Pediatric Palliative Epilepsy Surgery: A Report From the Pediatric Epilepsy Research Consortium (PERC) Surgery Database.

BACKGROUND: Epilepsy surgery is an underutilized resource for children with drug-resistant epilepsy. Palliative and definitive surgical options can reduce seizure burden and improve quality of life. Palliative epilepsy surgery is often seen as a "last resort" compared to definitive surgical options. We compare patient characteristics between palliative and definitive epilepsy surgical patients and present palliative surgical outcomes from the Pediatric Epilepsy Research Consortium surgical database. METHODS: The Pediatric Epilepsy Research Consortium Epilepsy Surgery database is a prospective registry of patients aged 0-18 years undergoing evaluation for epilepsy surgery at 20 pediatric epilepsy centers. We included all children with completed surgical therapy characterized as definitive or palliative. Demographics, epilepsy type, age of onset, age at referral, etiology of epilepsy, treatment history, time-to-referral/evaluation, number of failed anti-seizure medications (ASMs), imaging results, type of surgery, and postoperative outcome were acquired. RESULTS: Six hundred forty patients undergoing epilepsy surgery were identified. Patients undergoing palliative procedures were younger at seizure onset (median: 2.1 vs 4 years, P= 0.0008), failed more ASM trials before referral for presurgical evaluation (P=<0.0001), and had longer duration of epilepsy before referral for surgery (P=<0.0001). During presurgical evaluation, patients undergoing palliative surgery had shorter median duration of video-EEG data collected (P=0.007) but number of cases where ictal data were acquired was similar between groups. The most commonly performed palliative procedure was corpus callosotmy (31%), followed by lobectomy (21%) and neuromodulation (82% responsive neurostimulation vs 18% deep brain stimulation). Palliative patients were further categorized into traditionally palliative procedures vs traditionally definitive procedures. The majority of palliative patients had 50% reduction or better in seizure burden. Seizure free outcomes were significantly higher among those with traditional definitive surgeries, 41% (95% confidence interval: 26% to 57%) compared with traditional palliative surgeries and 9% (95% confidence interval: 2% to 17%). Rate of seizure freedom was 46% at 24 months or greater of follow-up in the traditional definitive group. CONCLUSIONS: Patients receiving palliative epilepsy surgery trialed more ASMs, were referred later after becoming drug resistant, and had longer gaps between drug resistance and epilepsy surgery compared with patients undergoing definitive epilepsy surgery. The extent of surgical evaluation is impacted if surgery is thought to be palliative. A majority of palliative surgery patients achieved >50% seizure reduction at follow-up, both in groups that received traditionally palliative and traditionally definitive surgical procedures. Palliative surgical patients can achieve greater seizure control and should be referred to an epilepsy surgery center promptly after failing two appropriate anti-seizure medications.

A comprehensive systematic literature review of the burden of illness of Lennox-Gastaut syndrome on patients, caregivers, and society.

Fully elucidating the burden that Lennox-Gastaut syndrome (LGS) places on individuals with the disease and their caregivers is critical to improving outcomes and quality of life (QoL). This systematic literature review evaluated the global burden of illness of LGS, including clinical symptom burden, care requirements, QoL, comorbidities, caregiver burden, economic burden, and treatment burden (PROSPERO ID: CRD42022317413). MEDLINE, Embase, and the Cochrane Library were searched for articles that met predetermined criteria. After screening 1442 deduplicated articles and supplementary manual searches, 113 articles were included for review. A high clinical symptom burden of LGS was identified, with high seizure frequency and nonseizure symptoms (including developmental delay and intellectual disability) leading to low QoL and substantial care requirements for individuals with LGS, with the latter including daily function assistance for mobility, eating, and toileting. Multiple comorbidities were identified, with intellectual disorders having the highest prevalence. Although based on few studies, a high caregiver burden was also identified, which was associated with physical problems (including fatigue and sleep disturbances), social isolation, poor mental health, and financial difficulties. Most economic analyses focused on the high direct costs of LGS, which arose predominantly from medically treated seizure events, inpatient costs, and medication requirements. Pharmacoresistance was common, and many individuals required polytherapy and treatment changes over time. Few studies focused on the humanistic burden. Quality concerns were noted for sample representativeness, disease and outcome measures, and reporting clarity. In summary, a high burden of LGS on individuals, caregivers, and health care systems was identified, which may be alleviated by reducing the clinical symptom burden. These findings highlight the need for a greater understanding of and better definitions for the broad spectrum of LGS symptoms and development of treatments to alleviate nonseizure symptoms.

