Timing the clinical onset of epileptic spasms in infantile epileptic spasms syndrome: A tertiary health center's experience.

Objective: Lead time to treatment (clinical onset of epileptic spasms [ES] to initiation of appropriate treatment) is known to predict outcomes in infantile epileptic spasms syndrome (IESS). Timing the clinical onset of ES is crucial to establish lead time. We investigated how often ES onset could be established to the nearest week.

Delays to care in infantile epileptic spasms syndrome: Racial and ethnic inequities.

Objective: Non-Hispanic (NH) Black children are less likely to receive a standard treatment course for infantile epileptic spasms syndrome (IESS) than White/NH children at pediatric tertiary care epilepsy centers in the United States. However, if inequities exist in time to diagnosis is unknown. Diagnostic delays as little as 1 week can be associated with worse developmental outcomes.

Utility of Exome Sequencing for Diagnosis in Unexplained Pediatric-Onset Epilepsy.

Importance: Genomic advances inform our understanding of epilepsy and can be translated to patients as precision diagnoses that influence clinical treatment, prognosis, and counseling.

Objective: To delineate the genetic landscape of pediatric epilepsy and clinical utility of genetic diagnoses for patients with epilepsy.

Design, Setting, And Participants: This cohort study used phenotypic data from medical records and treating clinicians at a pediatric hospital to identify patients with unexplained pediatric-onset epilepsy.

Clinical characteristics of children with infantile epileptic spasms syndrome from a tertiary-care hospital in Dhaka, Bangladesh.

Background: We describe patient characteristics and response to initial treatment in a large case series of children presenting with infantile epileptic spasms syndrome to a tertiary-care hospital with a pediatric neurology service in Bangladesh. The purpose of the study was to add to the growing body of literature on infantile epileptic spasms syndrome in low- and middle-income countries.

Methods: We enrolled 212 infants with new-onset infantile epileptic spasms syndrome (IESS) at the time of initial presentation to the National Institute of Neurosciences and Hospital (NINS) in Dhaka, Bangladesh, between January 2019 and August 2021.

Hospital readmissions in children with new-onset infantile epileptic spasms syndrome.

Objective: To describe inpatient resource use in the 2 years following infantile epileptic spasms syndrome (IESS) diagnosis, examine the association between clinical/demographic variables and incidence of readmission, and identify risk factors/reasons for frequent readmissions.

Methods: Retrospective cohort analysis of readmissions (scheduled/unscheduled) within the first 2 years following IESS diagnosis, details of readmissions (number/time between rehospitalizations, and length of stay), demographic/clinical variables, and reasons for readmissions were collected. Negative binomial regression analysis evaluated associations between incidence of readmissions (both scheduled/unscheduled and unscheduled alone) and demographic/clinical factors.

Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature.

Purpose: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD.

DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting.

Caloric restriction and acute fasting are known to reduce seizures but through unclear mechanisms. mTOR signaling has been suggested as a potential mechanism for seizure protection from fasting. We demonstrate that brain mTORC1 signaling is reduced after acute fasting of mice and that neuronal mTORC1 integrates GATOR1 complex-mediated amino acid and tuberous sclerosis complex (TSC)-mediated growth factor signaling.

Association of Time to Clinical Remission With Sustained Resolution in Children With New-Onset Infantile Spasms.

Background And Objectives: Standard therapies (adrenocorticotropic hormone [ACTH], oral steroids, or vigabatrin) fail to control infantile spasms in almost half of children. Early identification of nonresponders could enable rapid initiation of sequential therapy. We aimed to determine the time to clinical remission after appropriate infantile spasms treatment initiation and identify predictors of the time to infantile spasms treatment response.

The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2.

Purpose: Postzygotic (somatic) variants in the mTOR pathway genes cause a spectrum of distinct developmental abnormalities. Accurate classification of somatic variants in this group of disorders is crucial for affected individuals and their families.

Methods: The ClinGen Brain Malformation Variant Curation Expert Panel was formed to curate somatic variants associated with developmental brain malformations.

The non-essential TSC complex component TBC1D7 restricts tissue mTORC1 signaling and brain and neuron growth.

The tuberous sclerosis complex (TSC) 1 and 2 proteins associate with TBC1D7 to form the TSC complex, which is an essential suppressor of mTOR complex 1 (mTORC1), a ubiquitous driver of cell and tissue growth. Loss-of-function mutations in TSC1 or TSC2, but not TBC1D7, give rise to TSC, a pleiotropic disorder with aberrant activation of mTORC1 in various tissues. Here, we characterize mice with genetic deletion of Tbc1d7, which are viable with normal growth and development.

Infantile spasms: Assessing the diagnostic yield of an institutional guideline and the impact of etiology on long-term treatment response.

Objective: Neuroimaging and genetic testing have been proposed for diagnostic evaluation of infantile spasms (IS), establishing etiology in ~60% of multicenter IS cohorts. A retrospective analysis of the yield of diagnostic etiology following an institutionally established guideline for investigation/treatment of IS was conducted, and the association between etiological subgroups and sustained response to standard treatment was evaluated.

