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OBJECTIVE The aim of this study was to assess the safety and efficacy of combined active responsive neurostimulation (RNS) and vagus nerve stimulation (VNS) therapies in pediatric patients with drug-resistant epilepsy. METHODS A single-center retrospective chart review was conducted on pediatric patients implanted with the RNS System with a concomitant active VNS System (VNS+RNS) between 2015 and 2021. Patients with at least 1 month of overlapping concomitant VNS and RNS treatment were included. Patients who had an RNS device implanted after 21 years of age, those who had responsive neurostimulators implanted after their VNS was inactivated, or those in whom the VNS battery died and was not replaced before RNS System implantation were excluded. RESULTS Seven pediatric VNS+RNS patients were identified, and their courses of treatment were evaluated. All patients tolerated concurrent VNS and RNS treatment well, no device-device interactions were identified, and no major treatment-related adverse effects were noted. The median follow-up after RNS System implantation was 1.2 years. By electroclinical criteria, all 7 patients achieved 75%–99% reductions in the frequency of disabling seizures after RNS System implantation. By patient and caregiver report, 2 patients (28.6%) had 75%–99% reductions in the frequency of their disabling seizures, 2 patients (28.6%) achieved 50%–74% reductions, 2 patients achieved 1%–24% reduction in frequency of disabling seizures, and 1 patient (14.3%) experienced a 1%–24% increase in seizure frequency. The available VNS magnet swipe data identified 2 patients with 75%–99% reductions in seizure frequency as measured by magnet swipes, one with 25%–49% reductions and the other with 1%–24% increases in seizure frequency as measured by magnet swipes. CONCLUSIONS This study demonstrated that RNS and VNS therapies can safely be used simultaneously in pediatric patients. RNS may potentially augment the therapeutic effects of VNS treatment. Patients in whom a response to VNS has been suboptimal should still be considered for RNS therapy.

OBJECTIVE Despite antiepileptic drugs, more than 30% of people with epilepsy continue to have seizures. Patients with such drug-resistant epilepsy (DRE) may undergo invasive treatment such as resection, laser ablation of the epileptogenic focus, or vagus nerve stimulation, but many are not candidates for epilepsy surgery or fail to respond to such interventions. Responsive neurostimulation (RNS) provides a neuromodulatory option. In this study, the authors present a single-center experience with the use of RNS over the last 5 years to provide long-term control of seizures in patients with DRE with at least 1 year of follow-up. METHODS The authors performed a retrospective analysis of a prospectively collected single-center database of consecutive DRE patients who underwent RNS system implantation from September 2015 to December 2020. Patients were followed-up postoperatively to evaluate seizure freedom and complications. RESULTS One hundred patients underwent RNS placement. Seven patients developed infections: 2 responded to intravenous antibiotic therapy, 3 required partial removal and salvaging of the system, and 2 required complete removal of the RNS device. No postoperative tract hemorrhages, strokes, device migrations, or malfunctions were documented in this cohort. The average follow-up period was 26.3 months (range 1–5.2 years). In terms of seizure reduction, 8 patients had 0%–24% improvement, 14 had 25%–49% improvement, 29 experienced 50%–74% improvement, 30 had 75%–99% improvement, and 19 achieved seizure freedom. RNS showed significantly better outcomes over time: patients with more than 3 years of RNS therapy had 1.8 higher odds of achieving 75% or more seizure reduction (95% CI 1.07–3.09, p = 0.02). Also, patients who had undergone resective or ablative surgery prior to RNS implantation had 8.25 higher odds of experiencing 50% or more seizure reduction (95% CI 1.05–65.1, p = 0.04). CONCLUSIONS Responsive neurostimulator implantation achieved 50% or more seizure reduction in approximately 80% of patients. Even in patients who did not achieve seizure freedom, significant improvement in seizure duration, severity, or postictal state was reported in more than 68% of cases. Infection (7%) was the most common complication. Patients with prior resective or ablative procedures and those who had been treated with RNS for more than 3 years achieved better outcomes.

Long-lived phosphorescence has been observed at room temperature in two gold(i) complexes of a fluorenyl-substituted N-heterocyclic carbene.

Two sulfonate ester derivatives of anthraquinone, 1-tosyloxy-2-methoxy-9,10-anthraquinone (1a) and 1-trifluoromethylsulfonoxy-2-methoxy-9,10-anthraquinone (1b) were prepared and their ability to produce strong acids upon photoexcitation was examined. It is shown that these compounds generate acid with a yield that increases with light intensity when the applied photon dose is held constant. Additional experiments show that the rate of acid generation increases 4 fold when visible light (532 nm) laser pulses are combined with ultraviolet (355 nm) compared with ultraviolet alone. Continuous wave diode laser photolysis also effects acid generation with a rate that depends quadratically on the light intensity. Density functional theory calculations, laser flash photolysis, and chemical trapping experiments support a mechanism whereby an initially formed triplet state (T1) is excited to a higher triplet state which in turn undergoes homolysis of the RS(O2)–OAr bond. Secondary reactions of the initially formed sulfonyl radicals produce strong acids. It is demonstrated that high intensity photolysis of either 1a or 1b can initiate cationic polymerization of ethyl vinyl ether.

