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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Childhood Small Vessel Primary Angiitis of the Central Nervous System: A Treatable Cause of Super-refractory Status Epilepticus.

Childhood primary angiitis of the central nervous system (cPACNS) is a rare inflammatory disease of brain vessels. The small vessel subtype is diagnosed on brain biopsy and often presents with cognitive and behavioral changes, headaches, and seizures. However, there are few reported cases of super-refractory status epilepticus in children. We present a case of small vessel cPACNS complicated by super-refractory status epilepticus requiring burst suppression for 4 weeks in addition to multiple antiseizure medications and the ketogenic diet. Our patient was also treated with intravenous and oral steroids, intravenous immunoglobulin, and cyclophosphamide before starting maintenance therapy with mycophenolate mofetil. After prolonged rehabilitation, he recovered almost completely and has a normal neurologic examination with rare epileptiform activity on electroencephalogram (EEG). This is one of the longest cases of status epilepticus in small vessel cPACNS in the literature. We illustrate that super-refractory status epilepticus can be the first manifestation of small vessel cPACNS in previously healthy children and that symptomatic management of seizures with concurrent immunosuppression to treat the underlying pathology resulted in favorable neurologic outcomes.

Two Patients With KCNT1-Related Epilepsy Responding to Phenobarbital and Potassium Bromide.

KCNT1 encodes a sodium-activated potassium channel highly expressed in the brain, regulating hyperpolarization following repetitive firing. Mutations in KCNT1 were originally implicated in autosomal-dominant nocturnal frontal lobe epilepsy and epilepsy of infancy with migrating focal seizures. It is now known that there is variability in phenotypic expression and incomplete penetrance. We describe 2 patients with KCNT1-related epilepsy, one with epilepsy of infancy with migrating focal seizures and one with multifocal epilepsy. As most patients with KCNT1 variants have treatment-resistant epilepsy, drugs that specifically target the KCNT1 channel have been of great interest. Quinidine, a broad-spectrum potassium channel blocker, has shown promise; however, clinical trial results have been variable. Our patient with epilepsy of infancy with migrating focal seizures did not respond to a trial of quinidine at 6 weeks of age-one of the earliest reported quinidine trials in the literature for KCNT1-related epilepsy. This indicates that timing of treatment and response may not be related. Both patients responded to high-dose phenobarbital. The patient with epilepsy of infancy with migrating focal seizures also had a significant reduction in seizures with potassium bromide (KBr). Our data suggest that alternative therapies to quinidine should be considered as a therapeutic option for patients with KCNT1-related epilepsy. Although improved seizure control led to parent-reported improvements in neurodevelopment, it is unknown if phenobarbital and KBr impact the overall developmental trajectory of patients with KCNT1-related epilepsy. Further multicenter longitudinal studies are required.

Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-Onset Epilepsy.

Targeted whole-exome sequencing (WES) is a powerful diagnostic tool for a broad spectrum of heterogeneous neurological disorders. Here, we aim to examine the impact on diagnosis, treatment and cost with early use of targeted WES in early-onset epilepsy. WES was performed on 180 patients with early-onset epilepsy (≤5 years) of unknown cause. Patients were classified as Retrospective (epilepsy diagnosis >6 months) or Prospective (epilepsy diagnosis <6 months). WES was performed on an Ion Proton™ and variant reporting was restricted to the sequences of 620 known epilepsy genes. Diagnostic yield and time to diagnosis were calculated. An analysis of cost and impact on treatment was also performed. A molecular diagnoses (pathogenic/likely pathogenic variants) was achieved in 59/180 patients (33%). Clinical management changed following WES findings in 23 of 59 diagnosed patients (39%) or 13% of all patients. A possible diagnosis was identified in 21 additional patients (12%) for whom supporting evidence is pending. Time from epilepsy onset to a genetic diagnosis was faster when WES was performed early in the diagnostic process (mean: 145 days Prospective vs. 2,882 days Retrospective). Costs of prior negative tests averaged $8,344 per patient in the Retrospective group, suggesting savings of $5,110 per patient using WES. These results highlight the diagnostic yield, clinical utility and potential cost-effectiveness of using targeted WES early in the diagnostic workup of patients with unexplained early-onset epilepsy. The costs and clinical benefits are likely to continue to improve. Advances in precision medicine and further studies regarding impact on long-term clinical outcome will be important.

Clinical Significance of Incidental Rolandic Spikes in Children With Absence Epilepsy.

PURPOSE: Absence epilepsy and benign epilepsy of childhood with central temporal spikes are common childhood epilepsy syndromes. Although 3-Hz generalized spike-wave discharges are almost always associated with absence seizures, rolandic spikes can be present in individuals without rolandic seizures. The co-occurrence of 3-Hz generalized spike-wave and rolandic spikes is very rare. Our objective was to compare clinical features of patients with absence epilepsy with and without rolandic spikes, to determine if the additional feature of rolandic spikes has any clinical significance. METHODS: Clinical information of 17 children with absence epilepsy and rolandic spikes was compared to an age-matched control group of 90 children with absence epilepsy. RESULTS: Although most patients had excellent seizure control at follow-up, epilepsy comorbidities (cognitive and emotional problems) were observed. Comparing study vs control groups, there was no difference with anxiety (2 [11.8%] vs 8 [9%]), behavioral issues (4 [23.5%] vs 10 [11%]), mood disorders (0 vs 2 [2%]), and attention-deficit hyperactivity disorder (4 [24%] vs 10 [11%]). Significant differences were also observed: more global-developmental (5 [29%] vs 5 [6%], P < .009) and expressive-language (4 [24%] vs 5 [6%], P < .034) delay and more difficulties with school performance (11 [65%] vs 32 [36%], P < .025), especially with language-related tasks (6 [35%] vs 5 [6%], P < .001). CONCLUSION: Our results confirm the presence of additional epilepsy comorbidities in patients with absence epilepsy when rolandic spikes are present. Rolandic spikes in patients with absence epilepsy may be a marker of additional cognitive challenges that physicians should be aware of.