Anti-N-methyl D-aspartate Receptor Encephalitis Following ChAdOx1 nCoV-19 Vaccination: A Case Report.

As of December 2020, millions of people have been immunized using vaccines against SARS-CoV-2. A wide range of neurological adverse effects of SARS-CoV-2 vaccines have been reported so far. Here, we report a 23-year-old male who experienced psychiatric symptoms, loss of consciousness, language disintegration, and incontinency that happened 10 days after the first dosage of the COVID-19 AstraZeneca vaccine. Anti-NMDAR Encephalitis was diagnosed based on the results of the autoimmune panel. The patient responded to intravenous dexamethasone very well and experienced no other complications in 6 months of follow-up. Scientific reports of neurological side effects such as anti-NMDAR encephalitis after vaccination are necessary to optimize the safety and effectiveness of SARS-CoV-2 vaccines.

Allosteric Modulation of NMDARs Reverses Patients' Autoantibody Effects in Mice.

BACKGROUND AND OBJECTIVES: To demonstrate that an analog (SGE-301) of a brain-derived cholesterol metabolite, 24(S)-hydroxycholesterol, which is a selective positive allosteric modulator (PAM) of NMDA receptors (NMDARs), is able to reverse the memory and synaptic alterations caused by CSF from patients with anti-NMDAR encephalitis in an animal model of passive transfer of antibodies. METHODS: Four groups of mice received (days 1-14) patients' or controls' CSF via osmotic pumps connected to the cerebroventricular system and from day 11 were treated with daily subcutaneous injections of SGE-301 or vehicle (no drug). Visuospatial memory, locomotor activity (LA), synaptic NMDAR cluster density, hippocampal long-term potentiation (LTP), and paired-pulse facilitation (PPF) were assessed on days 10, 13, 18, and 26 using reported techniques. RESULTS: On day 10, mice infused with patients' CSF, but not controls' CSF, presented a significant visuospatial memory deficit, reduction of NMDAR clusters, and impairment of LTP, whereas LA and PPF were unaffected. These alterations persisted until day 18, the time of maximal deficits in this model. In contrast, mice that received patients' CSF but from day 11 were treated with SGE-301 showed memory recovery (day 13), and on day 18, all paradigms (memory, NMDAR clusters, and LTP) had reversed to values similar to those of controls. On day 26, no differences were observed among experimental groups. DISCUSSION: An oxysterol biology-based PAM of NMDARs is able to reverse the synaptic and memory deficits caused by CSF from patients with anti-NMDAR encephalitis. These findings suggest a novel adjuvant treatment approach that deserves future clinical evaluation.

Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis.

Seizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR antibody) encephalitis, a distinct neuro-immunological disorder in which specific human autoantibodies bind and crosslink the surface of NMDAR proteins thereby causing internalization and a state of NMDAR hypofunction. To further understand ictogenesis in this disorder, and to test a potential treatment compound, we developed an NMDAR antibody mediated rat seizure model that displays spontaneous epileptiform activity in vivo and in vitro. Using a combination of electrophysiological and dynamic causal modelling techniques we show that, contrary to expectation, reduction of synaptic excitatory, but not inhibitory, neurotransmission underlies the ictal events through alterations in the dynamical behaviour of microcircuits in brain tissue. Moreover, in vitro application of a neurosteroid, pregnenolone sulphate, that upregulates NMDARs, reduced established ictal activity. This proof-of-concept study highlights the complexity of circuit disturbances that may lead to seizures and the potential use of receptor-specific treatments in antibody-mediated seizures and epilepsy.

Potential autoimmune encephalitis following yellow fever vaccination: A report of three cases.

Meningoencephalitis following yellow fever vaccination is considered a viral neuroinvasive disease. We describe three patients with typical autoimmune encephalitis syndromes that developed 1-27 days following yellow fever vaccination. Anti-N-methyl-d-aspartate-r antibodies were identified in the CSF and serum of two patients and the other case was associated with anti-neurexin-3 antibodies. One case was confirmed as vaccine-associated neurotropic disease due to reactive CSF yellow fever IgM, which suggested an infectious-autoimmune overlap mechanism. Two aditional cases of Anti-N-methyl-d-aspartate-r encephalitis were identified in the literature review. Antibody-positive autoimmune encephalitis should be included in the differential diagnosis of neurologic adverse events following yellow fever vaccination.