Objective Approximately 75% of pediatric patients who suffer from epilepsy are successfully treated with antiepileptic drugs, while the disease is drug resistant in the remaining patients, who continue to have seizures. Patients with drug-resistant epilepsy (DRE) may have options to undergo invasive treatment such as resection, laser ablation of the epileptogenic focus, or vagus nerve stimulation. To date, treatment with responsive neurostimulation (RNS) has not been sufficiently studied in the pediatric population because the FDA has not approved the RNS device for patients younger than 18 years of age. Here, the authors sought to investigate the safety of RNS in pediatric patients. Methods The authors performed a retrospective single-center study of consecutive patients with DRE who had undergone RNS system implantation from September 2015 to December 2019. Patients were followed up postoperatively to evaluate seizure freedom and complications. Results Of the 27 patients studied, 3 developed infections and were treated with antibiotics. Of these 3 patients, one required partial removal and salvaging of a functioning system, and one required complete removal of the RNS device. No other complications, such as intracranial hemorrhage, stroke, or device malfunction, were seen. The average follow-up period was 22 months. All patients showed improvement in seizure frequency. Conclusions The authors demonstrated the safety and efficacy of RNS in pediatric patients, with infections being the main complication. Abbreviations DBS = deep brain stimulation; DRE = drug-resistant epilepsy; MDC = multidisciplinary conference; MER = microelectrode recording; MSHS = Mount Sinai Health System; RNS = responsive neurostimulation; SEEG = stereo-EEG; VNS = vagus nerve stimulation.

Circumstances of the COVID-19 pandemic have mandated a change to standard management of infantile spasms. On April 6, 2020, the Child Neurology Society issued an online statement of immediate recommendations to streamline diagnosis and treatment of infantile spasms with utilization of telemedicine, outpatient studies, and selection of first-line oral therapies as initial treatment. The rationale for the recommendations and specific guidance including follow-up assessment are provided in this manuscript. These recommendations are indicated as enduring if intended to outlast the pandemic, and limited if intended only for the pandemic health care crisis but may be applicable to future disruptions of health care delivery.

The rise in popularity of photochemically initiated reversible addition-fragmentation chain transfer (RAFT) polymerization (photoRAFT) along with the broad spectrum of proposed, and possible, initiation mechanisms result in the need for careful characterization of the photophysical properties of some common RAFT agents. Direct irradiation of the RAFT agent as a means to generate radicals, also known as the photoiniferter mechanism, is one commonly proposed mechanism. The current study shows that dithioesters and trithiocarbonates have the lowest singlet and triplet excited-state energy levels that are close to, or lower than, the C-S bond dissociation energies. Excitation of these agents into their S

Responsive neurostimulation (RNS) is an approved treatment for intractable epilepsy in the adult population but has not yet been approved for pediatric patients. We present here the first reported case of a 14-year-old adolescent with 22q13.3 syndrome (more commonly known as Phelan–McDermid syndrome) with intractable epilepsy who showed clinical improvement after implantation of an RNS device. The patient had trialed 10 antiepileptic drugs without improvement and despite magnetic resonance imaging (MRI) demonstrating left mesial temporal sclerosis (MTS), the patient was not considered as a candidate for temporal lobe resection due to multifocal seizure activity on electroencephalogram (EEG). At 23 months postoperatively, she has experienced 86.7% reduction in seizure frequency; a clinical improvement which emphasizes the importance of considering RNS treatment for those with intractable epilepsy in the pediatric population, even in the setting of known genetic syndromes.

The syntheses and photophysical characterization of five new gold(I) complexes bearing diphenylamine-substituted fluorenyl moieties are reported; four are characterized by X-ray diffraction crystallography. Ancillary ligation on gold(I) is provided by organophosphine and N-heterocyclic carbene ligands. Two complexes

We summarize the history of individuals with Sturge-Weber syndrome (SWS) to inform clinical trial design and identify variations in care.We performed retrospective chart review of individuals with SWS from centers in New York City. We characterized data quality using a novel scoring system. For 13 clinical concepts, we evaluated if data were present and if they were of high quality.We included 26 individuals with SWS (58% female; median age at initial visit 7 years; absolute range 1 month to 56 years]). Twenty-two had nevus flammeus, 13 glaucoma, four homonymous hemianopia, and 15 hemiparesis. Nineteen of 21 had at least one confirmed seizure with a known first seizure date, all before 24 months. Most (18 of 26, 69%) epilepsy was controlled. A plurality (10 of 23, 43%) had either normal cognitive function or mild cognitive delays. Aspirin use varied by site (P = 0.02)-at four sites, use was 0% (zero of three), 0% (zero of four), 80% (four of five), and 64% (nine of 14). Data were present for more than 75% of cases for 11 of 13 clinical concepts (missing: age of diagnosis, age of glaucoma onset). There were gaps in level of detail for motor impairments, glaucoma severity, seizure history, cognition, and medication history.Clinical charts have important gaps in the level of detail around core SWS clinical features, limiting value for some natural history studies. Any clinical trial in SWS designed to prevent epilepsy should begin in the first year of life. Variations in use of aspirin suggest de facto clinical equipoise and warrant a comparative effectiveness study.

Drug-resistant epilepsy (DRE) occurs at higher rates in children3 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 children3 years old who undergo epilepsy surgery evaluation as a means to assess contributors and potential solutions to health care disparities in this group.The Pediatric Epilepsy Research Consortium Epilepsy Surgery Database, a multicentered, cross-sectional collaboration of 21 US pediatric epilepsy centers, collects prospective data on children18 years of age referred for epilepsy surgery evaluation. We compared patient characteristics, diagnostic utilization, and surgical treatment between children3 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.The cohort included 437 children, of whom 71 (16%) were3 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).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.

