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.

Leptin Contributes to Neuropathic Pain via Extrasynaptic NMDAR-nNOS Activation

Leptin is an adipocytokine that is primarily secreted by white adipose tissue, and it contributes to the pathogenesis of neuropathic pain in collaboration with N-methyl-D-aspartate receptors (NMDARs). Functional NMDARs are a heteromeric complex that primarily comprise two NR1 subunits and two NR2 subunits. NR2A is preferentially located at synaptic sites, and NR2B is enriched at extrasynaptic sites. The roles of synaptic and extrasynaptic NMDARs in the contribution of leptin to neuropathic pain are not clear. The present study examined whether the important role of leptin in neuropathic pain was related to synaptic or extrasynaptic NMDARs. We used a rat model of spared nerve injury (SNI) and demonstrated that the intrathecal administration of the NR2A-selective antagonist NVP-AAM077 and the NR2B-selective antagonist Ro25-6981 prevented and reversed mechanical allodynia following SNI. Administration of exogenous leptin mimicked SNI-induced behavioral allodynia, which was also prevented by NVP-AAM077 and Ro25-6981. Mechanistic studies showed that leptin enhanced NR2B- but not NR2A-mediated currents in spinal lamina II neurons of naïve rats. Leptin also upregulated the expression of NR2B, which was blocked by the NR2B-selective antagonist Ro25-6981, in cultured dorsal root ganglion (DRG) neurons. Leptin enhanced neuronal nitric oxide synthase (nNOS) expression, which was also blocked by Ro25-6981, in cultured DRG cells. However, leptin did not change NR2A expression, and the NR2A-selective antagonist NVP-AAM077 had no effect on leptin-enhanced nNOS expression. Our data suggest an important cellular link between the spinal effects of leptin and the extrasynaptic NMDAR-nNOS-mediated cellular mechanism of neuropathic pain.

Clinical case of encephalitis with antibodies to NMDA receptors

Anti-NMDA receptor encephalitis is an autoimmune disease of the central nervous system caused by autoantibodies to the NR1 and NR2 subunits of the glutamate NMDA receptor, with the possibility of both death and rapid remission. The binding of these antibodies blocks receptors and causes slowly developing psychiatric disorders, motor disorders and seizures.Presented clinical observation in a 9-year-old patient. The disease debuted with prodromal flu-like symptoms, fever, headache and general weakness, after which neuropsychiatric symptoms, impaired memory and speech developed, further progression of the disease, convulsive status, and coma with a fatal outcome were noted. The final diagnosis of autoimmune encephalitis was made after identification of antibodies to the N-methyl-D-aspartate (NMDA) receptor in the blood.

Differential expression of antibodies to NMDA receptor in anti-NMDA receptor encephalitis and in neuropsychiatric systemic lupus erythematosus

ObjectiveAnti-NMDA receptor encephalitis is the most prevalent autoimmune encephalitis having characteristic clinical features with autoantibodies against tetrameric transmembrane channels composed of combinations of NR1 subunits of NMDA receptors with NR2 subunits, which are detected by cell-based assay (anti-NR1/NR2). On the other hand, antibodies against the linear epitope in NR2 subunit (anti-NR2) have been shown to be expressed in patients with diffuse psychiatric/neuropsychological syndromes of neuropsychiatric SLE (diffuse NPSLE). However, it has not been explored whether anti-NR1/NR2 might be detected in NPSLE, nor has it been clear whether anti-NR2 might have cross-reactivity with anti-NR1/NR2. The current study was therefore performed to explore the prevalence of anti-NR1/NR2 in NPSLE.MethodsSerum specimens were obtained from 31 patients with NPSLE (22 with diffuse NPSLE and 9 with neurological syndromes or polyneuropathy) and from 18 normal healthy subjects. Anti-NR2 and anti-NR1/NR2 were measured by ELISA and cell-based assay, respectively. The positivity for anti-NR2 was defined by a value exceeding mean+2 SD of normal healthy subjects.ResultsAnti-NR2 was positive in the sera of 19 of 31 patients with NPSLE (in 15 of 22 patients with diffuse NPSLE). By contrast, anti-NR1/NR2 was positive only in 2 of 31 patients with NPSLE (in 2 of 22 patients with diffuse SLE). The positivity for anti-NR1/NR2 was not correlated with anti-NR2 values.ConclusionsThese results demonstrate that the prevalence of anti-NR1/NR2 is extremely low in NPSLE. Moreover, the data also confirm that anti-NR2 antibodies do not have cross-reactivity with anti-NR1/NR2.

Effect of mutant NMDA receptors on the oscillations in a model of hippocampus

A computation approach to identify the effect of missense mutations on the protein function is proposed. Using molecular dynamics simulation we have analyzed the gating kinetics of mutant NMDA synaptic receptors carrying mutations in their NR2 subunits. Analysis of channel geometry and Mg ion binding allowed to estimate the receptor conductivity. As a result, it was possible to identify the effect of these mutations on the generation of theta and gamma rhythms by the hippocampal neural network. Obtained results can be adapted for the analysis and evaluation of possible cognitive impairments caused by neurological diseases or consequences of radiation and other negative factors.

Anti-N-methyl-d-aspartate receptor encephalitis: review of clinical presentation, diagnosis and treatment

SummaryAnti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a form of encephalitis occurring primarily in women and associated with antibodies against NR1 or NR2 subunits of the NMDA receptor. As a potentially treatable differential for symptoms and signs seen in neurology and psychiatric clinics, clinicians practising across the lifespan should be aware of this form of encephalitis. Common clinical features include auditory and visual hallucinations, delusions, behavioural change (frequently with agitation), impaired consciousness, motor disturbance (ranging from dyskinesia to catatonia), seizures, and autonomic dysfunction. We present a review of the literature on the disorder, including its clinical presentation, differential diagnosis, epidemiology, treatment and prognosis.