Effectiveness, safety and tolerability of perampanel by age group when used to treat people with focal and generalized epilepsy in clinical practice: The PERMIT Extension study.

OBJECTIVE: To assess the effectiveness and safety/tolerability of perampanel (PER) in people with epilepsy (PWE) treated in everyday clinical practice for focal and generalized seizures, both in the total cohort and by age group. METHODS: The PERMIT Extension study was a pooled analysis of data from PWE included in two large previous clinical practice studies (PERMIT and PROVE). Retention was assessed over 12 months. Effectiveness was assessed based on total seizures and by seizure type (focal and generalized) after 3, 6, and 12 months of PER treatment and at final follow-up (last observation carried forward; "last visit"); assessments included responder rate (≥50% seizure frequency reduction from baseline) and seizure freedom rate (no seizures since at least the previous visit). Safety/tolerability was assessed throughout PER treatment by evaluating adverse events (AEs). All assessments were conducted for the total population and by age category (<12, ≥12 to <18, ≥18 to <65, and ≥65 years at baseline). RESULTS: Full Analysis Set included 6,822 PWE (51.1% female; mean age, 36.9 years; mean duration of epilepsy 21.4 years) with 6,433, 4,648, and 6,233 PWE assessed for retention, effectiveness, and safety/tolerability, respectively. The majority of PWE (81.1%) were aged 18-64 at baseline, with 4.5% aged <12 years, 8.4% aged 12-17 years, and 5.9% aged ≥65 years. In the overall population, retention rates at 3, 6, and 12 months were 88.0%, 77.6%, and 61.4%, respectively; responder rates at 12 months were 58.5% for total seizures, 54.6% for focal seizures, and 77.7% for generalized seizures, and corresponding seizure freedom rates were 23.6%, 19.0%, and 51.3%, respectively. PER was effective regardless of age category, although effectiveness was greatest in PWE aged ≥65 years, for both focal and generalized seizures. In the overall population, the incidence of AEs was 49.2% and the most frequent AEs (≥5% of PWE) were dizziness/vertigo (13.4%), somnolence (8.8%), irritability (7.3%), and behavioral disorders (5.3%); AEs led to treatment discontinuation in 18.3% of PWE over 12 months. The incidence of AEs and the discontinuation rate due to AEs increased with increasing age (55.0% and 23.9%, respectively, in PWE aged ≥65 years). CONCLUSION: In this study, the largest pooled analysis of PER clinical practice data conducted to date, PER was shown to be effective and generally well tolerated when used to treat people with focal or generalized epilepsy in everyday clinical practice, regardless of age category. No new or unexpected side effects emerged following long-term use in the real-world setting.

Infantile Spasms and Trisomy 21: Unfavorable Outcomes with First-line Vigabatrin Therapy.

INTRODUCTION: Among children with infantile spasms (ISs), those with trisomy 21 (T21) and those with normal development at onset and no identifiable etiology (previously referred to as "idiopathic") are expected to have relatively favorable outcomes. The study objective is to determine if differences exist in treatment response, relapse, and subsequent epilepsy between these two groups when vigabatrin is used as first-line treatment. METHODS: In this retrospective study, patients were classified into the following groups and clinical features were compared: T21 (n = 24) and IS with normal development at onset and no identified etiology (n = 40; control group). RESULTS: There was no significant difference in the age of IS onset, sex distribution, or treatment lag between the groups. The T21 compared to the control group required a higher mean number of anti-seizure therapies (3.6 vs. 1.9, p < 0.001), had more relapses [10 (42%) vs. 4 (10%), p < 0.005)], and had higher risk of subsequent epilepsy [11 (46%) vs. 8 (20%), p < 0.003]. Relapses were often delayed in the T21 group, with a mean of 8 months after IS cessation. CONCLUSION: Our results differ from most studies using steroids as first-line treatment where the groups were shown to have similar treatment response and T21 patients had a low risk of relapse and subsequent epilepsy. Therefore, our results suggest that vigabatrin as first-line treatment in T21 with IS may be less favorable than steroids.

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy.

KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current. Exome sequencing identified de novo heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment-resistant epilepsy (in two of four). Comprehensive analysis of this potassium channel for the four variants expressed in frog oocytes revealed shifts in the voltage dependence of activation, including altered activation and deactivation kinetics. Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology.

Co-existence of Rolandic and 3 Hz Spike-Wave Discharges on EEG in Children with Epilepsy.