Patients often recognize unmet needs that can improve patient-provider experiences in disease treatment management. These needs are rarely captured and may be hard to quantify in difficult-to-treat disease states such as drug-resistant epilepsy (DRE). To further understand challenges living with and managing DRE, a team of medical anthropologists conducted ethnographic field assessments with patients to qualitatively understand their experience with DRE across the United States. In addition, healthcare provider assessments were conducted in community clinics and Comprehensive Epilepsy Centers to further uncover patient-provider treatment gaps. We identified four distinct stages of the treatment and management journey defined by patients' perceived control over their epilepsy: Gripped in the Panic Zone, Diligently Tracking to Plan, Riding a Rollercoaster in the Dark, and Reframing Priorities to Redefine Treatment Success. We found that patients sought resources to streamline communication with their care team, enhanced education on treatment options beyond medications, and long-term resources to protect against a decline in control over managing their epilepsy once drug-resistant. Likewise, treatment management optimization strategies are provided to improve current DRE standard of care with respect to identified patient-provider gaps. These include the use of digital disease management tools, standardizing neuropsychiatrists into patients' initial care team, and introducing surgical and non-pharmacological treatment options upon epilepsy and DRE diagnoses, respectively. This ethnographic study uncovers numerous patient-provider gaps, thereby presenting a conceptual framework to advance DRE treatment. Further Incentivization from professional societies and healthcare systems to support standardization of the treatment optimization strategies provided herein into clinical practice is needed.

Background The complex clinical presentation and progression of Lennox–Gastaut syndrome (LGS) can complicate the accurate diagnosis of this severe, lifelong, childhood-onset epilepsy, often resulting in suboptimal treatment. The Refractory Epilepsy Screening Tool for LGS (REST-LGS) was developed to improve the identification of patients with LGS. Methods Using the Modified Delphi Consensus, a group of experts developed and tested the REST-LGS Case Report Form (CRF) comprising 8 criteria (4 major, 4 minor) considered potentially indicative of LGS. Diagnosis-blinded specialist and nonspecialist raters at 2 epilepsy centers applied the CRF to deidentified patient records, including 1:1 records of patients with drug-resistant epilepsy or confirmed LGS. Interrater reliability was measured by Cohen's κ. Diagnosis was then unblinded to reveal common criteria for LGS or drug-resistant epilepsy. Cronbach's α was used to measure internal consistency between raters for all criteria combined. Results Of 200 patients, 81% to 85% met 1 to 3 major criteria. At both sites, moderate (κ, 0.41–0.60) to good (κ, 0.61–0.80) agreement on most criteria was reached between expert and nonexpert raters. Unblinding revealed that most patients with LGS met 3 major and 2 to 3 minor criteria, while patients with drug-resistant epilepsy met ≤ 1 major and only 1 to 2 minor criteria. Cronbach's α of raters at both sites was 0.64. Conclusions The combined number of major/minor criteria on the CRF may be particularly indicative of LGS. Therefore, the REST-LGS may be a valuable clinical tool in identifying patients requiring further diagnostic evaluation for LGS.

Increasingly, genomics is informing clinical practice, but challenges remain for medical professionals lacking genetics expertise, and in access to and clinical utility of genomic testing for minority and underrepresented populations. The latter is a particularly pernicious problem due to the historical lack of inclusion of racially and ethnically diverse populations in genomic research and genomic medicine. A further challenge is the rapidly changing landscape of genetic tests and considerations of cost, interpretation, and diagnostic yield for emerging modalities like whole-genome sequencing.The NYCKidSeq project is a randomized controlled trial recruiting 1130 children and young adults predominantly from Harlem and the Bronx with suspected genetic disorders in three disease categories: neurologic, cardiovascular, and immunologic. Two clinical genetic tests will be performed for each participant, either proband, duo, or trio whole-genome sequencing (depending on sample availability) and proband targeted gene panels. Clinical utility, cost, and diagnostic yield of both testing modalities will be assessed. This study will evaluate the use of a novel, digital platform (GUÍA) to digitize the return of genomic results experience and improve participant understanding for English- and Spanish-speaking families. Surveys will collect data at three study visits: baseline (0 months), result disclosure visit (ROR1, + 3 months), and follow-up visit (ROR2, + 9 months). Outcomes will assess parental understanding of and attitudes toward receiving genomic results for their child and behavioral, psychological, and social impact of results. We will also conduct a pilot study to assess a digital tool called GenomeDiver designed to enhance communication between clinicians and genetic testing labs. We will evaluate GenomeDiver's ability to increase the diagnostic yield compared to standard practices, improve clinician's ability to perform targeted reverse phenotyping, and increase the efficiency of genetic testing lab personnel.The NYCKidSeq project will contribute to the innovations and best practices in communicating genomic test results to diverse populations. This work will inform strategies for implementing genomic medicine in health systems serving diverse populations using methods that are clinically useful, technologically savvy, culturally sensitive, and ethically sound.ClinicalTrials.gov NCT03738098 . Registered on November 13, 2018 Trial Sponsor: Icahn School of Medicine at Mount Sinai Contact Name: Eimear Kenny, PhD (Principal Investigator) Address: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Pl., Box 1003, New York, NY 10029 Email: eimear.kenny@mssm.edu.

