BACKGROUND:Epilepsy is a core feature of Angelman syndrome (AS) and a major contributor to morbidity and caregiver burden. The current study provides updated caregiver-reported data on seizure characteristics, triggers, and management in AS. METHODS:Caregivers of 130 individuals with AS enrolled in the Linking Angelman and Dup15q Data for Expanded Research Database completed an online questionnaire assessing seizure characteristics, age at first seizure and diagnosis, perceived triggers, and management strategies. Participants were grouped by molecular subtype (deletion vs nondeletion). Descriptive statistics and group comparisons were conducted. RESULTS:Seizures were more frequently reported in individuals with deletion subtypes compared to those with nondeletion subtypes. The most common seizure-related manifestations (myoclonic, atonic, and atypical absence features) did not differ between groups. Individuals with deletion subtypes experienced earlier epilepsy diagnosis than those with nondeletion subtypes, though age at first seizure prompting medical attention did not differ significantly between the groups. About half of caregivers were unsure of seizure triggers; among identified triggers, illness or infection with a fever was most common. Pharmacologic treatment was the primary management approach, with levetiracetam most frequently reported. Side effects were the most common reason for medication discontinuation, and only 69% of caregivers reported access to or use of an acute seizure rescue medication. CONCLUSIONS:Caregiver-reported data from the Linking Angelman and Dup15q Data for Expanded Research Database provide an updated characterization of seizures in AS. Gaps in trigger identification and availability or use of rescue medications highlight opportunities to improve standard-of-care implementation in AS.

Angelman syndrome (AS) is a neurodevelopmental syndrome characterized by people with a characteristic happy demeanor, impaired expressive communication, sleep disruptions, and a variety of paroxysmal events, including seizures and movement disorders. Herein, we report three cases, one child and two adults with AS, of gelastic (laugh-related) spells. The phenomenology in all three is most consistent with gelastic syncope. A fourth example demonstrating transient breath-holding while laughing is included for reference. We subsequently review the differential for gelastic spells in AS, including seizures and cataplexy, and expound on the importance of their identification in the context of risk factors for cardiac arrhythmia. This work adds gelastic syncope to the list of paroxysmal events in AS and may serve to inform providers and parents of this phenotype and provide guidance for subsequent evaluation and treatment if indicated.

Background Angelman syndrome (AS) is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, a sociable demeanor, and abnormal movements. People with AS often exhibit multiple types of abnormal movements, including nonepileptic myoclonus, tremor, and dystonia, which hamper attempts to identify phenomenology and appropriate treatments. Objectives We sought to better clarify movement disorder phenomenology in AS to aid in diagnostic clarity and treatment identification. Methods Caregivers of people with AS completed a survey focused on abnormal movements in AS and submitted video examples of the movements, when possible. The video data were evaluated by a team of 10 movement disorder experts. Results Survey data were obtained for 47 subjects, of whom 20 had accompanying video data; 33% of subjects reported 3 or more abnormal movements, complicating the evaluation of the survey data. Expert review of video data demonstrated 9 people with myoclonus, 9 with dystonia, and 3 with tremor. Five people had both myoclonus and dystonia, and 1 had both tremor and dystonia. Three people demonstrated stereotypy, one of which also had a focal seizure. Dystonia onset averaged 18.1 years. Fever, constipation, and menses were the most notable triggers. According to caregivers, only 4 treatments, clonazepam, diazepam, lorazepam, and trihexyphenidyl, resulted in improvement in dystonic symptoms. Conclusions These data reinforce that dystonia is a common finding in people with AS, often in combination with myoclonus. The identification of both isolated dystonia and myoclonic dystonia in people with AS may suggest therapeutic options that heretofore may not have been widely considered.