OBJECTIVE: Benign epilepsy of childhood with central temporal spikes (BECTS) and absence epilepsy are common epilepsy syndromes in children with similar age of onset and favorable prognosis. However, the co-existence of the electrocardiogram (EEG) findings of rolandic spike and 3 Hz generalized spike-wave (GSW) discharges is extremely rare, with few cases reported in the literature. Our objective was to characterize the EEG findings of these syndromes in children in our center and review the electro-clinical features. METHODS: All EEGs at BC Children's Hospital are entered in a database, which include EEG findings and clinical data. Patients with both centro-temporal spikes and 3 Hz GSW discharges were identified from the database and clinical data were reviewed. RESULTS: Among the 43,061 patients in the database from 1992 to 2017, 1426 with isolated rolandic discharges and 528 patients with isolated 3 Hz GSW discharges were identified, and 20 (0.05%) patients had both findings: 3/20 had BECTS, and subsequently developed childhood absence epilepsy and 17/20 had no seizures characteristic for BECTS. At follow-up, 17 (85%) were seizure-free, 1 (5%) had rare, and 2 (10%) had frequent seizures. CONCLUSIONS: This is the largest reported group of patients to our knowledge with the co-existence of rolandic and 3 Hz GSW discharges on EEGs in one institution, not drug-induced. As the presence of both findings is extremely rare, distinct pathophysiological mechanisms are likely. The majority had excellent seizure control at follow-up, similar to what would be expected for each type of epilepsy alone.

OBJECTIF: L'épilepsie bénigne de l'enfance à pointes centro-temporales (ou épilepsie rolandique bénigne [ERB]) et l'absence épileptique sont des syndromes épileptiques communs chez des enfants dont le pronostic est favorable et dont l'apparition des premiers symptômes s'est produite à un âge similaire. Cependant, la coexistence, lors d'EEG, de résultats montrant des décharges rolandiques et des décharges à pointes-ondes continues de 3 Hz demeure extrêmement rare, peu de cas ayant été signalés dans la littérature scientifique. Notre objectif a donc consisté à décrire les résultats d'EEG liés à ces syndromes dans le cas d'enfants fréquentant notre établissement et à examiner leurs caractéristiques électro-cliniques. MÉTHODES: En plus de certaines données cliniques, tous les résultats d'EEG réalisés au BC Children's Hospital sont saisis dans une base de données. Tant les jeunes patients donnant à voir des décharges à pointes centro-temporales que ceux atteints de décharges à pointes-ondes continues de 3 Hz ont été identifiés à partir de cette base de données. Leurs données cliniques ont été ensuite passées en revue. RÉSULTATS: Sur un total de 43 061 jeunes patients présents dans la base de données de 1992 à 2017, nous en avons identifié 1426 avec des décharges rolandiques isolées et 528 avec des décharges isolées à pointes-ondes de 3 Hz. À noter que seulement vingt d'entre eux, soit 0,05 %, étaient concernés par ces deux types de décharge. À cet égard, 3 sur 20 étaient atteints d'ERB et ont développé ultérieurement un syndrome d'absence épileptique; chez les 17 autres, aucune convulsion caractéristique de l'ERB n'a été observée. Lors d'un suivi, 17 (85 %) d'entre eux n'avaient plus de crises convulsives tandis que 1 (5 %) avait exceptionnellement des crises et 2 (10 %), des crises fréquentes. CONCLUSIONS: À notre connaissance, il s'agit là du plus vaste groupe déclaré de patients donnant à voir, lors d'EGG menés au sein d'un seul établissement, une coexistence entre des décharges rolandiques et des décharges à pointes-ondes de 3 Hz, et ce, sans qu'elles n'aient été causées par des médicaments. Considérant que la présence de ces deux phénomènes est particulièrement inhabituelle, le rôle de divers mécanismes pathophysiologiques est fort probable. Fait à souligner, la majorité de ces patients ont pu montrer, au moment de leur suivi, une excellente maîtrise de leurs crises convulsives, maîtrise semblable à celle à laquelle on pourrait s'attendre pour chaque type d'épilepsie pris individuellement.

Lack of response to quinidine in KCNT1-related neonatal epilepsy.

