A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction.

De novo heterozygous variants in KCNC2 encoding the voltage-gated potassium (K+) channel subunit Kv3.2 are a recently described cause of developmental and epileptic encephalopathy (DEE). A de novo variant in KCNC2 c.374G > A (p.Cys125Tyr) was identified via exome sequencing in a patient with DEE. Relative to wild-type Kv3.2, Kv3.2-p.Cys125Tyr induces K+ currents exhibiting a large hyperpolarizing shift in the voltage dependence of activation, accelerated activation, and delayed deactivation consistent with a relative stabilization of the open conformation, along with increased current density. Leveraging the cryogenic electron microscopy (cryo-EM) structure of Kv3.1, molecular dynamic simulations suggest that a strong π-π stacking interaction between the variant Tyr125 and Tyr156 in the α-6 helix of the T1 domain promotes a relative stabilization of the open conformation of the channel, which underlies the observed gain of function. A multicompartment computational model of a Kv3-expressing parvalbumin-positive cerebral cortex fast-spiking γ-aminobutyric acidergic (GABAergic) interneuron (PV-IN) demonstrates how the Kv3.2-Cys125Tyr variant impairs neuronal excitability and dysregulates inhibition in cerebral cortex circuits to explain the resulting epilepsy.

Prenatal Brain Maturation is Delayed in Neonates with Congenital Diaphragmatic Hernia.

OBJECTIVE: To assess brain development in fetuses with congenital diaphragmatic hernia (CDH) using a fetal Total Maturation Score (fTMS). STUDY DESIGN: This is a retrospective cohort study using data from a single-center clinical registry. Neonates with an antenatal diagnosis of CDH between 2014 and 2020 and prenatal brain magnetic resonance imaging (MRI) (n = 48) were included. We compared our study sample with historical healthy controls (n = 48). The relationship between fTMS and gestational age (GA), as well as the association between fTMS and key prenatal variables and placental pathologic findings, were evaluated. RESULTS: Compared with healthy controls, neonates with CDH had a significant delay in fTMS (P value <.001). Within the CDH cohort, there was no significant difference in fTMS based on CDH severity, intrathoracic liver position, right vs left CDH, sex, presence of abnormal echocardiogram findings, treatment with extracorporeal membrane oxygenation (ECMO), or in-hospital mortality. Placentas of neonates with CDH had a high proportion of fetal vascular malperfusion (56%) and chronic inflammation (67%), and relatively large placentas had a protective effect on prenatal brain maturation (P value = .025). CONCLUSIONS: Prenatal brain maturation in neonates with CDH is delayed. Placental pathology may influence fetal brain development. The etiology and clinical impact of prenatal brain immaturity in neonates with CDH warrant further investigation.

Relationship of Neonatal Seizure Burden Before Treatment and Response to Initial Antiseizure Medication.

OBJECTIVE: To assess among a cohort of neonates with hypoxic-ischemic encephalopathy (HIE) the association of pretreatment maximal hourly seizure burden and total seizure duration with successful response to initial antiseizure medication (ASM). STUDY DESIGN: This was a retrospective review of data collected from infants enrolled in the HEAL Trial (NCT02811263) between January 25, 2017, and October 9, 2019. We evaluated a cohort of neonates born at ≥36 weeks of gestation with moderate-to-severe HIE who underwent continuous electroencephalogram monitoring and had acute symptomatic seizures. Poisson regression analyzed associations between (1) pretreatment maximal hourly seizure burden, (2) pretreatment total seizure duration, (3) time from first seizure to initial ASM, and (4) successful response to initial ASM. RESULTS: Among 39 neonates meeting inclusion criteria, greater pretreatment maximal hourly seizure burden was associated with lower chance of successful response to initial ASM (adjusted relative risk for each 5-minute increase in seizure burden 0.83, 95% CI 0.69-0.99). There was no association between pretreatment total seizure duration and chance of successful response. Shorter time-to-treatment was paradoxically associated with lower chance of successful response to treatment, although this difference was small in magnitude (relative risk 1.007, 95% CI 1.003-1.010). CONCLUSIONS: Maximal seizure burden may be more important than other, more commonly used measures in predicting response to acute seizure treatments.