Methods: Etiology of IS, neuroimaging, and genetic results were extracted from clinical records.

National assessment of anti-epileptic drug exposures among pre-teens and adolescents, 2000-2020.

Background And Objectives: Anti-epileptic drugs (AEDs) are increasingly used to treat psychiatric conditions, exposing many children to potentially harmful medications. This includes adolescents, who are at higher risk for self-harm. The purpose of this study was to describe the epidemiology of pediatric AED poisonings and assess which AEDs are associated with more severe clinical outcomes.

Confirmation of infantile spasms resolution by prolonged outpatient EEGs.

Objective: There is no consensus on the type or duration of the posttreatment EEG needed for assessing treatment response for infantile spasms (IS). We assessed whether outpatient electroencephalograms (EEGs) are sufficient to confirm infantile spasms (IS) treatment response.

Methods: Three-year retrospective review identified new-onset IS patients.

Factors influencing the acute pentylenetetrazole-induced seizure paradigm and a literature review.

Objective: To confirm the critical factors affecting seizure susceptibility in acute pentylenetetrazole (PTZ) mouse epilepsy models and evaluate the prior literature for these factors.

Methods: Serial cohorts of wild-type mice administered intraperitoneal (IP)-PTZ were aggregated and analyzed by multivariate logistic regression for the effect of sex, age, background strain, dose, and physiologic stress (i.e.

Hippocampal Involvement With Vigabatrin-Related MRI Signal Abnormalities in Patients With Infantile Spasms: A Novel Finding.

Background: In a subset of infants exhibiting typical vigabatrin-related magnetic resonance imaging (MRI) changes, the authors observed additional hippocampal signal abnormalities. The authors investigated occurrence and significance of additional signal abnormalities.

Methods: A retrospective review of infantile spasms patients with typical vigabatrin-related MRI abnormalities was performed.

Cost-effectiveness of adrenocorticotropic hormone versus oral steroids for infantile spasms.

Objective: To compare the effectiveness and cost-effectiveness of adrenocorticotropic hormone (ACTH) and oral steroids as first-line treatment for infantile spasm resolution, we performed a systematic review, meta-analysis, and cost-effectiveness study.

Methods: A decision analysis model was populated with effectiveness data from a systematic review and meta-analysis of existing literature and cost data from publicly available prices. Effectiveness was defined as the probability of clinical spasm resolution 14 days after treatment initiation.

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.

Management of Infantile Spasms During the COVID-19 Pandemic.

Circumstances of the COVID-19 pandemic have mandated a change to standard management of infantile spasms. On April 6, 2020, the Child Neurology Society issued an online statement of immediate recommendations to streamline diagnosis and treatment of infantile spasms with utilization of telemedicine, outpatient studies, and selection of first-line oral therapies as initial treatment. The rationale for the recommendations and specific guidance including follow-up assessment are provided in this manuscript.

Posterior Neocortex-Specific Regulation of Neuronal Migration by CEP85L Identifies Maternal Centriole-Dependent Activation of CDK5.

Genes mutated in human neuronal migration disorders encode tubulin proteins and a variety of tubulin-binding and -regulating proteins, but it is very poorly understood how these proteins function together to coordinate migration. Additionally, the way in which regional differences in neocortical migration are controlled is completely unknown. Here we describe a new syndrome with remarkably region-specific effects on neuronal migration in the posterior cortex, reflecting de novo variants in CEP85L.

Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.

DEPDC5 is now recognized as one of the genes most often implicated in familial/inherited focal epilepsy and brain malformations. Individuals with pathogenic variants in DEPDC5 are at risk for epilepsy, associated neuropsychiatric comorbidities and sudden unexplained death in epilepsy. Depdc5flox/flox-Syn1Cre (Depdc5cc+) neuronal-specific Depdc5 knockout mice exhibit seizures and neuronal mTORC1 hyperactivation.

Brain MRI abnormalities in patients with infantile spasms and Down syndrome.

Introduction: Infantile spasms (IS) are the most frequent epilepsy syndrome in children with Down syndrome (DS). In DS, cellular (synaptic/dendritic changes) and molecular mechanisms are believed to contribute to epileptogenesis, rather than gross structural anomalies. Neuroimaging is a standard part of the evaluation of newly diagnosed infantile epilepsy including IS and, in this age group, often requires sedation.

Infantile Spasms of Unknown Cause: Predictors of Outcome and Genotype-Phenotype Correlation.

Background: No large-scale studies have specifically evaluated the outcomes of infantile spasms (IS) of unknown cause, previously known as cryptogenic or idiopathic. The Epilepsy Phenome/Genome Project aimed to characterize IS of unknown cause by phenotype and genotype analysis.

Methods: We undertook a retrospective multicenter observational cohort of 133 individuals within the Epilepsy Phenome/Genome Project database met criteria for IS of unknown cause with at least six months of follow-up data.