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.

Surgical evaluation in children <3 years of age with drug-resistant epilepsy: Patient characteristics, diagnostic utilization, and potential for treatment delays.

OBJECTIVE: Drug-resistant epilepsy (DRE) occurs at higher rates in children <3 years old. Epilepsy surgery is effective, but rarely utilized in young children despite developmental benefits of early seizure freedom. The present study aims to identify unique patient characteristics and evaluation strategies in children <3 years old who undergo epilepsy surgery evaluation as a means to assess contributors and potential solutions to health care disparities in this group. METHODS: The Pediatric Epilepsy Research Consortium Epilepsy Surgery Database, a multicentered, cross-sectional collaboration of 21 US pediatric epilepsy centers, collects prospective data on children <18 years of age referred for epilepsy surgery evaluation. We compared patient characteristics, diagnostic utilization, and surgical treatment between children <3 years old and those older undergoing initial presurgical evaluation. We evaluated patient characteristics leading to delayed referral (>1 year) after DRE diagnosis in the very young. RESULTS: The cohort included 437 children, of whom 71 (16%) were <3 years of age at referral. Children evaluated before the age of 3 years more commonly had abnormal neurological examinations (p = .002) and daily seizures (p = .001). At least one ancillary test was used in 44% of evaluations. Fifty-nine percent were seizure-free following surgery (n = 34), with 35% undergoing limited focal resections. Children with delayed referrals more often had focal aware (p < .001) seizures and recommendation for palliative surgeries (p < .001). SIGNIFICANCE: There are relatively few studies of epilepsy surgery in the very young. Surgery is effective, but may be disproportionally offered to those with severe presentations. Relatively low utilization of ancillary testing may contribute to reduced surgical therapy for those without evident lesions on magnetic resonance imaging. Despite this, a sizeable portion of patients have favorable outcome after focal epilepsy surgery resections.

Interventions for ADHD in children & adolescents with epilepsy: A review and decision tree to guide clinicians.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common pediatric epilepsy comorbidities. Treating ADHD in the context of epilepsy can be overwhelming for parents and clinicians. Current frontline treatment for ADHD is stimulant medication. However, some parents of pediatric patients with epilepsy have concerns about adding additional medication to their child's epilepsy regimen and/or about adverse effects of stimulant medication. Non-medication ADHD treatments including psychosocial interventions and ketogenic diet have also shown success in improving ADHD symptoms. Our focused review provides an easy-to-use guide for clinicians on ADHD interventions and combinations of interventions for pediatric patients with epilepsy and ADHD. Our guide includes information from 8 electronic databases for peer-reviewed, English language studies of psychosocial treatments for youth with epilepsy and ADHD. One hundred eight studies were selected based on inclusion criteria (21 systematic reviews, 12 meta-analyses, 8 literature reviews, 6 population surveys, 31 clinical trials, 20 cross-sectional studies, and 10 retrospective reviews). Results indicated that stimulant medication is a frontline treatment for ADHD symptoms in youth with epilepsy, with important caveats and alternatives.

Underutilization of epilepsy surgery: Part II: Strategies to overcome barriers.

Interventions focused on utilization of epilepsy surgery can be divided into groups: those that improve patients' access to surgical evaluation and those that facilitate completion of the surgical evaluation and treatment. Educational intervention, technological innovation, and effective coordination and communication can significantly improve patients' access to surgery. Patient and public facing, individualized (analog and/or digital) communication can raise awareness and acceptance of epilepsy surgery. Educational interventions aimed at providers may mitigate knowledge gaps using practical and concise consensus statements and guidelines, while specific training can improve awareness around implicit bias. Innovative technology, such as clinical decision-making toolkits within the electronic medical record (EMR), machine learning techniques, online decision-support tools, nomograms, and scoring algorithms can facilitate timely identification of appropriate candidates for epilepsy surgery with individualized guidance regarding referral appropriateness, postoperative seizure freedom rate, and risks of complication after surgery. There are specific strategies applicable for epilepsy centers' success: building a multidisciplinary setup, maintaining/tracking volume and complexity of cases, collaborating with other centers, improving surgical outcome with reduced complications, utilizing advanced diagnostics tools, and considering minimally invasive surgical techniques. Established centers may use other strategies, such as multi-stage procedures for multifocal epilepsy, advanced functional mapping with tailored surgery for epilepsy involving the eloquent cortex, and generation of fresh hypotheses in cases of surgical failure. Finally, improved access to epilepsy surgery can be accomplished with policy changes (e.g., anti-discrimination policy, exemption in transportation cost, telehealth reimbursement policy, patient-centered epilepsy care models, pay-per-performance models, affordability and access to insurance, and increased funding for research). Every intervention should receive regular evaluation and feedback-driven modification to ensure appropriate utilization of epilepsy surgery.