Effects of Endotracheal Epinephrine on Pharmacokinetics and Survival in a Swine Pediatric Cardiac Arrest Model.

OBJECTIVES: The aim of this study was to compare the endotracheal tube (ET) and intravenous (IV) administration of epinephrine relative to concentration maximum, time to maximum concentration, mean concentration over time (MC), area under the curve, odds, and time to return of spontaneous circulation (ROSC) in a normovolemic pediatric cardiac arrest model. METHODS: Male swine weighing 24-37 kg were assigned to 4 groups: ET (n = 8), IV (n = 7), cardiopulmonary resuscitation (CPR) + defibrillation (CPR + Defib) (n = 5), and CPR only (n = 3). Swine were placed arrest for 2 minutes, and then CPR was initiated for 2 minutes. Epinephrine (0.1 mg/kg) for the ET group or 0.01 mg/kg for the IV was administered every 4 minutes or until ROSC. Defibrillation started at 3 minutes and continued every 2 minutes for 30 minutes or until ROSC for all groups except the CPR-only group. Blood samples were collected over a period of 5 minutes. RESULTS: The MC of plasma epinephrine for the IV group was significantly higher at the 30- and 60-second time points (P = 0.001). The ET group had a significantly higher MC of epinephrine at the 180- and 240-second time points (P < 0.05). The concentration maximum of plasma epinephrine was significantly lower for the ET group (195 ± 32 ng/mL) than for the IV group (428 ± 38 ng/mL) (P = 0.01). The time to maximum concentration was significantly longer for the ET group (145 ± 26 seconds) than for the IV group (42 ± 16 seconds) (P = 0.01). No significant difference existed in area under the curve between the 2 groups (P = 0.62). The odds of ROSC were 7.7 times greater for the ET versus IV group. Time to ROSC was not significantly different among the IV, ET, and CPR + Defib groups (P = 0.31). CONCLUSIONS: Based on the results of this study, the ET route of administration should be considered a first-line intervention.

A systematic literature review on the global epidemiology of Dravet syndrome and Lennox-Gastaut syndrome: Prevalence, incidence, diagnosis, and mortality.

Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies associated with seizure and nonseizure symptoms. A comprehensive understanding of how many individuals are affected globally, the diagnostic journey they face, and the extent of mortality associated with these conditions is lacking. Here, we summarize and evaluate published data on the epidemiology of DS and LGS in terms of prevalence, incidence, diagnosis, genetic mutations, and mortality and sudden unexpected death in epilepsy (SUDEP) rates. The full study protocol is registered on PROSPERO (CRD42022316930). After screening 2172 deduplicated records, 91 unique records were included; 67 provided data on DS only, 17 provided data on LGS only, and seven provided data on both. Case definitions varied considerably across studies, particularly for LGS. Incidence and prevalence estimates per 100 000 individuals were generally higher for LGS than for DS (LGS: incidence proportion = 14.5-28, prevalence = 5.8-60.8; DS: incidence proportion = 2.2-6.5, prevalence = 1.2-6.5). Diagnostic delay was frequently reported for LGS, with a wider age range at diagnosis reported than for DS (DS, 1.6-9.2 years; LGS, 2-15 years). Genetic screening data were reported by 63 studies; all screened for SCN1A variants, and only one study specifically focused on individuals with LGS. Individuals with DS had a higher mortality estimate per 1000 person-years than individuals with LGS (DS, 15.84; LGS, 6.12) and a lower median age at death. SUDEP was the most frequently reported cause of death for individuals with DS. Only four studies reported mortality information for LGS, none of which included SUDEP. This systematic review highlights the paucity of epidemiological data available for DS and especially LGS, demonstrating the need for further research and adoption of standardized diagnostic criteria.

Adaptive functioning and neurodevelopment in patients with Dravet syndrome: 12-month interim analysis of the BUTTERFLY observational study.

