Early role for a Na+,K+-ATPase (ATP1A3) in brain development.

Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na+) and potassium (K+) ions across the plasma membrane, a function catalyzed by the Na+,K+-ATPase α-subunit. Here, we describe ATP1A3 variants encoding dysfunctional α3-subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal ATP1A3 expression, we built an ATP1A3 transcriptional atlas of fetal cortical development using mRNA in situ hybridization and transcriptomic profiling of ∼125,000 individual cells with single-cell RNA sequencing (Drop-seq) from 11 areas of the midgestational human neocortex. We found that fetal expression of ATP1A3 is most abundant to a subset of excitatory neurons carrying transcriptional signatures of the developing subplate, yet also maintains expression in nonneuronal cell populations. Moving forward a year in human development, we profiled ∼52,000 nuclei from four areas of an infant neocortex and show that ATP1A3 expression persists throughout early postnatal development, most predominantly in inhibitory neurons, including parvalbumin interneurons in the frontal cortex. Finally, we discovered the heteromeric Na+,K+-ATPase pump complex may form nonredundant cell-type-specific α-ß isoform combinations, including α3-ß1 in excitatory neurons and α3-ß2 in inhibitory neurons. Together, the developmental malformation phenotype of affected individuals and single-cell ATP1A3 expression patterns point to a key role for α3 in human cortex development, as well as a cell-type basis for pre- and postnatal ATP1A3-associated diseases.

Added value of corpus callosotomy following vagus nerve stimulation in children with Lennox-Gastaut syndrome: A multicenter, multinational study.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a severe form of epileptic encephalopathy, presenting during the first years of life, and is very resistant to treatment. Once medical therapy has failed, palliative surgeries such as vagus nerve stimulation (VNS) or corpus callosotomy (CC) are considered. Although CC is more effective than VNS as the primary neurosurgical treatment for LGS-associated drop attacks, there are limited data regarding the added value of CC following VNS. This study aimed to assess the effectiveness of CC preceded by VNS. METHODS: This multinational, multicenter retrospective study focuses on LGS children who underwent CC before the age of 18 years, following prior VNS, which failed to achieve satisfactory seizure control. Collected data included epilepsy characteristics, surgical details, epilepsy outcomes, and complications. The primary outcome of this study was a 50% reduction in drop attacks. RESULTS: A total of 127 cases were reviewed (80 males). The median age at epilepsy onset was 6 months (interquartile range [IQR] = 3.12-22.75). The median age at VNS surgery was 7 years (IQR = 4-10), and CC was performed at a median age of 11 years (IQR = 8.76-15). The dominant seizure type was drop attacks (tonic or atonic) in 102 patients. Eighty-six patients underwent a single-stage complete CC, and 41 an anterior callosotomy. Ten patients who did not initially have a complete CC underwent a second surgery for completion of CC due to seizure persistence. Overall, there was at least a 50% reduction in drop attacks and other seizures in 83% and 60%, respectively. Permanent morbidity occurred in 1.5%, with no mortality. SIGNIFICANCE: CC is vital in seizure control in children with LGS in whom VNS has failed. Surgical risks are low. A complete CC has a tendency toward better effectiveness than anterior CC for some seizure types.

Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome.

OBJECTIVE: Developmental epileptic encephalopathies (DEEs) are genetically heterogeneous severe childhood-onset epilepsies with developmental delay or cognitive deficits. In this study, we explored the pathogenic mechanisms of DEE-associated de novo mutations in the CACNA1A gene. METHODS: We studied the functional impact of four de novo DEE-associated CACNA1A mutations, including the previously described p.A713T variant and three novel variants (p.V1396M, p.G230V, and p.I1357S). Mutant cDNAs were expressed in HEK293 cells, and whole-cell voltage-clamp recordings were conducted to test the impacts on CaV 2.1 channel function. Channel localization and structure were assessed with immunofluorescence microscopy and three-dimensional (3D) modeling. RESULTS: We find that the G230V and I1357S mutations result in loss-of-function effects with reduced whole-cell current densities and decreased channel expression at the cell membrane. By contrast, the A713T and V1396M variants resulted in gain-of-function effects with increased whole-cell currents and facilitated current activation (hyperpolarized shift). The A713T variant also resulted in slower current decay. 3D modeling predicts conformational changes favoring channel opening for A713T and V1396M. SIGNIFICANCE: Our findings suggest that both gain-of-function and loss-of-function CACNA1A mutations are associated with similarly severe DEEs and that functional validation is required to clarify the underlying molecular mechanisms and to guide therapies.