Loss of production of ubiquitin protein ligase E3A (UBE3A) in neurons leads to Angelman Syndrome (AS). There are limited methods to reliably measure UBE3A in cerebrospinal fluid (CSF), which negatively impacts therapeutic development. To overcome this gap, we developed and analytically validated a novel method for CSF UBE3A quantitation, which includes an immunoprecipitation protein capture step followed by tryptic digestion and high-resolution mass spectrometry detection of a unique UBE3A peptide. Our data suggest that we can reliably detect UBE3A at concentrations as low as 2.5 pg/mL. The assay was used to show that UBE3A could be detected in CSF samples of both healthy adults and patients with AS. As expected, CSF UBE3A levels in healthy adults (24.76 ± 6.75 pg/mL, N = 14) were significantly higher (p < 0.01) than the CSF UBE3A levels measured in two AS cohorts (5.30 ± 0.42 pg/mL, N = 19 and 5.59 ± 0.40 pg/mL, N = 10), with no significant difference in UBE3A levels observed between the two AS cohorts. There was also no significant difference in CSF UBE3A levels when comparing AS patients carrying either a mutation or chromosomal deletion in either cohort. Overall, these data demonstrate the utility of this novel CSF UBE3A assay for UBE3A quantitation in studies of AS.

BACKGROUND:Tuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors in the brain and other vital organs. The most debilitating symptoms result from involvement of the central nervous system and lead to a multitude of severe symptoms including seizures, intellectual disability, autism, and behavioral problems. TSC is caused by heterozygous mutations of either the TSC1 or TSC2 gene and dysregulation of mTOR kinase with its multifaceted downstream signaling alterations is central to disease pathogenesis. Although the neurological sequelae of the disease are well established, little is known about how these mutations might affect cellular components and the function of the blood-brain barrier (BBB). METHODS:We generated TSC disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies. RESULTS:Using microphysiological systems, we demonstrate that a BBB generated from TSC2 heterozygous mutant cells shows increased permeability. This can be rescued by wild type astrocytes or by treatment with rapamycin, an mTOR kinase inhibitor. CONCLUSION:Our results demonstrate the utility of microphysiological systems to study human neurological disorders and advance our knowledge of cell lineages contributing to TSC pathogenesis and informs future therapeutics.

BACKGROUND:The Accreditation Council for Graduate Medical Education (ACGME) milestones state that neurology residents should be able to "interpret common EEG abnormalities, recognize normal EEG variants, and create a report." Yet, recent studies have shown that only 43% of neurology residents express confidence in interpreting EEG without supervision and can recognize less than half of normal and abnormal EEG patterns. Our objective was to create a curriculum to improve both confidence and competence in reading EEGs. METHODS:At Vanderbilt University Medical Center (VUMC), adult and pediatric neurology residents have required EEG rotations in their first and second years of neurology residency and can choose an EEG elective in their third year. A curriculum consisting of specific learning objectives, self-directed modules, EEG lectures, epilepsy-related conferences, supplemental educational material, and tests was created for each of the three years of training. RESULTS:Since the implementation of an EEG curriculum at VUMC from September 2019 until November 2022, 12 adult and 21 pediatric neurology residents completed pre- and post-rotation tests. Among the 33 residents, there was a statistically significant improvement in post-rotation test scores, with a mean score improvement of 17% (60.0 ± 12.9 to 77.9 ± 11.8, n = 33, p < 0.0001). When differentiated by training, the mean improvement of 18.8% in the adult cohort was slightly higher than in the pediatric cohort, 17.3%, though it was not significantly different. Overall improvement was significantly increased in the junior resident cohort with a 22.6% improvement in contrast to 11.5% in the senior resident cohort (p = 0.0097 by Student's t-test, n = 14 junior residents and 15 senior residents). DISCUSSION:With the creation of an EEG curriculum specific to each year of neurology residency, adult and pediatric neurology residents demonstrated a statistically significant mean improvement between pre- and post-rotation test scores. The improvement was significantly higher in junior residents in contrast to senior residents. Our structured and comprehensive EEG curriculum objectively improved EEG knowledge in all neurology residents at our institution. The findings may suggest a model which other neurology training programs may consider for the implementation of a similar curriculum to both standardize and address gaps in resident EEG education.