OBJECTIVE: The BUTTERFLY observational study aims to elucidate the natural trajectory of Dravet syndrome (DS) and associated comorbidities in order to establish a baseline for clinical therapies. We present the 12-month interim analysis of the study. MATERIALS AND METHODS: Patients with a genetically confirmed diagnosis of DS were enrolled in the study. Adaptive functioning and neurodevelopmental status were measured using the Vineland Adaptive Behavior Scale, Third Edition (Vineland-III), Bayley Scales of Infant Development, Third Edition (BSID-III), and Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV). Executive function, ambulatory function and locomotor activities, and overall clinical status were measured using the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P) scale, Gillette Functional Assessment Questionnaire (Gillette FAQ), and Clinician or Caregiver Global Impression of Change scales (CGI-C or CaGI-C) respectively. RESULTS: Overall, 36 patients were enrolled across three age groups, with 35 patients completing at least part or all of one post-baseline visit through Month 12. Significant improvements in receptive communication, as assessed by Vineland-III and BSID-III raw scores, and in verbal comprehension subtests, as assessed by WPPSI-IV raw scores, were observed in BUTTERFLY patients for the all-patient group. Many patients performed on the impaired end of the BRIEF-P Global Executive Composite scale at baseline suggesting difficulties in executive function, and no significant change was observed in BRIEF-P scores for the all-patient group. Most patients performed in the dynamic range of the Gillette FAQ at baseline, and no significant change was observed in Gillette FAQ scores for the all-patient group. Lastly, there was significant improvement observed in the CaGI-C scores for the all-patient group. SIGNIFICANCE: This BUTTERFLY interim analysis shows small improvements in communication skills along with stability in other developmental abilities across patients with DS enrolled in the study from baseline to Month 12.

Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

A multi-center comparison of surgical techniques for corpus Callosotomy in pediatric drug-resistant epilepsy.

OBJECTIVES: Corpus callosotomy (CC) is used to reduce seizures, primarily in patients with generalized drug-resistant epilepsy (DRE). The invasive nature of the procedure contributes to underutilization despite its potential superiority to other palliative procedures. The goal of this study was to use a multi-institutional epilepsy surgery database to characterize the use of CC across participating centers. METHODS: Data were acquired from the Pediatric Epilepsy Research Consortium (PERC) Surgery Database, a prospective observational study collecting data on children 0-18 years referred for surgical evaluation of DRE across 22 U.S. pediatric epilepsy centers. Patient, epilepsy, and surgical characteristics were collected across multiple CC modalities. Outcomes and complications were recorded and analyzed statistically. RESULTS: Eighty-three patients undergoing 85 CC procedures at 14 participating epilepsy centers met inclusion criteria. Mean age at seizure onset was 2.3 years (0-9.4); mean age for Phase I evaluation and surgical intervention were 9.45 (.1-20) and 10.46 (.2-20.6) years, respectively. Generalized seizure types were the most common (59%). Complete CC was performed in 88%. The majority of CC procedures (57%) were via open craniotomy, followed by laser interstitial thermal therapy (LiTT) (20%) and mini-craniotomy/endoscopic (mc/e) (22%). Mean operative times were significantly longer for LiTT, whereas mean estimated blood loss was greater in open cases. Complications occurred in 11 cases (13%) and differed significantly between surgical techniques (p < .001). There was no statistically significant difference in length of postoperative stay across approaches. Mean follow-up was 12.8 months (range 1-39). Favorable Engel outcomes were experienced by 37 (78.7%) of the patients who underwent craniotomy, 10 (58.8%) with LiTT, and 12 (63.2%) with mc/e; these differences were not statistically significant. SIGNIFICANCE: CC is an effective surgical modality for children with DRE. Regardless of surgical modality, complication rates are acceptable and seizure outcomes generally favorable. Newer, less-invasive, surgical approaches may lead to increased adoption of this efficacious therapeutic option for pediatric DRE.

Epilepsy surgery as a treatment option for select patients with PCDH19-related epilepsy.

