NMDAR Encephalitis Research Articles

Editors' Note: Clinical, Neuroimmunologic, and CSF Investigations in First Episode Psychosis

In “Clinical, Neuroimmunologic, and CSF Investigations in First Episode Psychosis,” Guasp et al. and the Barcelona group reported that 21 of 105 patients with first-episode psychosis (FEP) met the criteria by Pollak et al. for possible or probable autoimmune psychosis (AP), none of whom had autoimmune antibodies or developed NMDAR encephalitis. In a separate cohort, 2 of 3 patients referred for a second opinion with FEP who had NMDA receptor antibodies did not meet the criteria by Pollak et al. for possible AP. They concluded that the criteria by Pollak et al. are overly dependent on neurologic features and propose their own algorithmic approach to screen for AP, which includes the performance of MRI, EEG, and testing for serum neuronal antibodies for all patients with FEP even in the absence of neurologic warning symptoms. Pollak et al. commented that all 3 patients in the one FEP cohort with autoimmune antibodies, in fact, met the criteria for possible AP because of the presence of a movement disorder and/or cognitive dysfunction. Furthermore, they questioned the recommendation by Guasp et al. to perform an extensive workup in the setting of FEP without neurologic symptoms because of concern that this is not only a poor use of resources but it is also not feasible in most psychiatric settings. Dalmau et al. and the Barcelona group respond that (1) although echolalia is one of the 12 features of catatonia, it can be present independently and (2) because there is a broad differential diagnosis for FEP, which includes systemic, neurologic, and psychiatric disorders, facilities that care for patients with FEP must be able to perform a thorough diagnostic evaluation themselves or transfer patients elsewhere. In “Clinical, Neuroimmunologic, and CSF Investigations in First Episode Psychosis,” Guasp et al. and the Barcelona group reported that 21 of 105 patients with first-episode psychosis (FEP) met the criteria by Pollak et al. for possible or probable autoimmune psychosis (AP), none of whom had autoimmune antibodies or developed NMDAR encephalitis. In a separate cohort, 2 of 3 patients referred for a second opinion with FEP who had NMDA receptor antibodies did not meet the criteria by Pollak et al. for possible AP. They concluded that the criteria by Pollak et al. are overly dependent on neurologic features and propose their own algorithmic approach to screen for AP, which includes the performance of MRI, EEG, and testing for serum neuronal antibodies for all patients with FEP even in the absence of neurologic warning symptoms. Pollak et al. commented that all 3 patients in the one FEP cohort with autoimmune antibodies, in fact, met the criteria for possible AP because of the presence of a movement disorder and/or cognitive dysfunction. Furthermore, they questioned the recommendation by Guasp et al. to perform an extensive workup in the setting of FEP without neurologic symptoms because of concern that this is not only a poor use of resources but it is also not feasible in most psychiatric settings. Dalmau et al. and the Barcelona group respond that (1) although echolalia is one of the 12 features of catatonia, it can be present independently and (2) because there is a broad differential diagnosis for FEP, which includes systemic, neurologic, and psychiatric disorders, facilities that care for patients with FEP must be able to perform a thorough diagnostic evaluation themselves or transfer patients elsewhere.

Comprehensive Meta-Analysis Supports Early Treatment for Best Outcome in NMDA Receptor Encephalitis

Comprehensive Meta-Analysis Supports Early Treatment for Best Outcome in NMDA Receptor Encephalitis

Anti-NMDAR Encephalitis: Multidisciplinary Development of a Clinical Practice Guideline.

Anti-NMDAR Encephalitis: Multidisciplinary Development of a Clinical Practice Guideline.