OBJECTIVE: To evaluate the clinical efficacy and safety of quinidine in patients with KCNT1-related epilepsy of infancy with migrating focal seizures (EIMFS) in the infantile period and to compare with the effect of quinidine on mutant channels in vitro. METHODS: We identified 4 patients with EIMFS with onset in the neonatal period, pathogenic variants in the KCNT1 gene, and lack of response to AEDs. Patients were prospectively enrolled, treated with quinidine, and monitored according to a predefined protocol. Electroclinical, neuroimaging, and genetic data were reviewed. Two patients had novel variants in the KCNT1 gene that were modeled in Xenopus oocytes with channel properties characterized using electrophysiology recordings. RESULTS: Three of four patients were treated with quinidine early in their disease course, prior to 6 months of age. No significant side effects were noted with quinidine therapy. In addition, there were no significant changes in electroencephalography (EEG)-confirmed seizure burden during therapy, and patients had near hourly seizures before, during, and after treatment. Two patients had previously reported gain-of-function mutations, which demonstrated sensitivity to high levels of quinidine in the oocyte assay. Two patients with novel variants, showed characteristic gain-of-function and were thus predicted to be pathogenic. Of interest, these variants were essentially insensitive to high levels of quinidine. SIGNIFICANCE: Patients had no reported benefit to quinidine therapy despite age at treatment initiation. Pharmacogenetic results in oocytes were consistent with clinical treatment failure in 2 patients, suggesting that single-dose pharmacologic assessment may be helpful in predicting which patients are exceedingly unlikely to achieve benefit with quinidine. In the 2 patients who had a lack of therapeutic benefit despite sensitivity to high concentrations of quinidine with in vitro oocyte assay, it is likely that the achievable exposure levels in the brain were too low to cause significant in vivo channel blockade.

Manifestations of Tuberous Sclerosis Complex: The Experience of a Provincial Clinic.

BACKGROUND: Tuberous sclerosis complex (TSC) is a neurocutaneous disorder with a wide spectrum of manifestations. Recent consensus recommendations stress the importance of multidisciplinary management of children with TSC. The objective of this study was to examine the manifestations of TSC at a large referral centre to determine the care needs of this population. METHODS: A retrospective, systematic chart review was performed of children with TSC managed at British Columbia Children's Hospital. Patients were identified through epilepsy and clinical neurophysiology databases. RESULTS: The study population comprised 81 patients, born between 1987 and 2014, who were a median of 10 years (range, 0.2-23.2) at most recent follow-up. Epilepsy occurred in 91% of patients, including 32% with a history of infantile spasms. Nineteen patients underwent epilepsy surgery, nine (47%) of whom were seizure-free at most recent follow-up. Overall, 61% of epilepsy patients had been seizure-free for at least 1 year at the time of last follow-up. Neuropsychiatric disorders were diagnosed in 49% of children, with autism (25%), attention deficit hyperactivity order (19%) and anxiety (16%) being the most common. Cardiac rhabdomyomata occurred in 35% of children and renal angiomyolipomas were seen in 43%. A total of 91% had skin manifestations. CONCLUSION: This study outlines the multisystem manifestations of TSC, observed through a large pediatric referral center. Epilepsy and neuropsychiatric disorders are the major source of morbidity in this age group and provide many challenges to the treating clinician. Because a subset of the study population is still quite young, the prevalence of neuropsychiatric disorders is likely underestimated.

Original Research: Clinical Significance of a Unique Pediatric EEG Configuration: Bi-Frontal Spikes With Simultaneous Bi-Occipital Positivity.

Introduction: Frontal-predominant epileptiform discharges (EDs) include generalized spike-wave (GSW) and frontal spikes (FS). However, negative bi-frontal ED with simultaneous occipital positivity (BFOD) are rare, leading to questions regarding physiological generators. Methods: To determine the clinical significance of BFOD, electroclinical features of children with BFOD (n = 40) were compared to control patients with GSW (n = 102) and FS (n = 100). Results: Results are presented in the following order: BFOD, GSW, and FS. Epilepsy was prevalent among the groups: 95.0%, 90.2%, and 77.0%, respectively. The median age of seizure-onset did not significantly differ between groups: 3.00, 4.00, and 2.25 years, respectively. Regarding EEG background features, the BFOD group had more disorganized sleep architecture than other groups, P < .005. There was a significant difference in the proportion of developmental delay (DD) between the groups (P < .005). BFOD had much higher odds of DD compared to GSW and FS groups: odds ratio (OR) (confidence interval [CI]) 19.44 [5.64, 64.05] and 3.98 [1.16, 13.34]. Furthermore, BFOD had much higher odds of severe DD compared to GSW and FS groups: 9.60 [2.75, 33.45] and 2.73 [1.03, 7.27]. A Gross Motor Function Classification System (GMFCS) score of ≥ 4 was more prevalent in BFOD (22.5%), than GSW (0%) and FS groups (9%). On neuroimaging, BFOD had more structural (P < .005) and multilobar structural (P < .05) abnormalities than control groups. Conclusion: Children with BFOD had particularly severe significant DD, considerable motor deficit (GMFCS ≥ 4), and brain structural abnormalities, often multilobar. This suggests BFOD is a marker of severe underlying brain dysfunction and not benign when encountered on routine EEG review.

Developmental and epileptic encephalopathies after successful treatment of pediatric ALL: A case series and review of literature.