PCDH19 is a common epilepsy gene causing medication resistant epilepsy with fever-related seizures. Traditionally, patients with PCDH19-related epilepsy have not been considered surgical candidates. This retrospective review evaluated three patients with pathogenic variants in PCDH19 who presented with seizures in childhood, had one seizure semiology, became medication resistant, and had concordant imaging, seizure semiology and electrographic findings. All three patients ultimately underwent temporal lobectomy, resulting in seizure freedom. These findings suggest epilepsy surgery can be an effective treatment option for select patients with PCDH19-related epilepsy and a single seizure semiology.

MB-DECTNet: a model-based unrolling network for accurate 3D dual-energy CT reconstruction from clinically acquired helical scans.

Objective.Over the past several decades, dual-energy CT (DECT) imaging has seen significant advancements due to its ability to distinguish between materials. DECT statistical iterative reconstruction (SIR) has exhibited potential for noise reduction and enhanced accuracy. However, its slow convergence and substantial computational demands render the elapsed time for 3D DECT SIR often clinically unacceptable. The objective of this study is to accelerate 3D DECT SIR while maintaining subpercentage or near-subpercentage accuracy.Approach.We incorporate DECT SIR into a deep-learning model-based unrolling network for 3D DECT reconstruction (MB-DECTNet), which can be trained end-to-end. This deep learning-based approach is designed to learn shortcuts between initial conditions and the stationary points of iterative algorithms while preserving the unbiased estimation property of model-based algorithms. MB-DECTNet comprises multiple stacked update blocks, each containing a data consistency layer (DC) and a spatial mixer layer, with the DC layer functioning as a one-step update from any traditional iterative algorithm.Main results.The quantitative results indicate that our proposed MB-DECTNet surpasses both the traditional image-domain technique (MB-DECTNet reduces average bias by a factor of 10) and a pure deep learning method (MB-DECTNet reduces average bias by a factor of 8.8), offering the potential for accurate attenuation coefficient estimation, akin to traditional statistical algorithms, but with considerably reduced computational costs. This approach achieves 0.13% bias and 1.92% mean absolute error and reconstructs a full image of a head in less than 12 min. Additionally, we show that the MB-DECTNet output can serve as an initializer for DECT SIR, leading to further improvements in results.Significance.This study presents a model-based deep unrolling network for accurate 3D DECT reconstruction, achieving subpercentage error in estimating virtual monoenergetic images for a full head at 60 and 150 keV in 30 min, representing a 40-fold speedup compared to traditional approaches. These findings have significant implications for accelerating DECT SIR and making it more clinically feasible.

Methods to predict the timing and status of biological maturation in male adolescent soccer players: A narrative systematic review.

The aim of this review was to summarise the methods used to predict and assess maturity status and timing in adolescent, male, academy soccer players. A systematic search was conducted on PubMed, Scopus, Web of Science, CINAHL, Medline and SPORTDiscus. Only experimental studies including male, academy players aged U9-U18 years registered with a professional soccer club were included. The methodological quality of the included studies was assessed using guidelines from the Framework of Potential Biases. Fifteen studies fulfilled our inclusion criteria. Studies were mainly conducted in European countries (n = 12). In total, 4,707 players were recruited across all 15 studies, with an age range of 8-18 years. Five studies were longitudinal, two studies were mixed-method designs and eight studies were cross-sectional. Due to high heterogeneity within the studies, a meta-analysis was not performed. Our findings provided no equivalent estimations of adult height, skeletal age, or age at PHV. Discrepancies were evident between actual and predicted adult height and age at PHV. The Bayley-Pinneau [1952], Tanner-Whitehouse 2 [1983] and Khamis-Roche [1994] methods produced estimates of adult height within 1cm of actual adult height. For age at PHV, both Moore [2015] equations produced the closest estimates to actual age at PHV, and the Fransen [2018] equation correlated highly with actual age at PHV (>90%), even when the period between chronological age and age at PHV was large. Medical imaging techniques (e.g., Magnetic Resonance Imaging, X-Ray, Dual energy X-ray Absorptiometry) demonstrated high intra/inter-rater reliability (ICC = 0.83-0.98) for skeletal maturity assessments. The poor concordance between invasive and non-invasive methods, is a warning to practitioners to not use these methods interchangeably for assessing maturational status and timing in academy soccer players. Further research with improved study designs is required to validate these results and improve our understanding of these methods when applied in this target population.