P.002 Successful Treatment of Supra-Refractory Status Epilepticus Secondary to Anti-N-Methyl-D- Aspartate Receptor Encephalitis With Electroconvulsive Therapy

Background: Anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis is an autoimmune disease associated with antibodies against heteromers NR1 and NR2 subunits of the cell surface of the NMDA receptors, causing many psychiatric and neurological symptoms. This includes new-onset refractory status epilepticus. Methods: A 33-year-old previously healthy female developed new-onset refractory status epilepticus caused by anti- NMDA receptor encephalitis without the presence of tumours. Results: The clinical course was complicated by prolonged status epilepticus, which was refractory to many antiepileptic drugs (levetiracetam, phenytoin, carbamazepine, topiramate, lacosamide, valproic acid), ketamine, propofol, midazolam, including inhalation agents (isoflurane). Also, she received first (intravenous immunoglobulin, intravenous methylprednisolone, and plasmapheresis), second-line immunotherapy (rituximab) and prophylaxis bilateral oophorectomy without clinical or electrographic improvement. However, the patient drug-resistant status epilepticus markedly improved both clinically and electrographically following seven sessions of electroconvulsive therapy. Conclusions: Electroconvulsive therapy should be considered as adjuvant therapy for the treatment of immunotherapy resistant encephalitis.

108 Comparing autoimmune encephalitis variants in a pediatric cohort from Hamilton, Ontario

Abstract Primary Subject area Neurology Background Autoimmune Encephalitis (AE) is an emerging cause of epilepsy with numerous variants, including anti NMDA-receptor encephalitis, for which there is a detectable antibody. However, it is believed that there are many variants of AE for which an antibody has not yet been discovered. Objectives This study aimed to determine the differences in disease course of AE patients with and without detectable anti-NMDA receptor antibody. Design/Methods This retrospective analysis is part of a Canada-wide project aimed at evaluating the epidemiology and characteristics of AE. Cases with suspected AE were retrieved and screened by two independent reviewers against AE criteria. Those that met criteria were analyzed for trends and stratified into NMDA receptor antibody positive (NMDAr) and negative categories for inter-group analysis. Of 23 cases reviewed, 11 met criteria (aged 1-17 years, 27% males), of which 7 were NMDAr positive. Results The NMDAr subgroup was characterized by behavioural changes, focal seizures, and prodromal fever on presentation, whereas the receptor negative subset had a much higher variability of symptoms, without any distinctive patterns. On average, the NMDAr positive group showed an increase in white blood cell count on CSF analysis, and a slight increase in the proportion of patients presenting with supratentorial lesions on MRI. Both groups had abnormal findings on EEG. However, despite the lack of gross differences in findings, all of the NMDAr positive cases received IVIG (most with corticosteroids as well) while only 2 NMDAr negative patients received immunomodulatory therapy. At discharge 6/7 of the NMDAr patients had some form of residual movement disorder while the NMDAr negative group had more variable residual symptoms at discharge. Conclusion Our findings show that a high index of suspicion in the diagnosis of AE is required due to the indistinct distribution and variety in its presentation. Negative antibody findings should not rule out AE due to the possibility of unidentified antibodies. Future studies should explore why differences in treatment between the two groups exist, and if slight differences in presentation influence clinical decision-making.

Long-Term Cognitive Outcome in Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

Cognitive dysfunction is a core symptom of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, but detailed studies on prevalence, characteristics of cognitive deficits, and the potential for recovery are missing. Here, we performed a prospective longitudinal study to assess cognitive long-term outcome and identify clinical predictors. Standardized comprehensive neuropsychological assessments were performed in 43 patients with NMDAR encephalitis 2.3 years and 4.9 years (median) after disease onset. Cognitive assessments covered executive function, working memory, verbal/visual episodic memory, attention, subjective complaints, and depression and anxiety levels. Cognitive performance of patients was compared to that of 30 healthy participants matched for age, sex, and education. All patients had persistent cognitive deficits 2.3 years after onset, with moderate or severe impairment in >80% of patients. Core deficits included memory and executive function. After 4.9 years, significant improvement of cognitive function was observed, but moderate to severe deficits persisted in two thirds of patients, despite favorable functional neurological outcomes (median modified Rankin Scale=1). Delayed treatment, higher disease severity, and longer duration of the acute phase were predictors for impaired cognitive outcome. The recovery process was time dependent, with greater gains earlier after the acute phase, although improvements were possible for several years after disease onset. Cognitive deficits are the main contributor to long-term morbidity in NMDAR encephalitis and persist beyond functional neurological recovery. Nonetheless, cognitive improvement is possible for several years after the acute phase and should be supported by continued cognitive rehabilitation. Cognition should be included as an outcome measure in future clinical studies. ANN NEUROL 2021;90:949-961.