Based on a multicenter cohort of people with anti-NMDA receptor encephalitis (anti-NMDARE), we describe seizure phenotypes, electroencephalographic (EEG) findings, and anti-seizure treatment strategies. We also investigated whether specific electrographic features are associated with persistent seizures or status epilepticus after acute presentation. In this retrospective cohort study, we reviewed records of children and adults with anti-NMDARE between 2010 and 2014 who were included in the Rare Epilepsy of New York City database, which included the text of physician notes from five academic medical centers. Clinical history (e.g., seizure semiology) and EEG features (e.g., background organization, slowing, epileptiform activity, seizures, sleep architecture, extreme delta brush) were abstracted. We compared clinical features associated with persistent seizures (ongoing seizures after one month from presentation) and status epilepticus, using bivariate and multivariable analyses. Among the 38 individuals with definite anti-NMDARE, 32 (84%) had seizures and 29 (76%) had seizures captured on EEG. Electrographic-only seizures were identified in five (13%) individuals. Seizures started at a median of four days after initial symptoms (IQR: 3-6 days). Frontal lobe-onset focal seizures were most common (n=12; 32%). Most individuals (31/38; 82%) were refractory to anti-seizure medications. Status epilepticus was associated with younger age (15 years [9-20] vs. 23 years [18-27]; p=0.04) and Hispanic ethnicity (30 [80%] vs. 8 [36%]; p=0.04). Persistent seizures (ongoing seizures after one month from presentation) were associated with younger age (nine years [3-14] vs. 22 years [15-28]; p

Objective We aimed to describe how often and why clinicians counsel people with epilepsy about sudden unexpected death in epilepsy (SUDEP). Understanding counseling gaps can help design interventions. Methods We searched clinical notes of 77,924 patients from 2010 to 2014 from six hospitals to find examples of SUDEP counseling and seizure safety counseling. Visits were coded for patient, clinician, and visit factors, and documented reasons for counseling. We evaluated factors associated with SUDEP vs. seizure safety counseling, and reasons for counseling using bivariate and multivariable statistics. Reasons for counseling included: poor medication adherence, lifestyle factors (e.g., poor sleep, drinking alcohol), patient/family reluctance to make recommended medication adjustment, epilepsy surgery considerations, and patient education only. Results Analysis was restricted to two of six hospitals where 91% of counseling occurred. Documentation of SUDEP counseling was rare (332 of 33,821 patients, 1.0%), almost exclusively by epileptologists (98.5% of counseling), and stable over time, X2 (4, n = 996) = 3.81, p = 0.43. Adult neurologists were more likely to document SUDEP counseling than pediatric (OR = 1.65, 95% CI = 1.12–2.44). Most SUDEP counseling was documented with a goal of seizure reduction (214 of 332, 64.5%), though some was for patient education only (118 of 332, 35.5%). By the time SUDEP counseling was documented, the majority of patients had refractory epilepsy (187 of 332, 56.3%) and/or a potentially modifiable risk factor (214 of 332, 64.5%). Neurologists with more years of clinical experience (OR = 2.18, 95% CI = 1.12–4.25) and more senior academic titles (OR = 2.25, 95% CI = 1.27–3.99) were more likely to document SUDEP counseling for patient education only. People with ≥2 anti-seizure medications (ASM) were more likely to receive counseling for patient education (OR = 2.72, 95% CI = 1.49–4.97). Conclusions Documentation of SUDEP is rare, and varies by clinician, hospital, and patient factors. Efforts to increase SUDEP counseling should focus on junior clinicians, and emphasize starting the conversation soon after onset of epilepsy

Background Increasingly, genomics is informing clinical practice, but challenges remain for medical professionals lacking genetics expertise, and in access to and clinical utility of genomic testing for minority and underrepresented populations. The latter is a particularly pernicious problem due to the historical lack of inclusion of racially and ethnically diverse populations in genomic research and genomic medicine. A further challenge is the rapidly changing landscape of genetic tests and considerations of cost, interpretation, and diagnostic yield for emerging modalities like whole-genome sequencing. Methods The NYCKidSeq project is a randomized controlled trial recruiting 1130 children and young adults predominantly from Harlem and the Bronx with suspected genetic disorders in three disease categories: neurologic, cardiovascular, and immunologic. Two clinical genetic tests will be performed for each participant, either proband, duo, or trio whole-genome sequencing (depending on sample availability) and proband targeted gene panels. Clinical utility, cost, and diagnostic yield of both testing modalities will be assessed. This study will evaluate the use of a novel, digital platform (GUÍA) to digitize the return of genomic results experience and improve participant understanding for English- and Spanish-speaking families. Surveys will collect data at three study visits: baseline (0 months), result disclosure visit (ROR1, + 3 months), and follow-up visit (ROR2, + 9 months). Outcomes will assess parental understanding of and attitudes toward receiving genomic results for their child and behavioral, psychological, and social impact of results. We will also conduct a pilot study to assess a digital tool called GenomeDiver designed to enhance communication between clinicians and genetic testing labs. We will evaluate GenomeDiver’s ability to increase the diagnostic yield compared to standard practices, improve clinician’s ability to perform targeted reverse phenotyping, and increase the efficiency of genetic testing lab personnel. Discussion The NYCKidSeq project will contribute to the innovations and best practices in communicating genomic test results to diverse populations. This work will inform strategies for implementing genomic medicine in health systems serving diverse populations using methods that are clinically useful, technologically savvy, culturally sensitive, and ethically sound. Trial registration ClinicalTrials.govNCT03738098. Registered on November 13, 2018 Trial Sponsor: Icahn School of Medicine at Mount Sinai Contact Name: Eimear Kenny, PhD (Principal Investigator) Address: Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Pl., Box 1003, New York, NY 10029 Email: eimear.kenny@mssm.edu