Frequency of technical success of ultrasound-guided arthrogram injections in children.

BACKGROUND: MR arthrography is an essential diagnostic tool to assess and guide management of labral, ligamentous, fibrocartilaginous, and capsular abnormalities in children. While fluoroscopy is traditionally used for intra-articular contrast administration, ultrasound offers advantages of portability and lack of ionizing radiation exposure for both the patient and proceduralist. OBJECTIVE: The purpose of this retrospective study is to quantify technical success and frequency of complications of ultrasound-guided arthrogram injections at our institution. MATERIALS AND METHODS: This retrospective analysis investigates the results of 217 ultrasound-guided arthrograms of the shoulder, elbow, and hip in patients aged 5-18 years. Successful injection of contrast into the target joint, clinical indication for MR arthrography, and complications were reviewed. RESULTS: Accurate ultrasound-guided intra-articular administration of contrast into the target joint was successful for 100% of shoulder cases (90/90), 97% of elbow cases (77/79), and 98% of hip cases (47/48). Leak of contrast outside the target joint occurred in 1.4% (3/217) of cases. No major side effects including excessive bleeding, paresthesia, allergic reactions, or infection occurred during or after the procedure. Additionally, no major vessel, nerve, or tendon complications were observed on MR images. CONCLUSION: Ultrasound guidance is a reliable, effective, and safe approach to arthrography in children.

Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial.

OBJECTIVE: This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2-18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6-week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration-maintenance period in patients given fenfluramine .7 mg/kg/day versus patients given placebo. RESULTS: A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7-18.0 per 28 days. Patients treated with fenfluramine .7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%-74.2%) greater reduction in MCSF compared with placebo (p < .0001). Following fenfluramine .7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p < .0001). The median longest seizure-free interval was 30 days in the fenfluramine .7 mg/kg/day group compared with 10 days in the placebo group (p < .0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected. SIGNIFICANCE: The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome.

Motion-compensated scheme for sequential scanned statistical iterative dual-energy CT reconstruction.

Objective.Dual-energy computed tomography (DECT) has been widely used to reconstruct numerous types of images due its ability to better discriminate tissue properties. Sequential scanning is a popular dual-energy data acquisition method as it requires no specialized hardware. However, patient motion between two sequential scans may lead to severe motion artifacts in DECT statistical iterative reconstructions (SIR) images. The objective is to reduce the motion artifacts in such reconstructions.Approach.We propose a motion-compensation scheme that incorporates a deformation vector field into any DECT SIR. The deformation vector field is estimated via the multi-modality symmetric deformable registration method. The precalculated registration mapping and its inverse or adjoint are then embedded into each iteration of the iterative DECT algorithm.Main results.Results from a simulated and clinical case show that the proposed framework is capable of reducing motion artifacts in DECT SIRs. Percentage mean square errors in regions of interest in the simulated and clinical cases were reduced from 4.6% to 0.5% and 6.8% to 0.8%, respectively. A perturbation analysis was then performed to determine errors in approximating the continuous deformation by using the deformation field and interpolation. Our findings show that errors in our method are mostly propagated through the target image and amplified by the inverse matrix of the combination of the Fisher information and Hessian of the penalty term.Significance.We have proposed a novel motion-compensation scheme to incorporate a 3D registration method into the joint statistical iterative DECT algorithm in order to reduce motion artifacts caused by inter-scan motion, and successfully demonstrate that interscan motion corrections can be integrated into the DECT SIR process, enabling accurate imaging of radiological quantities on conventional SECT scanners, without significant loss of either computational efficiency or accuracy.

Phase 2, placebo-controlled clinical study of oral ganaxolone in PCDH19-clustering epilepsy.

