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To describe the temporal trends in the cost and use of adrenocorticotropic hormone (ACTH), oral prednisolone, and vigabatrin, the first-line treatments for infantile epileptic spasms syndrome (IESS).Retrospective observational study using the MarketScan Commercial database from 2006 to 2020. We identified patients with IESS diagnosed between birth and 18 months of age who received at least one of the first-line treatments within 60 days of diagnosis. Costs were adjusted for inflation using the Gross Domestic Product Implicit Price Deflator.1,131 patients received at least one first-line treatment [median (pThe gap between the cost of ACTH and the cost of oral prednisolone or vigabatrin has markedly widened from 2006 to 2020, while the relative proportion of ACTH use has decreased.

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.

A total of 184 Djallonke (West African Dwarf) sheep of Burkina Faso were analysed for Copy Number Variations (CNV) using Ovine 50 K SNP BeadChip genotyping data and two different CNV calling platforms: PennCNV and QuantiSNP. Analyses allowed to identify a total of 63 candidate Copy Number Variations Regions (CNVR) on 11 different ovine chromosomes covering about 82.5 Mb of the sheep genome. Gene-annotation enrichment analysis allowed to identify a total of 751 potential candidate ovine genes located in the candidate CNVR bounds. Functional annotation allowed to identify five statistically significant Functional Clusters (FC; enrichment factor > 1.3) involving 61 candidate genes. All genes forming significantly enriched FC were located on ovine chromosome (OAR) 21. FC1 (22 genes including PAG4 and PAG6) and FC5 (three genes: CTSC, CTSW and CTSF), coding proteases (peptidases and cathepsins, respectively), were involved in reproductive performance and modulation of gestation. Both FC3 and FC4 were involved in inflammatory and immunologic response through coding serum amyloid A and B-box-type zinc finger proteins, respectively. Finally, FC2 consisted of 27 genes (including OR10G6 and OR8B8) involved in olfactory receptor activity, key for animals adapting to new food resources. CNVR identified on at least 15% of individuals were considered CNVR hotspots and further overlapped with previously reported quantitative trait loci (QTL). CNVR hotspots spanning genes putatively involved with lipid metabolism (SKP1, TCF7, JADE2, UBE2B and SAR1B) and differential expression in mammary gland (SEC24A and CDKN2AIPNL) on OAR5 and dairy traits (CCDC198 and SLC35F4) on OAR7 overlapped with QTL associated with lipid metabolism, milk protein yield and milk fat percentage. Information obtained from local sheep populations naturally adapted to harsh environments contributes to increase our understanding of the genomic importance of CNV.

To describe the demographics of epilepsy surgery utilization and its impact on health care resource use.Retrospective descriptive study using the MarketScan commercial claims database. We studied children and adults who underwent epilepsy surgery in the USA in the period 2006-2019. Our main outcome was health care resource utilization.Among the 87,368 patients with refractory epilepsy, 2,011 (2.3%) patients underwent resective epilepsy surgery, 188 (0.2%) patients underwent partial or total hemispherectomy, and 183 (0.2%) patients underwent corpus callosotomy. The proportion of patients undergoing epilepsy surgery has barely increased in the period 2006 to 2019. The year of resective epilepsy surgery was associated with high healthcare costs per person-year [median (pIn privately insured patients in the USA, resective epilepsy surgery and hemispherectomy substantially decrease healthcare utilization in subsequent years. Epilepsy surgery may help contain costs in the field of epilepsy.

OBJECTIVE: Describe hospital readmission for status epilepticus (SE) in the United States, and study potential risk factors for readmission. METHODS: This is a retrospective observational study using the Healthcare Cost and Utilization Project's 2016 Nationwide Readmissions Database. We studied patients of all ages admitted to the hospital due to SE. RESULTS: We included 32 327 patients admitted for SE in 2016. 8.4% of these patients were readmitted for SE at least one more time within 2016 (cross-sectional analysis). The incidence rate was 18 readmissions for SE per 1000 patient-months. Among the survivors of the index admission for SE who had at least 6 months of follow-up within this database (16 043 patients), the cumulative probability of having a readmission for SE at 1, 3, and 6 months from the index admission was approximately 3.5%, 7.5%, and 11%, respectively (time-to-event analysis). Patients with refractory epilepsy were more likely to have a readmission for SE compared to patients without refractory epilepsy (hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.23-1.82, adjusted P =.0006), and pediatric patients were more likely to have a readmission for SE compared to adult patients (HR 1.53, 95% CI 1.26-1.87, adjusted P = .0003) during 6-month follow-up. SIGNIFICANCE: Hospital readmissions for SE in the United States are frequent. Independent factors associated with readmission in this database were refractory epilepsy and pediatric age.

ObjectiveTo compare the effectiveness of initial treatment for infantile spasms.MethodsThe National Infantile Spasms Consortium prospectively followed up children with new-onset infantile spasms that began at age 2 to 24 months at 23 US centers (2012–2018). Freedom from treatment failure at 60 days required no second treatment for infantile spasms and no clinical spasms after 30 days of treatment initiation. We managed treatment selection bias with propensity score weighting and within-center correlation with generalized estimating equations.ResultsFreedom from treatment failure rates were as follows: adrenocorticotropic hormone (ACTH) 88 of 190 (46%), oral steroids 42 of 95 (44%), vigabatrin 32 of 87 (37%), and nonstandard therapy 4 of 51 (8%). Changing from oral steroids to ACTH was not estimated to affect response (observed 44% estimated to change to 44% [95% confidence interval 34%–54%]). Changing from nonstandard therapy to ACTH would improve response from 8% to 39% (17%–67%), and changing to oral steroids would improve response from 8% to 38% (15%–68%). There were large but not statistically significant estimated effects of changing from vigabatrin to ACTH (29% to 42% [15%–75%]), from vigabatrin to oral steroids (29% to 42% [28%–57%]), and from nonstandard therapy to vigabatrin (8% to 20% [6%–50%]). Among children treated with vigabatrin, those with tuberous sclerosis complex (TSC) responded more often than others (62% vs 29%;p< 0.05).DiscussionCompared to nonstandard therapy, ACTH and oral steroids are superior for initial treatment of infantile spasms. The estimated effectiveness of vigabatrin is between that of ACTH/oral steroids and nonstandard therapy, although the sample was underpowered for statistical confidence. When used, vigabatrin worked best for TSC.Classification of EvidenceThis study provides Class III evidence that for children with new-onset infantile spasms, ACTH or oral steroids were superior to nonstandard therapies.