Heart rate variability in epilepsy: A potential biomarker of sudden unexpected death in epilepsy risk.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is a tragic and devastating event for which the underlying pathophysiology remains poorly understood; this study investigated whether abnormalities in heart rate variability (HRV) are linked to SUDEP in patients with epilepsy due to mutations in sodium channel (SCN) genes. METHODS: We retrospectively evaluated HRV in epilepsy patients using electroencephalographic studies to study the potential contribution of autonomic dysregulation to SUDEP risk. We extracted HRV data, in wakefulness and sleep, from 80 patients with drug-resistant epilepsy, including 40 patients with mutations in SCN genes and 40 control patients with non-SCN drug-resistant epilepsy. From the SCN group, 10 patients had died of SUDEP. We compared HRV between SUDEP and non-SUDEP groups, specifically studying awake HRV and sleep:awake HRV ratios. RESULTS: The SUDEP patients had the most severe autonomic dysregulation, showing lower awake HRV and either extremely high or extremely low ratios of sleep-to-awake HRV in a subgroup analysis. A secondary analysis comparing the SCN and non-SCN groups indicated that autonomic dysfunction was slightly worse in the SCN epilepsy group. SIGNIFICANCE: These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of HRV to SUDEP merits further study; HRV may eventually have potential as a biomarker of SUDEP risk, which would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

Severe infantile onset developmental and epileptic encephalopathy caused by mutations in autophagy gene WDR45.

Heterozygous de novo variants in the autophagy gene, WDR45, are found in beta-propeller protein-associated neurodegeneration (BPAN). BPAN is characterized by adolescent onset dementia and dystonia; 66% patients have seizures. We asked whether WDR45 was associated with developmental and epileptic encephalopathy (DEE). We performed next generation sequencing of WDR45 in 655 patients with developmental and epileptic encephalopathies. We identified 3/655 patients with DEE plus 4 additional patients with de novo WDR45 pathogenic variants (6 truncations, 1 missense); all were female. Six presented with DEE and 1 with early onset focal seizures and profound regression. Median seizure onset was 12 months, 6 had multiple seizure types, and 5/7 had focal seizures. Three patients had magnetic resonance susceptibility-weighted imaging; blooming was noted in the globus pallidi and substantia nigra in the 2 older children aged 4 and 9 years, consistent with iron accumulation. We show that de novo pathogenic variants are associated with a range of developmental and epileptic encephalopathies with profound developmental consequences.

Synaptic plexi of U-fibre layer beneath focal cortical dysplasias: Role in epileptic networks.

AIMS: The purpose is to demonstrate heterotopic neurones and their synaptic plexi within the U-fibre layer beneath focal cortical dysplasias (FCD). MATERIALS AND METHODS: This prospective qualitative neuropathological study included 23 patients, ages from 3 months to 17 years: resections at epileptogenic foci in 10 FCD Ia; 6 FCD IIa,b; 2 FCD IIIa,d; 3 HME; 2 TSC; 8 controls. TECHNIQUES: immunoreactivities for synaptophysin, NeuN, MAP2, SMI32, calretinin, GFAP, vimentin, α-B-crystallin. Bielschowsky silver; LFB; mitochondrial enzyme histochemistry (frozen sections). RESULTS: Subcortical white matter in FCD exhibited neuronal dispersion within U-fibres in FCD I, II and also deep white matter neuronal clusters in FCD II, HME, TSC. Neurones reacted for NeuN, MAP2; few for calretinin. Synaptophysin well demonstrated elaborate U-fibre plexi including axones between U-fibre neurones and projecting to overlying cortex. Deep white matter axones interconnected heterotopia but did not penetrate U-fibres to reach cortex. Mitochondrial enzymatic activity was intense in some neurones, normal in others. Glial α-B-crystallin served as a marker of epileptogenic zones identified electrographically. CONCLUSION: U-fibre synaptic plexi contribute to excitatory circuitry in the cortex and thus to epileptic networks. Deep white matter neurones form local, less integrated plexi except transmantle dysplasias continuous with cortex. U-fibres may be a barrier to axonal penetration from deep heterotopia. Hypermetabolic neurones suggest repetitive ictogenic depolarizations. Gyral resections should include the U-fibre layer. Neuropathology reports should describe subcortical plexi. Synaptophysin immunoreactivity is a valuable supplement for this purpose.
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Introduction of Continuous Video EEG Monitoring into 2 Different NICU Models by Training Neonatal Nurses.