American Journal of Medical Genetics Part AVolume 191, Issue 7 p. 1681-1686 ISSUE INFORMATIONFree Access Table of Contents, Volume 191A, Number 7, July 2023 First published: 07 June 2023 https://doi.org/10.1002/ajmg.a.62813AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Volume191, Issue7July 2023Pages 1681-1686 RelatedInformation

OBJECTIVE To describe the development and implementation of a process for creating accurate Pediatric geni-tourinary 3D modeling and printing with multiphase postcontrast imaging for surgical planning. MATERIALS AND METHODS Additive manufacturing and 3D model present opportunities to support clinical planning, this manuscript's specific process and considerations for creating pediatric genitourinary 3D modeling to support urology. The process for creating the 3D models and prints covers 3 key aspects from image acquisition, imaging review and selection, and segmentation and modification (as needed). Each step is outlined with the key roles and procedures. RESULTS The described case had digital and printed models prepared with references to the optimized imag-ing sequence for 3D modeling of Pediatric genitourinary. Case shared include complex genitouri-nary reconstruction and Kideny with Wilms tumors. CONCLUSION The processes described have become a standard of practice for complex kidney tumors and exstro-phy planning. The team continues to work on ever-changing improvements to make the best pos-sible models to support clinical and surgical planning. (c) 2023 Elsevier Inc.

Objective: Conceptually, inpatient boarding is a result in the delay of admitting patients from the Emergency Department (ED) to inpatient units, but there is no consistent definition across academic EDs. The purpose of this study was to evaluate the definition of boarding across academic EDs, and to identify mitigation strategies used by EDs to alleviate crowd management.Methods: This was a cross-sectional survey of boarding-related questions (i.e., boarding definitions and practices) that were embedded into the annual benchmarking survey conducted by the Academy of Academic Administra -tors of Emergency Medicine and the Association of Academic Chairs of Emergency Medicine. Results were descriptively assessed and tabulated.Results: Of the 130 eligible institutions, 68 participated in the survey. Approximately 70% of institutions reported starting the boarding clock at the time of ED admission, while 19% reported that the clock started with the completion of inpatient orders. Approximately 35% of institutions considered patients boarded within 2 h, while 34% considered patients boarded >4 h after admission decision. In response to ED overcrowding brought on by inpatient boarding, 35% reported using hallway beds for patient care. Surge capacity measures reported included having a high census/surge capacity plan (81%), going on ambulance diversion (54%), and institutional use of a discharge lounge (49%).Conclusions: We found that definitions for boarding varied widely. Inpatient boarding has serious consequences to patient care and well-being, suggesting the need for standardized definitions to describe inpatient boarding.(c) 2023 Elsevier Inc. All rights reserved.

Angelman Syndrome is a rare neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, characteristic behavior, and movement disorders. Clinical gait analysis provides the opportunity for movement quantification to investigate an observed maladaptive change in gait pattern and offers an objective outcome of change. Pressure‐sensor‐based technology, inertial and activity monitoring, and instrumented gait analysis (IGA) were employed to define motor abnormalities in Angelman syndrome. Temporal–spatial gait parameters of persons with Angelman Syndrome (pwAS) show deficiencies in gait performance through walking speed, step length, step width, and walk ratio. pwAS walk with reduced step lengths, increased step width, and greater variability. Three‐dimensional motion kinematics showed increased anterior pelvic tilt, hip flexion, and knee flexion. PwAS have a walk ratio more than two standard deviations below controls. Dynamic electromyography showed prolonged activation of knee extensors, which was associated with a decreased range of motion and the presence of hip flexion contractures. Use of multiple gait tracking modalities revealed that pwAS exhibit a change in gait pattern to a flexed knee gait pattern. Cross‐sectional studies of individuals with AS show a regression toward this maladaptive gait pattern over development in pwAS ages 4‐11. PwAS unexpectedly did not have spasticity associated with change in gait pattern. Multiple quantitative measures of motor patterning may offer early biomarkers of gait decline consistent with critical periods of intervention, insight into appropriate management strategies, objective primary outcomes, and early indicators of adverse events.