Purpose Estimate the cost of status epilepticus (SE) admissions in the USA using claim databases based on ICD-10 codes. Method Descriptive retrospective study using national estimates for the year 2016 from the KID’s Inpatient Database (KID) for pediatric patients and from the National Inpatient Sample (NIS) for adults. These databases are comprehensive collections of all-payer, encounter-level hospital care data in the United States of America. Results From a population of 6,106,405 pediatric admissions there were 580 admissions related to SE. From a population of 29,274,158 adult admissions there were 1,405 admissions related to SE. The median (p25–p75) cost of pediatric admissions related to SE was $8,749 ($4,875–$19,067) in 2016 USA dollars [$9,295 ($5,180–$20,258) in inflation-adjusted 2019 USA dollars], and for adult admissions related to SE it was $14,678 ($7,203–$28,388) in 2016 USA dollars [$15,595 ($7,653–$30,161) in inflation-adjusted 2019 USA dollars]. Transforming to 2019 USA dollars, the values from the current study are consistent with prior estimates in the literature from the KID and NIS databases with a progressive increase, except for the cost of super-refractory SE in children that has increased disproportionately. Conclusions This study estimates that the cost of admissions related to SE in the USA is approximately $9,000 in children and $15,000 in adults and shows that the cost estimates have not markedly changed with the advent of ICD-10.

We aimed to determine whether clinical EEG reports obtained from children in the intensive care unit with refractory status epilepticus could provide data for comparative effectiveness research studies.We conducted a retrospective descriptive study to assess the documentation of key variables within clinical continuous EEG monitoring reports based on the American Clinical Neurophysiology Society's standardized EEG terminology for children with refractory status epilepticus from 10 academic centers. Two pediatric electroencephalographers reviewed the EEG reports. We compared reports generated using free text or templates.We reviewed 191 EEG reports. Agreement between the electroencephalographers regarding whether a variable was described in the report ranged from fair to very good. The presence of electrographic seizures (ES) was documented in 46% (87/191) of reports, and these reports documented the time of first ES in 64% (56/87), ES duration in 72% (63/85), and ES frequency in 68% (59/87). Reactivity was documented in 16% (31/191) of reports, and it was more often documented in template than in free-text reports (40% vs. 14%, P = 0.006). Other variables were not differentially reported in template versus free-text reports.Many key EEG features are not documented consistently in clinical continuous EEG monitoring reports, including ES characteristics and reactivity assessment. Standardization may be needed for clinical EEG reports to provide informative data for large multicenter observational studies.

Objective Describe basic science, animal models and clinical data related to timing of treatment in status epilepticus (SE). Methods We summarized the results of 15 studies that reported time to treatment in SE, and reviewed basic and clinical literature. Results SE is a life-threatening and time-sensitive emergency that requires immediate treatment. Current guidelines recommend escalation of anti-seizure medications (ASM) within specified time frames. Prolonged seizures may lead to changes in the composition and location of gamma-aminobutyric acid A receptors (GABAAR) and N-Methyl- d -aspartic acid receptors (NMDAR), leading to loss of inhibition and increased excitation. These biochemical changes are apparent in specific animal models having progressive resistance to benzodiazepines (BZD) with longer seizures. Later treatments lead to decreased response to BZD, longer seizures, greater need of continuous infusions, potential brain injury and increased in-hospital mortality. Despite mounting evidence that early treatment of SE is more effective and safer, treatment and ASM escalation is often delayed compared to protocols. Literature review of 2212 patients with SE showed an average time to treatment of 42.4 min and time to hospital arrival of 56 min. Also, only 51.8% of patients received treatment by emergency medical services and 12.8% by their families, including patients with a previous diagnosis of epilepsy or with prior SE. Conclusions Morbidity and mortality may be avoided with rapid, effective treatment of SE. Treatment application and escalation remains delayed especially in outpatient settings, potentially leading to suboptimal outcomes. Implementation techniques and quality improvement methodologies may provide avenues for improving outcomes in SE.

Small-sized and trypanotolerant West African taurine (Bos taurus) cattle are a unique case of human-mediated process of adaptation to a challenging environment. Extensive gene flow with Sahelian zebu (B. indicus), bigger and with some resistance to tick attack, occurred for centuries and allowed the apparition of stable crossbred populations (sanga) having intermediate characteristics. Up to 237 individuals belonging to 10 different taurine, zebu and sanga cattle populations sampled in Benin, Burkina Faso and Niger were typed using the BovineHD BeadChip of Illumina to identify signatures of selection, assessed using three different Extended-Haplotype-Homozygosity-based statistics, overlapping with ancient, originated 1024 or 2048 generations ago, Homozygosity-By-Descent segments in the cattle genome. Candidate genomic regions were defined ensuring their importance within cattle type and using zebu as reference. Functional annotation analysis identified four statistically significant Annotation Clusters in taurine cattle (from ACt1 to ACt4), one (ACs1) in sanga, and another (ACz1) in zebu cattle, fitting well with expectations. ACt1 included genes primarily associated with innate immunity; ACt2 involved bitter taste receptor genes of importance to adaptation to changing environments; ACt3 included 68 genes coding ATP-binding proteins, some of them located on trypanotolerance-related QTL regions, that can partially underlie immune response and the additive mechanism of trypanotolerance; ACt4 was associated with growth and small size (NPPC gene); ACs1 included genes involved in immune response; and ACz1 is related with ectoparasite resistance. Our results provide a new set of genomic areas and candidate genes giving new insights on the genomic impact of adaptation in West African cattle.

A subset of primary central nervous system lymphomas (PCNSL) are difficult to distinguish from glioblastoma multiforme (GBM) on magnetic resonance imaging (MRI). We developed a convolutional neural network (CNN) to distinguish these tumors on contrast-enhanced T1-weighted images. Preoperative brain tumor MRIs were retrospectively collected among 320 patients with either GBM (n = 160) and PCNSL (n = 160) from two academic institutions. The individual images from these MRIs consisted of a training set (n = 1894 GBM and 1245 PCNSL), a validation set (n = 339 GBM; 202 PCNSL), and a testing set (99 GBM and 108 PCNSL). Three CNNs using the EfficientNetB4 architecture were evaluated. To increase the size of the training set and minimize overfitting, random flips and changes to color were performed on the training set. Our transfer learning approach (with image augmentation and 292 epochs) yielded an AUC of 0.94 (95% CI: 0.91–0.97) for GBM and an AUC of 0.95 (95% CI: 0.92–0.98) for PCNL. In the second case (not augmented and 137 epochs), the images were augmented prior to training. The area under the curve for GBM was 0.92 (95% CI: 0.88–0.96) for GBM and an AUC of 0.94 (95% CI: 0.91–0.97) for PCNSL. For the last case (augmented, Gaussian noise and 238 epochs) the AUC for GBM was 0.93 (95% CI: 0.89–0.96) and an AUC 0.93 (95% CI = 0.89–0.96) for PCNSL. Even with a relatively small dataset, our transfer learning approach demonstrated CNNs may provide accurate diagnostic information to assist radiologists in distinguishing PCNSL and GBM.

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.

