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Background A 12-year-old female with JIA on biologic medication (IV abatacept every three weeks) presented with a first generalised tonic-clonic seizure on background of preceding headache and fatigue. The seizure self-terminated but disorientation and encephalopathy ensued. MRI brain demonstrated lesions with high signal intensity in the left periventricular and right occipital regions. The clinical picture and radiological imaging suggested a broad differential diagnosis including CNS infection, JC virus associated progressive multifocal leucoencephalomalacia (PML), acute disseminated encephalomyelitis (ADEM) and Anti-N-methyl-d-aspartate receptor (NMDAr) encephalitis. She was commenced on IV ceftriaxone, acyclovir and clarithromycin. All bloods including inflammatory markers and infection serology were unremarkable. CSF was acellular and JC virus PCR negative. NMDAr encephalitis was initially considered unlikely (pre-existing immunosuppression, abnormal MRI brain and no evidence of ovarian teratoma on abdominal MRI pelvis). However more classical clinical features developed including further seizures, significant movement disorder, cognitive dysfunction, sleep and speech dysfunction. Anti-NMDAr antibodies in both serum and CSF were positive. She made a good recovery following IV steroids, plasmapheresis and rituximab and was discharged home after a 10-week admission. NMDAr encephalitis developed three years after commencing abatacept treatment. Previous immune modulating treatment included methotrexate (since age 2 years), Etanercept (age 5-8 years) and Tocilizumab (aged 8-10 years). Flares of disease following a period of control necessitated the changes in therapy. Methods A literature review was conducted to explore the relationship between NMDAr encephalitis and biologic medication. A yellow card report and information request to abatacept manufacturer were also submitted. Results No previous cases of NMDAr encephalitis in patients on abatacept or paediatric cases related to biologic therapy are described. There are reports of adults developing NMDAr encephalitis on Adalumimab for Crohn’s disease and etanercept for rheumatoid arthritis. NMDAr encephalitis has also been described in patients on immune checkpoint inhibitors for malignant melanoma (nivolumab and ipilimumab). Known triggers of production of anti-NMDA receptor antibodies include tumours (ovarian teratoma; rarely associated in patients under 12 years) and viral infections. Developing autoimmune disorders on biologic medication is well reported, most notably psoriasis and inflammatory bowel disease. In relation to abatacept specifically, the development of anti-nuclear antibodies (ANA) and psoriasis have been described. However, patients with autoimmune disorders are known to be of increased risk for additional immune disease. A new cohort of patients are emerging who have received multiple biologic medications and the development of autoimmune conditions despite immunosuppression needs to be considered. Conclusion We describe the first case of NMDAr encephalitis occurring in a child on abatacept therapy, and the first case in JIA. We are unable to determine what contribution a history of autoimmune disease or immunomodulating therapy has made on its development in this case. Disclosures R. Close: None. P. Bale: None. K. Gallagher: None. G. Ambegaonkar: None. T. Rossor: None. N. Abbassi: None. K. Armon: None.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a serious autoimmune disorder characterized by psychiatric symptoms, seizures and movement disorder. Predisposing factors have been reported since the time it was described, and its pathophysiology has been tried to be clarified over the years. Although overlap with other demyelinating diseases had been reported, such an association between Multiple Sclerosis (MS) anti ANTI-NMDAR encephalitis is limited to only a few case reports. In this article, a patient diagnosed with relapsing remitting multiple sclerosis (RRMS) for ten years who then developed NMDA-R encephalitis while on disease modifying treatment will be presented and possible common pathophysiology with previously reported literature will be discussed.

NMDAR encephalitis may be more common among non-Caucasians. A population-based study was conducted to estimate its incidence in Sabah, Malaysia, where the population consists predominantly of Austronesians (84%), and with a Chinese minority. Registries of NMDAR encephalitis at neurology referral centers were reviewed for case ascertainment. The annual incidence was 2.29/million (Austronesians: 2.56/million, Chinese: 1.31/million). Among pediatric population, the incidence was: Austronesians: 3.63/million, Chinese: 2.59/million. Our study demonstrated a higher incidence of NMDAR encephalitis among Austronesians than the predominantly Caucasian populations in Europe (0.5-0.9/million; pediatric: 0.7-1.5/million). Racial and genetic factors may contribute to risks of developing NMDAR encephalitis.