Successful treatment of acute lymphoblastic leukemia (ALL) requires multiagent chemotherapy regimens and central nervous system prophylaxis, including intrathecal methotrexate. Although acute symptomatic seizures can occur during ALL treatment, epilepsy is less common. Furthermore, drug resistant epilepsy (DRE) is rare, presenting with two phenotypes: focal epilepsy, such as temporal lobe, or epileptic encephalopathies (EE), such as Lennox-Gastaut syndrome (LGS). For ALL survivors, the development of DRE has significant impact on morbidity, mortality, and quality of life. We describe four patients with ALL remission, who developed EEs, of which 3 had LGS. Mean age at ALL diagnosis was 1.9 years; range 1.1-2.5 years. All, but one, had normal development prior to ALL. No patient had CNS leukemic involvement. All patients received CNS prophylaxis with intrathecal methotrexate, without cranial radiotherapy. Three had symptomatic methotrexate neurotoxicity during treatment. The mean age at first seizure was 5.6 years; range 3.9-7.5 years, with a mean latency of 3.7 years from ALL diagnosis. All patients developed drug resistant EEs, moderate intellectual disability, and neuropsychiatric co-morbidities. Two patients had a minimal response to corpus callosotomy (CC), and one did not respond the ketogenic diet. Successful treatment of childhood ALL is rarely associated with the development of DRE and EEs. Young age at ALL diagnosis (<3 years) may be a predisposing factor. Palliative treatments, including ketogenic diet and CC have limited benefit in these patients. Individual genetic susceptibility to MTX toxicity is likely related to epileptogenesis, and further research is required for epilepsy biomarkers.

The Initial Experience of Eslicarbazepine in Children at Three Canadian Tertiary Pediatric Care Centers.

INTRODUCTION: Eslicarbazepine (ESL) is a once-daily, third-generation antiseizure medication for focal-onset seizures. The primary mechanism of action is enhancing the slow inactivation of voltage-gated sodium channels. The study objective was to review real-world experience regarding retention rate, efficacy, and tolerability of eslicarbazepine, soon after it became available for children in Canada. METHODS: A retrospective review was performed on all patients prescribed eslicarbazepine from September 2017 to June 2020, with at least 3 years of follow-up data, at 3 Canadian tertiary care pediatric centers. RESULTS: Fifty patients were identified, and the mean age of eslicarbazepine initiation was 12.4 years (range 3-19 years). Most patients had drug-resistant epilepsy, trying a mean of 5.04 (range 0-14) antiseizure medications before the initiation of eslicarbazepine. Twenty-four patients (48.0%) experienced adverse effects, including dizziness (n = 10), drowsiness (n = 6), dizziness and drowsiness (n = 1), nausea and abdominal pain (n = 4), transient unsteadiness and diplopia (n = 1), and negative mood changes (n = 2). None had serious adverse effects, including rash. The retention rate of eslicarbazepine at last follow-up was 70%. Fifteen (30%) had ≥50% seizure reduction, with 2 of these patients becoming seizure free. Ten (20%) had 25% to 50% reduction, 2 (4%) had worsening of seizures, and 17 (34%) had no change in seizure frequency. CONCLUSION: The study results support the long-term effectiveness and tolerability of eslicarbazepine in a cohort of children with predominantly drug-resistant epilepsy in a real-life setting from 3 Canadian centers with initial use after approval. Adverse effects were nonserious, infrequently leading to eslicarbazepine discontinuation.

A Comparison of CT Perfusion Output of RapidAI and Viz.ai Software in the Evaluation of Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Automated CTP postprocessing packages have been developed for managing acute ischemic stroke. These packages use image processing techniques to identify the ischemic core and penumbra. This study aimed to investigate the agreement of decision-making rules and output derived from RapidAI and Viz.ai software packages in early and late time windows and to identify predictors of inadequate quality CTP studies. MATERIALS AND METHODS: One hundred twenty-nine patients with acute ischemic stroke who had CTP performed on presentation were analyzed by RapidAI and Viz.ai. Volumetric outputs were compared between packages by performing Spearman rank-order correlation and Wilcoxon signed-rank tests with subanalysis performed at early (<6 hours) and extended (>6 hours) time windows. The concordance of selecting patients on the basis of DAWN and DEFUSE 3 eligibility criteria was assessed using the McNemar test. RESULTS: One hundred eight of 129 patients were found to have adequate-quality studies. Spearman rank-order correlation coefficients were calculated on time-to-maximum >6-second volume, time-to-maximum >10-second volume, CBF <30% volume, mismatch volume, and mismatch ratio between both software packages with correlation coefficients of 0.82, 0.65, 0.77, 0.78, 0.59, respectively. The Wilcoxon signed-rank test was also performed on time-to-maximum >6-second volume, time-to-maximum >10-second volume, CBF <30% volume, mismatch volume, and mismatch ratio with P values of .30, .016, <.001, .03, <.001, respectively. In a 1-sided test, CBF <30% was greater in Viz.ai (P < .001). Although this finding resulted in statistically significant differences, it did not cause clinically significant differences when applied to the DAWN and DEFUSE 3 criteria. A lower ejection fraction predicted an inadequate study in both software packages (P = .018; 95% CI, 0.01-0.113) and (P = .024; 95% CI, 0.008-0.109) for RapidAI and Viz.ai, respectively. CONCLUSIONS: Penumbra and infarct core predictions between Rapid and Viz.ai correlated but were statistically different and resulted in equivalent triage using DAWN and DEFUSE3 criteria. Viz.ai predicted higher ischemic core volumes than RapidAI. Viz.ai predicted lower combined core and penumbra values than RapidAI at lower volumes and higher estimates than RapidAI at higher volumes. Clinicians should be cautious when using different software packages for clinical decision-making.