Objective To develop and test a deep learning model to automatically detect malformations of cortical development (MCD). Methods : We trained a deep learning model to distinguish between diffuse cortical malformation (CM), periventricular nodular heterotopia (PVNH), and normal magnetic resonance imaging (MRI). We trained 4 different convolutional neural network (CNN) architectures. We used batch normalization, global average pooling, dropout layers, transfer learning, and data augmentation to minimize overfitting. Results There were 45 subjects (866 images) with a normal MRI, 52 subjects (790 images) with CM, and 32 subjects (750 images) with PVNH. There was no subject overlap between the training, validation, and test sets. The InceptionResNetV2 architecture performed best in the validation set in all models and was evaluated in the test set with the following results: 1) the model distinguishing between CM and normal MRI yielded an area under the curve (AUC) of 0.89 and accuracy of 0.81; 2) the model distinguishing between PVNH and normal MRI yielded an AUC of 0.90 and accuracy of 0.84; 3) the model distinguishing between the three classes (CM, PVNH, and normal MRI) yielded an AUC of 0.88 and accuracy of 0.74. Visualization with gradient-weighted class activation maps and saliency maps showed that the deep learning models classified images based on relevant areas within each image. Significance This study showed that CNNs can detect MCD at a clinically useful performance level with a fully automated workflow without image feature selection.

Background Time to treatment in pediatric refractory status epilepticus is delayed. We aimed to evaluate the influence of weekends and holidays on time to treatment of this pediatric emergency. Methods We performed a retrospective analysis of prospectively collected observational data of pediatric patients with refractory status epilepticus. Results We included 329 patients (56% males) with a median (p25 to p75) age of 3.8 (1.3 to 9) years. The median (p25 to p75) time to first BZD on weekdays and weekends/holidays was 20 (6.8 to 48.3) minutes versus 11 (5 to 35) minutes, P = 0.01; adjusted hazard ratio (HR) = 1.20 (95% confidence interval [CI]: 0.95 to 1.55), P = 0.12. The time to first non-BZD ASM was longer on weekdays than on weekends/holidays (68 [42.8 to 153.5] minutes versus 59 [27 to 120] minutes, P = 0.006; adjusted HR = 1.38 [95% CI: 1.08 to 1.76], P = 0.009). However, this difference was mainly driven by status epilepticus with in-hospital onset: among 108 patients, the time to first non-BZD ASM was longer during weekdays than during weekends/holidays (55.5 [28.8 to 103.5] minutes versus 28 [15.8 to 66.3] minutes, P = 0.003; adjusted HR = 1.65 [95% CI: 1.08 to 2.51], P = 0.01). Conclusions The time to first non-BZD ASM in pediatric refractory status epilepticus is shorter on weekends/holidays than on weekdays, mainly driven by in-hospital onset status epilepticus. Data on what might be causing this difference may help tailor policies to improve medication application timing.

Objective To describe the epidemiology and health resource utilization for convulsive status epilepticus (SE) in the emergency department (ED). Methods Retrospective descriptive study in the Nationwide Emergency Department Sample (NEDS). Primary SE and secondary SE (SE in a case who visited the ED for other primary reason) were compared with non-SE seizures. Secondary SE is expected to have worse outcomes and higher costs because of another primary cause for ED visit. Results In the period 2010–2014, there were 149,750 ED visits with primary SE; 83,459 ED with secondary SE; and 5,359,103 ED visits with non-SE seizures. On multivariable analysis adjusting for potential confounders, the odds of hospital admission were 7 times higher for primary SE than for non-SE seizures, and 5 times higher for secondary SE than for non-SE seizures; the odds of transfer to another hospital were 9 times higher for primary SE than for non-SE seizures, and 3 times higher for secondary SE than for non-SE seizures; the odds of death were 2.5 times higher for primary SE than for non-SE seizures, and 12 times higher for secondary SE than for non-SE seizures; and the charges (in January 2020 USA dollars) were $9000 higher in primary SE than in non-SE seizures, and $35,000 higher in secondary SE than in non-SE seizures. Conclusion Among all reasons for ED visits, SE, and in particular, secondary SE, are among the most resource-consuming conditions, being much more expensive than non-SE seizures in the ED.

Status epilepticus (SE) is one of the most common neurological emergencies in children and has a mortality of 2 to 4%. Admissions for SE are very resource-consuming, especially in refractory and super-refractory SE. An increasing understanding of the pathophysiology of SE leaves room for improving SE treatment protocols, including medication choice and timing. Selecting the most efficacious medications and giving them in a timely manner may improve outcomes. Benzodiazepines are commonly used as first line and they can be used in the prehospital setting, where most SE episodes begin. The diagnostic work-up should start simultaneously to initial treatment, or as soon as possible, to detect potentially treatable causes of SE. Although most etiologies are recognized after the first evaluation, the detection of more unusual causes may become challenging in selected cases. SE is a life-threatening medical emergency in which prompt and efficacious treatment may improve outcomes. We provide a summary of existing evidence to guide clinical decisions regarding the work-up and treatment of SE in pediatric patients.

A sample of 185 West African cattle belonging to nine different taurine, sanga, and zebu populations was typed using a set of 33 microsatellites and the BovineHD BeadChip of Illumina. The information provided by each type of marker was summarized via clustering methods and principal component analyses (PCA). The aim was to assess differences in performance between both marker types for the identification of population structure and the projection of genetic variability on geographical maps. In general, both microsatellites and Single Nucleotide Polymorphism (SNP) allowed us to differentiate taurine cattle from zebu and sanga cattle, which, in turn, would form a single population. Pearson and Spearman correlation coefficients computed among the admixture coefficients (fitting K = 2) and the eigenvectors corresponding to the first two factors identified using PCA on both microsatellite and SNP data were statistically significant (most of them having p &lt, 0.0001) and high. However, SNP data allowed for a better fine-scale identification of population structure within taurine cattle: Lagunaire cattle from Benin were separated from two different N&rsquo, Dama cattle samples. Furthermore, when clustering analyses assumed the existence of two parental populations only (K = 2), the SNPs could differentiate a different genetic background in Lagunaire and N&rsquo, Dama cattle. Although the two N&rsquo, Dama cattle populations had very different breeding histories, the microsatellite set could not separate the two N&rsquo, Dama cattle populations. Classic bidimensional dispersion plots constructed using factors identified via PCA gave different shapes for microsatellites and SNPs: plots constructed using microsatellite polymorphism would suggest the existence of weakly differentiated, highly intermingled, subpopulations. However, the projection of the factors identified on synthetic maps gave comparable images. This would suggest that results on population structuring must be interpreted with caution. The geographic projection of genetic variation on synthetic maps avoids interpretations that go beyond the results obtained, particularly when previous information on the analyzed populations is scant. Factors influencing the performance of the projection of genetic parameters on geographic maps, together with restrictions that may affect the election of a given type of markers, are discussed.