Purpose. Although its specificity has not previously been investigated in other cohorts, delta brush pattern (DBP) is increasingly reported in the EEGs of patients with anti- N-methyl-d-aspartate receptor (NMDAR) encephalitis. Methods. We aimed to investigate the DBP in the EEGs of 2 cohorts; patients with change in consciousness for various causes monitored in the intensive care unit (ICU) (n = 106) and patients with mesial temporal lobe epilepsy (MTLE) with or without antineuronal antibodies (n = 76). Results. These patients were investigated for the presence of DBP, defined as an EEG pattern characterized by delta activity at 1 to 3 Hz with superimposed bursts of rhythmic 12- to 30-Hz activity. Two investigators blindfolded for the clinical and immunological data independently analyzed the EEGs for recognition of this pattern. An EEG picture compatible with DBP was observed in 4 patients; only 1 of them (1.3%) belonged to the MTLE group. She did not bear any of the investigated autoantibodies and was seizure-free after epilepsy surgery. In the ICU group, there were 3 additional patients showing DBP with various diagnoses such as hypoxic encephalopathy, brain tumor, stroke, and metabolic derangements. All of them had died in 1-month period. Conclusions. Our results underlined that DBP is not unique to NMDAR encephalitis; it may very rarely occur in MTLE with good prognosis after surgery and second, in ICU patients who have high mortality rate. Therefore, the presence of this pattern should alert the clinician for NMDAR encephalitis but other possible etiologies should not be ignored.

Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, a recently reported autoimmune disorder, can be mistakenly diagnosed as a psychotic disorder, especially schizophrenia, as patients can present with prominent psychotic symptoms, in particular persecutory ideation, hallucinations and disturbed speech. In this study we used machine learning of the clinical data in a large cohort of persons with a positive psychosis history to ascertain whether we could predict NMDAR-positive cases, and which variables most accurately distinguished between NMDAR-positive and -negative cases. Methods SHIP collected nationally representative data from 1825 individuals with a psychotic illness. Plasma samples were available for n=472. To investigate the prevalence of NMDAR autoantibodies a recombinant indirect immunofluorescence test was performed (EuroImmun AG, Lübeck, Germany), with NMDAR transfected human embryonic kidney (HEK) 293 cells quantified using NIS Elements software. NMDAR-positive cases were estimated. Gradient boosting machine learning (the data were randomly split: 60% for initial ascertainment and 40% for validation) was subsequently performed using the clinical data available: 120 variables in total across various domains of sociodemographic, medical history, psychiatric diagnosis and current psychiatric symptoms. Only the variables found to have significant (or near significant) association with being NMDAR-positive were used to develop rules for identifying cases. Results There were 38 NMDAR-positive cases. They were more likely to be associated with a schizophrenia /schizoaffective and a depressive psychosis diagnosis, and less likely to be associated with a bipolar diagnosis, than antibody-negative cases. They were also more likely to be associated with a single episode with good recovery, and with anxiety symptoms and dizziness in the prior 12 months (which included light headedness, feeling faint and unsteady). For the present state symptoms, restricted affect was more likely to be present whereas poverty of speech was rare. Initial insomnia and a medical history that included epilepsy were not present for any of the NMDAR-positive cases. The machine learning algorithm was able to successfully classify 94% of cases to the correct antibody group. Discussion In this significant Australian epidemiological cohort, we have identified key clinical features associated with anti-NMDAR encephalitis, including diagnosis, and symptoms and clinical course. The novel and insightful analyses afforded by using machine learning should be replicated in other samples to confirm the important clinical findings reported in the current work.

Anti N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder and is considered to be one of the most common causes of encephalitis in children. Despite the fact that around half of all reported cases are of children, the number of studies that report infants and toddlers is very small. Furthermore, reports on children from the Middle East particularly are extremely rare.We report a 21-month-old Jordanian female toddler with NMDAR encephalitis, who initially presented with behavioral changes and some autistic features. She presented a diagnostic challenge due to a concurrent urinary tract infection and gastroenteritis. Multiple investigations were conducted and she was treated with methylprednisolone and intravenous immunoglobulin (IVIg) empirically as well as plasma exchange and rituximab once the diagnosis was confirmed. Her condition improved gradually. We discuss her clinical picture and the diagnostic challenges within this age group; we also review the current related literature. Keywords: Anti NMDA receptor encephalitis, Toddlers, Infants, Children, Jordan, Autism spectrum, Behavioral change

Diagnosis and treatment of anti-NMDAR encephalitis during pregnancy are challenging. We report a case of anti-NMDAR encephalitis in a 28-year-old, 24 weeks pregnant woman. Her brain magnetic resonance imaging was normal, but arterial spin labeling (ASL) showed increased cerebral blood flow in the right insula and temporal area. She was successfully treated with emergent cesarean section and immunotherapies including intravenous immunoglobulin, steroids, and rituximab. The newborn was healthy and she recovered fully. Early suspicion and proper management is important in treatment of anti-NMDAR encephalitis during pregnancy. ASL can help diagnosing anti-NMDAR encephalitis during pregnancy.