The impact of anti-seizure medications on psychiatric disorders among children with epilepsy: Both a challenge and an opportunity?

Psychiatric disorders are common co-existing conditions in children with epilepsy and can precede or follow epilepsy onset. Therefore, when selecting anti-seizure medications (ASMs) for children with epilepsy, in addition to seizure control, careful consideration of behavioral and psychotropic effects (BPEs) is critical, as they can have a negative impact on ASM adherence and quality of life. The goal in supporting children with epilepsy is an individualized approach to maximize seizure control and minimize negative BPEs. A previous history of a psychiatric disorder is the most significant risk factor for negative BPEs. Therefore, systematic screening for psychiatric symptoms can guide ASM selection and prompt intervention as needed. Besides familiarity with different ASM profiles, awareness of risk factors for negative BPEs including rapid dose titrations and weaning schedules, polypharmacy, high ASM doses, and drug interactions are important. In children with co-existing psychiatric disorders, ASMs with mood stabilizing, behavior regulating or anxiolytic properties may be preferred choices. Overall, a comprehensive and coordinated approach, with family psychoeducation and a mutual understanding of clinical aspects between the disciplines of neurology and psychiatry will enable better outcomes in children with epilepsy. Further pediatric "real-world" studies will expand knowledge of BPEs and potential risk factors. For some children, timely epilepsy surgery or precision therapies targeting a pathological defect may reduce the ASM burden in a child's life and subsequent BPEs. The ability to predict an individual child's susceptibility to negative BPEs with valid biomarkers may become available in the near future with advances in pharmacogenomics and technology.

Les troubles psychiatriques sont des états commun coexistants chez les enfants souffrant d'épilepsie et ils peuvent précéder ou suivre le début de l'épilepsie. Par conséquent, lorsqu'on choisit des médicaments anticonvulsivants (MAC) pour des enfants souffrant d'épilepsie, outre le contrôle des convulsions, il faut prendre sérieusement en considération les effets comportementaux et psychotropes (ECP) car ils peuvent avoir un effet négatif sur l'adhésion aux MAC et à la qualité de vie. Soutenir les enfants souffrant d'épilepsie a pour but une approche individualisée afin de maximiser le contrôle des convulsions et de minimiser les ECP négatifs. Des antécédents d'un trouble psychiatrique constituent le facteur de risque le plus significatif des ECP négatifs. Donc le dépistage systématique des symptômes psychiatriques peut guider la sélection des MAC et provoquer une intervention au besoin. Autre que la familiarité avec différents profils de MAC, la connaissance de facteurs de risque d'ECP négatifs englobe les titrages de dose rapides, et les calendriers de sevrage, la polypharmacie, les doses élevées de MAC, et les interactions des médicaments, tous importants. Chez les enfants souffrant de troubles psychiatriques coexistants, les MAC qui stabilisent l'humeur, régulent le comportement ou ont des propriétés anxiolytiques peuvent être préférés. Généralement, une approche détaillée et coordonnée avec la psychoéducation familiale et une compréhension mutuelle des aspects cliniques entre les disciplines de la neurologie et de la psychiatrie permettront de meilleurs résultats chez les enfants souffrant d'épilepsie. D'autres études psychiatriques « en situation réelle ¼ accroîtront les connaissances des ECP et les facteurs de risque potentiels. Chez certains enfants, une chirurgie de l'épilepsie en temps opportun ou des thérapies de précision ciblant un défaut pathologique peuvent réduire le fardeau des MAC dans la vie de l'enfant et les ECP subséquents. La capacité de prédire la susceptibilité individuelle d'un enfant aux ECP négatifs par des biomarqueurs valides peut être disponible dans un avenir rapproché grâce aux progrès de la pharmacogénomique et de la technologie.

Outcome of Absence Epilepsy With Onset at 8-11 Years of Age: Watershed Ages When Syndromes Overlap.

