in particular, altered time perceptions without disorganization syndrome. The information obtained for these patients may help clinicians differentiate anti-NMDAR encephalitis from other psychoses, e.g., schizophrenia.

Predictive values and specificity of electroencephalographic findings in autoimmune encephalitis diagnosis.

OBJECTIVE: Early diagnosis of autoimmune encephalitis (AE) to not delay treatment is challenging but needed in practice. Most previous evidences of electroencephalographic (EEG) findings in AE were derived from descriptive studies. Given paucity of evidence of specific EEG findings to help with early diagnosis of AE, this study aimed to ascertain specific EEG findings and assess their predictive values in diagnosis of AE. METHODS: We included all cases with AE in our institution from January 2013 to June 2017. Cases were matched with controls by age and level of consciousness (1:2 ratio). Potential confounders for EEG findings collected as baseline characteristics were compared. Two epileptologists independently reviewed EEGs. Standardized terminology, definitions, and scoring system of EEG findings were employed. Logistic regression analysis was performed, and diagnostic performance of significant EEG features was assessed. RESULTS: Twenty cases and 40 controls were included in this study. Poorly sustained posterior dominant rhythm (PDR) was significantly associated with AE (p = 0.007) and even more predictive in anti-N-methyl-d-aspartate (NMDA) encephalitis. Inter-rater agreement (kappa) was 0.714. None of the cases had normal EEG nor Grand Total EEG (GTE) score < 4 (negative predictive value (NPV) of 100%). Specificity of well sustained PDR to exclude the diagnosis of anti-NMDA encephalitis was high (91.67%). CONCLUSIONS: Simple EEG assessment can be used to help exclude AE. When AE is suspected, careful assessment of the sustainment of the PDR is warranted. The NPV of GTE score < 4 and specificity of well sustained PDR can be simply used to differentiate many conditions from AE.