Underutilization of epilepsy surgery: Part I: A scoping review of barriers.

One-third of persons with epilepsy have seizures despite appropriate medical therapy. Drug resistant epilepsy (DRE) is associated with neurocognitive and psychological decline, poor quality of life, increased risk of premature death, and greater economic burden. Epilepsy surgery is an effective and safe treatment for a subset of people with DRE but remains one of the most underutilized evidence-based treatments in modern medicine. The reasons for this quality gap are insufficiently understood. In this comprehensive review, we compile known significant barriers to epilepsy surgery, originating from both patient/family-related factors and physician/health system components. Important patient-related factors include individual and epilepsy characteristics which bias towards continued preferential use of poorly effective medications, as well as patient perspectives and misconceptions of surgical risks and benefits. Health system and physician-related barriers include demonstrable knowledge gaps among physicians, inadequate access to comprehensive epilepsy centers, complex presurgical evaluations, insufficient research, and socioeconomic bias when choosing appropriate surgical candidates.

Stereotactic MRI-guided laser interstitial thermal therapy for extratemporal lobe epilepsy.

OBJECTIVE: Magnetic resonance imaging (MRI)-guided laser interstitial thermal therapy (MRg-LITT) is an alternative to open epilepsy surgery. We assess safety and effectiveness of MRg-LITT for extratemporal lobe epilepsy (ETLE) in patients who are considered less favorable for open resection. METHODS: We retrospectively reviewed sequential cases of patients with focal ETLE who underwent MRg-LITT between 2012 and 2019. Epileptogenic zones were determined from standard clinical and imaging data ± stereoelectroencephalography (SEEG). Standard stereotactic techniques, MRI thermometry, and a commercial laser thermal therapy system were used for ablations. Anatomic MRI was used to calculate ablation volumes. Clinical outcomes were determined longitudinally. RESULTS: Thirty-five patients with mean epilepsy duration of 21.3 ± 12.2 years underwent MRg-LITT for focal ETLE at a mean age 36.4 ± 12.7 years. A mean 2.59 ± 1.45 trajectories per patient were used to obtain ablation volumes of 8.8 ± 7.5 cm3 . Mean follow-up was 27.3 ± 19.5 months. Of 32 patients with >12 months of follow-up, 17 (53%) achieved good outcomes (Engel class I + II) of whom 14 (44%) were Engel class I. Subgroup analysis revealed better outcomes for patients with lesional ETLE than for those who were nonlesional, multifocal, or who had failed prior interventions (P = .02). Of 13 patients showing favorable seizure-onset patterns (localized low voltage fast activity or rhythmic spiking on SEEG) prior to ablation, 9 (69%) achieved good outcomes, whereas only 3 of 11 (27%) who show other slower onset patterns achieved good outcomes. Minor adverse events included six patients with transient sensorimotor neurologic deficits and four patients with asymptomatic hemorrhages along the fiber tract. Major adverse events included one patient with a brain abscess that required stereotactic drainage and one patient with persistent hypothalamic obesity. Three deaths-two seizure-associated and one suicide-were unrelated to surgical procedures. SIGNIFICANCE: MRI-guided laser interstitial thermal therapy (or MRg-LITT) was well-tolerated and yielded good outcomes in a heterogeneous group of ETLE patients. Lesional epilepsy and favorable seizure-onset patterns on SEEG predicted higher likelihoods of success.