The benefits of continuous electroencephalography (cEEG) monitoring in the intensive care unit (ICU) are increasingly appreciated, though expanding indications for cEEG may strain resources. The current stan-dard of care in babies with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH) includes cEEG monitoring throughout the entire TH and rewarming process (at least 72 h). Recent cEEG data demonstrate that most seizures occur within the first 24 h of monitoring. We hypothesized that abnormal head imaging and EEG background could stratify seizure risk in babies with HIE undergo-ing TH to identify candidates for early cEEG discontinuation. In this retrospective review of 126 neonates undergoing TH and cEEG, we identified seizures in 38 (30%) neonates, 33 (87%) of whom seized within the first 24 h of cEEG monitoring. EEG background was graded and demonstrated that 90% of neonates with seizures had a moderately/markedly abnormal background versus 33% of neonates who did not seize (p < 0.0001). Additionally, while head ultrasound (HUS) obtained before EEG did not stratify seizure risk alone, no neonates with both a normal/mildly abnormal EEG background and a normal HUS (0/25) expe-rienced seizures in contrast to 60% (24/40) neonates with both an abnormal EEG background and an abnormal HUS (p < 0.0001). Our data suggest that neonates with abnormal EEG backgrounds and abnor-mal HUS should be monitored for seizures throughout TH and rewarming, while neonates with normal/ mildly abnormal EEG backgrounds and normal HUS are at low risk of seizures after 24 h of monitoring, and thus would be candidates for early cEEG discontinuation.(c) 2022 Elsevier Inc. All rights reserved.

BACKGROUND Angelman syndrome (AS) patients often respond to low glycemic index therapy to manage refractory seizures. These diets significantly affect quality of life and are challenging to implement. These formulations may have benefits in AS even in the absence of biomarkers suggesting ketosis. OBJECTIVES We aimed to compare an exogenous medical food ketone formulation (KF) with placebo for the dietary management of AS. METHODS This randomized, double-blind, placebo-controlled, crossover clinical trial was conducted in an academic center from 15 November, 2018 to 6 January, 2020. Thirteen participants with molecularly confirmed AS aged 4-11 y met the criteria and completed the 16-wk study. The study consisted of four 4-wk phases: a baseline phase, a blinded KF or placebo phase, a washout phase, and the crossover phase with alternate blinded KF or placebo. Primary outcomes were safety and tolerability rated by retention in the study and adherence to the formulation. Additional secondary outcomes of safety in this nonverbal population included blood chemistry, gastrointestinal health, seizure burden, cortical irritability, cognition, mobility, sleep, and developmental staging. RESULTS Data were compared between the baseline, KF, and placebo epochs. One participant exited the trial owing to difficulty consuming the formulation. Adverse events included an increase in cholesterol in 1 subject when consuming KF and a decrease in albumin in 1 subject when consuming placebo. Stool consistency improved with KF consumption, from 6.04 ± 1.61 at baseline and 6.35 ± 1.55 during placebo to 4.54 ± 1.19 during KF (P = 0.0027). Electroencephalograph trends showed a decrease in Δ frequency power during the KF arm and event-related potentials suggested a change in the frontal memory response. Vineland-3 showed improved fine motor skills in the KF arm. CONCLUSIONS The exogenous KF appears safe. More data are needed to determine the utility of exogenous ketones as a nutritional approach in children with AS.This trial was registered at clinicaltrials.gov as NCT03644693.

