Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections.

PURPOSE: We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor-like domains 1 (CRELD1) gene variants. METHODS: The impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells. RESULTS: Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with 1 recurrent variant, p.(Cys192Tyr), identified in 10 families. X tropicalis tadpoles with creld1 knockdown displayed developmental defects along with increased susceptibility to induced seizures compared with controls. Additionally, human CRELD1 harboring missense variants from affected individuals had reduced protein function, indicated by a diminished ability to induce craniofacial defects when overexpressed in X tropicalis. Finally, baseline analyses of peripheral blood mononuclear cells showed similar proportions of immune cell subtypes in patients compared with healthy donors. CONCLUSION: This patient cohort, combined with experimental data, provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1.

Preclinical pharmacokinetics and tolerability of a novel meglumine-based parenteral solution of topiramate and topiramate combinations for treatment of status epilepticus.

OBJECTIVE: For an antiseizure medication (ASM) to be effective in status epilepticus (SE), the drug should be administered intravenously (i.v.) to provide quick access to the brain. However, poor aqueous solubility is a major problem in the development of parenteral drug solutions. Given its multiple mechanisms of action, topiramate (TPM) is a promising candidate for the treatment of established or refractory SE, as supported by clinical studies using nasogastric tube TPM administration. However, TPM is not clinically available as a solution for i.v. administration, which hampers its use in the treatment of SE. Here, we describe a novel easy-to-use and easy-to-prepare i.v. TPM formulation using the U.S. Food and Drug Administration (FDA)-approved excipient meglumine. METHODS: During formulation development, we compared the solubility of TPM in bi-distilled water with vs without a range of meglumine concentrations. Furthermore, the solubility of combinations of TPM and levetiracetam and TPM, levetiracetam, and atorvastatin in aqueous meglumine concentrations was determined. Subsequently, the pharmacokinetics and tolerability of meglumine-based solutions of TPM and TPM combinations were evaluated in rats, including animals following fluid percussion injury or pilocarpine-induced SE. RESULTS: The amino sugar meglumine markedly enhances the aqueous solubility of TPM. A comparison with data on dissolving TPM using sulfobutylether-ß-cyclodextrin (Captisol) demonstrates that meglumine is much more effective for dissolving TPM. Furthermore, meglumine can be used to prepare drug cocktails where TPM is co-administered with another ASM for SE treatment. The tolerability studies of the meglumine-based TPM solution and meglumine-based TPM combinations in normal rats and the rat fluid percussion injury and pilocarpine-induced SE models demonstrate excellent tolerability of the novel drug solutions. Preclinical studies on antiseizure efficacy in the SE model are underway. SIGNIFICANCE: In conclusion, the novel meglumine-based solution of TPM presented here may be well suited for clinical development.

Altered closed state inactivation gating in Kv4.2 channels results in developmental and epileptic encephalopathies in human patients.

Kv4.2 subunits, encoded by KCND2, serve as the pore-forming components of voltage-gated, inactivating ISA K+ channels expressed in the brain. ISA channels inactivate without opening in response to subthreshold excitatory input, temporarily increasing neuronal excitability, the back propagation of action potentials, and Ca2+ influx into dendrites, thereby regulating mechanisms of spike timing-dependent synaptic plasticity. As previously described, a de novo variant in Kv4.2, p.Val404Met, is associated with an infant-onset developmental and epileptic encephalopathy in monozygotic twin boys. The p.Val404Met variant enhances inactivation directly from closed states, but dramatically impairs inactivation after channel opening. We now report the identification of a closely related, novel, de novo variant in Kv4.2, p.Val402Leu, in a boy with an early-onset pharmacoresistant epilepsy that evolved to an epileptic aphasia syndrome (Continuous Spike Wave during Sleep Syndrome). Like p.Val404Met, the p.Val402Leu variant increases the rate of inactivation from closed states, but significantly slows inactivation after the pore opens. Although quantitatively the p.Val402Leu mutation alters channel kinetics less dramatically than p.Val404Met, our results strongly support the conclusion that p.Val402Leu and p.Val404Met cause the clinical features seen in the affected individuals and underscore the importance of closed state inactivation in ISA channels in normal brain development and function.