Internalizing symptoms in intractable pediatric epilepsy: Structural and functional brain correlates.

Internalizing disorders (i.e., depression and anxiety) are common comorbidities in people with epilepsy. In adults with epilepsy, comorbid depression or anxiety is associated with worse seizure control and reduced quality of life, and may be linked to specific neural biomarkers. Less is known about brain correlates of internalizing symptoms in pediatric populations. In the current study, we performed a retrospective analysis of 45 youth between the ages of 6 and 18 years old with intractable epilepsy. Individuals were evaluated for internalizing symptoms on the Child Behavior Checklist (CBCL) and underwent magnetic resonance (MR) and fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging as part of the clinical evaluation for surgical treatment of epilepsy. Forty-two percent of patients experienced clinically significant internalizing symptoms based on parent report. Compared with individuals who scored in the normal range, youth with clinical levels of internalizing problems showed overall reductions in cortex volume, as well as widespread reductions in cortical thickness and functional activation in the bilateral occipital/parietal lobe, left temporal regions, and left inferior frontal cortex on MR and PET scans. There were no group differences in amygdala or hippocampus volumes, nor other patient- or illness-related variables such as age, sex, or the type, lateralization, or duration of epilepsy. Results suggest that high rates of internalizing disorders are present in youth with refractory epilepsy. Multifocal reductions in cortical thickness and function may be nonspecific risk factors for clinically meaningful internalizing symptoms in youth with chronic epilepsy. As such, the presence of broad cortical thinning and reduced glucose uptake upon radiological examination may warrant more focused clinical evaluation of psychological symptoms.

Blunted neural response to emotional faces in the fusiform and superior temporal gyrus may be marker of emotion recognition deficits in pediatric epilepsy.

Individuals with epilepsy are at risk for social cognition deficits, including impairments in the ability to recognize nonverbal cues of emotion (i.e., emotion recognition [ER] skills). Such deficits are particularly pronounced in adult patients with childhood-onset seizures and are already evident in children and adolescents with epilepsy. Though these impairments have been linked to blunted neural response to emotional information in faces in adult patients, little is known about the neural correlates of ER deficits in youth with epilepsy. The current study compared ER accuracy and neural response to emotional faces during functional magnetic resonance imaging (fMRI) in youth with intractable focal epilepsy and typically developing youth. Relative to typically developing participants, individuals with epilepsy showed a) reduced accuracy in the ER task and b) blunted response to emotional faces (vs. neutral faces) in the bilateral fusiform gyri and right superior temporal gyrus (STG). Activation in these regions was correlated with performance, suggesting that aberrant response within these face-responsive regions may play a functional role in ER impairments. Reduced engagement of neural circuits relevant to processing socioemotional cues may be markers of risk for social cognitive deficits in youth with focal epilepsy.

Preoperative evaluation and surgical management of infants and toddlers with drug-resistant epilepsy.

OBJECTIVE Despite perioperative risks, epilepsy surgery represents a legitimate curative or palliative treatment approach for children with drug-resistant epilepsy (DRE). Several factors characterizing infants and toddlers with DRE create unique challenges regarding optimal evaluation and management. Epilepsy surgery within children < 3 years of age has received moderate attention in the literature, including mainly case series and retrospective studies. This article presents a systematic literature review and explores multidisciplinary considerations for the preoperative evaluation and surgical management of infants and toddlers with DRE. METHODS The study team conducted a systematic literature review based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, targeting studies that investigated children < 3 years of age undergoing surgical treatment of DRE. Using the PubMed database, investigators selected peer-reviewed articles that reported seizure outcomes with or without developmental outcomes and/or perioperative complications. Studies were eliminated based on the following exclusion criteria: sample size < 5 patients; and inclusion of patients > 3 years of age, when demographic and outcomes data could not be separated from the cohort of patients < 3 years of age. RESULTS The study team identified 20 studies published between January 1990 and May 2017 that satisfied eligibility criteria. All selected studies represented retrospective reviews, observational studies, and uncontrolled case series. The compiled group of studies incorporated 465 patients who underwent resective or disconnective surgery (18 studies, 444 patients) or vagus nerve stimulator insertion (2 studies, 21 patients). Patient age at surgery ranged between 28 days and 36 months, with a mean of 16.8 months (1.4 years). DISCUSSION The study team provided a detailed summary of the literature review, focusing on the etiologies, preoperative evaluation, surgical treatments, seizure and developmental outcomes, and potential for functional recovery of infants and toddlers with DRE. Additionally, the authors discussed special considerations in this vulnerable age group from the perspective of multiple disciplines. CONCLUSIONS While presenting notable challenges, pediatric epilepsy surgery within infants and toddlers (children < 3 years of age) offers significant opportunities for improved seizure frequency, neuro-cognitive development, and quality of life. Successful evaluation and treatment of young children with DRE requires special consideration of multiple aspects related to neurological and physiological immaturity and surgical morbidity.