Introduction: Absence seizures occur in various epilepsy syndromes, including childhood and juvenile absence epilepsy and juvenile myoclonic epilepsy. When children present with absence seizures at ages when syndromes overlap, initial syndrome designation is not always possible, making early prognostication challenging. For these children, the study objective is to determine clinical and initial electroencephalograph (EEG) findings to predict the development of generalized tonic-clonic seizures, which is a factor that affects outcome. Methods: Children with new-onset absence seizures between 8 and 11 years of age with at least 5 years of follow-up data were studied through the review of medical records and initial EEG tracings. Results: Ninety-eight patients were included in the study. The median age of absence seizure onset was 9 years (interquartile range [IQR] = 8.00, 10.00) and follow-up was 15 years (IQR = 13.00, 18.00). Forty-six percent developed generalized tonic-clonic seizures and 20% developed myoclonic seizures. On multiple regression analysis, a history of myoclonic seizures, anxiety, as well as bifrontal slowing and mild background slowing on initial EEG (P < .05) were associated with generalized tonic-clonic seizures. Although not statistically significant, a shorter duration of shortest EEG burst on baseline EEG was also associated with generalized tonic-clonic seizures. Conclusion: On initial EEG, bifrontal and background slowing and myoclonic seizures and anxiety are associated with developing generalized tonic-clonic seizures, which is of prognostic significance when early syndrome designation is difficult.

Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5.

BACKGROUND AND OBJECTIVES: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. METHODS: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details. RESULTS: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. DISCUSSION: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.

School performance in children at the time of new-onset seizures and at long-term follow-up: A retrospective cohort study.

OBJECTIVE: School-performance difficulties (SPD) are common in children with epilepsy. The objectives of this study were to determine if the rate of SPD in children with seizures change from seizure-onset to follow-up and differ from children with psychiatric disorders. METHODS: School-aged children who required an initial electroencephalography (EEG) test in 2016 were reviewed and separated into two groups based on the presence or absence of seizures. Developmental delay and SPD were compared between groups at initial assessment and SPD was assessed after 2-4 years of follow-up. Analysis was also performed on a sub-set of patients with psychiatric disorders. RESULTS: At baseline, the rate of SPD was similar between the seizure (n = 146) and non-seizure (n = 332) groups [26% vs. 27%]. At follow-up, the seizure (n = 119) group had a significantly higher rate of SPD than the non-seizure (n = 215) group (54% vs. 43%). There was no difference in the rate of SPD between the seizure (n = 119) and psychiatric (n = 69) groups at baseline (31% vs. 43%) or follow-up (54% vs. 55%). CONCLUSION: Over time, children with recurrent seizures experience more SPD than children without seizures, but similar SPD to children with psychiatric disorders.

Resilience of adolescents and teenagers with self-limited and genetic-generalized epilepsy during the COVID-19 pandemic.

INTRODUCTION: The study-objective was to determine the emotional impact of the COVID-19 pandemic on children with self-limited and genetic-generalized epilepsy. METHODS: Patients completed the Children's Depression Inventory-2 (CDI-2) and Multidimensional Anxiety Scale for Children 2nd Edition (MASC-2) questionnaires before and during the pandemic. Via tele-visits, a pandemic-lifestyle survey and Obsession with COVID-19 Scale (OCS) was administered. RESULTS: Fifty subjects with a mean (SD) age of 14.44 (2.97) years and 4.85 (2.97) years of epilepsy were included. Overall, mood (62%), anxiety (61%), sleep (68%) and seizure frequency (88%) were unchanged/improved during the pandemic. There was no significant difference in pre-COVID-19 and during COVID-19 CDI-2 and MASC-2 total T-scores. In 24% with a worsening CDI-2 total T-score, associations included higher total OCS score (p = 0.001), poor sleep (p = 0.013) and pre-existing psychiatric history (p = 0.0450). In 28% with a worsening MASC-2 total T-score, associations included less exercise during the pandemic (p = 0.028) and lower maternal education history (p = 0.022). On OCS, 6% were in the dysfunctional range. CONCLUSIONS: This cohort demonstrated emotional resilience during the COVID-19 pandemic. However, screening is important, as a subgroup experienced disruptive changes, possibly related to modifiable factors, such as sleep and exercise. LAY SUMMARY: To determine the impact of the COVID-19 pandemic on children with epilepsy (CWE), 50 CWE completed a pandemic-lifestyle survey. Questionnaires for anxiety and depression completed before and during the COVID-19 pandemic were also compared. Overall, there was no worsening of seizures, anxiety, or depression during the pandemic. During the pandemic, 24% had more depressive symptoms (associations: poor sleep and psychiatric history) and 28% had more anxiety (associations: less exercise and lower maternal education).This cohort showed emotional resilience during the COVID-19 pandemic. Regular screening is important, as some CWE experienced disruptive changes, related to modifiable-factors, such as sleep and exercise.