BACKGROUND: Continuous video electroencephalographic (EEG) (cvEEG) monitoring is emerging as the standard of care for diagnosis and management of neonatal seizures. However, cvEEG is labor-intensive and the need to initiate and interpret studies on a 24-hour basis is a major limitation. PURPOSE: This study aims at establishing consistency in monitoring of newborns admitted to 2 different neonatal intensive care units (NICUs) managed by the same neurocritical care team. METHODS: Neonatal nurses were trained to apply scalp electrodes, troubleshoot technical issues, and identify amplitude-integrated EEG abnormalities. Guidelines, checklists, and visual training modules were developed. A central network system allowed remote access to the cvEEGs by the epileptologist for timely interpretation and feedback. A cohort of 100 infants with moderate to severe hypoxic-ischemic encephalopathy before and after the training program was compared. RESULTS: During the study period, 192 cvEEGs were obtained. The time to initiate brain monitoring decreased by 31.5 hours posttraining; this, in turn, led to an increase in electrographic seizure detection (20% before vs 34% after), decrease in seizure clinical misdiagnosis (65% before and 36% after), and reduction in antiseizure medication burden. IMPLICATIONS FOR PRACTICE: Training experienced NICU nurses to set up, start, and monitor cvEEGs can decrease the time to initiate cvEEGs, which may lead to better seizure diagnosis and management. IMPLICATIONS FOR RESEARCH: Further understanding of practice bundles for best supporting infants at risk and being treated for seizures needs to be evaluated for integration into practice.Video Abstract Available at https://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx.

Neuropsychological Outcome in Perinatal Stroke Associated With Epileptiform Discharges in Sleep.

BACKGROUND: Patients with arterial perinatal stroke often suffer long-term motor sequelae, difficulties in language, social development, and behaviour as well as epilepsy. Despite homogeneous lesions, long-term behavioural and cognitive outcomes are variable and unpredictable. Sleep-related epileptic encephalopathies can occur after early brain injury and are associated with global developmental delays. We hypothesized that sleep-potentiated epileptiform abnormalities are associated with worse developmental outcomes after perinatal stroke. METHODS: Participants were identified from a population-based cohort (Alberta Perinatal Stroke Project). Inclusion criteria were magnetic resonance imaging-confirmed arterial perinatal stroke, age 4 to 18 years, electroencephalogram (EEG) including sleep, and comprehensive neuropsychological evaluation. Sleep-related EEG abnormalities were categorized by an epileptologist blinded to the cognitive outcome. Associations between EEG classification and neuropsychological outcomes were explored (t tests, Bonferroni correction for multiple comparisons). RESULTS: Of 128 potentially eligible participants, 34 (53% female) had complete EEG (mean age, 8.1 years; range, 0.2-16.4) and neuropsychology testing (mean age, 9.8 years; range 4.4-16.7). Twelve (35%) were classified as having electrical status epilepticus in sleep. Patients with abnormal EEGs were more likely to have statistically worse scores when corrected for multiple comparisons, in receptive language (median, 1st percentile; IQR 1-7th percentile; p<0.05), and externalizing behaviours (median, 82nd percentile; IQR, 79-97th percentile; p<0.05). CONCLUSIONS: Developmental outcome in language and behaviour in children with arterial perinatal stroke is associated with electrical status epilepticus in sleep. Increased screening with sleep EEG is suggested, whereas further studies are necessary to determine if treatment of EEG abnormalities can improve outcome.

Does treatment have an impact on incidence and risk factors for autism spectrum disorders in children with infantile spasms?