Anti-NMDAR encephalitis induced in mice by active immunization with a peptide from the amino-terminal domain of the GluN1 subunit.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesia, and seizures. However, the underlying mechanisms of this disease remain unclear, in part because of a lack of suitable animal models. METHODS: This study describes a novel female C57BL/6 mouse model of anti-NMDAR encephalitis that was induced by active immunization against NMDARs using an amino terminal domain (ATD) peptide from the GluN1 subunit (GluN1356-385). RESULTS: Twelve weeks after immunization, the immunized mice showed significant memory loss. Furthermore, antibodies from the cerebrospinal fluid of immunized mice decreased the surface NMDAR cluster density in hippocampal neurons which was similar to the effect induced by the anti-NMDAR encephalitis patients' antibodies. Immunization also impaired long-term potentiation at Schaffer collateral-CA1 synapses and reduced NMDAR-induced calcium influx. CONCLUSION: We established a novel anti-NMDAR encephalitis model using active immunization with peptide GluN1356-385 targeting the ATD of GluN1. This novel model may allow further research into the pathogenesis of anti-NMDAR encephalitis and aid in the development of new therapies for this disease.

A Case of Anti-NMDA Receptor Encephalitis During Dinutuximab Therapy for Neuroblastoma.

Dinutuximab is a monoclonal antibody administered to patients with high-risk neuroblastoma, usually after an autologous stem cell transplant. Dinutuximab is associated with immune mediated and neurologic toxicities, but fatal adverse events are rare. A case is presented of high-risk neuroblastoma with development of encephalopathy shortly after the first course of dinutuximab. The patient had extensive evaluation for etiology of the symptoms and received aggressive interventions, but ultimately expired. Postmortem diagnosis of anti-N-methyl D-aspartate receptor encephalitis, an autoimmune phenomenon often triggered by infection or malignancy, was made. The potential association of autoimmune encephalitis with dinutuximab and with previous autologous transplant is discussed.

Anti-NMDA Receptor Encephalitis, Vaccination and Virus.

Anti-N-methyl-d-aspartate (Anti-NMDA) receptor encephalitis is an acute autoimmune disorder. The symptoms range from psychiatric symptoms, movement disorders, cognitive impairment, and autonomic dysfunction. Previous studies revealed that vaccination might induce this disease. A few cases were reported to be related to H1N1 vaccine, tetanus/diphtheria/pertussis and polio vaccine, and Japanese encephalitis vaccine. Although vaccination is a useful strategy to prevent infectious diseases, in a low risk, it may trigger serious neurological symptoms. In addition to anti-NMDA receptor encephalitis, other neurological diseases were reported to be associated with a number of vaccines. In this paper, the anti-NMDA receptor encephalitis cases related to a number of vaccines and other neurological symptoms that might be induced by these vaccines were reviewed. In addition, anti-NMDA receptor encephalitis cases that were induced by virus infection were also reviewed.

EEG with extreme delta brush in young female with methotrexate neurotoxicity supports NMDA receptor involvement.

Sub-acute neurotoxicity is a well-known complication to high-dose and intrathecal methotrexate (MTX) treatment of children with leukemia. Symptoms can be treated safely by dextromethorphan, a non-competitive antagonist to N-methyl-D-aspartic acid receptor (NMDAR). In a female with subacute MTX neurotoxicity, we observed an electroencephalographic (EEG) with extreme delta brush. Extreme delta brush is an EEG pattern previously described in patients with NMDAR autoimmune encephalitis. The observations suggest that the mechanism of this neurotoxicity may be mediated by the NMDAR. Furthermore, extreme EEG delta brush should suggest a diagnosis of MTX associated subacute neurotoxicity.