Two patients with an anti-N-methyl-D-aspartate receptor antibody syndrome-like presentation and negative results of testing for autoantibodies. Pediatr Neurol

abstract We describe two boys whose distinct and remarkable clinical pictures suggested the possibility of anti-Nmethyl-D-aspartate receptor antibody encephalitis. Both patients responded to immunotherapy, but neither manifested that antibody. Patient 1 exhibited florid encephalopathy with psychotic manifestations including inappropriate affect, intermittent delirium, visual hallucinations, severe anorexia, agitation, paranoid ideation, and abnormal electroencephalogram results. He responded to intravenous immunoglobulin, with steady improvement over 3 months to almost complete remission for 1 year, followed by a relapse that again responded, more quickly, to intravenous immunoglobulin. A second relapse occurred 1 month later, and again responded to intravenous immunoglobulin. Patient 2 exhibited progressive, severely debilitating limb dystonia that worsened over 1.5 years, with milder psychiatric symptoms including mood instability, aggressiveness, impulsivity, and depression. When he developed thymic hyperplasia 1.5 years into his illness, he underwent a thymectomy, and improved significantly on a regimen of plasmapheresis and intravenous immunoglobulin. Patients presenting with symptoms suggestive of autoimmune encephalitis, but without antibodies, may still respond to immunotherapy

Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient

Autoimmune encephalitis (AE) is an important and treatable cause of acute encephalitis. Diagnosis of AE in a developing child is challenging because of overlap in clinical presentations with other diseases and complexity of normal behavior changes. Existing diagnostic criteria for adult AE require modification to be applied to children, who differ from adults in their clinical presentations, paraclinical findings, autoantibody profiles, treatment response, and long-term outcomes.A subcommittee of the Autoimmune Encephalitis International Working Group collaborated through conference calls and email correspondence to consider the pediatric-specific approach to AE. The subcommittee reviewed the literature of relevant AE studies and sought additional input from other expert clinicians and researchers.Existing consensus criteria for adult AE were refined for use in children. Provisional pediatric AE classification criteria and an algorithm to facilitate early diagnosis are proposed. There is also discussion about how to distinguish pediatric AE from conditions within the differential diagnosis.Diagnosing AE is based on the combination of a clinical history consistent with pediatric AE and supportive diagnostic testing, which includes but is not dependent on antibody testing. The proposed criteria and algorithm require validation in prospective pediatric cohorts.Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

International Consensus Recommendations for the Treatment of Pediatric NMDAR Antibody Encephalitis

To create an international consensus treatment recommendation for pediatric NMDA receptor antibody encephalitis (NMDARE).After selection of a panel of 27 experts with representation from all continents, a 2-step Delphi method was adopted to develop consensus on relevant treatment regimens and statements, along with key definitions in pediatric NMDARE (disease severity, failure to improve, and relapse). Finally, an online face-to-face meeting was held to reach consensus (defined as ?75% agreement).Corticosteroids are recommended in all children with NMDARE (pulsed IV preferred), with additional IV immunoglobulin or plasma exchange in severe patients. Prolonged first-line immunotherapy can be offered for up to 3-12 months (oral corticosteroids or monthly IV corticosteroids/immunoglobulin), dependent on disease severity. Second-line treatments are recommended for cases refractory to first-line therapies (rituximab preferred over cyclophosphamide) and should be considered about 2 weeks after first-line initiation. Further immunotherapies for refractory disease 1-3 months after second-line initiation include another second-line treatment (such as cyclophosphamide) and escalation to tocilizumab. Maintenance immune suppression beyond 6 months (such as rituximab redosing or mycophenolate mofetil) is generally not required, except for patients with a more severe course or prolonged impairments and hospitalization. For patients with relapsing disease, second-line and prolonged maintenance therapy should be considered. The treatment of NMDARE following herpes simplex encephalitis should be similar to idiopathic NMDARE. Broad guidance is provided for the total treatment duration (first line, second line, and maintenance), which is dictated by the severity and clinical course (i.e., median 3, 9 and 18 months in the best, average, and worst responders, respectively). Recommendations on the timing of oncologic searches are provided.These international consensus recommendations for the management of pediatric NMDARE aim to standardize the treatment and provide practical guidance for clinicians, rather than absolute rules. A similar recommendation could be applicable to adult patients.Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studie

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies

Safe use of the ketogenic diet in an infant with microcephaly, epilepsy, and diabetes syndrome: a case report

