Incidence and phenotypes of childhood-onset genetic epilepsies:a prospective population-based national cohort

Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children’s hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9–57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26–14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93–12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24–9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07–7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy

Vulnerable: The Law, Policy and Ethics of COVID-19

Vulnerable: The Law, Policy and Ethics of COVID-19 confronts the vulnerabilities that have been revealed by the pandemic and its consequences. It examines vulnerabilities for people who have been harmed or will be harmed by the virus directly and those harmed by measures taken to slow its relentless march; vulnerabilities exposed in our institutions, governance, and legal structures; and vulnerabilities in other countries and at the global level where persistent injustices affect us all. COVID-19 has forced us to not only reflect on how we govern and how we set policy priorities, but also to ensure that pandemic preparedness, precautions, and recovery include all individuals, not just some.● TABLE OF CONTENTS ● INTRODUCTION : Overview of COVID-19: Old and New Vulnerabilities - Colleen M. Flood, Vanessa MacDonnell, Jane Philpott, Sophie Thériault and Sridhar Venkatapuram ●● SECTION A: WHO DOES WHAT? CHALLENGES AND DEMANDS OF CANADIAN FEDERALISM ● CHAPTER A-1: Have the Post-SARS Reforms Prepared Us for COVID-19? Mapping the Institutional Landscape - Katherine Fierlbeck and Lorian Hardcastle ● CHAPTER A-2: COVID-19 and First Nations’ Responses - Aimée Craft, Deborah McGregor, and Jeffery Hewitt ● CHAPITRE A-3 : Réflexions sur la mise en œuvre de la Loi sur la santé publique au Québec dans le contexte de la pandémie de COVID-19 - Michelle Giroux ● CHAPITRE A-4 : La COVID-19 au Canada : le fédéralisme coopératif à pied d’œuvre - David Robitaille ● CHAPTER A-5: Pandemic Data Sharing: How the Canadian Constitution Has Turned into a Suicide Pact - Amir Attaran and Adam R. Houston ● CHAPTER A-6: The Federal Emergencies Act: A Hollow Promise in the Face of COVID-19? - Colleen M. Flood and Bryan Thomas ● CHAPTER A-7: Resisting the Siren’s Call: Emergency Powers, Federalism, and Public Policy - Carissima Mathen ● CHAPTER A-8: Municipal Power and Democratic Legitimacy in the Time of COVID-19 - Alexandra Flynn ●● SECTION B: MAKING SURE SOMEONE IS ACCOUNTABLE: PUBLIC AND PRIVATE RESPONSIBILITIES ● CHAPTER B-1: Ensuring Executive and Legislative Accountability in a Pandemic -Vanessa MacDonnell ● CHAPTER B-2: Good Governance: Institutions, Processes, and People - Mel Cappe ● CHAPTER B-3: The Duty to Govern and the Rule of Law in an Emergency - Grégoire Webber ● CHAPTER B-4: Does Debunking Work? Correcting COVID-19 Misinformation on Social Media - Timothy Caulfield ● CHAPTER B-5: The Media Paradox and the COVID-19 Pandemic - Jeffrey Simpson ● CHAPTER B-6: Governmental Power and COVID-19: The Limits of Judicial Review - Paul Daly ● CHAPTER B-7: Liability of the Crown in Times of Pandemic - Marie-France Fortin ● CHAPTER B-8: Balancing Risk and Reward in the Time of COVID-19: Bridging the Gap Between Public Interest and the “Best Interests of the Corporation” - Jennifer A. Quaid ●● SECTION C: CIVIL LIBERTIES VS. IDEAS OF PUBLIC HEALTH ● CHAPTER C-1: Civil Liberties vs. Public Health - Colleen M. Flood, Bryan Thomas, and