Perioperative Neuromonitoring in Children with Congenital Heart Disease.

Although neonates and children with congenital heart disease are primarily hospitalized for cardiac and pulmonary diseases, they are also at an increased risk for neurologic injury due to both empiric differences that can exist in their nervous systems and acquired injury from cardiopulmonary pathology and interventions. Although early efforts in care focused on survival after reparative cardiac surgery, as surgical and anesthetic techniques have evolved and survival rates accordingly improved, the focus has now shifted to maximizing outcomes among survivors. Children and neonates with congenital heart disease experience seizures and poor neurodevelopmental outcomes at a higher rate than age-matched counterparts. The aim of neuromonitoring is to help clinicians identify patients at highest risk for these outcomes to implement strategies to mitigate these risks and to also help with neuroprognostication after an injury has occurred. The mainstays of neuromonitoring are (1) electroencephalographic monitoring to evaluate brain activity for abnormal patterns or changes and to identify seizures, (2) neuroimaging to reveal structural changes and evidence of physical injury in and around the brain, and (3) near-infrared spectroscopy to monitor brain tissue oxygenation and detect changes in perfusion. This review will detail the aforementioned techniques and their use in the care of pediatric patients with congenital heart disease.

SCN1A gain-of-function mutation causing an early onset epileptic encephalopathy.

OBJECTIVE: Loss-of-function variants in SCN1A cause Dravet syndrome, the most common genetic developmental and epileptic encephalopathy (DEE). However, emerging evidence suggests separate entities of SCN1A-related disorders due to gain-of-function variants. Here, we aim to refine the clinical, genetic, and functional electrophysiological features of a recurrent p.R1636Q gain-of-function variant, identified in four individuals at a single center. METHODS: Individuals carrying the recurrent SCN1A p.R1636Q variant were identified through diagnostic testing. Whole cell voltage-clamp electrophysiological recording in HEK-293 T cells was performed to compare the properties of sodium channels containing wild-type Nav 1.1 or Nav 1.1-R1636Q along with both Nav ß1 and Nav ß2 subunits, including response to oxcarbazepine. To delineate differences from other SCN1A-related epilepsies, we analyzed electronic medical records. RESULTS: All four individuals had an early onset DEE characterized by focal tonic seizures and additional seizure types starting in the first few weeks of life. Electrophysiological analysis showed a mixed gain-of-function effect with normal current density, a leftward (hyperpolarized) shift of steady-state inactivation, and slower inactivation kinetics leading to a prominent late sodium current. The observed functional changes closely paralleled effects of pathogenic variants in SCN3A and SCN8A at corresponding positions. Both wild type and variant exhibited sensitivity to block by oxcarbazepine, partially correcting electrophysiological abnormalities of the SCN1A p.R1636Q variant. Clinically, a single individual responded to treatment with oxcarbazepine. Across 51 individuals with SCN1A-related epilepsies, those with the recurrent p.R1636Q variants had the earliest ages at onset. SIGNIFICANCE: The recurrent SCN1A p.R1636Q variant causes a clinical entity with a wider clinical spectrum than previously reported, characterized by neonatal onset epilepsy and absence of prominent movement disorder. Functional consequences of this variant lead to mixed loss and gain of function that is partially corrected by oxcarbazepine. The recurrent p.R1636Q variant represents one of the most common causes of early onset SCN1A-related epilepsies with separate treatment and prognosis implications.

Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo.

BACKGROUND: An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo. METHODS: Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models. RESULTS: Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo). CONCLUSION: In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia. IMPACT: In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

Extracorporeal Membrane Oxygenation for Neonates With Congenital Diaphragmatic Hernia: Prevalence of Seizures and Outcomes.