Next Generation Sequencing of Cerebrospinal Fluid B Cell Repertoires in Multiple Sclerosis and Other Neuro-Inflammatory Diseases-A Comprehensive Review.

During the last few decades, the role of B cells has been well established and redefined in neuro-inflammatory diseases, including multiple sclerosis and autoantibody-associated diseases. In particular, B cell maturation and trafficking across the blood–brain barrier (BBB) has recently been deciphered with the development of next-generation sequencing (NGS) approaches, which allow the assessment of representative cerebrospinal fluid (CSF) and peripheral blood B cell repertoires. In this review, we perform literature research focusing on NGS studies that allow further insights into B cell pathophysiology during neuro-inflammation. Besides the analysis of CSF B cells, the paralleled assessment of peripheral blood B cell repertoire provides deep insights into not only the CSF compartment, but also in B cell trafficking patterns across the BBB. In multiple sclerosis, CSF-specific B cell maturation, in combination with a bidirectional exchange of B cells across the BBB, is consistently detectable. These data suggest that B cells most likely encounter antigen(s) within the CSF and migrate across the BBB, with further maturation also taking place in the periphery. Autoantibody-mediated diseases, such as neuromyelitis optica spectrum disorder and LGI1 / NMDAR encephalitis, also show features of a CSF-specific B cell maturation and clonal connectivity with peripheral blood. In conclusion, these data suggest an intense exchange of B cells across the BBB, possibly feeding autoimmune circuits. Further developments in sequencing technologies will help to dissect the exact pathophysiologic mechanisms of B cells during neuro-inflammation.

Bortezomib in N-methyl-d-aspartate receptor encephalitis: A systematic review

N-methyl-D-aspartate receptor (NMDAR) encephalitis is a potentially treatable condition, although a small proportion of patients remains refractory to immunotherapy. Recently, bortezomib, a proteasome inhibitor used in multiple myeloma, has been used in NMDAR encephalitis and neuromyelitis optica. We performed a systematic review regarding the use of bortezomib in NMDAR encephalitis.

Uncommon association of NMDA receptor encephalitis with intracranial germ cell tumour

N-methyl-d-aspartate receptor encephalitis (NMDARE) has significant association with ovarian teratoma; meticulous search and removal of the same is a key step in the management. We describe challenges in the management odyssey of a 21-year-old lady with NMDARE.

Anti-NMDAR encephalitis preceded by infection: Systematic literature review with comparison of non-HSV and HSV related anti- NMDAR encephalitis

Anti-NMDAR encephalitis preceded by infection: Systematic literature review with comparison of non-HSV and HSV related anti- NMDAR encephalitis

Understanding Seizures and Prognosis of the Extreme Delta Brush Pattern in Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: A Systematic Review.

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (ANMDARE) is an autoimmune disorder with neurological and psychiatric features. The disease presents with a viral prodrome, followed by psychiatric manifestations. In the next phase, movement disorders or/and seizures occur. Finally, in the last phase, there is a decrease in the level of consciousness. Central hypoventilation and autonomic dysfunction can occur. Recently a unique EEG (electroencephalogram) pattern has been associated with anti-NMDA receptor encephalitis, the extreme delta brush (EDB). Although the association of the EDB with ANMDARE is known by the medical community, its significance is mainly unknown. A systematic review on NMDARE is also scarce. We decided to conduct a systematic review on this topic to consolidate the knowledge and establish the importance of the EDB as a prognostic factor. To conduct this systematic review, we used only studies conducted in humans, written in English, and published in the last 20 years. We used PubMed as a database and searched the following search terms: ("NMDA encephalitis"[Title/] AND "Epilepsy"[Title/]) OR (NMDA encephalitis"[Title/] AND "seizures" [Title/]) OR ("NMDA encephalitis"[Title/] AND "extreme delta brush"[Title/]). The protocol used for this systematic review was the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) protocol, and to analyze the bias of the studies, we used the ROBINS-1 tool.Eight studies were collected from our search strategy. Our data pulling showed that seizures were present in 178/249 (71.48%) patients. Status Epilepticus was reported in 29/96 (30.20%), and the EBD was seen in 30.89% (55/178) patients with seizures. The range of EDB was 5.9%-33% among the studies. Because the sample size was small, the statistical power was decreased. We had a low overall risk of bias. The wide range in the results could be related to the timing of the EEG recording. EDB was associated overall with increased length of hospital stay, increased ICU admission, and incidence of status epilepticus. The etiology of the EDB remains mainly unknown. However, it has been postulated that in NMDAR encephalitis, there is a disruption of the rhythmic neuronal activity. When antibodies block/target the NMDAR, the rhythmic neuronal activity is disrupted, leading to the unique EDB pattern. Another theory suggests that delta activity is caused because of focal abnormalities in the brain, and the superimposition of the beta waves is related to the alterations of the NMDA receptors.