Comparison of semiologies between tilt-induced psychogenic nonsyncopal collapse and psychogenic nonepileptic seizures.

We sought to characterize the clinical features of tilt-induced psychogenic nonsyncopal collapse (PNSC) from a cohort of young patients and to compare the semiologies between PNSC and EEG-confirmed psychogenic nonepileptic seizures (PNES). A PNSC diagnosis was made if a clinical event occurred during tilt-table testing that the patient regarded as fainting, but neither hypotension nor EEG changes were present. A diagnosis of PNSC was made in 17.6% of all patients referred during the 15-month study period. Cohorts with psychogenic nonsyncopal collapse (n=40) and PNES (n=40) did not differ in age (15.5±2.2 versus 14.6±2.7, p=.11) or female gender (80% versus 72.5%, p=.43). Psychogenic nonsyncopal collapse events were briefer than PNES events (median: 45 versus 201.5s, p<.001). Negative motor signs (head drop, body limpness) predominated in PNSC (85% versus 20%, p<.001), while the positive motor signs of convulsion occurred more often with PNES (90% versus 30%, p<.001). Behavioral arrest (25% versus 32.5%, p=.46) and eye closure (85% versus 72.5%, p=.21) did not differ between PNSC and PNES. Patients with PNSC were more likely to be tearful before (30% versus 7.5%, p=.02) and after (62.5% versus 7.5%, p<.001) an event. In conclusion, although overlap exists, the features of PNSC generally appear similar to neurally mediated syncope, while the features of PNES generally appear similar to epileptic seizures. Psychogenic nonsyncopal collapse and PNES likely represent similar disorders that differ primarily by clinical semiologies and referral patterns.

Patient-centered design criteria for wearable seizure detection devices.

INTRODUCTION: Epilepsy is a common neurological condition. Seizure diary reports and patient- or caregiver-reported seizure counts are often inaccurate and underestimated. Many caregivers express stress and anxiety about the patient with epilepsy having seizures when they are not present. Therefore, a need exists for the ability to recognize and/or detect a seizure in the home setting. However, few studies have inquired on detection device features that are important to patients and their caregivers. METHODS: A survey instrument utilizing a population of patients and caregivers was created to obtain information on the design criteria most desired for patients with epilepsy in regard to wearable devices. RESULTS: One thousand one hundred sixty-eight responses were collected. Respondents thought that sensors for muscle signal (61.4%) and heart rate (58.0%) would be most helpful followed by the O2 sensor (41.4%). There was more interest in these three sensor types than for an accelerometer (25.5%). There was very little interest in a microphone (8.9%), galvanic skin response sensor (8.0%), or a barometer (4.9%). Based on a rating scale of 1-5 with 5 being the most important, respondents felt that "detecting all seizures" (4.73) is the most important device feature followed by "text/email alerts" (4.53), "comfort" (4.46), and "battery life" (4.43) as an equally important group of features. Respondents felt that "not knowing device is for seizures" (2.60) and "multiple uses" (2.57) were equally the least important device features. Average ratings differed significantly across age groups for the following features: button, multiuse, not knowing device is for seizures, alarm, style, and text ability. The p-values were all<0.002. Eighty-two point five percent of respondents [95% confidence interval: 80.0%, 84.7%] were willing to pay more than $100 for a wearable seizure detection device, and 42.8% of respondents [95% confidence interval: 39.8%, 45.9%] were willing to pay more than $200. CONCLUSIONS: Our survey results demonstrated that patients and caregivers have design features that are important to them in regard to a wearable seizure detection device. Overall, the ability to detect all seizures rated highest among respondents which continues to be an unmet need in the community with epilepsy in regard to seizure detection. Additional uses for a wearable were not as important. Based on our results, it is important that an alert (via test and/or email) for events be a portion of the system. A reasonable price point appears to be around $200 to $300. An accelerometer was less important to those surveyed when compared with the use of heart rate, oxygen saturation, or muscle twitches/signals. As further products become developed for use in other health arenas, it will be important to consider patient and caregiver desires in order to meet the need and address the gap in devices that currently exist.