Abstract Background Microcephaly, epilepsy, and diabetes syndrome (MEDS) is a rare syndromic form of monogenic diabetes caused by bi-allelic loss of function mutations in IER3IP1. In vitro studies have shown that loss of IER31P leads to apoptosis in both neurons and pancreatic β-cells. Simultaneous management of seizures and diabetes is challenging in patients with MEDS. We present the challenges and successes in the use of ketogenic diet in an infant with insulinopenic diabetes. Case presentation Our term female proband presented at 2 months of age with new onset multifocal seizures followed by the onset of infantile spasms (IS) at 4 months of age. An epilepsy gene panel identified bi-allelic variants, c.239T > G (p.Leu80*) and c.2T > A (initiator codon), in IER3IP1 that were subsequently shown to be inherited in trans. Following initiation of steroid therapy for IS, the patient developed clinically apparent insulin requiring diabetes. Her epilepsy was ultimately refractory to multiple antiseizure medications, thus the ketogenic diet (KD) was initiated. We were able to successfully titrate to a therapeutic KD ratio of 3:1 and maintain a ketotic state without diabetic ketoacidosis (DKA). With intercurrent illnesses, however, the patient had rapid decompensation and mild DKA due to delays in treatment, and for this reason, KD was discontinued after 5 months. Conclusions We report two novel IER31P1 mutations in a patient with MEDS and the successful management of the cooccurring conditions of IS and insulinopenic diabetes with the KD. Our experience underscores the importance of careful monitoring during KD as our patient had DKA more easily when on the KD

Electroencephalography Leads Placed by Nontechnologists Using a Template System Produce Signals Equal in Quality to Technologist-Applied, Collodion Disk Leads

Summary: The purpose of this study was to compare the quality of the electroencephalographic (EEG) data obtained with a BraiNet template in a practical use setting, to that obtained with standard 10/20 spaced, technologist-applied, collodion-based disk leads. Pairs of 8-hour blocks of EEG data were prospectively collected from 32 patients with a Glasgow coma score of #9 and clinical concern for underlying nonconvulsive status epilepticus over a 6-month period in the Neurocritical Care Unit at the Duke University Medical Center. The studies were initiated with the BraiNet template system applied by critical care nurse practitioners or physicians, followed by standard, collodion leads applied by registered technologists using the 10/20 system of placement. Impedances were measured at the beginning and end of each block recorded and variance in impedance, mean impedance, and the largest differences in impedances found within a given lead set were compared. Physicians experienced in reading EEG performed a masked review of the EEG segments obtained to assess the subjective quality of the recordings obtained with the templates. We found no clinically significant differences in the impedance measures. There was a 3-hour reduction in the time required to initiate EEG recording using the templates (P , 0.001). There was no difference in the overall subjective quality distributions for template-applied versus technologist-applied EEG leads. The templates were also found to be well accepted by the primary users in the intensive care unit. The findings suggest that the EEG data obtained with this approach are comparable with that obtained by registered technologist-applied leads and represents a possible solution to the growing clinical need for continuous EEG recording availability in the critical care setting

Reorganization and Stability for Motor and Language Areas Using Cortical Stimulation: Case Example and Review of the Literature

The cerebral organization of language in epilepsy patients has been studied with invasive procedures such as Wada testing and electrical cortical stimulation mapping and more recently with noninvasive neuroimaging techniques, such as functional MRI. In the setting of a chronic seizure disorder, clinical variables have been shown to contribute to cerebral language reorganization underscoring the need for language lateralization and localization procedures. We present a 14-year-old pediatric patient with a refractory epilepsy disorder who underwent two neurosurgical resections of a left frontal epileptic focus separated by a year. He was mapped extraoperatively through a subdural grid using cortical stimulation to preserve motor and language functions. The clinical history and extensive workup prior to surgery is discussed as well as the opportunity to compare the cortical maps for language, motor, and sensory function before each resection. Reorganization in cortical tongue sensory areas was seen concomitant with a new zone of ictal and interictal activity in the previous tongue sensory area. Detailed neuropsychological data is presented before and after any surgical intervention to hypothesize about the extent of reorganization between epochs. We conclude that intrahemispheric cortical plasticity does occur following frontal lobe resective surgery in a teenager with medically refractory seizures

Pediatric ICU EEG monitoring: Current resources and practice in the United States and Canada

PURPOSE: To describe current continuous EEG (cEEG) utilization in critically ill children. METHODS: An online survey of pediatric neurologists from 50 United States (U.S.) and 11 Canadian institutions was conducted in August 2011. RESULTS: Responses were received from 58 of 61 (95%) surveyed institutions. Common cEEG indications are altered mental status after a seizure or status epilepticus (97%), altered mental status of unknown etiology (88%), or altered mental status with an acute primary neurological condition (88%). The median number of patients undergoing cEEG per month per center increased from August 2010 to August 2011 (6 to 10 per month in U.S., 2 to 3 per month in Canada). Few institutions have clinical pathways addressing cEEG use (31%). Physicians most commonly review cEEG twice per day (37%). There is variability regarding which services can order cEEG, the degree of neurology involvement, technologist availability, and whether technologists perform cEEG screening. CONCLUSIONS: Among the surveyed institutions, which included primarily large academic centers, cEEG use in pediatric intensive care units is increasing and is often considered indicated for children with altered mental status at risk for non-convulsive seizures. However, there remains substantial variability in cEEG access and utilization among institutions