OBJECTIVE: Infantile spasms (IS) are a severe form of childhood epilepsy associated with autism spectrum disorders (ASD) in up to 35% of cases. The objective of this post hoc analysis of our randomized control trial was to determine whether rapid diagnosis and treatment of IS could limit the incidence of ASD while identifying risk factors related to ASD outcome. METHODS: Patients with IS were randomized in a standardized diagnostic and treatment protocol. Clinical and electroencephalogram (EEG) evaluations were completed at all eight visits over 5 years, while cognitive evaluations were administered at 0, 6, 24 and 60 months, respectively. Autism was initially screened by means of the Checklist for Autism in Toddlers (CHAT) at 24 months, and formally assessed at the 30-and 60-month follow-ups using the Autism Diagnostic Observation Schedule-Generic (ADOS-G). RESULTS: Of the 69 patients included in the study, 25 could not be assessed due to severe delay or death. Eleven of the 42 patients screened with CHAT, were found to be at risk of an ASD outcome. ADOS was performed in 44 and 10 were diagnosed with ASD. The CHAT proved to correlate highly with the ADOS (80% ppv). Only patients with symptomatic IS developed ASD (p = 0.003). Earlier diagnosis or successful treatment did not correlate with a reduced rate of ASD. Other risk factors were identified such as having chronic epileptic discharges in the frontotemporal areas after disappearance of hypsarrhythmia (p = 0.005 and p = 0.007) and being of nonwhite origin (p = 0.009). SIGNIFICANCE: ASD was only observed in children with sympyomatic IS. Other clinical risk factors include chronic frontotemporal epileptic activity and being of non-white origin. Early diagnosis and treatment did not prevent ASD as an outcome of IS. However, patients at risk for ASD could be identified early on and should in the future benefit from early intervention to potentially improve their long-term outcome.

Infraslow status epilepticus: A new form of subclinical status epilepticus recorded in a child with Sturge-Weber syndrome.

BACKGROUND: Analysis of infraslow EEG activity (ISA) has shown potential in the evaluation of patients with epilepsy and in the differentiation between focal and generalized epilepsies. Infraslow EEG activity analysis may also provide insights into the pathophysiology of refractory clinical and subclinical status epilepticus. The purpose of this report is to describe a girl with Sturge-Weber syndrome (SWS) who presented with a 96-h refractory encephalopathy and nonischemic hemiparesis and who was identified to have infraslow status epilepticus (ISSE), which successfully resolved after midazolam administration. METHODS: The continuous EEG recording of a 5-year-old girl with known structural epilepsy due to Sturge-Weber syndrome is presented. The patient presented to the ED with acute confusion, eye deviation, and right hemiparesis similar to two previous admissions. Despite administration of lorazepam, fosphenytoin, phenobarbital, and valproic loads, the patient showed no improvement in the clinical condition after 48 h. The continuous video-EEG monitoring (VEM) showed continuous severe diffuse nonrhythmic asymmetric slowing but no apparent ictal activity on continuous conventional EEG recording settings. As brain CT, CTA, CTV, and complete MRI scans including DWI obtained within 72 h of presentation failed to demonstrate any ischemic changes, analysis of the EEG infraslow (ISA) activity was undertaken using LFF: 0.01 Hz and HFF: of 0.1 Hz, respectively. RESULTS: Continuous subclinical unilateral rhythmic ictal ISA was identified. This was only evident on the left hemisphere which correlated with the structural changes due to SWS. A trial of continuous 120 to 240 µg/kg/h of IV midazolam resulted in immediate resolution of the contralateral hemiparesis and encephalopathy. CONCLUSION: Continuous prolonged rhythmic ictal infraslow activity (ISA) can cause super-refractory subclinical focal status epilepticus. This has not been previously reported, and we propose that this be called infraslow status epilepticus (ISSE). Infraslow EEG activity analysis should be performed in all patients with unexplained subclinical status epilepticus. This article is part of a Special Issue entitled "Status Epilepticus".

Reliability and variability of diffusion tensor imaging (DTI) tractography in pediatric epilepsy.