Severe CNS involvement in WWOX mutations: Description of five new cases.

Recently, mutations in WWOX have been identified in the setting of central nervous system (CNS) disorders, highlighting a previously unrevealed role of this gene in the normal development and function of the CNS. In this report, we add five patients from two seemingly unrelated families presenting with a primarily neurological phenotype. All the children were product of consanguineous marriages. Whole exome sequencing revealed the same homozygous mutation (NM_016373.3:c.606-1G>A) of WWOX in all five patients. All patients and carriers in the family share the same haplotype indicating the families are in fact related to one another. The clinical presentation included progressive microcephaly, early onset of spasticity in the first 3 months of life, intractable epilepsy, severe failure to thrive, and profound developmental delay. Retinopathy was observed in two patients. All five patients died before their third birthday. Neuroimaging showed extensive neurodegeneration characterized by periventricular white matter volume loss and atrophy of the corpus callosum. Additional degeneration selectively affecting the mediodorsal nucleus of the thalamus was observed in one patient. Our findings in five new patients affected by WWOX mutation with early infantile phenotype confirm the features of the disease represented by early infantile epileptic encephalopathy. We suggest that neuroimaging in these patients reveals a characteristic pattern of neurodegeneration in which the cerebellum is spared that could help with early diagnosis in the appropriate clinical setting.

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.

Mapping the Central Sulcus Extraoperatively Using Stereoelectroencephalography: A New Application of an Established Method.

PURPOSE: Central sulcus localization is undertaken intraoperatively with subdural electrodes through a phase reversal technique using somatosensory evoked potentials from sensorimotor cortices. Extraoperative central sulcus localization using stereoelectroencephalography has not been described previously. METHODS: Six pediatric patients (aged 12-18 years, 50% females) were investigated with stereoelectroencephalography. Peripheral median and posterior tibial nerve stimulation were performed while recording somatosensory evoked potentials from stereoelectroencephalography electrodes. RESULTS: Central sulcus was successfully localized by this novel method, and this was further supplemented by cortical stimulation data. CONCLUSIONS: This is the first report of somatosensory evoked potentials gained using stereoelectroencephalography in primary motor and sensory cortices. This can further supplement other data for safe surgical resection in the eloquent cortex.

NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype.

PURPOSE: Neurofibromatosis, type 1 (NF1) is an autosomal dominant disorder caused by mutations of the neurofibromin 1 (NF1) gene at 17q11.2. Approximately 5% of individuals with NF1 have a 1.4-Mb heterozygous 17q11.2 deletion encompassing NF1, formed through nonallelic homologous recombination (NAHR) between the low-copy repeats that flank this region. NF1 microdeletion syndrome is more severe than NF1 caused by gene mutations, with individuals exhibiting facial dysmorphisms, developmental delay (DD), intellectual disability (ID), and excessive neurofibromas. Although NAHR can also cause reciprocal microduplications, reciprocal NF1 duplications have been previously reported in just one multigenerational family and a second unrelated proband. METHODS: We analyzed the clinical features in seven individuals with NF1 microduplications, identified among 48,817 probands tested in our laboratory by array-based comparative genomic hybridization. RESULTS: The only clinical features present in more than one individual were variable DD/ID, facial dysmorphisms, and seizures. No neurofibromas were present. Three sets of parents were tested: one duplication was apparently de novo, one inherited from an affected mother, and one inherited from a clinically normal father. CONCLUSION: This is the first report comparing the phenotypes of nonrelated individuals with NF1 microduplications. This comparison will allow for further definition of this emerging microduplication syndrome.