OBJECTIVES: We aimed to determine the prevalence of electrographic seizures and associated odds of adverse outcomes of electrographic seizures in neonates with congenital diaphragmatic hernia (CDH) receiving extracorporeal membrane oxygenation (ECMO). DESIGN: Retrospective, descriptive case series. SETTING: Neonatal ICU (NICU) in a quaternary care institution. PATIENTS: All neonates with CDH receiving ECMO undergoing continuous electroencephalographic monitoring (CEEG) and follow-up between January 2012 and December 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All eligible neonates with CDH receiving ECMO underwent CEEG (n = 75). Electrographic seizures occurred in 14 of 75 (19%): they were exclusively electrographic-only in nine of 14, both electrographic-only and electroclinical in three of 14, and electroclinical only in two of 14. Two neonates developed status epilepticus. We identified an association between presence of seizures, rather than not, and longer duration of initial session of CEEG monitoring (55.7 hr [48.2-87.3 hr] vs 48.0 hr [43.0-48.3 hr]; p = 0.001). We also found an association between presence of seizures, rather than not, and greater odds of use of a second CEEG monitoring (12/14 vs 21/61; odds ratio [OR], 11.43 [95% CI, 2.34-55.90; p = 0.0026). Most neonates with seizures (10/14), experienced their onset of seizures more than 96 hours after the start of ECMO. Overall, the presence of electrographic seizures, compared with not, was associated with lower odds of survival to NICU discharge (4/14 vs 49/61; OR 0.10 [95% CI 0.03 to 0.37], p = 0.0006). Also, the presence of seizures-rather than not-was associated with greater odds of a composite of death and all abnormal outcomes on follow-up (13/14 vs 26/61; OR, 17.5; 95% CI, 2.15-142.39; p = 0.0074). CONCLUSIONS: Nearly one in five neonates with CDH receiving ECMO developed seizures during the ECMO course. Seizures were predominantly electrographic-only and when present were associated with great odds of adverse outcomes. The current study provides evidence to support standardized CEEG in this population.

Advanced Neuromonitoring Modalities on the Horizon: Detection and Management of Acute Brain Injury in Children.

Timely detection and monitoring of acute brain injury in children is essential to mitigate causes of injury and prevent secondary insults. Increasing survival in critically ill children has emphasized the importance of neuroprotective management strategies for long-term quality of life. In emergent and critical care settings, traditional neuroimaging modalities, such as computed tomography and magnetic resonance imaging (MRI), remain frontline diagnostic techniques to detect acute brain injury. Although detection of structural and anatomical abnormalities remains crucial, advanced MRI sequences assessing functional alterations in cerebral physiology provide unique diagnostic utility. Head ultrasound has emerged as a portable neuroimaging modality for point-of-care diagnosis via assessments of anatomical and perfusion abnormalities. Application of electroencephalography and near-infrared spectroscopy provides the opportunity for real-time detection and goal-directed management of neurological abnormalities at the bedside. In this review, we describe recent technological advancements in these neurodiagnostic modalities and elaborate on their current and potential utility in the detection and management of acute brain injury.

Quantitative electroencephalogram in term neonates under different sleep states.

Electroencephalogram (EEG) can be used to assess depth of consciousness, but interpreting EEG can be challenging, especially in neonates whose EEG undergo rapid changes during the perinatal course. EEG can be processed into quantitative EEG (QEEG), but limited data exist on the range of QEEG for normal term neonates during wakefulness and sleep, baseline information that would be useful to determine changes during sedation or anesthesia. We aimed to determine the range of QEEG in neonates during awake, active sleep and quiet sleep states, and identified the ones best at discriminating between the three states. Normal neonatal EEG from 37 to 46 weeks were analyzed and classified as awake, quiet sleep, or active sleep. After processing and artifact removal, total power, power ratio, coherence, entropy, and spectral edge frequency (SEF) 50 and 90 were calculated. Descriptive statistics were used to summarize the QEEG in each of the three states. Receiver operating characteristic (ROC) curves were used to assess discriminatory ability of QEEG. 30 neonates were analyzed. QEEG were different between awake vs asleep states, but similar between active vs quiet sleep states. Entropy beta, delta2 power %, coherence delta2, and SEF50 were best at discriminating awake vs active sleep. Entropy beta had the highest AUC-ROC ≥ 0.84. Entropy beta, entropy delta1, theta power %, and SEF50 were best at discriminating awake vs quiet sleep. All had AUC-ROC ≥ 0.78. In active sleep vs quiet sleep, theta power % had highest AUC-ROC > 0.69, lower than the other comparisons. We determined the QEEG range in healthy neonates in different states of consciousness. Entropy beta and SEF50 were best at discriminating between awake and sleep states. QEEG were not as good at discriminating between quiet and active sleep. In the future, QEEG with high discriminatory power can be combined to further improve ability to differentiate between states of consciousness.