Objective:To evaluate the safety and tolerability of adjunctive eslicarbazepine acetate (ESL) in pediatric patients (aged 4-17 years) with refractory focal seizures.Methods:Pooled safety data from patients aged 4-17 years in Study 208 (NCT01527513) and Study 305 (NCT00988156) were analyzed. Both were randomized, double-blind, placebo-controlled studies of ESL as adjunctive treatment in pediatric patients with refractory focal seizures receiving 1 or 2 antiepileptic drugs. Incidences of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to discontinuation, and TEAEs of special interest were evaluated.Results:The safety population comprised 362 patients (placebo, n = 160; ESL, n = 202). The overall incidence of TEAEs was similar between the ESL (67.8%) and placebo groups (65.6%), with no clear dose-response relationship. The most frequently reported TEAEs with ESL were headache, somnolence, vomiting, and diplopia. Overall incidences of SAEs and TEAEs leading to discontinuation were higher with ESL versus placebo (9.9% vs 5.0% and 5.9% vs 2.5%, respectively). The majority of SAEs with ESL occurred in Study 305. Two deaths were reported, 1 with ESL (0.5%) due to cluster seizures (resulting in herniation of the cerebellar tonsils) and 1 with placebo (0.6%) due to asphyxia. TEAEs related to allergic reaction, hyponatremia, hypothyroidism, cytopenia, seizure exacerbation, cognitive dysfunction, psychiatric disorders, or suicide occurred infrequently (Conclusion:Adjunctive ESL was generally well tolerated in children aged 4-17 years with focal seizures. The safety profile of ESL in children was comparable to that observed in adults.

Summary Identifying individuals with rare epilepsy syndromes in electronic data sources is difficult, in part because of missing codes in the International Classification of Diseases (ICD) system. Our objectives were the following: (1) to describe the representation of rare epilepsies in other medical vocabularies, to identify gaps; and (2) to compile synonyms and associated terms for rare epilepsies, to facilitate text and natural language processing tools for cohort identification and population‐based surveillance. We describe the representation of 33 epilepsies in 3 vocabularies: Orphanet, SNOMED‐CT, and UMLS‐Metathesaurus. We compiled terms via 2 surveys, correspondence with parent advocates, and review of web resources and standard vocabularies. UMLS‐Metathesaurus had entries for all 33 epilepsies, Orphanet 32, and SNOMED‐CT 25. The vocabularies had redundancies and missing phenotypes. Emerging epilepsies (SCN2A‐, SCN8A‐, KCNQ2‐, SLC13A5‐, and SYNGAP‐related epilepsies) were underrepresented. Survey and correspondence respondents included 160 providers, 375 caregivers, and 11 advocacy group leaders. Each epilepsy syndrome had a median of 15 (range 6–28) synonyms. Nineteen had associated terms, with a median of 4 (range 1–41). We conclude that medical vocabularies should fill gaps in representation of rare epilepsies to improve their value for epilepsy research. We encourage epilepsy researchers to use this resource to develop tools to identify individuals with rare epilepsies in electronic data sources.

OBJECTIVE Sudden unexpected death in epilepsy (SUDEP) is an important cause of mortality in epilepsy. However, there is a gap in how often providers counsel patients about SUDEP. One potential solution is to electronically prompt clinicians to provide counseling via automated detection of risk factors in electronic medical records (EMRs). We evaluated (1) the feasibility and generalizability of using regular expressions to identify risk factors in EMRs and (2) barriers to generalizability. METHODS Data included physician notes for 3000 patients from one medical center (home) and 1000 from five additional centers (away). Through chart review, we identified three SUDEP risk factors: (1) generalized tonic-clonic seizures, (2) refractory epilepsy, and (3) epilepsy surgery candidacy. Regular expressions of risk factors were manually created with home training data, and performance was evaluated with home test and away test data. Performance was evaluated by sensitivity, positive predictive value, and F-measure. Generalizability was defined as an absolute decrease in performance by

Knowledge of the order of the effective nonlinear absorption in multiphoton photoresists is a key element in the development of improved materials for multiphoton absorption polymerization (MAP). The direct measurement of this nonlinearity has proven challenging. A new technique called 2-beam initiation threshold (2-BIT) is presented that allows for the unambiguous, in situ measurement of the order of the effective nonlinear absorption using a simple optical arrangement that can be employed with virtually any MAP setup. This technique is benchmarked using three common commercial photoinitiators that have been used previously in MAP and one common dye that acts as a photoinitiator. The linear absorption spectrum is demonstrated to be a poor predictor of the effective order of nonlinear absorption at a given wavelength. Surprisingly, for two of these initiators the effective nonlinear absorption process is dominated by 3-photon absorption in the 800 nm wavelength range, suggesting that 2-BIT is a valuable means of identifying initiators that can improve the resolution of MAP.