Postictal Death Is Associated with Tonic Phase Apnea in a Mouse Model of Sudden Unexpected Death in Epilepsy.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of epilepsy that is believed to be due to cardiorespiratory failure immediately after generalized convulsive seizures. METHODS: We performed cardiorespiratory monitoring of seizure-induced death in mice carrying either a p.Arg1872Trp or p.Asn1768Asp mutation in a single Scn8a allele-mutations identified from patients who died from SUDEP-and of seizure-induced death in pentylenetetrazole-treated wild-type mice. RESULTS: The primary cause of seizure-induced death for all mice was apnea, as (1) apnea began during a seizure and continued for tens of minutes until terminal asystole, and (2) death was prevented by mechanical ventilation. Fatal seizures always included a tonic phase that was coincident with apnea. This tonic phase apnea was not sufficient to produce death, as it also occurred during many nonfatal seizures; however, all seizures that were fatal had tonic phase apnea. We also made the novel observation that continuous tonic diaphragm contraction occurred during tonic phase apnea, which likely contributes to apnea by preventing exhalation, and this was only fatal when breathing did not resume after the tonic phase ended. Finally, recorded seizures from a patient with developmental epileptic encephalopathy with a previously undocumented SCN8A likely pathogenic variant (p.Leu257Val) revealed similarities to those of the mice, namely, an extended tonic phase that was accompanied by apnea. INTERPRETATION: We conclude that apnea coincident with the tonic phase of a seizure, and subsequent failure to resume breathing, are the determining events that cause seizure-induced death in Scn8a mutant mice. ANN NEUROL 2021;89:1023-1035.

Pediatric Epilepsy Learning Healthcare System Quality of Life (PELHS-QOL-2): A novel health-related quality of life prompt for children with epilepsy.

OBJECTIVE: Pediatric epilepsy is often associated with diminished health-related quality of life (HRQOL). Our aim was to establish the validity of the Pediatric Epilepsy Learning Healthcare System Quality of Life (PELHS-QOL-2) questions, a novel two-item HRQOL prompt for children with epilepsy, primarily for use in clinical care. METHODS: We performed a multicenter cross-sectional study to validate the PELHS-QOL-2. Construct validity was established through bivariate comparisons with four comparator measures and known drivers of quality of life in children with epilepsy, as well as by creating an a priori multivariable model to predict the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55). Validity generalization was established through bivariate comparisons with demographic and clinical information. Content validity and clinical utility were established by assessing how well the PELHS-QOL-2 met eight design criteria for an HRQOL prompt established by a multistakeholder group of experts. RESULTS: The final participant sample included 154 English-speaking caregivers of children with epilepsy (mean age = 9.7 years, range = .5-18, 49% female, 70% White). The PELHS-QOL-2 correlated with the four comparator instruments (ρ = .44-.56), was significantly associated with several known drivers of quality of life in children with epilepsy (p < .05), and predicted QOLCE-55 scores in the multivariate model (adjusted R2 = .54). The PELHS-QOL-2 item was not associated with the age, sex, and ethnicity of the children nor with the setting and location of data collection, although PELHS-QOL-Medications was significantly associated with race (worse for White race). Following both quantitative and qualitative analysis, the PELHS-QOL-2 met seven of eight design criteria. SIGNIFICANCE: The PELHS-QOL-2 is a valid HRQOL prompt and is well suited for use in clinical care as a mechanism to routinely initiate conversations with caregivers about quality of life in children with epilepsy. The association of PELHS-QOL-Medications with race merits further study.

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.

Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort).

OBJECTIVE: We aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE). METHODS: Patients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks-24 h), and without fever. RESULTS: Of 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function. SIGNIFICANCE: Among pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection-related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes.

Factors associated with long-term outcomes in pediatric refractory status epilepticus.