Characteristics of Neonates with Cardiopulmonary Disease Who Experience Seizures: A Multicenter Study.

OBJECTIVE: To compare key seizure and outcome characteristics between neonates with and without cardiopulmonary disease. STUDY DESIGN: The Neonatal Seizure Registry is a multicenter, prospectively acquired cohort of neonates with clinical or electroencephalographic (EEG)-confirmed seizures. Cardiopulmonary disease was defined as congenital heart disease, congenital diaphragmatic hernia, and exposure to extracorporeal membrane oxygenation. We assessed continuous EEG monitoring strategy, seizure characteristics, seizure management, and outcomes for neonates with and without cardiopulmonary disease. RESULTS: We evaluated 83 neonates with cardiopulmonary disease and 271 neonates without cardiopulmonary disease. Neonates with cardiopulmonary disease were more likely to have EEG-only seizures (40% vs 21%, P < .001) and experience their first seizure later than those without cardiopulmonary disease (174 vs 21 hours of age, P < .001), but they had similar seizure exposure (many-recurrent electrographic seizures 39% vs 43%, P = .27). Phenobarbital was the primary initial antiseizure medication for both groups (90%), and both groups had similarly high rates of incomplete response to initial antiseizure medication administration (66% vs 68%, P = .75). Neonates with cardiopulmonary disease were discharged from the hospital later (hazard ratio 0.34, 95% CI 0.25-0.45, P < .001), although rates of in-hospital mortality were similar between the groups (hazard ratio 1.13, 95% CI 0.66-1.94, P = .64). CONCLUSION: Neonates with and without cardiopulmonary disease had a similarly high seizure exposure, but neonates with cardiopulmonary disease were more likely to experience EEG-only seizures and had seizure onset later in the clinical course. Phenobarbital was the most common seizure treatment, but seizures were often refractory to initial antiseizure medication. These data support guidelines recommending continuous EEG in neonates with cardiopulmonary disease and indicate a need for optimized therapeutic strategies.

Seizure Severity and Treatment Response in Newborn Infants with Seizures Attributed to Intracranial Hemorrhage.

OBJECTIVE: We sought to characterize intracranial hemorrhage (ICH) as a seizure etiology in infants born term and preterm. For infants born term, we sought to compare seizure severity and treatment response for multisite vs single-site ICH and hypoxic-ischemic encephalopathy (HIE) with vs without ICH. STUDY DESIGN: We studied 112 newborn infants with seizures attributed to ICH and 201 infants born at term with seizures attributed to HIE, using a cohort of consecutive infants with clinically diagnosed and/or electrographic seizures prospectively enrolled in the multicenter Neonatal Seizure Registry. We compared seizure severity and treatment response among infants with complicated ICH, defined as multisite vs single-site ICH and HIE with vs without ICH. RESULTS: ICH was a more common seizure etiology in infants born preterm vs term (27% vs 10%, P < .001). Most infants had subclinical seizures (74%) and an incomplete response to initial antiseizure medication (ASM) (68%). In infants born term, multisite ICH was associated with more subclinical seizures than single-site ICH (93% vs 66%, P = .05) and an incomplete response to the initial ASM (100% vs 66%, P = .02). Status epilepticus was more common in HIE with ICH vs HIE alone (38% vs 17%, P = .05). CONCLUSIONS: Seizure severity was greater and treatment response was lower among infants born term with complicated ICH. These data support the use of continuous video electroencephalogram monitoring to accurately detect seizures and a multistep treatment plan that considers early use of multiple ASMs, particularly with parenchymal and high-grade intraventricular hemorrhage and complicated ICH.