BACKGROUND: Diffusion tensor imaging (DTI) tractography is useful for isolating white matter (WM) trajectories and exploring microstructural integrity. Tractography can be performed on atypical brain anatomy when landmarks are malformed or displaced but has been criticized for its subjectivity even when investigators have advanced anatomical knowledge. Also, little is known about the variability and reliability of tractography as a tool for assessing white matter damage in clinical populations such as children with pediatric epilepsy. METHODS: Children diagnosed with epilepsy [N=43, mean age=11.7 years, standard deviation=3.7 years, 53% male] underwent a DTI sequence (6 directions, 2×2×3 mm voxels). Tractography for six white matter tracts (anterior forceps, fornices, bilateral arcuate fasciculi, and bilateral anterior cingula) was conducted twice by two experienced tractographers. Percent coefficient of variation (CV; for measuring variability) and intraclass correlation coefficients (ICCs; for measuring reliability) were calculated for tract volume and diffusion variables (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD] and radial diffusivity [RD]). RESULTS: Diffusion variables showed low variability (CV=2.7-8.8%) and very high reliability (ICC=.97-.99) except for limbic tracts [fornix (ICC=.75-.94); cingulum (ICC=.71-.98)]. Tract volume measurements showed high variability (CV=21.9-62.0%) and moderate reliability (ICC=.54-.99). Overall, tract volume measurements were much more variable and less reliable than diffusion characteristics. Limbic structures showed more variability compared with others. CONCLUSIONS: This suggests that DTI tractography and resulting diffusivity variables can reliably inform on the integrity of WM structures in a clinical sample with pediatric epilepsy and highlights the importance of reporting reliability information in studies that aim to answer clinical questions about WM integrity.

Neuropsychological profiles of two patients with differing SCN8A-pathogenic variants.

The impact of gene-related early infancy onset epilepsies in cognitive development can be potentially devastating. Here we report two cases of SCN8A-related epilepsy that highlight the neuropsychological heterogeneity seen with differing de-novo pathogenic variants. Case 1 is a 6-year-old right-handed girl who presented with SCN8A-developmental and epileptic encephalopathy (SCN8A-DEE) and a missense pathogenic variant (c.802A > C), not previously documented in the literature. Her history includes speech and motor delay, with focal motor seizures starting at 4-months. Early EEG showed bilateral centroparietal epileptiform discharges. She shows motor and language delays and prominent motor tics. Testing documented Intellectual Disability (ID) (Mild) with widespread neuropsychological deficits (i.e., academics, attention/executive functions, memory, visual-spatial skills, fine motor, language). Case 2 is an 8-year-old right-handed girl who presented with SCN8A-related epilepsy with c.5630A > G pathogenic variant with seizure onset at 5-months. Her initial EEG showed right occipital spikes. She shows low average intellect and average academics, but evaluation documented attention deficits, fine motor delays, and behavioral issues in addition to tics; she was diagnosed with Attention-Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, Obsessive Compulsive Disorder, and Tourette's. These cases expand limited knowledge regarding neuropsychological functioning of children with SCN8A-related epilepsy with unique de-novo pathogenic variants. While SCN8A-DEE is clearly associated with ID, other pathogenic variants may show better preserved intellect, despite other neuropsychological and behavioral concerns.

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.

Mitochondrial "hypermetabolic" neurons in paediatric epileptic foci.

BACKGROUND: Repetitively discharging neurons in epileptic foci have a high energy requirement that might be demonstrated histochemically as increased mitochondrial enzymatic activity in brain resections for epilepsy in children. MATERIALS AND METHODS: Frozen sections were studied histochemically of 10 brain resections from 7 epileptic children, 2 months to 17 years of age. None had mitochondrial disease. Three patients had tuberous sclerosis (TS) or hemimegalencephy (HME). Tissues included hippocampus and neocortex. Oxidative enzymes were studied for respiratory chain complexes I, II, IV, using the muscle biopsy protocol. In addition, immunoreactivities of α-B-crystallin and transmission electron microscopy (EM) were performed. RESULTS: Oxidative activities were variable in adjacent neurons within a field: a minority were intense, adjacent to neurons with weaker mitochondrial activity exhibiting poor contrast of the soma because of similar oxidative activity in surrounding neuropil. Endothelium of vessels uniformly exhibits strong activity. Alpha-B-crystallin reactivity was strong at these foci. EM confirmed an abundance of neuronal mitochondria with normal cristae. In TS and HME, many dysplastic neurons showed intense activity; balloon cells had sparse activity. CONCLUSIONS: Histochemistry of mitochondrial oxidative enzymes reveals scattered and clustered neurons with stronger activities than others at epileptic foci. Such intensely staining neurons may be functionally "hypermetabolic" but they do not signify mitochondrial disease. Individual intensely stained neurons might be epileptogenic, but do not denote an epileptogenic field in the same manner as α-B-crystallin, which also was strongly reactive in these foci.