OBJECTIVE: This study was undertaken to describe long-term clinical and developmental outcomes in pediatric refractory status epilepticus (RSE) and identify factors associated with new neurological deficits after RSE. METHODS: We performed retrospective analyses of prospectively collected observational data from June 2011 to March 2020 on pediatric patients with RSE. We analyzed clinical outcomes from at least 30 days after RSE and, in a subanalysis, we assessed developmental outcomes and evaluated risk factors in previously normally developed patients. RESULTS: Follow-up data on outcomes were available in 276 patients (56.5% males). The median (interquartile range [IQR]) follow-up duration was 1.6 (.9-2.7) years. The in-hospital mortality rate was 4% (16/403 patients), and 15 (5.4%) patients had died after hospital discharge. One hundred sixty-six (62.9%) patients had subsequent unprovoked seizures, and 44 (16.9%) patients had a repeated RSE episode. Among 116 patients with normal development before RSE, 42 of 107 (39.3%) patients with available data had new neurological deficits (cognitive, behavioral, or motor). Patients with new deficits had longer median (IQR) electroclinical RSE duration than patients without new deficits (10.3 [2.1-134.5] h vs. 4 [1.6-16] h, p = .011, adjusted odds ratio = 1.003, 95% confidence interval = 1.0008-1.0069, p = .027). The proportion of patients with an unfavorable functional outcome (Glasgow Outcome Scale-Extended score ≥ 4) was 22 of 90 (24.4%), and they were more likely to have received a continuous infusion. SIGNIFICANCE: About one third of patients without prior epilepsy developed recurrent unprovoked seizures after the RSE episode. In previously normally developing patients, 39% presented with new deficits during follow-up, with longer electroclinical RSE duration as a predictor.

Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus.

OBJECTIVE: This study was undertaken to evaluate benzodiazepine (BZD) administration patterns before transitioning to non-BZD antiseizure medication (ASM) in pediatric patients with refractory convulsive status epilepticus (rSE). METHODS: This retrospective multicenter study in the United States and Canada used prospectively collected observational data from children admitted with rSE between 2011 and 2020. Outcome variables were the number of BZDs given before the first non-BZD ASM, and the number of BZDs administered after 30 and 45 min from seizure onset and before escalating to non-BZD ASM. RESULTS: We included 293 patients with a median (interquartile range) age of 3.8 (1.3-9.3) years. Thirty-six percent received more than two BZDs before escalating, and the later the treatment initiation was after seizure onset, the less likely patients were to receive multiple BZD doses before transitioning (incidence rate ratio [IRR] = .998, 95% confidence interval [CI] = .997-.999 per minute, p = .01). Patients received BZDs beyond 30 and 45 min in 57.3% and 44.0% of cases, respectively. Patients with out-of-hospital seizure onset were more likely to receive more doses of BZDs beyond 30 min (IRR = 2.43, 95% CI = 1.73-3.46, p < .0001) and beyond 45 min (IRR = 3.75, 95% CI = 2.40-6.03, p < .0001) compared to patients with in-hospital seizure onset. Intermittent SE was a risk factor for more BZDs administered beyond 45 min compared to continuous SE (IRR = 1.44, 95% CI = 1.01-2.06, p = .04). Forty-seven percent of patients (n = 94) with out-of-hospital onset did not receive treatment before hospital arrival. Among patients with out-of-hospital onset who received at least two BZDs before hospital arrival (n = 54), 48.1% received additional BZDs at hospital arrival. SIGNIFICANCE: Failure to escalate from BZDs to non-BZD ASMs occurs mainly in out-of-hospital rSE onset. Delays in the implementation of medical guidelines may be reduced by initiating treatment before hospital arrival and facilitating a transition to non-BZD ASMs after two BZD doses during handoffs between prehospital and in-hospital settings.

Super-Refractory Status Epilepticus in Children: A Retrospective Cohort Study.