Periodic and rhythmic patterns in critically ill children: Incidence, interrater agreement, and seizures.

OBJECTIVES: We aimed to determine the incidence of periodic and rhythmic patterns (PRP), assess the interrater agreement between electroencephalographers scoring PRP using standardized terminology, and analyze associations between PRP and electrographic seizures (ES) in critically ill children. METHODS: This was a prospective observational study of consecutive critically ill children undergoing continuous electroencephalographic monitoring (CEEG). PRP were identified by one electroencephalographer, and then two pediatric electroencephalographers independently scored the first 1-h epoch that contained PRP using standardized terminology. We determined the incidence of PRPs, evaluated interrater agreement between electroencephalographers scoring PRP, and evaluated associations between PRP and ES. RESULTS: One thousand three hundred ninety-nine patients underwent CEEG. ES occurred in 345 (25%) subjects. PRP, ES + PRP, and ictal-interictal continuum (IIC) patterns occurred in 142 (10%), 81 (6%), and 93 (7%) subjects, respectively. The most common PRP were generalized periodic discharges (GPD; 43, 30%), lateralized periodic discharges (LPD; 34, 24%), generalized rhythmic delta activity (GRDA; 34, 24%), bilateral independent periodic discharges (BIPD; 14, 10%), and lateralized rhythmic delta activity (LRDA; 11, 8%). ES risk varied by PRP type (p < .01). ES occurrence was associated with GPD (odds ratio [OR] = 6.35, p < .01), LPD (OR = 10.45, p < .01), BIPD (OR = 6.77, p < .01), and LRDA (OR = 6.58, p < .01). Some modifying features increased the risk of ES for each of those PRP. GRDA was not significantly associated with ES (OR = 1.34, p = .44). Each of the IIC patterns was associated with ES (OR = 6.83-8.81, p < .01). ES and PRP occurred within 6 h (before or after) in 45 (56%) subjects. SIGNIFICANCE: PRP occurred in 10% of critically ill children who underwent CEEG. The most common patterns were GPD, LPD, GRDA, BIPD, and LRDA. The GPD, LPD, BIPD, LRDA, and IIC patterns were associated with ES. GRDA was not associated with ES.

Early-life epilepsy after acute symptomatic neonatal seizures: A prospective multicenter study.

OBJECTIVE: We aimed to evaluate early-life epilepsy incidence, seizure types, severity, risk factors, and treatments among survivors of acute neonatal seizures. METHODS: Neonates with acute symptomatic seizures born 7/2015-3/2018 were prospectively enrolled at nine Neonatal Seizure Registry sites. One-hour EEG was recorded at age three months. Post-neonatal epilepsy and functional development (Warner Initial Developmental Evaluation of Adaptive and Functional Skills - WIDEA-FS) were assessed. Cox regression was used to assess epilepsy-free survival. RESULTS: Among 282 infants, 37 (13%) had post-neonatal epilepsy by 24-months [median age of onset 7-months (IQR 3-14)]. Among those with post-neonatal epilepsy, 13/37 (35%) had infantile spasms and 12/37 (32%) had drug-resistant epilepsy. Most children with post-neonatal epilepsy had abnormal neurodevelopment at 24-months (WIDEA-FS >2SD below normal population mean for 81% of children with epilepsy vs 27% without epilepsy, RR 7.9, 95% CI 3.6-17.3). Infants with severely abnormal neonatal EEG background patterns were more likely to develop epilepsy than those with mild/moderate abnormalities (HR 3.7, 95% CI 1.9-5.9). Neonatal EEG with ≥3 days of seizures also predicted hazard of epilepsy (HR 2.9, 95% CI 1.4-5.9). In an adjusted model, days of neonatal EEG-confirmed seizures (HR 1.4 per day, 95% CI 1.2-1.6) and abnormal discharge examination (HR 3.9, 95% CI 1.9-7.8) were independently associated with time to epilepsy onset. Abnormal (vs. normal) three-month EEG was not associated with epilepsy. SIGNIFICANCE: In this multicenter study, only 13% of infants with acute symptomatic neonatal seizures developed post-neonatal epilepsy by age 24-months. However, there was a high risk of severe neurodevelopmental impairment and drug-resistant seizures among children with post-neonatal epilepsy. Days of EEG-confirmed neonatal seizures was a potentially modifiable epilepsy risk factor. An EEG at three months was not clinically useful for predicting epilepsy. These practice changing findings have implications for family counseling, clinical follow-up planning, and future research to prevent post-neonatal epilepsy.