Objective To determine whether publication of evidence on delays in time to treatment shortens time to treatment in pediatric refractory convulsive status epilepticus (rSE), we compared time to treatment before (2011-2014) and after (2015-2019) publication of evidence of delays in treatment of rSE in the Pediatric Status Epilepticus Research Group (pSERG) as assessed by patient interviews and record review. Methods We performed a retrospective analysis of a prospectively collected dataset from June 2011 to September 2019 on pediatric patients (1 month-21 years of age) with rSE. Results We studied 328 patients (56% male) with median (25th-75th percentile [p(25)-p(75)]) age of 3.8 (1.3-9.4) years. There were no differences in the median (p(25)-p(75)) time to first benzodiazepine (BZD) (20 [5-52.5] vs 15 [5-38] minutes,p= 0.3919), time to first non-BZD antiseizure medication (68 [34.5-163.5] vs 65 [33-142] minutes,p= 0.7328), and time to first continuous infusion (186 [124.2-571] vs 160 [89.5-495] minutes,p= 0.2236). Among 157 patients with out-of-hospital onset whose time to hospital arrival was available, the proportion who received at least 1 BZD before hospital arrival increased after publication of evidence of delays (41 of 81 [50.6%] vs 57 of 76 [75%],p= 0.0018), and the odds ratio (OR) was also increased in multivariable logistic regression (OR 4.35 [95% confidence interval 1.96-10.3],p= 0.0005). Conclusion Publication of evidence on delays in time to treatment was not associated with improvements in time to treatment of rSE, although it was associated with an increase in the proportion of patients who received at least 1 BZD before hospital arrival., This study and consortium were funded by the Epilepsy Research Fund, the Epilepsy Foundation of America (EF-213583, Targeted Initiative for Health Outcomes), by the American Epilepsy Society/Epilepsy Foundation of America Infrastructure Award, and by the Pediatric Epilepsy Research Foundation.

A sample of Burkina Faso Djallonk&eacute, (West African Dwarf) sheep was analyzed to identify stretches of homozygous segments (runs of homozygosity, ROH) overlapping with ancient homozygosity-by-descent (HBD) segments. HBD segments were considered ancient if they were likely to be inherited from ancestors living from 1024 to 2048 generations ago, roughly coinciding with the time in which sheep entered into West Africa. It is hypothesized that such homozygous segments can inform on the effect of the sheep genome of human-mediated selection for adaptation to this harsh environment. PLINK analyses allowed to identify a total of 510 ROH segments in 127 different individuals that could be summarized into 124 different ROH. A total of 32,968 HBD segments were identified on 119 individuals using the software ZooRoH. HBD segments inherited from ancestors living 1024 and 2048 generations ago were identified on 61 individuals. The overlap between consensus ROH identified using PLINK and HBD fragments putatively assigned to generations 1024 and 2048 gave 108 genomic areas located on 17 different ovine chromosomes which were considered candidate regions for gene-annotation enrichment analyses. Functional annotation allowed to identify six statistically significant functional clusters involving 50 candidate genes. Cluster 1 was involved in homeostasis and coagulation, functional clusters 2, 3, and 6 were associated to innate immunity, defense against infections, and white blood cells proliferation and migration, respectively, cluster 4 was involved in parasite resistance, and functional cluster 5, formed by 20 genes, was involved in response to stress. The current analysis confirms the importance of genomic areas associated to immunity, disease resistance, and response to stress for adaptation of sheep to the challenging environment of humid Sub-Saharan West Africa.

OBJECTIVE: Treatments for convulsive status epilepticus (SE) have a wide range of effectiveness. The estimated effectiveness of non-intravenous benzodiazepines (non-IV BZDs) ranges from approximately 70% to 90% and the estimated effectiveness of non-benzodiazepine antiseizure medications (non-BZD ASMs) ranges from approximately 50% to 80%. This study aimed to quantify the clinical and economic burden of decisional uncertainty in the treatment of SE. METHODS: We performed a decision analysis that evaluates how decisional uncertainty on treatment choices for SE impacts hospital admissions, intensive care unit (ICU) admissions, and costs in the United States. We evaluated treatment effectiveness based on the available literature. RESULTS: Use of a non-IV BZD with high estimated effectiveness, like intranasal midazolam, rather than one with low estimated effectiveness, like rectal diazepam, would result in a median (p(25) -p(75) ) reduction in hospital admissions from 6 (3.9-8.8) to 1.1 (0.7-1.8) per 100 cases and associated cost reductions of $638 ($289-$1064) per pediatric patient and $1107 ($972-$1281) per adult patient. For BZD-resistant SE, use of a non-BZD ASM with high estimated effectiveness, like phenobarbital, rather than one with low estimated effectiveness, like phenytoin/fosphenytoin, would result in a reduction in ICU admissions from 9.1 (7.3-11.2) to 3.9 (2.6-5.5) per 100 cases and associated cost reduction of $1261 ($445-$2223) per pediatric patient and $319 ($-93-$806) per adult patient. Sensitivity analyses showed that relatively minor improvements in effectiveness may lead to substantial reductions in downstream hospital admissions, ICU admissions, and costs. SIGNIFICANCE: Decreasing decisional uncertainty and using the most effective treatments for SE may substantially decrease hospital admissions, ICU admissions, and costs.

The Djallonké (West African Dwarf) sheep is a small-sized haired sheep resulting from a costly evolutionary process of natural adaptation to the harsh environment of West Africa including trypanosome challenge. However, genomic studies carried out in this sheep are scant. In this research, genomic data of 184 Djallonké sheep (and 12 Burkina-Sahel sheep as an outgroup) generated using medium-density SNP Chips were analyzed. Three different statistics (iHS, XP-EHH and nSL) were applied to identify candidate selection sweep regions spanning genes putatively associated with adaptation of sheep to the West African environment. A total of 207 candidate selection sweep regions were defined. Gene-annotation enrichment and functional annotation analyses allowed to identify three statistically significant functional clusters involving 12 candidate genes. Genes included in Functional Clusters associated to selection signatures were mainly related to metabolic response to stress, including regulation of oxidative and metabolic stress and thermotolerance. The bovine chromosomal areas carrying QTLs for cattle trypanotolerance were compared with the regions on which the orthologous functional candidate cattle genes were located. The importance of cattle BTA4 for trypanotolerant response might have been conserved between species. The current research provides new insights on the genomic basis for adaptation and highlights the importance of obtaining information from non-cosmopolite livestock populations managed in harsh environments.

All tropically adapted humped cattle (Bos indicus or “zebu”), descend from a domestication process that took place >8,000 years ago in South Asia. Here we present an intercontinental survey of Y-chromosome diversity and a comprehensive reconstruction of male-lineage zebu cattle history and diversity patterns. Phylogenetic analysis revealed that all the zebu Y-chromosome haplotypes in our dataset group within three different lineages: Y3A, the most predominant and cosmopolitan lineage; Y3B, only observed in West Africa; and Y3C, predominant in South and Northeast India. The divergence times estimated for these three Zebu-specific lineages predate domestication. Coalescent demographic models support either de novo domestication of genetically divergent paternal lineages or more complex process including gene flow between wild and domestic animals. Our data suggest export of varied zebu lineages from domestication centres through time. The almost exclusive presence of Y3A haplotypes in East Africa is consistent with recent cattle restocking in this area. The cryptic presence of Y3B haplotypes in West Africa, found nowhere else, suggests that these haplotypes might represent the oldest zebu lineage introduced to Africa ca. 3,000 B.P. and subsequently replaced in most of the world. The informative ability of Interspersed Multilocus Microsatellites and Y-specific microsatellites to identify genetic structuring in cattle populations is confirmed.