OBJECTIVES: To characterize the pediatric super-refractory status epilepticus population by describing treatment variability in super-refractory status epilepticus patients and comparing relevant clinical characteristics, including outcomes, between super-refractory status epilepticus, and nonsuper-refractory status epilepticus patients. DESIGN: Retrospective cohort study with prospectively collected data between June 2011 and January 2019. SETTING: Seventeen academic hospitals in the United States. PATIENTS: We included patients 1 month to 21 years old presenting with convulsive refractory status epilepticus. We defined super-refractory status epilepticus as continuous or intermittent seizures lasting greater than or equal to 24 hours following initiation of continuous infusion and divided the cohort into super-refractory status epilepticus and nonsuper-refractory status epilepticus groups. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 281 patients (157 males) with a median age of 4.1 years (1.3-9.5 yr), including 31 super-refractory status epilepticus patients. Compared with nonsuper-refractory status epilepticus group, super-refractory status epilepticus patients had delayed initiation of first nonbenzodiazepine-antiseizure medication (149 min [55-491.5 min] vs 62 min [33.3-120.8 min]; p = 0.030) and of continuous infusion (495 min [177.5-1,255 min] vs 150 min [90-318.5 min]; p = 0.003); prolonged seizure duration (120 hr [58-368 hr] vs 3 hr [1.4-5.9 hr]; p < 0.001) and length of ICU stay (17 d [9.5-40 d] vs [1.8-8.8 d]; p < 0.001); more medical complications (18/31 [58.1%] vs 55/250 [22.2%] patients; p < 0.001); lower return to baseline function (7/31 [22.6%] vs 182/250 [73.4%] patients; p < 0.001); and higher mortality (4/31 [12.9%] vs 5/250 [2%]; p = 0.010). Within the super-refractory status epilepticus group, status epilepticus resolution was attained with a single continuous infusion in 15 of 31 patients (48.4%), two in 10 of 31 (32.3%), and three or more in six of 31 (19.4%). Most super-refractory status epilepticus patients (30/31, 96.8%) received midazolam as first choice. About 17 of 31 patients (54.8%) received additional treatments. CONCLUSIONS: Super-refractory status epilepticus patients had delayed initiation of nonbenzodiazepine antiseizure medication treatment, higher number of medical complications and mortality, and lower return to neurologic baseline than nonsuper-refractory status epilepticus patients, although these associations were not adjusted for potential confounders. Treatment approaches following the first continuous infusion were heterogeneous, reflecting limited information to guide clinical decision-making in super-refractory status epilepticus.

A deletion in Eml1 leads to bilateral subcortical heterotopia in the tish rat.

Children with malformations of cortical development (MCD) are at risk for epilepsy, developmental delays, behavioral disorders, and intellectual disabilities. For a subset of these children, antiseizure medications or epilepsy surgery may result in seizure freedom. However, there are limited options for treating or curing the other conditions, and epilepsy surgery is not an option in all cases of pharmacoresistant epilepsy. Understanding the genetic and neurobiological mechanisms underlying MCD is a necessary step in elucidating novel therapeutic targets. The tish (telencephalic internal structural heterotopia) rat is a unique model of MCD with spontaneous seizures, but the underlying genetic mutation(s) have remained unknown. DNA and RNA-sequencing revealed that a deletion encompassing a previously unannotated first exon markedly diminished Eml1 transcript and protein abundance in the tish brain. Developmental electrographic characterization of the tish rat revealed early-onset of spontaneous spike-wave discharge (SWD) bursts beginning at postnatal day (P) 17. A dihybrid cross demonstrated that the mutant Eml1 allele segregates with the observed dysplastic cortex and the early-onset SWD bursts in monogenic autosomal recessive frequencies. Our data link the development of the bilateral, heterotopic dysplastic cortex of the tish rat to a deletion in Eml1.

Implementation of an Intravenous Dihydroergotamine Protocol for Refractory Migraine in Children.