I can\u2019t count, but I can beat you playing cards: a case report on autoimmune encephalitis

BackgroundAutoimmune encephalitis (AE) is a rare inflammatory disorder characterized by important psychiatric and neurologic symptoms. The literature documents high rates of neuropsychological dysfunction in N-methyl D-aspartate-receptor (NMDAr) encephalitis but papers don’t consider specifically calculation disturbances between the long-term deficits, although deficits in executive control and episodic memory were less likely to resolve.Case reportHere we present a severe case of NMDAr encephalitis in a young patient without a relevant past medical history. Upon first examination he presented psycho-motor slowdown, speech disorders, severe cognitive deficits in all areas: concentration, attention, memory, language, dual task functions, increased latency in responses, severe dyscalculia. Upon first evaluation, the young patient underwent a battery of neuropsychological tests and he showed a dysexecutive syndrome with performances significantly low for age and education. Our patient hence underwent 1 month of intensive cognitive rehabilitation. After the rehabilitation treatment, he presented an amelioration in all domains except calculations.ConclusionsIn our patient the calculation disorder has proved to be the most relevant problem and the most difficult to treat. Clinicians should consider a careful approach to determine the prognosis of this syndrome because of the wide range of deficits, the need of prolonged treatment and the rate of long-term sequelae.

Intrathecal Antibody Production Against Epstein-Barr, Herpes Simplex, and Other Neurotropic Viruses in Autoimmune Encephalitis.

Background and ObjectivesNeurotropic viruses are suspected to play a role in the pathogenesis of autoimmune diseases of the CNS such as the association between the Epstein-Barr virus (EBV) and multiple sclerosis (MS). A group of autoimmune encephalitis (AE) is linked to antibodies against neuronal cell surface proteins. Because CNS infection with the herpes simplex virus can trigger anti–NMDA receptor (NMDAR) encephalitis, a similar mechanism for EBV and other neurotropic viruses could be postulated. To investigate for previous viral infections of the CNS, intrathecally produced virus-specific antibody synthesis was determined in patients with AE.MethodsAntibody-specific indices (AIs) against EBV and measles, rubella, varicella zoster, herpes simplex virus, and cytomegalovirus were determined in 27 patients having AE (anti-NMDAR encephalitis, n = 21, and LGI1 encephalitis, n = 6) and in 2 control groups comprising of 30 patients with MS and 21 patients with noninflammatory CNS diseases (NIND), which were sex and age matched.ResultsAn intrathecal synthesis of antibodies against EBV was found in 5/27 (19%) patients with AE and 2/30 (7%) of the patients with MS. All these patients had also at least 1 additional elevated virus-specific AI. In contrast, in none of the patients with NIND, an elevated virus-specific AI was detected.DiscussionIntrathecally produced antibodies against EBV can be found in patients with AE and MS but only together with antibodies against different neurotropic viruses. Evidence of these antibodies is the result of a polyspecific immune response similar yet distinct from MS response rather than an elapsed infection of the CNS.

NMDA-receptor encephalitis in Denmark from 2009 to 2019: a national cohort study.