ObjectiveAnti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a severe, but treatable, autoimmune disorder, characterized by autoantibodies causing hypofunction of blocking NMDA receptors leading to a unique constellation of cognitive, motor, and psychiatric symptoms. Neuropsychological and psychopathological outcome has not been fully explored, particularly in children. Aim of this study was to investigate pediatric anti-NMDAR encephalitis as a model of impairment of the complex frontal-subcortical circuits who are implicated in several of the childhood neuropsychiatric disorders.MethodSeven children diagnosed with anti-NMDAR encephalitis at our department underwent an evaluation of the global mental functioning before discharge, a neuropsychological and psychological/behavioral standardized examination within one month after discharge and subsequently were followed up longitudinally for mean 35 months (range 24–48 months). Collected neuropsychological data were evaluated retrospectively.ResultsDeficits in attention, executive functions and/or visual motor functions involving executive functions were seen in all children within one month after discharge. These deficits were long lasting in about a half of the patients. In addition, four patients developed persistent psychopathological dysfunctions: difficulties to regulate their own behavior, impulsivity, hyperactivity, irritability, apathy, and obsessive-compulsive symptoms.ConclusionsOur data are in line with research suggesting a crucial role of the executive functions impairments in cognitive outcome disturbance of anti-NMDAR encephalitis. We found also behavioral and psychological deficits pointing to a more comprehensive framework of frontal-subcortical dysfunction, in which the NMDA mediated transmission appear to have a role, as suggested by neurobiological, pharmacological, and neuroimaging studies.

We describe the case of a woman with Parkinson disease who developed an N-methyl-d-aspartate receptor antibody-mediated encephalitis. As a novelty, the encephalitis presentation mimicked a worsening of the pre-existing extrapyramidal syndrome, manifesting mainly as severe bradykinesia and, eventually, akinesia. Brain MRI was normal, whereas cerebrospinal fluid (CSF) analysis disclosed unique-to-CSF oligoclonal bands. Prompt identification and timely immunotherapy led to a complete recovery.

Autoimmunenzephalitiden sind eine wesentliche Differenzialdiagnose neu aufgetretener Epilepsien. Bietet die Histopathologie eindeutige oder wesentliche morphologische Korrelate von Autoimmunenzephalitiden differenzieller Genese? Auswertung der Literatur und eigener Befunde. Bei vielen Autoimmunenzephalitiden liegen nur begrenzte Veroffentlichungen neuropathologischer Befunde vor. Vergleichsweise gut charakterisiert ist die Rasmussen-Enzephalitis, bei welcher der neuropathologische Befund eine Unterteilung unterschiedlicher Stadien zulasst und eine zytotoxische Zellschadigung belegt. Autoimmunenzephalitiden mit Antikorpern gegen intrazellulare oder oberflachenassoziierte Antigene stellen histopathologisch ein heterogenes Krankheitsbild dar. In den vorliegenden Publikationen variiert die Quantitat und Zusammensetzung der Entzundungszellinfiltrate sowie das Vorliegen einer Komplementaktivierung zwischen den unterschiedlichen Erkrankungen. Bei limbischen Enzephalitiden mit Antikorpern gegen intrazellulare Zielantigene dominieren zytotoxische Entzundungsreaktionen. Bei limbischen Enzephalitiden mit Antikorpern gegen Bestandteile des Kaliumkanalkomplexes sind auch Komplementablagerungen zu erkennen. Bei der NMDAR-Enzephalitis finden sich weniger T-Lymphozyten und kein Nachweis einer Komplementaktivierung. Histopathologische Befunde konnen bei der Einordnung der Ursache von entzundlich bedingten Epilepsien wesentlich unterstutzen und liefern essenzielle Informationen fur das Verstandnis der Atiologie von Autoimmunenzephalitiden. Die Vergleichbarkeit der wenigen veroffentlichten neuropathologischen Untersuchungen an Gewebe autoantikorperpositiver Patienten ist jedoch aufgrund unterschiedlich langer Krankheitsverlaufe, unterschiedlicher praoperativer Medikation sowie der Heterogenitat der untersuchten Gehirnregion limitiert.