INTRODUCTION: Protocadherin-19 (PCDH19)-clustering epilepsy is a distinct developmental and epileptic encephalopathy characterized by early-onset seizures that are often treatment refractory. Caused by a mutation of the PCDH19 gene on the X chromosome, this rare epilepsy syndrome primarily affects females with seizure onset commonly in the first year of life. A global, randomized, double-blind, placebo-controlled, phase 2 trial was conducted to evaluate the efficacy, safety, and tolerability of ganaxolone compared with placebo as adjunctive therapy to a standard antiseizure medication regimen in patients with PCDH19-clustering epilepsy (VIOLET; NCT03865732). METHODS: Females aged 1-17 years with a molecularly confirmed pathogenic or likely pathogenic PCDH19 variant who were experiencing ≥12 seizures during a 12-week screening period were stratified by baseline allopregnanolone sulfate (Allo-S) levels (low: ≤2.5 ng/mL; high: >2.5 ng/mL) at screening and randomized 1:1 within each strata to receive ganaxolone (maximum daily dose of 63 mg/kg/day if ≤28 kg or 1800 mg/day if >28 kg) or matching placebo in addition to their standard antiseizure treatment for the 17-week double-blind phase. The primary efficacy endpoint was the median percentage change in 28-day seizure frequency from baseline to the 17-week double-blind phase. Treatment-emergent adverse events (TEAEs) were tabulated by overall, system organ class, and preferred term. RESULTS: Of the 29 patients screened, 21 (median age, 7.0 years; IQR, 5.0-10.0 years) were randomized to receive either ganaxolone (n = 10) or placebo (n = 11). After the 17-week double-blind phase, the median (IQR) percentage change in 28-day seizure frequency from baseline was - 61.5% (-95.9% to -33.4%) among patients in the ganaxolone group and - 24.0% (-88.2% to -4.9%) among patients in the placebo group (Wilcoxon rank-sum test, p = 0.17). TEAEs were reported by 7 of 10 (70.0%) patients in the ganaxolone group and 11 of 11 (100%) patients in the placebo group. Somnolence was the most common TEAE (40.0% ganaxolone vs 27.3% placebo); serious TEAEs were more common in the placebo group (10.0% ganaxolone vs 45.5% placebo); and 1 (10.0%) patient in the ganaxolone group discontinued the study versus none in the placebo group. CONCLUSIONS: Ganaxolone was generally well tolerated and led to a greater reduction in the frequency of PCDH19-clustering seizures compared to placebo; however, the trend did not reach statistical significance. Novel trial designs are likely needed to evaluate the effectiveness of antiseizure treatments for PCDH19-clustering epilepsy.

Flat-panel detector CT to assess intracranial hemorrhage immediately following mechanical thrombectomy.

BACKGROUND AND PURPOSE: The risk of symptomatic intracranial hemorrhage (ICH) approaches 5% despite mechanical thrombectomy (MT) efficacy for ischemic stroke secondary to large vessel occlusion. Flat-panel detector CT (FDCT) imaging with Syngo Dyna CT imaging (Siemens Medical Solutions, Malvern, PA) can be used immediately following MT to detect ICH. PURPOSE: To evaluate the accuracy and reliability of FDCT imaging with Dyna CT compared to conventional post-MT CT and MRI. METHODS: Head FDCT (20 second, 70 kV) was performed immediately following MT on 26 consecutive patients; postprocedural CT or MRI was obtained ∼24 hours later. Two blinded, independent neuroradiologists evaluated all imaging, identifying ICH, stroke, and presence of subarachnoid contrast. Cohen's κ statistic was used to assess interrater agreement for each imaging outcome and compared the FDCT to conventional imaging. RESULTS: FDCT for ICH demonstrated a strong degree of interrater reliability (κ = 0.896; 95% confidence interval [CI], 0.734-1.057). Negligible reliability was seen for ischemia determination on immediate post-MT FDCT (κ = 0.149; 95% CI, -0.243 to 0.541). ICH evaluation between FDCT and post-MT conventional CT revealed modest interrater reliability (κ = 0.432; 95% CI, -0.100 to 0.965), which did not reach statistical significance. There was no substantive reliability in the evaluation of ICH between FDCT and post-MT MRI (κ = 0.118, 95% CI, -0.345 to 0.580). CONCLUSION: FDCT, such as Dyna CT, immediately post-MT is a promising tool that can expedite the detection of ICH with a high degree of reliability, although the detection of ischemic parenchymal changes is limited.

Dravet Syndrome as an Example of Precision Medicine in Epilepsy.