Physicians' Perspectives on Presurgical Discussion and Shared Decision-Making in Pediatric Epilepsy Surgery.

Objective: To qualitatively explore the approach of pediatric epilepsy providers when counseling regarding surgical options for epilepsy, presenting risks and benefits of surgery, overcoming resistance to surgery, and fostering shared decision making with patients and families. Methods: We conducted in-depth interviews with 11 academic clinicians (5- neurologists, 5- epileptologists, 1- neurosurgeon) from a Level 4 pediatric epilepsy center to explore how physicians communicate and pursue surgical decision-making. Results: A blended inductive-deductive analysis revealed three key themes (with subthemes) of presurgical discussions: (1) Candidate selection and initial discussion about epilepsy surgery (neurologists compared to epileptologists, the timing of the discussion, reluctant families) (2) Detailed individualized counseling about epilepsy surgery (shared decision-making [enablers and barriers] and risk-benefit analysis [balancing risks and benefits, statistical benefit estimation, discussion about SUDEP, prognostication about cognitive and behavioral outcomes, risks of surgery]) (3) Tools to improve decision-making (educational interventions for patients and families and provider- and organization-specific interventions). Significance: Presurgical discussions lack uniformity among physicians who treat epilepsy. Despite general interest in collaborative decision-making, experts raised concern about lack of exposure to communication training and clinical tools for optimizing decision-making, a high number of families who do not feel equipped to share the decision making leaving the decision-making entirely to the physician, and paucity of practical resources for individualized risk-benefit counseling. Clinical practice guidelines should be developed to reduce existing practice variations in presurgical counseling. Further consensus is needed about when and how to initiate the conversation about epilepsy surgery, essential components of the discussion, and the utility of various tools to improve the utilization of epilepsy surgery.

Association of EEG and Blood-Based Brain Injury Biomarker Accuracy to Prognosticate Mortality After Pediatric Cardiac Arrest: An Exploratory Study.

BACKGROUND: Evaluate the accuracy of brain-based blood biomarkers neuron-specific enolase (NSE) and S100b and electroencephalography (EEG) features alone and in combination with prognosticate 6-month mortality after pediatric cardiac arrest. We hypothesized that the combination of blood brain-based biomarkers and EEG features would have superior classification accuracy of outcome versus either alone. METHODS: Children (n = 58) aged between 1 week and 17 years admitted to the ICU following cardiac arrest at a tertiary care children's hopital were eligible for this secondary study. Blood NSE and S100b were measured closest to 24 hours after return of spontaneous circulation (ROSC). EEGs closest to 24 hours (median 11, interquartile range [IQR] 6 to 16 h) post-ROSC were evaluated by two epileptologists. EEG grade was informed by background frequency, amplitude, and continuity. Sleep spindles were present or absent. Mortality was assessed at six months post-ROSC. Area under the receiver operator curve (AUC) was performed for individual and combined brain-based biomarkers and EEG features. RESULTS: Children were aged 2.6 (IQR 0.6 to 10.4) years, and 25 (43%) died. Children who died had increased blood NSE (49.7 [28.0 to 63.1] vs 18.2 [9.8 to 31.8] ng/mL) and S100b (0.118 [0.036 to 0.296] vs 0.012 [0.003 to 0.021] ng/mL) and poor (discontinuous or isoelectric) EEG grade (76% vs 33%) more frequently than survivors (P < 0.05). AUC for NSE to predict mortality was 0.789, and was 0.841 when combined with EEG grade and spindles. S100b AUC for mortality was 0.856 and was optimal alone. CONCLUSIONS: In this exploratory study, the combination of brain-based biomarkers and EEG features may provide more accurate prognostication than either test alone after pediatric cardiac arrest.

Electroencephalography Technologist Inter-rater Agreement and Interpretation of Pediatric Critical Care Electroencephalography.