OBJECTIVE: Retrospective chart review to assess the effectiveness of an institutional intravenous (IV) dihydroergotamine (DHE) therapy protocol for refractory migraine in the pediatric population. BACKGROUND: Limited high-quality evidence exists to guide the approach to treatment of refractory migraine with IV DHE, particularly in the pediatric population. This study reviews our institutional experience in implementing an IV DHE protocol in children to identify areas for improvement. We specifically sought to determine whether the outcome differed at follow-up between children who completed the full course of DHE (8 or 9 doses) as specified in our institutional protocol and those who did not. In addition, given the limited Food and Drug Administration-approved treatments for chronic migraine (CM) in the pediatric population, re-evaluating the response rate in this group of patients was of particular interest. METHODS: A retrospective cohort based on a chart review of 159 consecutive pediatric patients who received IV DHE while inpatient at University of Virginia Children's Hospital over a 9-year period (January 2011-January 2019) was identified. Patients were classified according to the International Classification of Headache Disorders, 3rd edition criteria as having CM, status migrainosus, or, in a small number of patients, Other headache with migrainous features. To investigate any benefit of completing the full course of DHE, patients were categorized as having completed the DHE protocol ("Protocol Complete" 8 or 9 doses) or not completing the protocol ("Protocol Incomplete" <8 doses). Patient-reported pain scores upon admission and discharge were recorded, and follow-up outcomes were categorized as headache freedom, >50% relief, <50% relief, or no relief. Pain outcomes were analyzed with respect to DHE protocol complete status and headache classification. RESULTS: A total of 159 patients were included in the analysis. The headache diagnosis was CM in 49% (78/159), status migrainosus in 44% (70/159), and Other headache with migrainous features in 7% (11/159). At discharge, 60% (96/159) of patients achieved headache freedom, and no statistically significant difference was found in relative change in headache among the CM, status migrainosus, and Other headache groups. Patients who completed the full 8 or 9 dose IV DHE protocol were more likely to have persistent headache at discharge, with a median pain score of 1.0 (IQR 0.0-4.0) compared to a score of 0.0 (IQR 0.0-1.0) in the DHE incomplete group (P < .001). No difference was found in pain relief outcomes at follow-up in the DHE protocol complete and DHE protocol incomplete groups. CONCLUSIONS: Although limited by the absence of a control group, our data support repetitive IV DHE as an abortive therapy for pediatric patients with status migrainosus or CM, with no evidence of differential efficacy in these groups. A higher rate of headache at discharge in the DHE protocol complete group reflects in large part the common decision to discontinue treatment once headache freedom was achieved, resulting in nonresponders being more likely to complete the full course of DHE. In our cohort, there was no difference in pain relief at follow-up between patients who completed the full 8 or 9 doses of DHE and those that did not. Discontinuing DHE once the patient has achieved headache freedom would therefore achieve the therapeutic goal while shortening the hospital stay. To potentially impact longer term pain relief, incorporation of a comprehensive treatment approach into the IV DHE admission is of interest for future study and quality improvement initiatives.

Prominent role of forebrain excitatory neurons in SCN8A encephalopathy.

De novo mutations of the sodium channel gene SCN8A result in an epileptic encephalopathy with refractory seizures, developmental delay, and elevated risk of sudden death. p.Arg1872Trp is a recurrent de novo SCN8A mutation reported in 14 unrelated individuals with epileptic encephalopathy that included seizure onset in the prenatal or infantile period and severe verbal and ambulatory comorbidities. The major biophysical effect of the mutation was previously shown to be impaired channel inactivation accompanied by increased current density. We have generated a conditional mouse mutation in which expression of this severe gain-of-function mutation is dependent upon Cre recombinase. Global activation of p.Arg1872Trp by EIIa-Cre resulted in convulsive seizures and lethality at 2 weeks of age. Neural activation of the p.Arg1872Trp mutation by Nestin-Cre also resulted in early onset seizures and death. Restriction of p.Arg1872Trp expression to excitatory neurons using Emx1-Cre recapitulated seizures and juvenile lethality between 1 and 2 months of age. In contrast, activation of p.Arg1872Trp in inhibitory neurons by Gad2-Cre or Dlx5/6-Cre did not induce seizures or overt neurological dysfunction. The sodium channel modulator GS967/Prax330 prolonged survival of mice with global expression of R1872W and also modulated the activity of the mutant channel in transfected cells. Activation of the p.Arg1872Trp mutation in adult mice was sufficient to generate seizures and death, indicating that successful therapy will require lifelong treatment. These findings provide insight into the pathogenic mechanism of this gain-of-function mutation of SCN8A and identify excitatory neurons as critical targets for therapeutic intervention.

Is the Neurological Disorders Depression Inventory-Epilepsy for Youth (NDDI-E-Y) more sensitive than a neurologist? A quality improvement project.