We reviewed 37 studies reporting long-term outcomes after a status epilepticus (SE) episode in pediatric and adult populations. Study design, length of follow-up, outcome measures, domains investigated (mortality, SE recurrence, subsequent epilepsy, cognitive outcome, functional outcome, or quality of life), and predictors of long-term outcomes are summarized. Despite heterogeneity in the design of prior studies, overall risk of poor long-term outcome after SE is high in both children and adults. Etiology is the main determinant of outcome, and the effect of age or SE duration is often difficult to distinguish from the underlying cause. The effect of the treatment on long-term outcome after SE is still unknown., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose To describe the efficacy and safety of ketogenic diet (KD) for convulsive refractory status epilepticus (RSE). Methods RSE patients treated with KD at the 6/11 participating institutions of the pediatric Status Epilepticus Research Group from January-2011 to December-2016 were included. Patients receiving KD prior to the index RSE episode were excluded. RSE was defined as failure of ≥2 anti-seizure medications, including at least one non-benzodiazepine drug. Ketosis was defined as serum beta-hydroxybutyrate levels >20 mg/dl (1.9 mmol/l). Outcomes included proportion of patients with electrographic (EEG) seizure resolution within 7 days of starting KD, defined as absence of seizures and ≥50% suppression below 10 μV on longitudinal bipolar montage (suppression-burst ratio ≥50%); time to start KD after onset of RSE; time to achieve ketosis after starting KD; and the proportion of patients weaned off continuous infusions 2 weeks after KD initiation. Treatment-emergent adverse effects (TEAEs) were also recorded. Results Fourteen patients received KD for treatment of RSE (median age 4.7 years, interquartile range [IQR] 5.6). KD was started via enteral route in 11/14 (78.6%) patients. KD was initiated a median of 13 days (IQR 12.5) after the onset of RSE, at 4:1 ratio in 8/14 (57.1%) patients. Ketosis was achieved within a median of 2 days (IQR 2.0) after starting KD. EEG seizure resolution was achieved within 7 days of starting KD in 10/14 (71.4%) patients. Also, 11/14 (78.6%) patients were weaned off their continuous infusions within 2 weeks of starting KD. TEAEs, potentially attributable to KD, occurred in 3/14 (21.4%) patients, including gastro-intestinal paresis and hypertriglyceridemia. Three month outcomes were available for 12/14 (85.7%) patients, with 4 patients being seizure-free, and 3 others with decreased seizure frequency compared to pre-RSE baseline. Conclusions This series suggests efficacy and safety of KD for treatment of pediatric RSE.

The aim of this study was to evaluate the performance of models predicting in-hospital mortality in critically ill children undergoing continuous electroencephalography (cEEG) in the intensive care unit (ICU). We evaluated the performance of machine learning algorithms for predicting mortality in a database of 414 critically ill children undergoing cEEG in the ICU. The area under the receiver operating characteristic curve (AUC) in the test subset was highest for stepwise selection/elimination models (AUC = 0.82) followed by least absolute shrinkage and selection operator (LASSO) and support vector machine with linear kernel (AUC = 0.79), and random forest (AUC = 0.71). The explanatory models had the poorest discriminative performance (AUC = 0.63 for the model without considering etiology and AUC = 0.45 for the model considering etiology). Using few variables and a relatively small number of patients, machine learning techniques added information to explanatory models for prediction of in-hospital mortality.

The main aim of the current study was to exemplify the usefulness of pedigree-free animal models in scenarios in which available information is limited. Up to 271 Djallonke sheep individuals of Burkina Faso were typed for 29 microsatellites. Performance records were obtained from a trial designed to assess environmental factors affecting gastrointestinal parasite resistance. Packed cell volume (PCV), log-transformed fecal egg count (lnFEC) and FAffa Malan CHArt (FAMACHA) eye scores were analyzed fitting univariate and multivariate animal models. Molecular information was used to: a) construct an artificial pedigree maximizing the correlation between the molecular coancestry matrix and the coancestry of the artificial genealogies (P* Matrix); and b) computing the Ritland’s estimator of between-individuals molecular coancestry (R Matrix). All animal models fitted included as fixed effects the contemporary group, day of assessment after deworming and body weight as a linear covariate. As random effects, models included the additive genetic effect and the permanent environment associated to individual. Multivariate models further included the covariances between permanent environmental and additive genetic effects. Univariate models had difficulties to separate between additive genetic and permanent environmental effects. The P* Matrix gave higher estimates of additive genetic variance than the R Matrix. Independently of the Matrix used, multivariate models gave more consistent estimates of heritability (h2) and permanent environmental effect: estimates of h2 for lnFEC varied from 0.063 ± 0.037 to 0.173 ± 0.076; estimates of h2 for FAMACHA scores ranged from 0.206 ± 0.070 to 0. 343 ± 0.111; and c) estimates of h2 for PCV ranged from 0.073 ± 0.045 to 0.142 ± 0.084. Genetic correlations estimated for the pair lnFEC-FAMACHA using multivariate models were significant in all cases varying from 0.548 ± 0.247 to 0.785 ± 0.242. Pedigree-free animal models may be advantageous in developing countries at the beginning of selection programmes or to improve the outcome of trials designed to assess performance of local breeds for economically interesting traits.

Purpose Describe timing from intensive care unit (ICU) admission to initiation of continuous electroencephalogram (cEEG) in repeated ICU admissions. Method We performed a retrospective observational study in pediatric patients who underwent repeated ICU admissions with cEEG from 2011 to 2013. The main outcome measure was time from ICU admission to cEEG. Results There were 41 patients (54% males) with at least 2 ICU admissions with cEEG (median (p25-p75) age at first admission: 3.3 (0.3–8.4) years, at second admission: 3.9 (1.1–9.4) years), 7 patients (57% males, 9.9 (2.9–11.5) years) with at least 3 ICU admissions, and 5 patients (60% males, 10.1 (4–10.5) years) with at least 4 ICU admissions. One patient had 21 ICU admissions. The median (p25-p75) time from ICU admission to cEEG was not different during the first and second ICU admissions [10.7 (1.9–22.9) hours versus 13 (0.2–36.7) hours; p =0.908]. Among patients with electrographic seizures on first admission, time to cEEG was not different during the first and second admissions [7.9 (0.5–23.4) hours versus 14.5 (−2 to 44.5) hours; p =0.636]. Among patients with status epilepticus during the first admission, time to cEEG was not different between the first and second admissions [15.3 (9–79) hours versus 40.7 (19.3–42.6) hours; p =0.75]. Conclusions The time from ICU admission to the initiation of cEEG did not decrease in second or subsequent ICU admissions, even in patients with seizures or status epilepticus on the first admission.