Assessing seizure burden in pediatric epilepsy using an electronic medical record-based tool through a common data element approach.

OBJECTIVE: Improvement in epilepsy care requires standardized methods to assess disease severity. We report the results of implementing common data elements (CDEs) to document epilepsy history data in the electronic medical record (EMR) after 12 months of clinical use in outpatient encounters. METHODS: Data regarding seizure frequency were collected during routine clinical encounters using a CDE-based form within our EMR. We extracted CDE data from the EMR and developed measurements for seizure severity and seizure improvement scores. Seizure burden and improvement was evaluated by patient demographic and encounter variables for in-person and telemedicine encounters. RESULTS: We assessed a total of 1696 encounters in 1038 individuals with childhood epilepsies between September 6, 2019 and September 11, 2020 contributed by 32 distinct providers. Childhood absence epilepsy (n = 121), Lennox-Gastaut syndrome (n = 86), and Dravet syndrome (n = 42) were the most common epilepsy syndromes. Overall, 43% (737/1696) of individuals had at least monthly seizures, 17% (296/1696) had a least daily seizures, and 18% (311/1696) were seizure-free for >12 months. Quantification of absolute seizure burden and changes in seizure burden over time differed between epilepsy syndromes, including high and persistent seizure burden in patients with Lennox-Gastaut syndrome. Individuals seen via telemedicine or in-person encounters had comparable seizure frequencies. Individuals identifying as Hispanic/Latino, particularly from postal codes with lower median household incomes, were more likely to have ongoing seizures that worsened over time. SIGNIFICANCE: Standardized documentation of clinical data in childhood epilepsies through CDE can be implemented in routine clinical care at scale and enables assessment of disease burden, including characterization of seizure burden over time. Our data provide insights into heterogeneous patterns of seizure control in common pediatric epilepsy syndromes and will inform future initiatives focusing on patient-centered outcomes in childhood epilepsies, including the impact of telemedicine and health care disparities.

Design and implementation of electronic health record common data elements for pediatric epilepsy: Foundations for a learning health care system.

OBJECTIVE: Common data elements (CDEs) are standardized questions and answer choices that allow aggregation, analysis, and comparison of observations from multiple sources. Clinical CDEs are foundational for learning health care systems, a data-driven approach to health care focused on continuous improvement of outcomes. We aimed to create clinical CDEs for pediatric epilepsy. METHODS: A multiple stakeholder group (clinicians, researchers, parents, caregivers, advocates, and electronic health record [EHR] vendors) developed clinical CDEs for routine care of children with epilepsy. Initial drafts drew from clinical epilepsy note templates, CDEs created for clinical research, items in existing registries, consensus documents and guidelines, quality metrics, and outcomes needed for demonstration projects. The CDEs were refined through discussion and field testing. We describe the development process, rationale for CDE selection, findings from piloting, and the CDEs themselves. We also describe early implementation, including experience with EHR systems and compatibility with the International League Against Epilepsy classification of seizure types. RESULTS: Common data elements were drafted in August 2017 and finalized in January 2020. Prioritized outcomes included seizure control, seizure freedom, American Academy of Neurology quality measures, presence of common comorbidities, and quality of life. The CDEs were piloted at 224 visits at 10 centers. The final CDEs included 36 questions in nine sections (number of questions): diagnosis (1), seizure frequency (9), quality of life (2), epilepsy history (6), etiology (8), comorbidities (2), treatment (2), process measures (5), and longitudinal history notes (1). Seizures are categorized as generalized tonic-clonic (regardless of onset), motor, nonmotor, and epileptic spasms. Focality is collected as epilepsy type rather than seizure type. Seizure frequency is measured in nine levels (all used during piloting). The CDEs were implemented in three vendor systems. Early clinical adoption included 1294 encounters at one center. SIGNIFICANCE: We created, piloted, refined, finalized, and implemented a novel set of clinical CDEs for pediatric epilepsy.