Epilepsy Surgery in Children.

Epilepsy in children continues to present a major medical and economic burden on society. Left untreated, seizures can present the risk of sudden death and severe cognitive impairment. It is understood that primary care providers having concerns about abnormal movements or behaviors in children will make a prompt referral to a trusted pediatric neurologist. The authors present a brief introduction to seizure types, classification, and management with particular focus on what surgery for epilepsy can offer. Improved seizure control and its attendant improvements in quality of life can be achieved with timely referral and intervention.

What is the optimal duration for vigabatrin monotherapy in patients with infantile spasms: 6 months or longer?

Vigabatrin (VGB) is approved as monotherapy for pediatric patients with Infantile Spasms (IS). Duration of VGB use should be limited because of the risk of retinal and neurotoxicity, but the optimal length of treatment is unknown. Our study aimed to determine the risk of spasms relapse after 6 months of VGB as first-line therapy in IS patients deemed VGB good responders. The participants were 44 infants with IS who demonstrated both absence of clinical spasms and hypsarrhythmia four weeks after starting VGB, obtained from two cohorts: 29 patients from a multicenter prospective cohort and 15 patients from a retrospective single-center cohort. We divided them post hoc into two groups according to the duration of VGB treatment: 6-month group (n=34) and >6-month group (n=10) and compared outcome between the two groups. No patient in either group had a relapse of spasms. For patients with non-identified etiology (NIE) in the 6 months treatment group, no other seizure types were observed. Late epilepsy, in the form of focal seizures, emerged in only 5/37 patients (3/30 in the 6-month treatment group; 2/7 in the extended treatment group); all within the first 6-9 months after VGB initiation. Our study provides substantial evidence that a shortened VGB course of 6 months could be sufficient to treat and prevent relapse of spasms in children with IS, particularly those with NIE.

Contribution of rare genetic variants to drug response in absence epilepsy.

OBJECTIVE: We investigated the possible significance of rare genetic variants to response to valproic acid (VPA) and ethosuximide (ETX) in patients with absence epilepsy. Our primary hypothesis was that rare CACNA1H variants are more frequent in ETX-non-responsive patients compared to ETX-responsive. Our secondary hypothesis was that rare variants in GABA-receptor genes are more frequent in VPA-non-responsive patients compared to VPA-responsive. METHODS: We recruited patients with absence epilepsy treated with both VPA and ETX, and performed whole exome sequencing in order to investigate the potential role of rare variants in CACNA1H, other voltage-gated calcium channel (VGCC) genes, or GABA-receptor genes in predicting response to ETX or VPA. RESULTS: Sixty-two patients were included; 12 were ETX-responsive, 14 VPA-responsive, and 36 did not have a clear positive response to either medication. We did not find significant enrichment inCACNA1H rare variants in ETX-responsive patients (odds ratio 3.43; 0.43-27.65; p = 0.20), nor was there enrichment for other VGCC genes. No significant enrichment of GABA-receptor gene rare variants was seen for VPA-non-responsive patients versus VPA-responsive. We found enrichment of rare GABA-receptor variants in our absence cohort compared to controls (odds ratio 3.82; 1.68-8.69). There was no difference in frequency of CACNA1H rs61734410 and CACNA1I rs3747178 polymorphisms between ETX-responsive and ETX-non-responsive groups; these polymorphisms have previously been reported to predict lack of response to ETX in absence epilepsy. SIGNIFICANCE: We conclude that if CACNA1H rare variants predict lack of response to ETX, a larger sample is necessary to test this with sufficient power. Increased GABA-receptor gene rare variant frequency in absence epilepsy patients who fail initial anti-seizure therapy suggests subtle GABA receptor dysfunction may contribute to the underlying pathophysiology.

Creation and implementation of an electronic health record note for quality improvement in pediatric epilepsy: Practical considerations and lessons learned.