Anti-N-methyl-D-aspartate-Receptor (NMDAR) encephalitis is an autoimmune disorder with a multifaceted presentation that involves memory deficits, psychiatric symptoms, and autonomic instability. This case report describes the classic presentation of Anti-NMDAR encephalitis and highlights its association with ovarian teratomas. We present a 26 -year-old female who came in with new onset seizures and altered mentation who subsequently developed automatism. Electroencephalograms (EEG) showed left frontal spikes and right temporal delta activity. Magnetic resonance imaging (MRI) revealed right temporal hyper-intensity. The diagnosis was established with positive anti-NMDAR antibodies in the cerebrospinal fluid (CSF). The patient was initially treated with steroids and valproic acid, however, her condition progressively worsened. A five-day course of intravenous immunoglobulins (IVIG) was started followed by rituximab. The clinical course was complicated with the patient developing neutropenic fever and cerebrospinal fluid cultures (CSF) growing methicillin-sensitive Staphylococcus aureus (MSSA). She underwent pelvic imaging which showed a right ovarian teratoma. Evidence suggests that removal of ovarian tumor leads to better clinical and mortality outcomes in patients with Anti-NMDAR encephalitis. It is important for the internist to consider paraneoplastic syndromes in patients with Anti-NMDAR encephalitis.

Supplemental Digital Content is available in the text, Background: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis responds to immunnotherapy, and approximately 80% of patients with this disorder fully recover or have only minor sequelae. Brain magnetic resonance imaging (MRI) does not show a specific abnormality, but some patients have progressive cerebral atrophy. The cerebral atrophy can become reversible after clinical improvement. Methods: We describe 3 patients with diffuse cerebral atrophy (DCA) on serial brain MRI. Results: Two women had the typical spectrum of this disorder, and one man had mainly psychiatric symptoms. In a woman with an ovarian tumor, DCA was reversible and DCA developed within about a half month. In another woman without a tumor, DCA was evident within 19 days and had progressed over the course of 4 years. The titers of anti-NMDAR antibodies in serum and cerebrospinal fluid (CSF) initially decreased, and low titers of the antibodies persisted. In a man without a tumor, DCA progressed within 14 days, and during this short period, he did not receive prolonged treatment with corticosteroids, various antiepileptic agents, or propofol, and he was free of seizures and ventilatory support. Conclusion: Not only a woman but also a man with anti-NMDAR encephalitis can have DCA in the early phase of this disorder. However, DCA can be reversible after clinical improvements. The early progression of DCA is not necessarily a poor prognostic factor.

Objective Autoimmune encephalitis is most frequently associated with anti-NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody-producing clones, and characterize their antibody signatures in recombinant form. Methods Patients with recent onset typical anti-NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy- (IgH) and light-chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance. Results Intrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen-driven intrathecal immune response. Consistently, a single recombinant human GluN1-specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo. Interpretation A CNS-specific humoral immune response is present in anti-NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti-NMDAR encephalitis as a humorally mediated autoimmune disease.

In “Clinical Reasoning: A 56-year-old woman with acute vertigo and diplopia,” Sharma et al. presented the case of a patient with a pontine infarct attributed to varicella-zoster virus reactivation in the setting of immunosuppression by bortezomib for treatment of light-chain amyloidosis. In response, Dr. Ambrose reminds neurologists that bortezomib, which is increasingly being used for antibody-mediated autoimmune diseases, including NMDAR encephalitis, can cause a pan-immunodeficiency. Authors Flanagan and Sharma agree that bortezomib has broad therapeutic potential, but that the risks of administration must be acknowledged.

In “Clinical Reasoning: A 56-year-old woman with acute vertigo and diplopia,” Sharma et al. presented the case of a patient with a pontine infarct attributed to varicella-zoster virus reactivation in the setting of immunosuppression by bortezomib for treatment of light-chain amyloidosis. In response, Dr. Ambrose reminds neurologists that bortezomib, which is increasingly being used for antibody-mediated autoimmune diseases, including NMDAR encephalitis, can cause a pan-immunodeficiency. Authors Flanagan and Sharma agree that bortezomib has broad therapeutic potential, but that the risks of administration must be acknowledged. In “Clinical Reasoning: A 56-year-old woman with acute vertigo and diplopia,” Sharma et al. presented the case of a patient with a pontine infarct attributed to varicella-zoster virus reactivation in the setting of immunosuppression by bortezomib for treatment of light-chain amyloidosis. In response, Dr. Ambrose reminds neurologists that bortezomib, which is increasingly being used for antibody-mediated autoimmune diseases, including NMDAR encephalitis, can cause a pan-immunodeficiency.