Epilepsy is one of the most common neurological disorders and, despite optimally chosen and dosed antiepileptic drugs (AEDs), approximately 20%-30% of patients will continue to have seizures. Behavior and cognition are negatively impacted by seizures, but AEDs are also a major contributor to behavioral and cognitive deficits. However, the cognitive and behavioral effect of AEDs in children is insufficiently emphasized in the literature. This review summarizes the cognitive and behavioral effects of AEDs in the pediatric population with the objective of helping pediatricians and pediatric neurologists to select the AEDs with the best profile for their individual patient's needs.

A total of 357 adult cows and 29 sires belonging to the long-horned Niger Zebu Bororo cattle population were assessed for 13 body measurements and 11 qualitative traits. Data were jointly analysed with 311 cows and 64 sires belonging to other four West African zebu cattle populations, sampled in Burkina Faso and Benin, representative of both the short-horned and the long-horned West African zebu groups using multivariate statistical methods. Besides the other long-horned zebu breed analysed (Zebu Mbororo of Burkina Faso), Zebu Bororo cattle tended to have the highest mean values for all body measurements. Mahalanobis distance matrices further informed that pairs involving Zebu Bororo cattle had the higher differentiation of the dataset. However, contour plots constructed using eigenvalues computed via principal component analysis (PCA) illustrated a lack of differentiation among West African zebu cattle populations at the body measurements level. Correspondence analysis carried out on the 11 qualitative traits recorded allowed for ascertaining a clear differentiation between the Zebu Bororo and the other zebu cattle populations analysed which, in turn, did not show a clear differentiation at the qualitative type traits level. In our data, Zebu Bororo cattle had in high frequency qualitative features such as dropped ears, lyre-shaped horns and red-pied coat colour that are not frequently present in the other West African zebu populations analysed. A directional selection due to a rough consensus of the stock-keepers may be hypothesised. Performance of further analyses to assess the degree in which such breeding differences may be related to genetic or production differences are advised.

The aim is to describe the epidemiology of epilepsy surgery in children and adults in the United States. We performed a descriptive study of the National Inpatient Sample (NIS) for the year 2012 and the Kids' Inpatient Database (KID) for the period 2010-2012, the largest all-payer databases on inpatient data in the USA. These databases estimate 97% of all inpatient hospital discharges in the USA. In the KID, 12,899 (0.2%) of admission records had brain surgery and 600 of the 4900 (12.2%) admissions with focal refractory epilepsy underwent epilepsy surgery. Epilepsy surgery occurred in 60% of Whites, 7% of Blacks, 15% of Hispanics, and 10% of other races. In the NIS, 99,650 (0.3%) of admission records had brain surgery and 1170 of the 9775 (12%) admissions with focal refractory epilepsy underwent epilepsy surgery. Epilepsy surgery occurred in 69% of Whites, 7% of Blacks, 9% of Hispanics, and 8% of other races. In both the KID and the NIS, lower socioeconomic status was mildly underrepresented in epilepsy surgery. In both pediatric and adult admissions, there was an overrepresentation of Whites and underrepresentation of Blacks, which persisted after stratifying by socioeconomic status. Females were underrepresented in epilepsy surgery, but gender disparities were partially explained by differences in socioeconomic status. Epilepsy surgery is not equally distributed across races in the USA and these differences are not fully attributable to differences in socioeconomic status. Racial disparities in epilepsy surgery similarly affect children and adults.

By definition, unprovoked seizures are not precipitated by an identifiable factor, such as fever or trauma. A thorough history and physical examination are essential to caring for pediatric patients with a potential first unprovoked seizure. Differential diagnosis, EEG, neuroimaging, laboratory tests, and initiation of treatment will be reviewed. Treatment is typically initiated after 2 unprovoked seizures, or after 1 seizure in select patients with distinct epilepsy syndromes. Recent expansion of the definition of epilepsy by the ILAE allows for the diagnosis of epilepsy to be made after the first seizure if the clinical presentation and supporting diagnostic studies suggest a greater than 60% chance of a second seizure. This review summarizes the current literature on the diagnostic and therapeutic management of first unprovoked seizure in children and adolescents while taking into consideration the revised diagnostic criteria of epilepsy.

The objective of the study was to estimate the proportion of patients who receive an electroencephalogram (EEG) among five common indications for EEG monitoring in the intensive care unit: traumatic brain injury (TBI), extracorporeal membrane oxygenation (ECMO), cardiac arrest, cardiac surgery and hypoxic-ischemic encephalopathy (HIE). We performed a retrospective cross-sectional descriptive study utilizing the Kids' Inpatient Database (KID) for the years 2010-2012. The KID is the largest pediatric inpatient database in the USA and it is based on discharge reports created by hospitals for billing purposes. We evaluated the use of electroencephalogram (EEG) or video-electroencephalogram in critically ill children who were mechanically ventilated. The KID database had a population of approximately 6,000,000 pediatric admissions. Among 22,127 admissions of critically ill children who had mechanical ventilation, 1504 (6.8%) admissions had ECMO, 9201 (41.6%) TBI, 4068 (18.4%) HIE, 2774 (12.5%) cardiac arrest, and 4580 (20.7%) cardiac surgery. All five conditions had a higher proportion of males, with the highest (69.8%) in the TBI group. The mortality rates ranged from 7.02 to 39.9% (lowest in cardiac surgery and highest in ECMO). The estimated use of EEG was 1.6% in cardiac surgery, 4.1% in TBI, 7.2% in ECMO, 8.2% in cardiac arrest, and 12.1% in HIE, with an overall use of 5.8%. Among common indications for EEG monitoring in critically ill children and neonates, the estimated proportion of patients actually having an EEG is low.