Objective Rolandic epilepsy is a common genetic focal epilepsy of childhood characterized by centrotemporal sharp waves on electroencephalogram. In previous genome‐wide analysis, we had reported linkage of centrotemporal sharp waves to chromosome 11p13, and fine mapping with 44 SNPs identified the ELP4‐PAX6 locus in two independent US and Canadian case–control samples. Here, we aimed to find a causative variant for centrotemporal sharp waves using a larger sample and higher resolution genotyping array. Methods We fine‐mapped the ELP4‐PAX6 locus in 186 individuals from rolandic epilepsy families and 1000 population controls of European origin using the Illumina HumanCoreExome‐12 v1.0 BeadChip. Controls were matched to cases on ethnicity using principal component analysis. We used generalized estimating equations to assess association, followed up with a bioinformatics survey and literature search to evaluate functional significance. Results Homozygosity at the T allele of SNP rs662702 in the 3′ untranslated region of PAX6 conferred increased risk of CTS: Odds ratio = 12.29 (95% CI: 3.20–47.22), P = 2.6 × 10−4 and is seen in 3.9% of cases but only 0.3% of controls. Interpretation The minor T allele of SNP rs662702 disrupts regulation by microRNA‐328, which is known to result in increased PAX6 expression in vitro. This study provides, for the first time, evidence of a noncoding genomic variant contributing to the etiology of a common human epilepsy via a posttranscriptional regulatory mechanism.

Objective The high prevalence and impact of neurodevelopmental comorbidities in childhood epilepsy are now well known, as are the increased risks and familial aggregation of reading disability (RD) and speech sound disorder (SSD) in rolandic epilepsy (RE). The risk factors for RD in the general population include male sex, SSD, and ADHD, but it is not known if these are the same in RE or whether there is a contributory role of seizure and treatment-related variables. Methods An observational study of 108 probands with RE (age range: 3.6–22 years) and their 159 siblings (age range: 1–29 years; 83 with EEG data) were singly ascertained in the US or UK through a proband affected by RE. We used a nested case–control design, multiple logistic regression, and generalized estimating equations to test the hypothesis of an association between RD and seizure variables or antiepileptic drug treatment in RE; we also assessed an association between EEG focal sharp waves and RD in siblings. Results Reading disability was reported in 42% of probands and 22% of siblings. Among probands, RD was strongly associated with a history of SSD (OR: 9.64, 95% CI: 2.45–37.21), ADHD symptoms (OR: 10.31, 95% CI: 2.15–49.44), and male sex (OR: 3.62, 95% CI: 1.11–11.75) but not with seizure or treatment variables. Among siblings, RD was independently associated only with SSD (OR: 4.30, 95% CI: 1.42–13.0) and not with the presence of interictal EEG focal sharp waves. Significance The principal risk factors for RD in RE are SSD, ADHD, and male sex, the same risk factors as for RD without epilepsy. Seizure or treatment variables do not appear to be important risk factors for RD in probands with RE, and there was no evidence to support interictal EEG focal sharp waves as a risk factor for RD in siblings. Future studies should focus on the precise neuropsychological characterization of RD in families with RE and on the effectiveness of standard oral-language and reading interventions.

Multicolor photolithography using visible light holds the promise of achieving wafer-scale patterning at pitches on the 10 nm scale. Although substantial progress has been made on multicolor techniques, a number of challenges remain to be met before the ultimate resolution of these methods can be reached. These challenges include the development of improved materials, creation of high-quality thin films, transitioning to exposure schemes that rely completely on linear absorption, scaling up to large-area patterning, and developing methods for effective pattern transfer. This paper discusses the state of the art in multicolor photolithography, presents some of the most recent advances in this field, and examines the prospects moving forward.

Three-color lithography (3CL) can produce high-resolution features using visible light. This technique uses one beam to pre-activate a photoresist, a second beam to deactivate it, and a third beam to activate the pre-activated regions that have not been deactivated. The deactivation beam is used to trim features, allowing for improved feature size and resolution. Although this 3CL was pioneered with 2-photon excitation, the ultimate goal is to use thin films with linear excitation, such that it is compatible with industrial requirements. We will discuss the first thin-film 3CL studies, which are a promising step towards large-area patterning.

Background Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases. Objective To identify rare, causal CNV in patients with RE. Methods We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India. Results We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin. Conclusion Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.

The responsive neurostimulation (RNS) system, an adjunctive treatment for pharmacoresistant partial-onset seizures with 1 or 2 foci, has been available to patients aged 18 years or older since the device’s FDA approval in 2013. Herein, the authors describe their off-label application of this technology in 2 pediatric patients and the consequent therapeutic benefit without surgical complications or treatment side effects. A 14-year-old nonambulatory, nonverbal male with severe developmental delay was considered for RNS therapy for medically and surgically refractory epilepsy with bilateral seizure onsets in the setting of a normal radiological examination and a known neuropathological diagnosis of type I cortical dysplasia. The RNS system was implanted with strip electrodes placed on the left lateral frontal and right lateral temporal neocortex. At 19 months’ follow-up, cortical stimulation resulted in sustained reduction in both seizure frequency—3 seizures per day down from 15 to 30 per day—and seizure severity. The patient subsequently underwent a trial of corticothalamic stimulation with a right temporal cortical strip and a left thalamic depth electrode, which resulted in a further 50% reduction in seizure frequency. In a second case, a 9-year-old right-handed female with radiological evidence of a small watershed infarct on the left and medically refractory seizures was referred for presurgical evaluation. Invasive monitoring revealed an unresectable seizure focus in the eloquent cortex of the left posterior frontal and parietal lobes. The RNS device was implanted with cortical leads placed at the putative seizure focus. At 21 months after surgery, the patient had been seizure free for 4 months, following a 17-month period in which the seizure frequency had decreased from 12 per month to 2 per month, with associated functional and behavioral improvement. The authors’ results suggest that RNS may be a palliative option for children with intractable seizures whose condition warrants off-label use of the surgical device. The improved therapeutic effect noted with time and sustained RNS treatment points to a possible neuromodulatory effect.