Socioeconomic and Comorbid Factors Affecting Mortality and Length of Stay in COVID-19 Patients.

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic exposed and exacerbated health disparities between socioeconomic groups. Our purpose was to determine if age, sex, race, insurance, and comorbidities predicted patients' length of stay (LOS) in the hospital and in-hospital mortality in patients diagnosed with coronavirus disease 2019 (COVID-19) during the early pandemic. Methods Utilizing retrospective, secondarily sourced electronic health record (EHR) data for patients who tested positive for COVID-19 from HCA Healthcare facilities, predictors of LOS and in-hospital mortality were assessed using regression. LOS and in-hospital mortality were assessed using logistic regression and negative binomial regression, respectively. All models included age, insurance status, and sex, while additional covariates were selected using the least absolute shrinkage and selection operator (LASSO) regression. LOS data were presented as incidence rate ratios (IRR), and in-hospital mortality was presented as odds ratios (OR), followed by their 95% confidence intervals (CI). Results There were 111,849 qualifying patient records from March 1, 2020, to August 23, 2020. After excluding those with missing data (n = 7), without clinically confirmed COVID-19 (n = 27,225), and those from a carceral environment (n = 1,861), there were 84,624 eligible patients. Compared to the population of the United States of America, our COVID-19 cohort had a larger proportion of African American patients (23.17% versus 13.4%). The African American patients were more likely to have private insurance providers (28.52% versus 23.68%) and shorter LOS (IRR = 0.88, 95% CI = 0.86-0.90) than the White patient cohort. In addition, the African American versus White patients did not have increased odds (OR = 0.98, 95% CI = 0.96-1.00) of in-hospital mortality. Patients on Medicaid (OR = 1.04, 95% CI = 1.01-1.07) and self-pay (OR = 1.07, 95% CI = 1.00-1.14, noninclusive endpoints) had higher in-hospital mortality than private insurance. Several comorbidities were predictive of an increased LOS, including anxiety (IRR = 1.94, 95% CI = 1.87-2.01) and sedative abuse (IRR = 2.07, 95% CI = 1.63-2.64). Conclusions Race was not associated with increased LOS or in-hospital mortality in patients with COVID-19 infections during the early pandemic. Insurance type, psychiatric comorbidities, and medical comorbidities significantly impacted outcomes in patients with COVID-19. This research and future research in the field should help to determine rational public policies to help mitigate the risk of diseases and their impact on future pandemics.

Effect of Training on Visual Identification of High Frequency Oscillations-A Delphi-Style Intervention.

OBJECTIVE: We examined the effect of a simple Delphi-method feedback on visual identification of high frequency oscillations (HFOs) in the ripple (80-250 Hz) band, and assessed the impact of this training intervention on the interrater reliability and generalizability of HFO evaluations. METHODS: We employed a morphology detector to identify potential HFOs at two thresholds and presented them to visual reviewers to assess the probability of each epoch containing an HFO. We recruited 19 board-certified epileptologists with various levels of experience to complete a series of HFO evaluations during three sessions. A Delphi-style intervention was used to provide feedback on the performance of each reviewer relative to their peers. A delayed-intervention paradigm was used, in which reviewers received feedback either before or after the second session. ANOVAs were used to assess the effect of the intervention on the reviewers' evaluations. Generalizability theory was used to assess the interrater reliability before and after the intervention. RESULTS: The intervention, regardless of when it occurred, resulted in a significant reduction in the variability between reviewers in both groups (p GroupDI = 0.037, p GroupEI = 0.003). Prior to the delayed-intervention, the group receiving the early intervention showed a significant reduction in variability (p GroupEI = 0.041), but the delayed-intervention group did not (p GroupDI = 0.414). Following the intervention, the projected number of reviewers required to achieve strong generalizability decreased from 35 to 16. SIGNIFICANCE: This study shows a robust effect of a Delphi-style intervention on the interrater variability, reliability, and generalizability of HFO evaluations. The observed decreases in HFO marking discrepancies across 14 of the 15 reviewers are encouraging: they are necessarily associated with an increase in interrater reliability, and therefore with a corresponding decrease in the number of reviewers required to achieve strong generalizability. Indeed, the reliability of all reviewers following the intervention was similar to that of experienced reviewers prior to intervention. Therefore, a Delphi-style intervention could be implemented either to sufficiently train any reviewer, or to further refine the interrater reliability of experienced reviewers. In either case, a Delphi-style intervention would help facilitate the standardization of HFO evaluations and its implementation in clinical care.

Hypnagogic Frontal EEG Bursts in Children: Epileptic or Not?