To describe the national Danish N-methyl-D-aspartate receptor encephalitis (NMDARE) cohort. All NMDAR immunoglobulin G (IgG) positive cases in Denmark from 2009 to 2019 were included. Medical information was assessed retrospectively for clinical phenotype, workup, treatment and outcome. Seventy-seven patients were NMDAR IgG positive in serum/CSF. Fifty-five fulfilled the criteria of NMDARE, 18 did not and 4 had missing data. Incidence was 0.17/100,000 persons per year in 2018, and incidence rates increased since 2009. Of the 55 NMDARE patients (median age 27; 60% female), 9 had post-herpes simplex (HSE) NMDARE and 7 had a tumor (four teratomas). MRI was normal in 51% of patients. Brain FDG PET was performed in 17 patients, and was abnormal in 47% of patients with a normal MRI. First-line therapy was administered to 91%, and 24% required second-line therapy. Maintenance therapy during recovery was given 84% of patients, with no effect on relapse-risk. ICU admission occurred in 29%. Poor outcome (mRS > 2) was reported in 27% and dependent on age and etiology. Patients > 45years had a poorer outcome (71% vs 8%, p < 0.0001), more frequently post-HSE NMDARE (47% vs 3%, p < 0.0001) and underlying malignancies (18% vs 0%). The incidence of NMDARE in Denmark is currently 0.17/100,000 persons per year, and has increased since 2009. NMDARE patients in Denmark display a higher median age, lower female:male ratio, a less frequent tumor association and need for ICU admission. Maintenance therapy did not reduce relapse rate. Poor outcome was seen with higher age, likely related to underlying etiology.

Autoantibodies against NMDA receptor 1 modify rather than cause encephalitis

The etiology and pathogenesis of “anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis” and the role of autoantibodies (AB) in this condition are still obscure. While NMDAR1-AB exert NMDAR-antagonistic properties by receptor internalization, no firm evidence exists to date that NMDAR1-AB by themselves induce brain inflammation/encephalitis. NMDAR1-AB of all immunoglobulin classes are highly frequent across mammals with multiple possible inducers and boosters. We hypothesized that “NMDAR encephalitis” results from any primary brain inflammation coinciding with the presence of NMDAR1-AB, which may shape the encephalitis phenotype. Thus, we tested whether following immunization with a “cocktail” of 4 NMDAR1 peptides, induction of a spatially and temporally defined sterile encephalitis by diphtheria toxin-mediated ablation of pyramidal neurons (“DTA” mice) would modify/aggravate the ensuing phenotype. In addition, we tried to replicate a recent report claiming that immunizing just against the NMDAR1-N368/G369 region induced brain inflammation. Mice after DTA induction revealed a syndrome comprising hyperactivity, hippocampal learning/memory deficits, prefrontal cortical network dysfunction, lasting blood brain-barrier impairment, brain inflammation, mainly in hippocampal and cortical regions with pyramidal neuronal death, microgliosis, astrogliosis, modest immune cell infiltration, regional atrophy, and relative increases in parvalbumin-positive interneurons. The presence of NMDAR1-AB enhanced the hyperactivity (psychosis-like) phenotype, whereas all other readouts were identical to control-immunized DTA mice. Non-DTA mice with or without NMDAR1-AB were free of any encephalitic signs. Replication of the reported NMDAR1-N368/G369-immunizing protocol in two large independent cohorts of wild-type mice completely failed. To conclude, while NMDAR1-AB can contribute to the behavioral phenotype of an underlying encephalitis, induction of an encephalitis by NMDAR1-AB themselves remains to be proven.

Capgras syndrome and confabulation unfurling anti NMDAR encephalitis with classical papillary thyroid carcinoma: First reported case

Anti NMDA Receptor encephalitis (ANMDARE) is an immune mediated disease of the central nervous system, caused by circulating antibodies against the NMDA receptor present on neuronal surface. It is known to cause a spectrum of disease ranging from mild behavioral and psychiatric manifestations to full blown seizures, dyskinesias and altered sensorium. It can also be paraneoplastic presentation of a hidden tumor, most commonly ovarian teratoma. Here we present a case of ANMDARE with intriguing presentation of Capgras syndrome and confabulations, who was found to have a malignant papillary thyroid carcinoma, which has been rarely reported.