Background The relationship between temporal lobe epilepsy and focal limb dystonia is a well-recognized phenomenon, yet its pathogenesis and anatomic foundation are not well understood. Here, we describe 2 patients with refractory focal epilepsy and contralateral focal limb dystonia whose seizures and dystonic symptoms simultaneously resolved after anterior temporal lobectomy and amygdalohippocampectomy. Case Description We identified 2 patients within the Mount Sinai Health system with improvement in dystonia after medial temporal lobectomy. Retrospective chart reviews for the clinical history were performed. Patient 1 suffered a traumatic injury of the right temporal lobe, developing left hemidystonia and epilepsy. He received a right amygdala-hippocampectomy, which resolved both. Patient 2 has a history of right temporal glioma resection complicated by an infarct, resulting in left hemidystonia and epilepsy. He received a right medial temporal resection, which nearly resolved both. Conclusion Our cases demonstrate a medial temporal-basal ganglia network dysfunction in dystonia-epilepsy that was modulated and cured by resective surgery. We hypothesize that the mechanisms behind these observed phenomena were due to a pathologic connectivity of the basal ganglia and amygdala-hippocampus. To our knowledge, these are the first reported cases of dystonia and concomitant epilepsy resolving with temporal lobectomy and provide valuable prognostic information for similarly affected patients.

Object The risk of developing epilepsy after perinatal stroke, hypoxic/ischemic injury, and intracerebral hemorrhage is significant, and seizures may become medically refractory in approximately 25% of these patients. Surgical management can be difficult due to multilobar or bilateral cortical injury, nonfocal or poorly lateralizing video electroencephalography (EEG) findings, and limited functional reserve. In this study the authors describe the surgical approaches, seizure outcomes, and complications in patients with epilepsy due to vascular etiologies in the perinatal period and early infancy. Methods The records were analyzed of 19 consecutive children and adults with medically refractory epilepsy and evidence of perinatal arterial branch occlusions, hypoxic/ischemic insult, or hemorrhagic strokes, who underwent surgery at the Comprehensive Epilepsy Center of Beth Israel Medical Center and St. Luke's-Roosevelt Hospital Center. Preoperative findings including MRI, video EEG, functional MRI, and neuropsychological testing were analyzed. The majority of patients underwent staged operations with invasive mapping, and all patients had either extra- or intraoperative functional mapping. Results In 7 patients with large porencephalic cysts due to major arterial branch occlusions, periinsular functional hemispherotomy was performed in 4 children, and in 3 patients, multilobar resections/disconnections were performed, with 1 patient undergoing additional resections 3 years after initial surgery due to recurrence of seizures. All of these patients have been seizure free (Engel Class IA) after a mean 4.5-year follow-up (range 15–77 months). Another 8 patients had intervascular border-zone ischemic infarcts and encephalomalacia, and in this cohort 2 hemispherotomies, 5 multilobar resections/disconnections, and 1 focal cortical resection were performed. Seven of these patients remain seizure free (Engel Class IA) after a mean 4.5-year follow-up (range 9–94 months), and 1 patient suffered a single seizure after 2.5 years of seizure freedom (Engel Class IB, 33-month follow-up). In the final 4 patients with vascular malformation-associated hemorrhagic or ischemic infarction in the perinatal period, a hemispherotomy was performed in 1 case, multilobar resections in 2 cases, and in 1 patient a partial temporal lobectomy was performed, followed 6 months later by a complete temporal and occipital lobectomy due to ongoing seizures. All of these patients have had seizure freedom (Engel Class IA) with a mean follow-up of 4.5 years (range 10–80 months). Complications included transient monoparesis or hemiparesis in 3 patients, transient mutism in 1 patient, infection in 1 patient, and a single case of permanent distal lower-extremity weakness. Transient mood disorders (depression and anxiety) were observed in 2 patients and required medical/therapeutic intervention. Conclusions Epilepsy surgery is effective in controlling medically intractable seizures after perinatal vascular insults. Seizure foci tend to be widespread and rarely limited to the area of injury identified through neuroimaging, with invasive monitoring directing multilobar resections in many cases. Long-term functional outcomes have been good in these patients, with significant improvements in independence, quality of life, cognitive development, and motor skills, despite transient postoperative monoparesis or hemiparesis and occasional mood disorders.

Migraine headaches are a common comorbidity in Rolandic epilepsy (RE) and familial aggregation of migraine in RE families suggests a genetic basis not mediated by seizures. We performed a genome-wide linkage analysis of the migraine phenotype in 38 families with RE to localize potential genetic contribution, with a follow-up in an additional 21 families at linked loci. We used two-point and multipoint LOD (logarithm of the odds) score methods for linkage, maximized over genetic models. We found evidence of linkage to migraine at chromosome 17q12-22 [multipoint HLOD (heterogeneity LOD) 4.40, recessive, 99% penetrance], replicated in the second dataset (HLOD 2.61), and suggestive evidence at 1q23.1-23.2, centering over the FHM2 locus (two-point LOD 3.00 and MP HLOD 2.52). Sanger sequencing in 14 migraine-affected individuals found no coding mutations in the FHM2 gene ATP1A2. There was no evidence of pleiotropy for migraine and either reading or speech disorder, or the electroencephalographic endophenotype of RE when the affected definition was redefined as those with migraine or the comorbid phenotype, and pedigrees were reanalyzed for linkage. In summary, we report a novel migraine susceptibility locus at 17q12-22, and a second locus that may contribute to migraine in the general population at 1q23.1-23.2. Comorbid migraine in RE appears genetically influenced, but we did not obtain evidence that the identified susceptibility loci are consistent with pleiotropic effects on other comorbidities in RE. Loci identified here should be fine-mapped in individuals from RE families with migraine, and prioritized for analysis in other types of epilepsy-associated migraine.