PURPOSE: Various EEG patterns emerge in drowsiness. Intermittent bilateral midfrontal slowing (BFS) and hypnogogic frontal predominant sharply contoured waveforms (HFSC), maximal at (Fz, F3-4, and Fp1-2), are often encountered. These do not meet the criteria for epileptiform discharges. The study objective was to determine the clinical significance of BFS and HFSC. METHODS: Clinical information of children with BFS (n = 49) and HFSC (n = 99) was compared with control subjects with generalized spike-wave (GSW) discharges (n = 102) and normal EEGs (n = 100). RESULTS: HFSC was present in younger children (mean age was 3.5 ± 3.6 years), whereas BFS was present in older children (mean 12.9 ± 4.8 years). Seizures occurred in the normal EEG, BFS, HFSC, and GSW groups, respectively, as follows: 22 (22%), 15 (31%), 42 (43%), and 100 (98%) patients, whereas epilepsy occurred in 17 (17%), 10 (20%), 35 (35%), and 95 (93%) patients. The GSW group had more seizures and epilepsy than the other groups (P < 0.001), but the HFSC group also had more seizures (P < 0.001) and epilepsy (P < 0.003) than the normal EEG group. Seizures and neurodevelopmental and psychiatric comorbidities were similar between the BFS and normal EEG groups. Notably, the HFSC group had more developmental delay than the normal EEG group [33 (33%) versus 18 (18%), P < 0.009] but were similar to the GSW group 22 (22%). CONCLUSIONS: Bilateral midfrontal slowing and HFSC have had unclear significance. Our results suggest that HFSC may be a marker of increased risk of seizure, epilepsy, and developmental delay as compared to children with normal EEGs and has similar risk of developmental delay to those with GSW.

Children With Trisomy 21 and Lennox-Gastaut Syndrome With Predominant Myoclonic Seizures.

INTRODUCTION: Lennox-Gastaut syndrome is a severe form of pediatric epilepsy that is classically defined by a triad of drug-resistant seizures, including atonic, tonic, and atypical absence seizures; slow spike-and-wave discharges and paroxysmal fast activity on electroencephalography (EEG); and cognitive and behavioral dysfunction. In the vast majority, Lennox-Gastaut syndrome develops in patients with an identified etiology, including genetic or structural brain abnormalities. Long-term prognosis is generally poor with progressive intellectual deterioration and persistent seizures. At present, there are few reported cases of Lennox-Gastaut syndrome and trisomy 21 in the literature. To further delineate the spectrum of epilepsy in trisomy 21, we reviewed children with trisomy 21 and Lennox-Gastaut syndrome at one center over 28 years. METHODS: This is a retrospective case series. At our institution, all EEG results are entered into a database, which was queried for patients with trisomy 21 from 1992 to 2019. Pertinent electroclinical data was obtained from medical records. RESULTS: Of 63 patients with trisomy 21 and epilepsy, 6 (10%) had Lennox-Gastaut syndrome and were included in the study. Four of the 6 patients were male and 5 of 6 had neuroimaging, which was normal. Follow-up ranged from 3 to 20 years. Notably, 5 of 6 had predominant myoclonic seizures throughout the course of their epilepsy, associated with generalized spike-wave discharges, <100 milliseconds. CONCLUSION: We observed myoclonic seizures to be a predominant seizure type in patients with trisomy 21, suggestive that trisomy 21 patients may have a unique pattern of Lennox-Gastaut syndrome.

Pediatric Occipital Spikes at a Single Center Over 26 Years and the Significance of Tangential Dipole.

BACKGROUND: Pediatric occipital epileptiform discharges occur in various clinical settings, including self-limited and treatment-resistant epilepsies. The study objective is to determine electro-clinical predictors for prognosis in children with occipital epileptiform discharges. METHODS: 205 patients with occipital epileptiform discharges were classified into seizure groups: self-limited occipital (SLO) (n = 57), including Panayiotopoulos and Gastaut syndrome; non-self-limited occipital (non-SLO) (n = 98), including various seizure etiologies; genetic-generalized (n = 18); febrile (n = 5); and no-seizure (n = 27) groups. Electro-clinical features of the SLO and non-SLO were compared, as this is of most clinical relevance. RESULTS: The median age of seizure onset was 3 years (range: 0-19). Occipital epileptiform discharges with frontal/central positivity were present in both groups, but more common in the SLO than non-SLO groups; 21/57 (36.8%) and 19/98 (19.4%), respectively (P < .022). However, when occipital epileptiform discharges with tangential dipoles (P < .048) were accompanied by abnormal ictal eye movements (P < .037), they were predictive of SLO epilepsy. CONCLUSIONS: In our cohort, occipital epileptiform discharges with tangential dipole detected by visual analysis and abnormal ictal eye movements were predictive of SLO epilepsy.