Donkey was introduced into the Americas soon after its discovery in the 15th century. However, there is no historical consensus on how they spread across the continent. In a previous study, two distinct genetic pools (Clusters A -Southern part - and B -Northern part of South America and Central America) were identified, with likely confluence in Colombia. The aim of this study was to evaluate whether the main genetic diversity parameters, such as gene diversity (GD) and allelic richness (k), or the relative contributions of various breeds to these parameters are useful indicators to give genetic support to historical information on putative routes of the spreading of donkeys across the American continent. In full agreement with historical sources suggesting that Greater Antilles were the first breeding nucleus, both total contributions to gene diversity (gGDT) and to allelic richness (CT(k)) showed a higher ability to identify the "abundant centre" of the species on the Continent. Even though there are historical reports suggesting various entry points of the donkey into the continent (e.g. in Brazil), these parameters suggested that, in our dataset, the Cuban donkey population was the more likely representative of the first breeding nucleus of the species. Central and South American donkey populations in the surroundings of the Caribbean Gulf would more likely be early derivatives of Antillean donkey. The strong North-South genetic structure was confirmed for the American donkey metapopulation. Current analyses suggest that populations classified into Cluster A (South) are essentially a sample of the genetic background of Cluster B (North). The Andean route had the highest importance in the formation of the South American populations. The extinction of either population belonging to Cluster B could lead to a decrease in overall genetic diversity both at the gene diversity level (negative gGDT values) and the allelic richness level (positive CT(k) contributions). The opposite pattern is found for populations belonging to Cluster A. The extinction of the populations belonging to Cluster B would decrease the overall American donkey gene diversity in roughly 8% and would dramatically affect the number of alleles in the metapopulation (19.1%). However, the extinction of the donkey populations classified into Cluster A would increase overall gene diversity by 2.2%. Although, the genetic scenario of each individual population varies substantially, the joint conservation of the donkey populations classified into both Clusters A and B is highly advised.

Purpose Conventional video-EEG monitoring is required to diagnose seizures accurately in neonates. This tool is resource-intense and has limited availability in many centers. Seizure prediction models could help allocate resources by improving efficiency in which conventional video-EEG monitoring is used to detect subclinical seizures. The aim of this retrospective study was to create a neonate-specific seizure prediction model using clinical characteristics and EEG background findings. Methods We conducted a 3-year retrospective study of all consecutive neonates who underwent conventional video-EEG monitoring at a tertiary care pediatric hospital. Variables including age, EEG indication, high-risk clinical characteristics, and EEG background informed seizure prediction models based on a multivariable logistic regression model. A Cox proportional hazard regression model was used to construct time to first EEG seizure. Results Prediction models with clinical variables or background EEG features alone versus combined clinical and background EEG features were created from 210 neonates who met inclusion criteria. The combined clinical and EEG model had a higher area under the curve for combined sensitivity and specificity to 83.0% when compared to the clinical model (76.4%) or EEG model (66.2%). The same trend of higher sensitivity of the combined model was found for time to seizure outcome. Conclusions While both clinical and EEG background features were predictive of neonatal seizures, the combination improved overall prediction of seizure occurrence and prediction of time to first seizure as compared with prediction models based solely on clinical or EEG features alone. With prospective validation, this model may improve efficiency of patient-oriented EEG monitoring.

SummaryObjective To identify factors associated with in-hospital mortality in neonates and children undergoing continuous electroencephalography (cEEG) monitoring in the intensive care unit (ICU). Methods We performed a retrospective observational study in patients from birth to 21 years of age who underwent clinically indicated cEEG in the ICU from 2011 to 2013. The main outcome measure was in-hospital mortality. Results Six-hundred and twenty-five patients (54.2% male) met eligibility criteria, of whom 211 were neonates (55% male, 24.8% premature) and 414 were pediatric patients (53.9% male). Electrographic seizures occurred in 176 patients (28.2%) and status epilepticus (SE) occurred in 20 (11.4%). The time from ICU admission to cEEG initiation was 16.7 (5.1–94.4) h. Eighty-nine patients (14.2%) (30 [14.2%] neonates, and 59 [14.3%] pediatric patients) died in the hospital. In neonates—after controlling for gender and prematurity—independent factors associated with mortality were prematurity (odds ratio [OR] 2.63. 95% confidence interval [CI] 1.06–6.5, p = 0.037), presence of status epilepticus (SE); OR 8.82, 95% CI 1.74–44.57, p = 0.008), and time from ICU admission to initiation of cEEG (OR 1.002, 95% CI 1.001–1.004 per hour, p = 0.008]. In pediatric patients—after controlling for gender and age—independent factors associated with mortality were the absence of seizures factors associated with mortality were absence of seizures (OR = 4.3, (95% CI: 1.5–12.4), p = 0.007), the presence of SE (OR 7.76, 95% CI 1.47–40.91, p = 0.016), and the time from ICU admission to initiation of cEEG (OR 1.001, 95% CI 1.0002–1.001, per hour, p = 0.005]. Significance Both presence of electrographic SE and time from ICU admission to cEEG initiation were independent factors associated with mortality in neonates and pediatric patients with cEEG in the ICU.

To describe pediatric patients with convulsive refractory status epilepticus in whom there is intention to use an IV anesthetic for seizure control.Two-year prospective observational study evaluating patients (age range, 1 mo to 21 yr) with refractory status epilepticus not responding to two antiepileptic drug classes and treated with continuous infusion of anesthetic agent.Nine pediatric hospitals in the United States.In a cohort of 111 patients with refractory status epilepticus (median age, 3.7 yr; 50% male), 54 (49%) underwent continuous infusion of anesthetic treatment.The median (interquartile range) ICU length of stay was 10 (3-20) days. Up to four "cycles" of serial anesthetic therapy were used, and seizure termination was achieved in 94% by the second cycle. Seizure duration in controlled patients was 5.9 (1.9-34) hours for the first cycle and longer when a second cycle was required (30 [4-120] hr; p = 0.048). Midazolam was the most frequent first-line anesthetic agent (78%); pentobarbital was the most frequently used second-line agent after midazolam failure (82%). An electroencephalographic endpoint was used in over half of the patients; higher midazolam dosing was used with a burst suppression endpoint. In midazolam nonresponders, transition to a second agent occurred after a median of 1 day. Most patients (94%) experienced seizure termination with these two therapies.Midazolam and pentobarbital remain the mainstay of continuous infusion therapy for refractory status epilepticus in the pediatric patient. The majority of patients experience seizure termination within a median of 30 hours. These data have implications for the design and feasibility of future intervention trials. That is, testing a new anesthetic anticonvulsant after failure of both midazolam and pentobarbital is unlikely to be feasible in a pediatric study, whereas a decision to test an alternative to pentobarbital, after midazolam failure, may be possible in a multicenter multinational study.

Clobazam treatment tailored to the timing of patient's seizures may improve seizure control. We aim to describe the safety and efficacy of higher-evening differential dose of clobazam as add-on therapy in patients with night-time/early morning seizures.Differential dosing with higher evening dosing was started based on a high proportion of seizures (80%) at nighttime (6p.m. to 6a.m.). Differential dosing was defined as providing more than 50% of the total daily dose of clobazam after 6p.m.Twenty-seven patients were treated with clobazam differential dosing as an add-on therapy. The median age was 9.1 years, with 11 (40.7%) females and median of the first follow-up was 2.7 months. Patients with differential dosing tolerated a higher median total clobazam dose of 0.8mg/kg/d at first follow-up, as compared to 0.6mg/kg/d in controls. In differential dose, the median percentage of the total clobazam dose administered in the evening was 66.7%. Differential dose patients exhibited a median seizure reduction of 75% as compared to 50% in controls (p0.005). Patients with generalized seizures benefited the most from differential dosing with a 77.5% median seizure reduction, as compared to 50% in controls (p=0.017).Higher-evening differential dose of clobazam improved seizure control in patients with predominantly nighttime and early-morning seizures. Chronotherapy tailored to the patients' seizure susceptibility patterns may improve care in epilepsy patients as differential dosing may allow for higher overall treatment doses at times of greatest seizure susceptibility without increased side effects at other times.