OBJECTIVES: Electroencephalography (EEG) technologists commonly screen continuous EEG. Until now, the inter-rater agreement or sensitivity for important EEG findings has been unknown in this group. METHODS: Twenty-nine EEG technologists and three clinical neurophysiologists interpreted 90 five-minute samples of pediatric critical care EEG. Inter-rater agreement was examined with Cohen's kappa and Fleiss' kappa for EEG findings. A gold-standard consensus agreement was developed for examining sensitivity and specificity for seizures or discontinuity. Kruskal-Wallis tests with Benjamani-Hochberg corrections for multiple comparisons were utilized to examine associations between correct scoring and certification status and years of experience. RESULTS: Aggregate agreement was moderate for seizures and fair for EEG background continuity among EEG technologists. Individual agreement for seizures and continuity varied from slight to substantial. For individual EEG technologists, sensitivity for seizures ranged from 44 to 93% and sensitivity for continuity ranged from 81 to 100%. Raters with Certified Long Term Monitoring credentials were more likely to identify seizures correctly. SIGNIFICANCE: This is the first study to evaluate inter-rater agreement and interpretation correctness among EEG technologists interpreting pediatric critical care EEG. EEG technologists demonstrated better aggregate agreement for seizure detection than other EEG findings, yet individual results and internal consistency varied widely. These data provide important insight into the common practice of utilizing EEG technologists for screening critical care EEG.

The Missed Value of Underutilizing Pediatric Epilepsy Surgery: A Systematic Review.

Pediatric epilepsy surgery is underutilized. Only 1%-11% of children with drug resistant epilepsy (DRE) undergo surgical treatment, or less than half of those estimated to benefit. We conducted a systematic review of articles published in PubMed, EMBASE, and Web of Science in order to study the factors related to surgery underutilization as well as the impact on both the individual and the healthcare system. Our review demonstrates multiple factors leading to underutilization, including family misconceptions about epilepsy surgery, lack of provider knowledge, as well as systemic health disparities. While the upfront cost of epilepsy surgery is significant, the long-term financial benefits and reduced health resource utilization tilt the economic advantage in favor of surgery in children with DRE. Additionally, timely interventions improve seizure and cognitive outcomes with low risk of complications. Further interventions are needed at the levels of family, provider, and the healthcare system to increase access to pediatric epilepsy surgery.

Recurrent seizure-related GRIN1 variant: Molecular mechanism and targeted therapy.

OBJECTIVE: Genetic variants in the GRIN genes that encode N-methyl-D-aspartate receptor (NMDAR) subunits have been identified in various neurodevelopmental disorders, including epilepsy. We identified a GRIN1 variant from an individual with early-onset epileptic encephalopathy, evaluated functional changes to NMDAR properties caused by the variant, and screened FDA-approved therapeutic compounds as potential treatments for the patient. METHODS: Whole exome sequencing identified a missense variant in GRIN1. Electrophysiological recordings were made from Xenopus oocytes and transfected HEK cells to determine the NMDAR biophysical properties as well as the sensitivity to agonists and FDA-approved drugs that inhibit NMDARs. A beta-lactamase reporter assay in transfected HEK cells evaluated the effects of the variant on the NMDAR surface expression. RESULTS: A recurrent de novo missense variant in GRIN1 (c.1923G>A, p.Met641Ile), which encodes the GluN1 subunit, was identified in a pediatric patient with drug-resistant seizures and early-onset epileptic encephalopathy. In vitro analysis indicates that GluN1-M641I containing NMDARs showed enhanced agonist potency and reduced Mg2+ block, which may be associated with the patient's phenotype. Results from screening FDA-approved drugs suggested that GluN1-M641I containing NMDARs are more sensitive to the NMDAR channel blockers memantine, ketamine, and dextromethorphan compared to the wild-type receptors. The addition of memantine to the seizure treatment regimen significantly reduced the patient's seizure burden. INTERPRETATION: Our finding contributes to the understanding of the phenotype-genotype correlations of patients with GRIN1 gene variants, provides a molecular mechanism underlying the actions of this variant, and explores therapeutic strategies for treating GRIN1-related neurological conditions.