Mutations in DEP domain containing 5 (DEPDC5) are increasingly appreciated as one of the most common causes of inherited focal epilepsy. Epilepsies due to DEPDC5 mutations are often associated with brain malformations, tend to be drug-resistant, and have been linked to an increased risk of sudden unexplained death in epilepsy (SUDEP). Generation of epilepsy models to define mechanisms of epileptogenesis remains vital for future therapies. Here, we describe a novel mouse model of Depdc5 deficiency with a severe epilepsy phenotype, generated by conditional deletion of Depdc5 in dorsal telencephalic neuroprogenitor cells. In contrast to control and heterozygous mice, Depdc5-Emx1-Cre conditional knockout (CKO) mice demonstrated macrocephaly, spontaneous seizures and premature death. Consistent with increased mTORC1 activation, targeted neurons were enlarged and both neurons and astrocytes demonstrated increased S6 phosphorylation. Electrophysiologic characterization of miniature inhibitory post-synaptic currents in excitatory neurons was consistent with impaired post-synaptic response to GABAergic input, suggesting a potential mechanism for neuronal hyperexcitability. mTORC1 inhibition with rapamycin significantly improved survival of CKO animals and prevented observed seizures, including for up to 40 days following rapamycin withdrawal. These data not only support a primary role for mTORC1 hyperactivation in epilepsy following homozygous loss of Depdc5, but also suggest a developmental window for treatment which may have a durable benefit for some time even after withdrawal.

Angelman syndrome (AS) is a rare neurodevelopmental disorder that is characterized by developmental delay, intellectual disability, seizures, a characteristic happy personality, gait ataxia, tremulousness of the limbs, microcephaly, and anxiety. Severe sleep disturbances with the diminished need for sleep and abnormal sleep-wake cycles are seen in up to 90

The use of e-cigarettes, or "vaping," has been touted as a healthier alternative to smoking and as an aid in smoking cessation. The presumed safety of vaping and its wide availability have made vaping popular with teenagers. From 2017 to 2018, the prevalence of vaping nicotine or flavoring increased by nearly 10% to 25% in high-school seniors. 1 Miech R. Johnston L. O'Malley P.M. Bachman J.G. Patrick M.E. Adolescent vaping and nicotine use in 2017–2018—U.S. Nationaional Estimates. N Engl J Med. 2019; 380: 192-193 Crossref PubMed Scopus (94) Google Scholar Thus, teenaged patients with epilepsy will likely be exposed to and may partake in vaping.

Mutations in the DEPDC5 gene can cause epilepsy, including forms with and without brain malformations. The goal of this study was to investigate the contribution of DEPDC5 gene dosage to the underlying neuropathology of DEPDC5-related epilepsies. We generated induced pluripotent stem cells (iPSCs) from epilepsy patients harboring heterozygous loss of function mutations in DEPDC5. Patient iPSCs displayed increases in both phosphorylation of ribosomal protein S6 and proliferation rate, consistent with elevated mTORC1 activation. In line with these findings, we observed increased soma size in patient iPSC-derived cortical neurons that was rescued with rapamycin treatment. These data indicate that human cells heterozygous for DEPDC5 loss-of-function mutations are haploinsufficient for control of mTORC1 signaling. Our findings suggest that human pathology differs from mouse models of DEPDC5-related epilepsies, which do not show consistent phenotypic differences in heterozygous neurons, and support the need for human-based models to affirm and augment the findings from animal models of DEPDC5-related epilepsy.

We report a novel case of an infant with neurofibromatosis type 1 (NF1) who presented with new onset presumed focal impaired awareness seizures with motor onset followed by rapid progression to infantile spasms (IS). Electroencephalography (EEG) captured evolution from focal epileptiform discharges to multifocal and generalized discharges, then to hypsarrhythmia over three days. Development of IS within days of focal seizure onset is rapid, and to our knowledge, has not been demonstrated electrographically. The pattern of rapid ictal transition to hypsarrhythmia is essential for neurologists to be able to recognize as it can help lead to early treatment, which is necessary for improved outcomes in IS.

I read with interest the article by Wharton et al. 1 Wharton J.D. Kozek L.K. Carson R.P. Increased seizure frequency temporally related to vaping: where there’s vapor, there’s seizures?. Pediatr Neurol. 2020; 104: 66-67 Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar describing a 16-year-old young woman with generalized epilepsy who had an exacerbation of seizures in the setting of vaping after a seizure-free period of seven months on lamotrigine monotherapy. It is important to seek a few additional clinical details to bolster the proposed association between vaping and the worsening of seizures.