Dr. Kumanan Wilson ● CHAPTER C-2: Privacy, Ethics, and Contact-Tracing Apps - Teresa Scassa, Jason Millar, and Kelly Bronson ● CHAPTER C-3: Should Immunity Licences be an Ingredient in our Policy Response to COVID-19? - Daniel Weinstock and Vardit Ravitsky ● CHAPTER C-4: The Punitive Impact of Physical Distancing Laws on Homeless People - Terry Skolnik ● CHAPTER C-5: The Right of Citizens Abroad to Return During a Pandemic - Yves Le Bouthillier and Delphine Nakache ●● SECTION D: EQUITY AND COVID-19 ● CHAPTER D-1: How Should We Allocate Health and Social Resources During a Pandemic? - Sridhar Venkatapuram ● CHAPITRE D-2 : COVID-19 et âgisme : crise annoncée dans les centres de soins de longue durée et réponse improvisée ? - Martine Lagacé, Linda Garcia et Louise Bélanger-Hardy ● CHAPTER D-3: Fault Lines: COVID-19, the Charter, and Long-term Care - Martha Jackman ● CHAPTER D-4: The Front line Defence: Housing and Human Rights in the Time of COVID-19 - Leilani Farha and Kaitlin Schwan ● CHAPTER D-5: COVID-19 in Canadian Prisons: Policies, Practices and Concerns - Adelina Iftene ● CHAPTER D-6: Systemic Discrimination in Government Services and Programs and Its Impact on First Nations Peoples During the COVID-19 Pandemic - Anne Levesque and Sophie Thériault ● CHAPTER D-7: Preventing the Spread of Anti-Asian Racism: Including Critical Race Analysis in a Pandemic Plan - Jamie Chai Yun Liew ● CHAPTER D-8: Migrant Health in a Time of Pandemic: Fallacies of Us-Versus-Them - Y.Y. Brandon Chen ● CHAPTER D-9: Not All in This Together: Disability Rights and COVID-19 - Tess Sheldon and Ravi Malhotra ● CHAPTER D-10: Weighing Public Health and Mental Health Responses to Non-Compliance with Public Health Directives in the Context of Mental Illness - Jennifer A. Chandler, Yasmin Khaliq, Mona Gupta, Kwame McKenzie, Simon Hatcher, and Olivia Lee ●● SECTION E: THIS JOB IS GONNA KILL ME: WORKING AND COVID-19 ● CHAPTER E-1: Privatization and COVID-19: A Deadly Combination for Nursing Homes - Pat Armstrong, Hugh Armstrong, and Ivy Bourgeault ● CHAPTER E-2: A View from the Front Lines of a COVID-19 Outbreak - Jane Philpott ● CHAPTER E-3: Occupational Health and Safety and COVID-19: Whose Rights Come First in a Pandemic? - Katherine Lippel ● CHAPTER E-4: Risking It All: Providing Patient Care and Whistleblowing During a Pandemic - Vanessa Gruben and Louise Bélanger-Hardy ● CHAPTER E-5: Worked to the Bone: COVID-19, the Agrifood Labour Force, and the Need for More Compassionate Post-Pandemic Food Systems - Sarah Berger Richardson ●● SECTION F: GLOBAL HEALTH AND GOVERNANCE ● CHAPTER F-1: “Flattening the Curve” Through COVID-19 Contagion Containment - Anis Chowdhury and Jomo Kwame Sundaram ● CHAPTER F-2: The Plausibility and Resolvability of Legal Claims Against China and WHO under the International Health Regulations (2005) - Sam Halabi and Kumanan Wilson ● CHAPTER F-3: COVID-19 and Africa: Does “One Size Fit All” in Public Health Intervention? - Chidi Oguamanam ● CHAPTER F-4: Border Closures: A Pandemic of Symbolic Acts in the Time of COVID-19 - Steven J. Hoffman and Patrick Fafard ● CHAPTER F-5: COVID-19 and Accountable Artificial Intelligence in a Global Context - Céline Castets-Renard and Eleonore Fournier-Tombs ● CHAPTER F-6: International Trade, Intellectual Property, and Innovation Policy: Lessons from a Pandemic - Jeremy de Beer and E. Richard Gold ● CHAPTER F-7: COVID-19 Vaccines as Global Public Goods - Jason W. Nickerson and Matthew Herderhttps://press.uottawa.ca/vulnerable.htm