Associations between Infant and Parent Characteristics and Measures of Family Well-Being in Neonates with Seizures: A Cohort Study.

OBJECTIVE: To characterize and determine risk factors for key dimensions of well-being at hospital discharge in families of neonates with acute symptomatic seizures. STUDY DESIGN: This prospective, observational cohort study enrolled 144 parent-infant dyads among neonates with acute symptomatic seizures from 9 pediatric hospitals in the Neonatal Seizure Registry. One parent per family completed a discharge survey, which included measures of anxiety and depression, health-related quality of life, and impact on the family. Multivariable regression analyses adjusted for site were constructed to examine parent and infant characteristics associated with well-being. RESULTS: At discharge, 54% of parents reported symptoms of anxiety and 32% reported symptoms of depression. Parents of infants with hypoxic-ischemic encephalopathy reported more depression and worse quality of life than parents of infants with other seizure etiologies. Parental quality of life was also lower with greater infant age at discharge. A higher level of maternal education was associated with greater impact on the family. All these differences were medium to large effect sizes, ranging from 0.52 to 0.78. CONCLUSIONS: Symptoms of anxiety and depression are common in parents of infants with neonatal seizures, and several parent and infant characteristics are associated with poorer parental quality of life and family well-being. These findings are a call to action to improve mental health screening and services for parents of infants with neonatal seizures.

A retrospective comparison of phenobarbital and levetiracetam for the treatment of seizures following cardiac surgery in neonates.

OBJECTIVE: To compare the safety and efficacy of phenobarbital and levetiracetam in a cohort of neonates with seizures following cardiac surgery. METHODS: We performed a retrospective single-center study of consecutive neonates with electrographically confirmed seizures managed with antiseizure medication after cardiac surgery from June 15, 2012 to December 31, 2018. We compared the safety and efficacy of phenobarbital and levetiracetam as first-line therapy. RESULTS: First-line therapy was phenobarbital in 31 neonates and levetiracetam in 22 neonates. Phenobarbital was associated with more adverse events (P = .006). Eight neonates (14%) experienced an adverse event related to phenobarbital use, including seven with hypotension and one with respiratory depression. No adverse events were reported with levetiracetam use. The cessation of electrographic seizures was similar in both groups, including 18 neonates (58%) with seizure cessation after phenobarbital and 12 neonates (55%) with seizure cessation after levetiracetam (P = 1.0). The combined cessation rates of phenobarbital and levetiracetam when used as first- or second-line therapy were 58% and 47%, respectively (P = .47). SIGNIFICANCE: Phenobarbital was associated with more adverse events than levetiracetam, and the two drugs were equally but incompletely effective in treating electrographically confirmed seizures in neonates following cardiac surgery. Given its more acceptable safety profile and potential noninferiority, levetiracetam may be a reasonable option for first-line therapy for treatment of seizures in this population. Further prospective studies are needed to confirm these results.

Risk for infantile spasms after acute symptomatic neonatal seizures.

