Timing of referral to evaluate for epilepsy surgery: Expert Consensus Recommendations from the Surgical Therapies Commission of the International League Against Epilepsy

Epilepsy surgery is the treatment of choice for patients with drug-resistant seizures. A timely evaluation for surgical candidacy can be life-saving for patients who are identified as appropriate surgical candidates, and may also enhance the care of nonsurgical candidates through improvement in diagnosis, optimization of therapy, and treatment of comorbidities. Yet, referral for surgical evaluations is often delayed while palliative options are pursued, with significant adverse consequences due to increased morbidity and mortality associated with intractable epilepsy. The Surgical Therapies Commission of the International League Against Epilepsy (ILAE) sought to address these clinical gaps and clarify when to initiate a surgical evaluation. We conducted a Delphi consensus process with 61 epileptologists, epilepsy neurosurgeons, neurologists, neuropsychiatrists, and neuropsychologists with a median of 22 years in practice, from 28 countries in all six ILAE world regions. After three rounds of Delphi surveys, evaluating 51 unique scenarios, we reached the following Expert Consensus Recommendations: (1) Referral for a surgical evaluation should be offered to every patient with drug-resistant epilepsy (up to 70 years of age), as soon as drug resistance is ascertained, regardless of epilepsy duration, sex, socioeconomic status, seizure type, epilepsy type (including epileptic encephalopathies), localization, and comorbidities (including severe psychiatric comorbidity like psychogenic nonepileptic seizures [PNES] or substance abuse) if patients are cooperative with management; (2) A surgical referral should be considered for older patients with drug-resistant epilepsy who have no surgical contraindication, and for patients (adults and children) who are seizure-free on 1-2 antiseizure medications (ASMs) but have a brain lesion in noneloquent cortex; and (3) referral for surgery should not be offered to patients with active substance abuse who are noncooperative with management. We present the Delphi consensus results leading up to these Expert Consensus Recommendations and discuss the data supporting our conclusions. High level evidence will be required to permit creation of clinical practice guidelines

Highlights From the Annual Meeting of the American Epilepsy Society 2022

With more than 6000 attendees between in-person and virtual offerings, the American Epilepsy Society Meeting 2022 in Nashville, felt as busy as in prepandemic times. An ever-growing number of physicians, scientists, and allied health professionals gathered to learn a variety of topics about epilepsy. The program was carefully tailored to meet the needs of professionals with different interests and career stages. This article summarizes the different symposia presented at the meeting. Basic science lectures addressed the primary elements of seizure generation and pathophysiology of epilepsy in different disease states. Scientists congregated to learn about anti-seizure medications, mechanisms of action, and new tools to treat epilepsy including surgery and neurostimulation. Some symposia were also dedicated to discuss epilepsy comorbidities and practical issues regarding epilepsy care. An increasing number of patient advocates discussing their stories were intertwined within scientific activities. Many smaller group sessions targeted more specific topics to encourage member participation, including Special Interest Groups, Investigator, and Skills Workshops. Special lectures included the renown Hoyer and Lombroso, an ILAE/IBE joint session, a spotlight on the impact of Dobbs v. Jackson on reproductive health in epilepsy, and a joint session with the NAEC on coding and reimbursement policies. The hot topics symposium was focused on traumatic brain injury and post-traumatic epilepsy. A balanced collaboration with the industry allowed presentations of the latest pharmaceutical and engineering advances in satellite symposia

Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies

Genome-wide association meta-analyses of drug-resistant epilepsy

Background Epilepsy is one of the most common neurological disorders, affecting over 50 million people worldwide. One-third of people with epilepsy do not respond to currently available anti-seizure medications, constituting one of the most important problems in epilepsy. Little is known about the molecular pathology of drug resistance in epilepsy, in particular, possible underlying genetic factors are largely unknown. Methods We performed a genome-wide association study (GWAS) in two epilepsy cohorts of European ancestry, comparing drug-resistant (N = 4208) to drug-responsive individuals (N = 2618) followed by meta-analyses across the studies. Next, we performed subanalyses split into two broad subtypes: acquired or non-acquired focal and genetic generalized epilepsy. Findings Our drug-resistant versus drug-responsive epilepsy GWAS meta-analysis showed no significant loci when combining all epilepsy types. Sub-analyses on individuals with focal epilepsy (FE) identified a significant locus on chromosome 1q42.11-q42.12 (lead SNP: rs35915186, P = 1·51 × 10−8, OR[C] = 0·74). This locus was not associated with any epilepsy subtype in the latest epilepsy GWAS (lowest uncorrected P = 0·009 for FE vs. healthy controls), and drug resistance in FE was not genetically correlated with susceptibility to FE itself. Seven genome-wide significant SNPs within this locus, encompassing the genes CNIH4, WDR26, and CNIH3, were identified to protect against drug-resistant FE. Further transcriptome-wide association studies (TWAS) imply significantly higher expression levels of CNIH3 and WDR26 in drug-resistant FE than in drug-responsive FE. CNIH3 is implicated in AMPA receptor assembly and function, while WDR26 haploinsufficiency is linked to intellectual disability and seizures. These findings suggest that CNIH3 and WDR26 may play a role in mediating drug response in focal epilepsy. Interpretation We identified a contribution of common genetic variation to drug-resistant focal epilepsy. These findings provide insights into possible mechanisms underlying drug response variability in epilepsy, offering potential targets for personalised treatment approaches

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Educational entrepreneurs and the founding of charter schools in New York City

In recent years, public education in the United States has become increasingly receptive to entrepreneurial activity. Charter schools, in particular, have received significant attention in the literature with research suggesting that growing numbers of educational entrepreneurs are increasingly involved with charter schools, particularly in New York City (Hentschke, 2010; Higgins et al., 2011; Hess et al, 2010). While much is known about charter schools in general, the role of the individuals who found these schools has not been well studied. Based on interviews with 23 charter school founders in NYC, this work examines these individuals specifically and explores whether and how they are—or see themselves as—entrepreneurs. This study examines the various ways charter school founders have been influenced by their own experiences, and how their educational, professional, and ideological backgrounds have inspired their decisions to create charter schools. One of the most significant findings in this study was the significant variation in entrepreneurial skills and actions taken by charter school founders, resulting in the development of a typology placing charter school founders along a continuum of entrepreneurial activity. This typology lends nuance to this charter school founder/ educational entrepreneur discussion, arguing there are variations of entrepreneurship that depend on a founder's prior professional background, their reasons for founding charter schools, their charter school ideologies, and their relationships with the community. The findings also confirm the belief that a significant group of charter school founders are non-educators driven by the ideology that the private or quasi-private sector is more efficient and autonomous than the public sector

Nivolumab for hepatocellular carcinoma (HCC) in a real-world context.

e15675 Background: Novel immunotherapies may be effective in patients with HCC; however, patients with advanced liver disease are often excluded from clinical trials. The goal of our study was to evaluate the safety and efficacy of nivolumab for HCC in a real-world context, including among patients with advanced liver disease. Methods: We examined all cases of HCC initiated on off-study nivolumab alone or in combination with locoregional therapy at our institution from 2/2017 to 7/2018. Our sample included 14 patients. We report participant demographics, baseline liver function, treatment toxicity, and overall survival (OS). Results: The majority of participants were male (71%) and Caucasian (57%). NAFLD (36%) and HCV (43%) were the most frequently cited risk factors for HCC. Patients had variable liver disease at baseline, with 36% Child-Turcotte-Pugh (CTP) A, 36% CTP B, and 21% CTP C disease. Patients received either nivolumab only (50%), or nivolumab with locoregional therapy (LRT) (50%). All patients with CTP C disease received nivolumab alone. Treatment was generally safe, with only grade 1 or 2 toxicities reported, most commonly fatigue. Median OS was 7 months. Of note, one patient with baseline CTP C disease showed complete response to nivolumab treatment but experienced recurrence off nivolumab. Conclusions: Our study is the first to report the use of nivolumab in patients with HCC and CTP C disease. Nivolumab was well-tolerated in a real-world context in this small patient cohort, including among patients with advanced cirrhosis. Further study in larger patient populations is warranted. [Table: see text] </jats:p