ObjectiveTo compare the cost-effectiveness of genetic testing strategies in patients with epilepsy of unknown etiology.MethodsThis meta-analysis and cost-effectiveness study compared strategies involving 3 genetic tests: chromosomal microarray (CMA), epilepsy panel (EP) with deletion/duplication testing, and whole-exome sequencing (WES) in a cost-effectiveness model, using “no genetic testing” as a point of comparison.ResultsTwenty studies provided information on the diagnostic yield of CMA (8 studies), EP (9 studies), and WES (6 studies). The diagnostic yield was highest for WES: 0.45 (95% confidence interval [CI]: 0.33–0.57) (0.32 [95% CI: 0.22–0.44] adjusting for potential publication bias), followed by EP: 0.23 (95% CI: 0.18–0.29), and CMA: 0.08 (95% CI: 0.06–0.12). The most cost-effective test was WES with an incremental cost-effectiveness ratio (ICER) of $15,000/diagnosis. However, after adjusting for potential publication bias, the most cost-effective test was EP (ICER: $15,848/diagnosis) followed by WES (ICER: $34,500/diagnosis). Among combination strategies, the most cost-effective strategy was WES, then if nondiagnostic, EP, then if nondiagnostic, CMA (ICER: $15,336/diagnosis), although adjusting for potential publication bias, the most cost-effective strategy was EP ± CMA ± WES (ICER: $18,385/diagnosis). While the cost-effectiveness of individual tests and testing strategies overlapped, CMA was consistently less cost-effective than WES and EP.ConclusionWES and EP are the most cost-effective genetic tests for epilepsy. Our analyses support, for a broad population of patients with unexplained epilepsy, starting with these tests. Although less expensive, CMA has lower yield, and its use as the first-tier test is thus not supported from a cost-effectiveness perspective.

New research indicates that most patients with epilepsy exhibit cyclic (24 h or multi-day) seizure patterns. The findings could have important implications for the design of antiseizure drug regimens.

ObjectiveCompare the cost and effectiveness of nonbenzodiazepine antiepileptic drugs (non-BZD AEDs) for treatment of BZD-resistant convulsive status epilepticus (SE).MethodsDecision analysis model populated with effectiveness data from a systematic review and meta-analysis of the literature, and cost data from publicly available prices. The primary outcome was cost per seizure stopped ($/SS). Sensitivity analyses evaluated the robustness of the results across a wide variation of the input parameters.ResultsWe included 24 studies with 1,185 SE episodes. The most effective non-BZD AED was phenobarbital (PB) with a probability of SS of 0.8 (95% confidence interval [CI]: 0.69–0.88), followed by valproate (VPA) (0.71 [95% CI: 0.61–0.79]), lacosamide (0.66 [95% CI: 0.51–0.79]), levetiracetam (LEV) (0.62 [95% CI: 0.5–0.73]), and phenytoin/fosphenytoin (PHT) (0.53 [95% CI: 0.39–0.67]). In pairwise comparisons, PB was more effective than PHT (p= 0.002), VPA was more effective than PHT (p= 0.043), and PB was more effective than LEV (p= 0.018). The most cost-effective non-BZD AED was LEV (incremental cost-effectiveness ratio [ICER]: $18.55/SS), followed by VPA (ICER: $94.44/SS), and lastly PB (ICER: $847.22/SS). PHT and lacosamide were not cost-effective compared to the other options. Sensitivity analyses showed marked overlap in cost-effectiveness, but PHT was consistently less cost-effective than LEV, VPA, and PB.ConclusionVPA and PB were more effective than PHT for SE. There is substantial overlap in the cost-effectiveness of non-BZD AEDs for SE, but available evidence does not support the preeminence of PHT, neither in terms of effectiveness nor in terms of cost-effectiveness.

Purpose To evaluate whether the onset of pediatric refractory status epilepticus (rSE) is related to time of day. Method We analyzed the time of day for the onset of rSE in this prospective observational study performed from June 2011 to May 2019 in pediatric patients (1 month to 21 years of age). We evaluated the temporal distribution of pediatric rSE utilizing a cosinor analysis. We calculated the midline estimating statistic of rhythm (MESOR) and amplitude. MESOR is the estimated mean number of rSE episodes per hour if they were evenly distributed. Amplitude is the difference between MESOR and maximum rSE episodes/hour, or between MESOR and minimum rSE episodes/hour. We also evaluated the temporal distribution of time to treatment. Results We analyzed 368 patients (58% males) with a median (p25 – p75) age of 4.2 (1.3–9.7) years. The MESOR was 15.3 (95% CI: 13.9–16.8) and the amplitude was 3.2 (95% CI: 1.1–5.3), p = 0.0024, demonstrating that the distribution is not uniform, but better described as varying throughout the day with a peak in the morning (11am–12 pm) and trough at night (11 pm–12 am). The duration from rSE onset to application of the first non-benzodiazepine antiseizure medication peaked during the early morning (2am–3 am) with a minimum during the afternoon (2 pm–3 pm) (p = 0.0179). Conclusions The distribution of rSE onset is not uniform during the day. rSE onset shows a 24-h distribution with a peak in the mid-morning (11am–12 pm) and a trough at night (11 pm-12am).

Purpose Rescue medications for status epilepticus (SE) have a relatively high rate of failure. The purpose of this review is to summarize the evidence for the efficacy of novel drugs and early polypharmacotherapy for SE. Method Literature review. Results New drugs and treatment strategies aim to target the pathophysiology of SE in order to improve seizure control and outcomes. Changes at the synapse level during SE include a progressive decrease in synaptic GABAA receptors and increase in synaptic NMDA receptors. These changes tend to promote self-sustaining seizures. Current SE guidelines recommend a rapid stepwise treatment using benzodiazepines in monotherapy as the first-line treatment, targeting GABAA synaptic receptors. Novel treatment approaches target GABAA synaptic and extrasynaptic receptors with allopregnanolone, and NMDA receptors with ketamine. Novel rescue treatments used for SE include topiramate, brivaracetam, and perampanel, which are already marketed in epilepsy. Some available drugs not marketed for use in epilepsy have been used in the treatment of SE, and other agents are being studied for this purpose. Early polytherapy, most frequently combining a benzodiazepine with a second-line drug or an NMDA receptor antagonist, might potentially increase seizure control with relatively minor increase in side effects. Although many preclinical studies support novel drugs and early polytherapy in SE, human studies are scarce and inconclusive. Currently, evidence is lacking to recommend specific combinations of these new agents. Conclusions Novel drugs and strategies target the underlying pathophysiology of SE with the intent to improve seizure control and outcomes.