Immune encephalitis is a diverse group of disorders that share some unique diagnostic approaches and specific treatments. Some of the initial manifestations are non-specific and difficult to distinguish from encephalitis of other aetiologies, and even with modern diagnostic tools there are still a number of cases for which definitive causes cannot be clarified. Among these, N-methyl- d -aspartate receptor (NMDAR) encephalitis is a particular form of immune encephalitis that has some distinctive clinical manifestations, which allows the clinical evaluator to suggest a more accurate diagnosis and start treatments even in the absence of specific laboratory tests. Three paediatric patients, who were treated for NMDAR encephalitis are described in this article, as well as comparing their clinical presentation. This specific disorder and some of the more relevant features of its physiopathology are reviewed in order to explain the initial psychiatric manifestations, for which early recognition is critical for an appropriate diagnosis and treatment.

Introduction: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an inflammatory disorder of the brain that has garnered significant interest within the medical and lay communities. There is a need for formal guidelines to assist physicians in identifying patients who should undergo testing for NMDAR encephalitis, recognizing the high potential for this potentially treatable disease to mimic more common disorders, and consequently remain undiagnosed.Areas covered: This review highlights the impact of the discovery of NMDAR encephalitis on the fields of neurology and psychiatry, and discusses the steps that are necessary to improve recognition and treatment of NMDAR encephalitis.Expert commentary: While much progress has been made in our understanding of NMDAR encephalitis, much work remains to be done to delineate the underlying disease mechanisms and their relevance to brain function.

N-methyl-D-aspartate receptor (NMDAR) encephalitis is a life-threatening paraneoplastic neuropsychiatric encephalitis that predominantly affects young women and has a strong association with ovarian teratomas. Removal of the ovarian teratomas improves the prognosis and decreases the risk of recurrence. We present an 11-year-old girl with NMDAR encephalitis with small bilateral teratomas not initially appreciated on abdominal CT or pelvic MRI. A 12-mm teratoma was identified in the right ovary and a 7-mm teratoma was identified in the left ovary on US follow-up at 5 months. Intraoperative sonography was used to localize the teratomas for excision. In NMDAR encephalitis, the ovarian teratomas can be very small, particularly in children, and easily missed on cross-sectional imaging. Awareness of the association of NMDAR encephalitis and ovarian teratomas will improve the diagnostic accuracy and imaging interpretation. Periodic sonography and MRI might be warranted in children if the initial study is negative.

Patients with anti-NMDA receptor (anti-NMDAR) encephalitis frequently suffer from autonomic dysfunctions, which can cause substantial morbidity. This study assessed cardiac autonomic functions in patients with anti-NMDAR encephalitis using heart rate variability (HRV) analysis. This was a retrospective single-center case-control study. Eleven patients with anti-NMDAR encephalitis and 15 age- and sex-matched controls were included in this study. To ensure that autonomic dysfunction does not occur in any encephalitis, we additionally analyzed HRV of 9 patients with herpes encephalitis (HSE) and compared with that of NMDAR encephalitis patients and controls. Five minute resting stationary electrocardiogram was collected from each subject, and HRV was analyzed. Total power and low frequency (LF) power were lower in anti-NMDAR encephalitis patients than those in controls (p=0.005, 0.001 respectively), indicating cardiac autonomic dysfunction especially in sympathetic system. Patients with HSE showed no significant difference in HRV parameters compared with that of controls. Cardiac autonomic dysfunction was associated with 3 month functional outcome in anti-NMDAR encephalitis patients.

Anti-N-Methyl-D-Aspartate receptor (NMDAR) encephalitis is probably the most common paraneoplastic encephalitis. In children, seizures, behavioral disturbances and abnormal movements are the most frequent symptoms. Electroencephalogram is abnormal in most patients. We report a child with anti- NMDAR encephalitis presenting extreme delta brushes in the EEG. This new EEG feature is described in patients with anti-NMDAR encephalitis, mostly adults. The identification of this EEG pattern may guide to an early diagnosis and treatment of anti-NMDAR encephalitis.

Background: Anti NMDA receptor (anti NMDAR) encephalitis is a well-characterized entity in children associating movement disorders, psychiatric features and speech difficulties. Novel phenotypes have been described in adults. Methods and Results: A 4-year-old girl presented partial seizures which evolved towards sudden and isolated Broca's aphasia. Anti NMDAR antibodies were positive in CSF and serum confirming anti NMDAR encephalitis. Clinical recovery was observed after a specific treatment. Conclusion: This case widens the clinical spectrum of anti-NMDAR encephalitis in children and awareness of this newly identified symptom is important as early treatment is a predictor of good outcome

Investigators at University of Toronto, Canada, report detection of atypical (dysplastic) neuronal elements in 4 of 5 teratomas resected from cases with NMDAR encephalitis but not in 39 controls.