High incidence of NMDAR encephalitis among Austronesians: A population-based study in Sabah, Malaysia

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.

Pediatric N-Methyl-d-Aspartate (NMDA) Receptor Encephalitis, With and Without Herpes Encephalitis.

To compare clinical, diagnostic, management, and outcome factors in children with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis and a history of herpes simplex encephalitis (HSE) to children with NMDAR encephalitis without a history of HSE. All patients with anti-NMDAR antibodies in cerebrospinal fluid treated at our institution between 2012 and 2019 were identified and divided into those with a history of HSE (HSE+NMDAR group) and those without a history of HSE (NMDAR-only group). Demographic data, clinical characteristics, immunotherapy, and outcome data were collected on all patients and compared between the 2 groups. Seventeen patients were identified with anti-NMDAR antibodies in cerebrospinal fluid, 6 of whom had a history of HSE. Mean age in the HSE+NMDAR cohort was significantly younger in the HSE+NMDAR cohort, as 5 of the 6 patients were infants. Of HSE+NMDAR patients, 50% had behavioral symptoms, 67% had movement disorders, and 100% had seizures at disease nadir. In the NMDAR-only group, 100% had behavioral symptoms, 73% had movement disorders, and 73% had seizures at nadir. HSE+NMDAR patients received a median of 1 immunotherapy, compared to a median of 4.5 immunotherapies in the NMDAR-only group. Behavioral symptoms were more common in NMDAR-only patients, whereas seizures were more common in HSE+NMDAR patients. Both groups had significant disability at disease nadir, with more improvement in disability over time in the NMDAR-only group. HSE+NMDAR patients received fewer immunotherapies than NMDAR-only patients. Outcomes of infants with HSE appear to primarily reflect sequelae from HSE.

Refractory NMDA-receptor encephalitis in a teenager: A novel use of Bortezomib

We report the case of a 14-year-old girl who was diagnosed with N-methyl-d-aspartate (NMDA)-receptor encephalitis, with severe features and autonomic instability, requiring intensive care unit admission. She had poor clinical response to the first-line therapies, she was then started on Rituximab and 6 cycles of Cytoxan infusion. She responded to Bortezomib therapy within 2 weeks of initiation, and with long-term sustenance of improvement in the long-term, also demonstrated by an improvement in NMDA titers . As far as we know, this is the first report of use of Bortezomib therapy in a child with refractory NMDA-receptor encephalitis.

Symptomatologic pathomechanism of N-methyl D-aspartate receptor encephalitis.

N-methyl D-aspartate receptor (NMDAR) encephalitis is a well-characterized clinical syndrome. The main molecular mechanism of NMDAR encephalitis is autoantibody-mediated NMDAR hypofunction in the neuronal synapse. Several pathomechanistic hypotheses might explain how NMDAR hypofunction causes the typical symptoms and prognosis of NMDAR encephalitis. Suppression of NMDAR-dependent gamma-aminobutyric acid interneurons provokes an accelerated activation of the positive feedback loops of the dorsolateral prefrontal cortex/subiculum-nucleus accumbens circuit in the striatum, the ventral tegmental area (VTA), and the nucleus reuniens in the thalamus-hippocampus-VTA loop. Dysregulated activation of the VTA and cortex via those positive feedback loops may explain the rapid clinical deterioration at acute stages of the disease and the well-characterized syndrome that includes limbic system dysfunction, intractable seizures, dyskinesia, coma, and the characteristic extreme delta brush. Progressive cerebellar atrophy is correlated with cumulative disease burden and is associated with worse long-term outcomes, which might be explained by the NMDAR-dependent pathways required to maintain neuronal survival. Those pathomechanistic hypotheses for NMDAR encephalitis support the rationale for the early introduction of combination immunotherapy and the use of adjuvant immunotherapy in patients with persisting symptoms in chronic disease phases.