OBJECTIVE: Infantile spasms (IS) is a severe epilepsy in early childhood. Early treatment of IS provides the best chance of seizure remission and favorable developmental outcome. We aimed to develop a prediction rule to accurately predict which neonates with acute symptomatic seizures will develop IS. METHODS: We used data from the Neonatal Seizure Registry, a prospective, multicenter cohort of infants with acute symptomatic neonatal seizures born from July 2015 to March 2018. Neonates with acute symptomatic seizures who received clinical electroencephalography (EEG) and magnetic resonance imaging (MRI) and were younger than 2 years of age at the time of enrollment were included. We evaluated the association of neonatal EEG, MRI, and clinical factors with subsequent IS using bivariate analysis and best subsets logistic regression. We selected a final model through a consensus process that balanced statistical significance with clinical relevance. RESULTS: IS developed in 12 of 204 infants (6%). Multiple potential predictors were associated with IS, including Apgar scores, EEG features, seizure characteristics, MRI abnormalities, and clinical status at hospital discharge. The final model included three risk factors: (a) severely abnormal EEG or ≥3 days with seizures recorded on EEG, (b) deep gray or brainstem injury on MRI, and (c) abnormal tone on discharge exam. The stratified risk of IS was the following: no factors 0% (0/82, 95% confidence interval [CI] 0%-4%), one or two factors 4% (4/108, 95% CI 1%-9%), and all three factors 57% (8/14, 95% CI 29%-83%). SIGNIFICANCE: IS risk after acute symptomatic neonatal seizures can be stratified using commonly available clinical data. No child without risk factors, vs >50% of those with all three factors, developed IS. This risk prediction rule may be valuable for clinical counseling as well as for selecting participants for clinical trials to prevent post-neonatal epilepsy. This tailored approach may lead to earlier diagnosis and treatment and improve outcomes for a devastating early life epilepsy.

Population Pharmacokinetics of IV Phenobarbital in Neonates After Congenital Heart Surgery.

OBJECTIVES: To develop a population pharmacokinetic model for IV phenobarbital in neonates following cardiac surgery and perform simulations to identify optimal dosing regimens. DESIGN: Retrospective single-center pharmacokinetic study. SETTING: Cardiac ICU at Children's Hospital of Philadelphia. PATIENTS: Consecutive neonates who received greater than or equal to one dose of IV phenobarbital and had greater than or equal to one phenobarbital concentration drawn per standard of care from June 15, 2012, to October 15, 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Simulations were performed using the final model variables. Optimal phenobarbital loading doses were determined based on attainment of peak and maintenance concentrations between 20 and 40 mg/L. A total of 37 neonates contributed 159 pharmacokinetic samples. The median (range) weight, postmenstrual age, and postnatal age were 3.2 kg (1.3-3.8), 39 2/7 weeks (28 2/7 to 42 6/7), and 5 days (0-26 d), respectively. Twelve patients (32%) were on extracorporeal membrane oxygenation. An one-compartment model best described the data. The final population pharmacokinetic model included (1) weight and postnatal age for clearance and (2) weight, extracorporeal membrane oxygenation, and albumin for volume of distribution. In neonates not on extracorporeal membrane oxygenation, loading doses of 30 and 20 mg/kg reached goal concentration with albumin values less than or equal to 3 and 3.5 mg/dL, respectively. Loading doses of 30 mg/kg reached goal concentration on extracorporeal membrane oxygenation regardless of albumin values. Maintenance doses of 4-5 mg/kg/d reached goal concentration in all neonates. CONCLUSIONS: In neonates following cardiac surgery, phenobarbital clearance increased with postnatal age. Volume of distribution increased with extracorporeal membrane oxygenation and lower albumin values. Loading doses of 30 mg/kg on extracorporeal membrane oxygenation and 20-30 mg/kg without extracorporeal membrane oxygenation were needed to reach goal concentration based on simulations.

Response to antiseizure medications in neonates with acute symptomatic seizures.

In a prospective cohort of 534 neonates with acute symptomatic seizures, 66% had incomplete response to the initial loading dose of antiseizure medication (ASM). Treatment response did not differ by gestational age, sex, medication, or dose. The risk of incomplete response was highest for seizures due to intracranial hemorrhage and lowest for hypoxic-ischemic encephalopathy, although the difference was not significant after adjusting for high seizure burden and therapeutic hypothermia treatment. Future trial design may test ASMs in neonates with all acute symptomatic seizure etiologies and could target neonates with seizures refractory to an initial ASM.