OBJECTIVE The purpose of this study was to report outcomes of epilepsy surgery in 56 consecutive patients with autism spectrum disorder. METHODS Medical records of 56 consecutive patients with autism who underwent epilepsy surgery were reviewed with regard to clinical characteristics, surgical management, postoperative seizure control, and behavioral changes. RESULTS Of the 56 patients with autism, 39 were male, 45 were severely autistic, 27 had a history of clinically significant levels of aggression and other disruptive behaviors, and 30 were considered nonverbal at baseline. Etiology of the epilepsy was known in 32 cases, and included structural lesions, medical history, and developmental and genetic factors. Twenty-nine patients underwent resective treatments (in 8 cases combined with palliative procedures), 24 patients had only palliative treatments, and 3 patients had only subdural electroencephalography. Eighteen of the 56 patients had more than one operation. The mean age at surgery was 11 ± 6.5 years (range 1.5–35 years). At a mean follow-up of 47 ± 30 months (range 2–117 months), seizure outcomes included 20 Engel Class I, 12 Engel Class II, 18 Engel Class III, and 3 Engel Class IV cases. The age and follow-up times are stated as the mean ± SD. Three patients were able to discontinue all antiepileptic drugs (AEDs). Aggression and other aberrant behaviors observed in the clinical setting improved in 24 patients. According to caregivers, most patients also experienced some degree of improvement in daily social and cognitive function. Three patients had no functional or behavioral changes associated with seizure reduction, and 2 patients experienced worsening of seizures and behavioral symptoms. CONCLUSIONS Epilepsy surgery in patients with autism is feasible, with no indication that the comorbidity of autism should preclude a good outcome. Resective and palliative treatments brought seizure freedom or seizure reduction to the majority of patients, although one-third of the patients in this study required more than one procedure to achieve worthwhile improvement in the long term, and few patients were able to discontinue all AEDs. The number of palliative procedures performed, the need for multiple interventions, and continued use of AEDs highlight the complex etiology of epilepsy in patients with autism spectrum disorder. These considerations underscore the need for continued analysis, review, and reporting of surgical outcomes in patients with autism, which may aid in better identification and management of surgical candidates. The reduction in aberrant behaviors observed in this series suggests that some behaviors previously attributed to autism may be associated with intractable epilepsy, and further highlights the need for systematic evaluation of the relationship between the symptoms of autism and refractory seizures.

An 18-year-old right-handed neurologically normal woman has new onset focal epilepsy, presenting with a secondary generalized tonic-clonic seizure after a year-long history of episodes of deja vu associated with mild confusion lasting 1–2 min. She has a normal MRI, no risk factors for epilepsy, and an EEG that shows right temporal spikes. What is your decision pathway in terms of diagnostic and treatment approaches for her?

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Rolandic epilepsy (RE) is the most common human epilepsy, affecting children between 3 and 12 years of age, boys more often than girls (3:2). Focal sharp waves in the centrotemporal area define the electroencephalographic (EEG) trait for the syndrome, are a feature of several related childhood epilepsies and are frequently observed in common developmental disorders (eg, speech dyspraxia, attention deficit hyperactivity disorder and developmental coordination disorder). Here we report the first genome-wide linkage scan in RE for the EEG trait, centrotemporal sharp waves (CTS), with genome-wide linkage of CTS to 11p13 (HLOD 4.30). Pure likelihood statistical analysis refined our linkage peak by fine mapping CTS to variants in Elongator Protein Complex 4 (ELP4) in two independent data sets; the strongest evidence was with rs986527 in intron 9 of ELP4, providing a likelihood ratio of 629:1 (P=0.0002) in favor of an association. Resequencing of ELP4 coding, flanking and promoter regions revealed no significant exonic polymorphisms. This is the first report of a gene implicated in a common focal epilepsy and the first human disease association of ELP4. ELP4 is a component of the Elongator complex, involved in transcription and tRNA modification. Elongator depletion results in the brain-specific downregulation of genes implicated in cell motility and migration. We hypothesize that a non-coding mutation in ELP4 impairs brain-specific Elongator-mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.

Seizures are alarming and can be life-threatening. It is essential that pediatric providers be able to identify those paroxysmal events most likely to be seizures and to know which require immediate evaluation. Severity can range from childhood syndromes that are controlled relatively easily and usually outgrown to epileptic encephalopathies that are associated with severe developmental delay and sometimes death. Familiarity with seizure semiology can guide early diagnosis and treatment. [ Pediatr Ann . 2015;44(2):e24–e29.]

It is not unusual for the primary care provider to have a child present with unusual paroxysmal events or dermatological lesions that bear further investigation. Although most children with epilepsy are treated and managed by pediatric neurologists, it is imperative that the primary care provider have a clear understanding of associated comorbidities, as well as information on the available anti-epileptic drugs, their side effects, and the need for further monitoring. Those children with epilepsy whose seizures become intractable, failing to be controlled with three or more medications used appropriately at adequate doses, should be referred to a comprehensive epilepsy center for consideration for other treatments. These may include the ketogenic diet, vagal nerve stimulation, or epilepsy surgery.