PURPOSE: Depression is one of the most prevalent psychiatric comorbidities in epilepsy. This quality improvement project compared a standardized rating scale, the Neurological Disorders Depression Inventory-Epilepsy for Youth (NDDI-E-Y), with physician opinion to see if it improved sensitivity to depressive symptoms. RESULTS: A convenience sample of thirty adolescents with epilepsy ages 12-17 (mean [M] = 15.02, standard deviation [SD] = 1.81; 53% female) participated in the screening. Thirteen percent of the sample scored in the Elevated range on the NDDI-E-Y (exceeded cutoff). Seven percent of the sample were rated by the physician as definitely showing signs of depression. There were two false negatives when the NDDI-E-Y score exceeded the established cutoff, but physician rating was negative for depressive symptoms. CONCLUSION: This pilot project shows that the NDDI-E-Y is a convenient clinical tool with the potential to improve sensitivity in the detection of depressive symptoms in adolescents with epilepsy.

Status epilepticus: Role for etiology in determining response to benzodiazepines.

OBJECTIVE: Clinical factors contributing to benzodiazepine failure in treating status epilepticus (SE) include suboptimal dosing and seizure duration. As many benzodiazepine-refractory episodes of SE arise from acute etiologies, we sought to determine whether etiology impacts SE treatment. METHODS: The potency of diazepam to terminate SE induced by lithium-pilocarpine (LiPilo-SE) or kainic acid (KA-SE) in 3-week-old rats was studied by video-electroencephalography. Synaptic γ-aminobutyric acid type A receptor (GABAR)-mediated currents were recorded from dentate granule cells using voltage-clamp electrophysiology. Surface expression of γ2 subunit-containing GABARs and Kv4.2 potassium channels in hippocampal slices was determined using a biotinylation assay. Expression of phosphorylated forms of ß2/3 and γ2 subunits was determined using phosphospecific antibodies and Western blotting. RESULTS: Diazepam failed to terminate late SE in LiPilo-SE animals but was successful in terminating KA-SE of 1- and 3-hour duration. One hour after SE onset, GABAR-mediated synaptic inhibition and γ2 subunit-containing GABAR surface expression were reduced in LiPilo-SE animals. These were unchanged in KA-SE animals at 1 and 3 hours. Phosphorylation of γ2 subunit residue S327 was unchanged in both models, although GABAR ß3 subunit S408/409 residues were dephosphorylated in the LiPilo-SE animals. Kv4.2 potassium channel surface expression was increased in LiPilo-SE animals but reduced in KA-SE animals. INTERPRETATION: SE-model-dependent differences support a novel hypothesis that the development of benzodiazepine pharmacoresistance may be etiologically predetermined. Further studies are required to investigate the mechanisms that underlie such etiological differences during SE and whether etiology-dependent protocols for the treatment of SE need to be developed. Ann Neurol 2018;83:830-841.

Disruption of Rapid Eye Movement Sleep Homeostasis in Adolescent Rats after Neonatal Anesthesia.

BACKGROUND: Previous studies suggest that rapid eye movement sleep rebound and disruption of rapid eye movement sleep architecture occur during the first 24 h after general anesthesia with volatile anesthetics in adult rats. However, it is unknown whether rapid eye movement sleep alterations persist beyond the anesthetic recovery phase in neonatal rats. This study tested the hypothesis that rapid eye movement sleep disturbances would be present in adolescent rats treated with anesthesia on postnatal day 7. METHODS: Forty-four neonatal rats were randomly allocated to treatment with anesthesia consisting of midazolam, nitrous oxide, and isoflurane or control conditions for 2 h or 6 h. Electroencephalographic and electromyographic electrodes were implanted and recordings obtained between postnatal days 26 and 34. The primary outcome was time spent in rapid eye movement sleep. Data were analyzed using two-tailed unpaired t tests and two-way repeated measures analysis of variance. RESULTS: Rats treated with midazolam, nitrous oxide, and isoflurane exhibited a significant increase in rapid eye movement sleep three weeks later when compared with control rats, regardless of whether they were treated for 2 h (174.0 ± 7.2 min in anesthetized, 108.6 ± 5.3 in controls, P < 0.0001) or 6 h (151.6 ± 9.9 min in anesthetized, 108.8 ± 7.1 in controls, P = 0.002). CONCLUSIONS: Treatment with midazolam, nitrous oxide, and isoflurane on postnatal day 7 increases rapid eye movement sleep three weeks later in rats.