Clinical Outcomes among Diagnostic Subgroups of Infants with Severe Bronchopulmonary Dysplasia through 2 Years of Age

Objective This article aimed to identify readmission risk factors through 2 years of life for infants with severe bronchopulmonary dysplasia (BPD) who do not require tracheostomy and ventilatory support after neonatal intensive care unit (NICU) discharge. It also aimed to identify if clinical differences exist between the subcategories of severe BPD. Study Design A retrospective chart review was performed on 182 infants with severe BPD born between 2010 and 2015. A total of 130 infants met the inclusion criteria and were stratified into three groups based on their respiratory status at 36 weeks of gestational age: group A—oxygen (O2), group B—assisted ventilation (AV), group C—both O2 and AV. NICU clinical risk factors for readmission were assessed at set time points (6/12/18/24 months). Reasons for readmission were assessed for the entire cohort and severe BPD subgroups. Conclusion An NICU diagnosis of neurologic abnormality, necrotizing enterocolitis, invasive NICU infection, dysphagia, and O2 at NICU discharge differed between the three subgroups of severe BPD. The most common cause of readmission was viral respiratory tract infection. Inhaled steroid use remained stable over time, while oxygen use and diuretic use declined over time. Risk factors for readmission in the entire cohort included g-tube, O2 use, and diuretic use at 12 months. There was no significant difference in readmission rates between the three BPD subgroups.</jats:p

Neuronal antibody prevalence in children with seizures under 3 years

ObjectiveTo report the prevalence of anti-neuronal antibodies in a prospective whole-nation cohort of children presenting with seizures before their third birthday.MethodsThis was a prospective population-based national cohort study involving all children presenting with new-onset epilepsy or complex febrile seizures before their third birthday over a 3-year period. Patients with previously identified structural, metabolic, or infectious cause for seizures were excluded. Serum samples were obtained at first presentation and tested for 7 neuronal antibodies using live cell-based assays. Clinical data were collected with structured proformas at recruitment and 24 months after presentation. In addition, patients with seizures and clinically suspected autoimmune encephalitis were independently identified by a review of the case records of all children &lt;3 years of age in Scotland who had undergone EEG.ResultsTwo hundred ninety-eight patients were identified and recruited and underwent autoantibody testing. Antibody positivity was identified in 18 of 298 (6.0%). The antibodies identified were GABA receptor B (n = 8, 2.7%), contactin-associated protein 2 (n = 4, 1.3%), glycine receptor (n = 3, 1.0%), leucine-rich glioma inactivated 1 (n = 2, 0.7%), NMDA receptor (n = 1, 0.3%), and GABA receptor A (n = 1, 0.3%). None of these patients had a clinical picture of autoimmune encephalitis. Seizure classification and clinical phenotype did not correlate with antibody positivity.ConclusionsAutoimmune encephalitis is very rare in early childhood. However serum neuronal antibodies are identified in 6.4% of children presenting with seizures at &lt;3 years of age. Antibody testing should not be a routine clinical test in early childhood-onset epilepsy because, in the absence of other features of autoimmune encephalitis, antibody positivity is of doubtful clinical significance. Antibody testing should be reserved for patients with additional features of encephalitis.</jats:sec

Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort

Abstract Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (&amp;gt;10 min) febrile seizures; febrile or afebrile status epilepticus (&amp;gt;30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children’s hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9–57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26–14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93–12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24–9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07–7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.</jats:p

Neuronal antibody prevalence in children with seizures under 3 years:a prospective national cohort

Objective: To report the prevalence of anti-neuronal antibodies in a prospectively whole nation cohort of children presenting with seizures before their third birthday. Methods: This was a prospective population-based national cohort study involving all children presenting with new onset epilepsy or complex febrile seizures before their 3rd birthday over a three-year period. Patients with previously identified structural, metabolic or infectious cause for seizures were excluded. Serum samples were obtained at first presentation and tested for seven neuronal antibodies using live cell-based assays. Clinical data were collected using structured proformas at recruitment, and 24 months after presentation. In addition, patients with seizures and clinically suspected autoimmune encephalitis were independently identified by reviewing the case records of all children &lt; 3 years in Scotland who had undergone electroencephalography (EEG). Results: 298 patients were identified, recruited and underwent autoantibody testing. Antibody positivity was identified in 18/298 (6.0%). The antibodies identified were: GABABR (n = 8, 2.7%), CASPR2 (n = 4, 1.3%), GlyR (n = 3, 1.0%), LGI1 (n = 2, 0.7%), NMDAR (n = 1, 0.3%), and GABAAR (n = 1, 0.3%). None of these patients had a clinical picture of autoimmune encephalitis. Seizure classification and clinical phenotype did not correlate with antibody positivity. Conclusions: Autoimmune encephalitis is very rare in early childhood. However serum neuronal antibodies are identified in 6.4% of children presenting with seizures &lt; 3 years. Antibody testing should not be a routine clinical test in early childhood-onset epilepsy as in the absence of other features of autoimmune encephalitis antibody-positivity is of doubtful clinical significance. Antibody testing should be reserved for patients with additional features of encephalitis