OBJECTIVE: To describe the development of the Pediatric Epilepsy Outcome-Informatics Project (PEOIP) at Alberta Children's Hospital (ACH), which was created to provide standardized, point-of-care data entry; near-time data analysis; and availability of outcome dashboards as a baseline on which to pursue quality improvement. METHODS: Stakeholders involved in the PEOIP met weekly to determine the most important outcomes for patients diagnosed with epilepsy, create a standardized electronic note with defined fields (patient demographics, seizure and syndrome type and frequency and specific outcomes- seizure type and frequency, adverse effects, emergency department visits, hospitalization, and care pathways for clinical decision support. These were embedded in the electronic health record from which the fields were extracted into a data display platform that provided patient- and population-level dashboards updated every 36 hours. Provider satisfaction and family experience surveys were performed to assess the impact of the standardized electronic note. RESULTS: In the last 5 years, 3,245 unique patients involving 13, 831 encounters had prospective, longitudinal, standardized epilepsy data accrued via point-of-care data entry into an electronic note as part of routine clinical care. A provider satisfaction survey of the small number of users involved indicated that the vast majority believed that the note makes documentation more efficient. A family experience survey indicated that being provided with the note was considered "valuable" or "really valuable" by 86% of respondents and facilitated communication with family members, school, and advocacy organizations. SIGNIFICANCE: The PEOIP serves as a proof of principle that information obtained as part of routine clinical care can be collected in a prospective, standardized, efficient manner and be used to construct filterable process/outcome dashboards, updated in near time (36 hours). This information will provide the necessary baseline data on which multiple of QI projects to improve meaningful outcomes for children with epilepsy will be based.

Single-center experience with Beta-propeller protein-associated neurodegeneration (BPAN); expanding the phenotypic spectrum.

Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) that presents with childhood developmental delay (especially speech delay), occasionally associated with epileptic encephalopathy, autism, or Rett-like syndrome. The majority of children described to date have been severely affected, with little to no expressive speech function, severe developmental delay, and cognitive impairment. Herein, five additional patients with BPAN identified in the same center in Canada are described, four with the typical severe phenotype and one with a milder phenotype. Our findings provide further evidence that a spectrum of severity exists for this rare and newly described condition. Challenges in identifying iron accumulation on brain MRI are also addressed. Additionally, the importance of including the WDR45 gene on epilepsy and Rett-like syndrome genetic panels is highlighted.

Implementation of Neonatal Neurocritical Care Program Improved Short-Term Outcomes in Neonates With Moderate-to-Severe Hypoxic Ischemic Encephalopathy.

BACKGROUND: Despite the introduction of therapeutic hypothermia, infants with moderate-to-severe hypoxic-ischemic encephalopathy remain at risk of mortality and morbidity. A dedicated service with standardized management protocols and improved communication may help improve care. We aimed to evaluate the impact of a dedicated neonatal neurocritical care service on short-term outcomes in infants with hypoxic-ischemic encephalopathy. METHODS: We performed a retrospective cohort study (July 2008 to December 2017) on term and near-term infants admitted to two tertiary neonatal intensive care units with moderate-to-severe hypoxic-ischemic encephalopathy, before and after neonatal neurocritical care service implementation. The primary outcome was brain magnetic resonance imaging findings consistent with those of hypoxic-ischemic encephalopathy. Secondary outcomes included the cooling initiation rate, hospital stay duration, antiseizure medication use, and inotrope use. Regression analysis and interrupted time series analysis were performed after adjusting for confounding factors. RESULTS: In total, 216 infants with moderate-to-severe hypoxic-ischemic encephalopathy were analyzed-109 before and 107 after neonatal neurocritical care implementation. After adjusting for confounding factors, there was a significant reduction in primary outcomes (adjusted odds ratio: 0.3, confidence interval: 0.15 to 0.57, P < 0.001) after neonatal neurocritical care implementation. Average hospital stay duration reduced by 5.2 days per infant (P = 0.03), identification of eligible infants for cooling improved (P < 0.001), antiseizure medication use reduced (P = 0.001), and early inotropes use reduced (P = 0.04). CONCLUSION: Implementation of a neonatal neurocritical care service associated with decreased brain injury shortened the hospital stay duration and improved the care of infants with moderate-to-severe hypoxic-ischemic encephalopathy.