Stiripentol: A Novel Antiseizure Medication for the Management of Dravet Syndrome.

Objective: To describe the pharmacology, efficacy, and safety of stiripentol in the treatment of refractory seizures in patients with Dravet syndrome. Data Sources: A search of the English language literature was conducted using PubMed and MEDLINE (1978 to April 2019) with the search terms stiripentol, Dravet syndrome, and refractory epilepsy. Other resources included article bibliographies, prescribing information, and relevant trials at https://clinicaltrials.gov/ . Study Selection and Data Extraction: All phase 1, 2, or 3 trials; observational studies; and retrospective studies were analyzed. Data Synthesis: In controlled studies, stiripentol has been shown to reduce seizure frequency by 50% or more in 40% to 70% of patients with Dravet syndrome. Reductions in seizure duration and episodes of status epilepticus have also been documented. Common adverse effects include somnolence and anorexia. Stiripentol inhibits the metabolism of clobazam and valproate, often requiring dose adjustment. Relevance to Patient Care and Clinical Practice: Stiripentol, a direct allosteric modulator of GABAA receptors, offers a novel approach to treatment in patients with Dravet syndrome, both with and without pathogenic variants of the sodium channel α-1 subunit gene, and potentially other refractory seizures. Although available outside the United States for a decade, it was only recently approved by the Food and Drug Administration for patients 2 years of age and older with Dravet syndrome taking clobazam. Conclusions: Stiripentol is an effective adjunctive therapy for reducing the frequency and duration of refractory seizures in patients with Dravet syndrome. Its role in the treatment of other refractory epilepsies requires further study.

Parental perspectives on provider adherence to AAN epilepsy quality measures in rural and urban tertiary care centers.

Several American Academy of Neurology (AAN) epilepsy practice guidelines recommend conversations that neurologists should have with patients and their parents. We sought to determine whether parents of pediatric patients with epilepsy had knowledge of epilepsy quality measures (EQMs) and whether they recalled having discussions with their child's neurologist about each of the EQM. Surveys were distributed to parents at five clinic sites associated with epilepsy centers in Washington, DC and Charlottesville, Virginia. Key questions on the parent survey included whether neurologists had discussed, or parents had knowledge of, EQM topics which included medication side effects, safety, reproductive health, transition to adult care, learning and attention problems, bone health, sudden unexpected death in epilepsy (SUDEP), and risk of epilepsy-related death. No data were collected from the neurologist or the medical record about EQM discussions. Among 233 completed surveys, parental knowledge and neurologist discussion of EQM were highly correlated (p < .00001). Epilepsy quality measures most discussed with high parental knowledge were medication side effects, safety, learning and attention problems, and bone health. Sudden unexpected death in epilepsy was least discussed and known. We found consistent care practices in adherence to EQM across settings from urban to rural communities, with patients of all ages and epilepsy severities and staffed by neurologists with various levels of epilepsy expertise. Despite reported high rates of adherence on several measures, we identified opportunities for improvement. Querying and counseling about EQM should be an ongoing conversation which evolves with the child's age and epilepsy-associated risks.

Sudden Death in Epilepsy: Knowledge among Pediatric Providers.

A survey of 146 pediatric care providers (PCPs) revealed that 75.3% were unaware that children with epilepsy were at risk of death, specifically from sudden unexpected (or unexplained) death in epilepsy (SUDEP). PCPs assume that the treating neurologist discusses these risks. Increasing PCPs' knowledge of SUDEP will help address the care gap related to informing families about SUDEP.

Methodological standards for in vitro models of epilepsy and epileptic seizures. A TASK1-WG4 report of the AES/ILAE Translational Task Force of the ILAE.

In vitro preparations are a powerful tool to explore the mechanisms and processes underlying epileptogenesis and ictogenesis. In this review, we critically review the numerous in vitro methodologies utilized in epilepsy research. We provide support for the inclusion of detailed descriptions of techniques, including often ignored parameters with unpredictable yet significant effects on study reproducibility and outcomes. In addition, we explore how recent developments in brain slice preparation relate to their use as models of epileptic activity.