Dravet syndrome (DS) is a drug-resistant, early-onset, developmental and epileptic encephalopathy where there have been many recently approved therapies with many more in development. With the availability of more syndrome specific treatment options coupled with an earlier diagnosis, DS is well-positioned to be an example of how a precise syndromic diagnosis can guide treatment choices and improve overall outcomes and also allow for the development of potential disease modifying therapies to address more than just seizures. In this review we summarize the current state of DS approved therapies and those that are in various stages of development.

Defibrillation effectiveness and safety of the shock waveform used in a contemporary wearable cardioverter defibrillator: Results from animal and human studies.

INTRODUCTION: The wearable cardioverter defibrillator (WCD) is used to protect patients at risk for sudden cardiac arrest. We examined defibrillation efficacy and safety of a biphasic truncated exponential waveform designed for use in a contemporary WCD in three animal studies and a human study. METHODS: Animal (swine) studies: #1: Efficacy comparison of a 170J BTE waveform (SHOCK A) to a 150J BTE waveform (SHOCK B) that approximates another commercially available waveform. Primary endpoint first shock success rate. #2: Efficacy comparison of the two waveforms at attenuated charge voltages in swine at three prespecified impedances. Primary endpoint first shock success rate. #3: Safety comparison of SHOCK A and SHOCK B in swine. Primary endpoint cardiac biomarker level changes baseline to 6 and 24 hours post-shock. Human Study: Efficacy comparison of SHOCK A to prespecified goal and safety evaluation. Primary endpoint cumulative first and second shock success rate. Safety endpoint adverse events. RESULTS: Animal Studies #1: 120 VF episodes in six swine. First shock success rates for SHOCK A and SHOCK B were 100%; SHOCK A non-inferior to SHOCK B (entire 95% CI of rate difference above -10% margin, p < .001). #2: 2,160 VF episodes in thirty-six swine. Attenuated SHOCK A was non-inferior to attenuated SHOCK B at each impedance (entire 95% CI of rate difference above -10% margin, p < .001). #3: Ten swine, five shocked five times each with SHOCK A, five shocked five times each with SHOCK B. No significant difference in troponin I (p = 0.658) or creatine phosphokinase (p = 0.855) changes from baseline between SHOCK A and SHOCK B. Human Study: Thirteen patients, 100% VF conversion rate. Mild skin irritation from adhesive defibrillation pads in three patients. CONCLUSIONS: The BTE waveform effectively and safely terminated induced VF in swine and a small sample in humans. TRIAL REGISTRATION: Human study clinical trial registration: URL: https://clinicaltrials.gov; Unique identifier: NCT04132466.

The value of routine radiographic follow up in the postoperative management of canine medial patellar luxation.

OBJECTIVE: To determine the influence of radiographic examination on the recommendations made at the time of planned re-evaluation of dogs after medial patellar luxation (MPL) surgery. STUDY DESIGN: Retrospective multi-institutional case series. ANIMALS: Client-owned dogs (N = 825) that underwent MPL surgery. METHODS: Records of 10 referral institutions were searched for dogs that had been treated surgically for unilateral MPL and underwent a planned follow-up visit, including radiographs. The frequency of, and reasons for, changes in further recovery recommendations were investigated. RESULTS: Follow up was performed at a median of 6 (range, 4-20) weeks postoperatively. Isolated radiographic abnormalities were identified in 3.3% (27/825) of dogs following MPL surgery and led to a change in recommendations in 3% (13/432) of dogs that were presented without owner or clinician concerns. Lameness, administration of analgesia at follow up, and history of unplanned visits prior to routine re-examination were associated with a change in postoperative plan (P < .001). In the absence of owner and clinician concerns, the odds of having a change in convalescence plans were not different, whether or not isolated radiographic abnormalities were present (P = .641). CONCLUSION: Routine radiographs at follow up did not influence postoperative management of most dogs after MPL surgery in the absence of abnormalities on clinical history or orthopedic examination. CLINICAL SIGNIFICANCE: Dogs that were presented for routine follow up after unilateral MPL surgery without owner concerns, lameness, analgesic treatment or a history of unplanned visits, and for which examination by a surgical specialist was unremarkable, were unlikely to benefit from radiographs.