Medicine (Austin & Northern Health) - Research Publications

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    COVID-19 vaccine in patients with Dravet syndrome: Observations and real-world experiences
    Hood, V ; Berg, AT ; Knupp, KG ; Koh, S ; Laux, L ; Meskis, MA ; Zulfiqar-Ali, Q ; Perry, MS ; Scheffer, IE ; Sullivan, J ; Wirrell, E ; Andrade, DM (WILEY, 2022-04-20)
    OBJECTIVE: Vaccination against the SARS-CoV-2 virus is a primary tool to combat the COVID-19 pandemic. However, vaccination is a common seizure trigger in individuals with Dravet syndrome (DS). Information surrounding COVID-19 vaccine side effects in patients with DS would aid caregivers and providers in decisions for and management of COVID-19 vaccination. METHODS: A survey was emailed to the Dravet Syndrome Foundation's Family Network and posted to the Dravet Parent & Caregiver Support Group on Facebook between May and August 2021. Deidentified information obtained included demographics and vaccination status for individuals with DS. Vaccine type, side effects, preventative measures, and changes in seizure activity following COVID-19 vaccination were recorded. For unvaccinated individuals, caregivers were asked about intent to vaccinate and reasons for their decision. RESULTS: Of 278 survey responses, 120 represented vaccinated individuals with DS (median age = 19.5 years), with 50% reporting no side effects from COVID-19 vaccination. Increased seizures following COVID-19 vaccination were reported in 16 individuals, but none had status epilepticus. Of the 158 individuals who had not received a COVID-19 vaccination, 37 were older than 12 years (i.e., eligible at time of study), and only six of these caregivers indicated intent to seek vaccination. The remaining 121 responses were caregivers to children younger than 12 years, 60 of whom indicated they would not seek COVID-19 vaccination when their child with DS became eligible. Reasons for vaccine hesitancy were fear of increased seizure activity and concerns about vaccine safety. SIGNIFICANCE: These results indicate COVID-19 vaccination is well tolerated by individuals with DS. One main reason for vaccine hesitancy was fear of increased seizure activity, which occurred in only 13% of vaccinated individuals, and none had status epilepticus. This study provides critical and reassuring insights for caregivers and health care providers making decisions about the safety of COVID-19 vaccinations for individuals with DS.
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    ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions
    Zuberi, SM ; Wirrell, E ; Yozawitz, E ; Wilmshurst, JM ; Specchio, N ; Riney, K ; Pressler, R ; Auvin, S ; Samia, P ; Hirsch, E ; Galicchio, S ; Triki, C ; Snead, OC ; Wiebe, S ; Cross, JH ; Tinuper, P ; Scheffer, IE ; Perucca, E ; Moshe, SL ; Nabbout, R (WILEY, 2022-05-03)
    The International League Against Epilepsy (ILAE) Task Force on Nosology and Definitions proposes a classification and definition of epilepsy syndromes in the neonate and infant with seizure onset up to 2 years of age. The incidence of epilepsy is high in this age group and epilepsy is frequently associated with significant comorbidities and mortality. The licensing of syndrome specific antiseizure medications following randomized controlled trials and the development of precision, gene-related therapies are two of the drivers defining the electroclinical phenotypes of syndromes with onset in infancy. The principal aim of this proposal, consistent with the 2017 ILAE Classification of the Epilepsies, is to support epilepsy diagnosis and emphasize the importance of classifying epilepsy in an individual both by syndrome and etiology. For each syndrome, we report epidemiology, clinical course, seizure types, electroencephalography (EEG), neuroimaging, genetics, and differential diagnosis. Syndromes are separated into self-limited syndromes, where there is likely to be spontaneous remission and developmental and epileptic encephalopathies, diseases where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. The emerging class of etiology-specific epilepsy syndromes, where there is a specific etiology for the epilepsy that is associated with a clearly defined, relatively uniform, and distinct clinical phenotype in most affected individuals as well as consistent EEG, neuroimaging, and/or genetic correlates, is presented. The number of etiology-defined syndromes will continue to increase, and these newly described syndromes will in time be incorporated into this classification. The tables summarize mandatory features, cautionary alerts, and exclusionary features for the common syndromes. Guidance is given on the criteria for syndrome diagnosis in resource-limited regions where laboratory confirmation, including EEG, MRI, and genetic testing, might not be available.
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    Methodology for classification and definition of epilepsy syndromes with list of syndromes: Report of the ILAE Task Force on Nosology and Definitions
    Wirrell, EC ; Nabbout, R ; Scheffer, IE ; Alsaadi, T ; Bogacz, A ; French, JA ; Hirsch, E ; Jain, S ; Kaneko, S ; Riney, K ; Samia, P ; Snead, OC ; Somerville, E ; Specchio, N ; Trinka, E ; Zuberi, SM ; Balestrini, S ; Wiebe, S ; Cross, JH ; Perucca, E ; Moshe, SL ; Tinuper, P (WILEY, 2022-05-03)
    Epilepsy syndromes have been recognized for >50 years, as distinct electroclinical phenotypes with therapeutic and prognostic implications. Nonetheless, no formally accepted International League Against Epilepsy (ILAE) classification of epilepsy syndromes has existed. The ILAE Task Force on Nosology and Definitions was established to reach consensus regarding which entities fulfilled criteria for an epilepsy syndrome and to provide definitions for each syndrome. We defined an epilepsy syndrome as "a characteristic cluster of clinical and electroencephalographic features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious)." The diagnosis of a syndrome in an individual with epilepsy frequently carries prognostic and treatment implications. Syndromes often have age-dependent presentations and a range of specific comorbidities. This paper describes the guiding principles and process for syndrome identification in both children and adults, and the template of clinical data included for each syndrome. We divided syndromes into typical age at onset, and further characterized them based on seizure and epilepsy types and association with developmental and/or epileptic encephalopathy or progressive neurological deterioration. Definitions for each specific syndrome are contained within the corresponding position papers.
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    ILAE definition of the Idiopathic Generalized Epilepsy Syndromes: Position statement by the ILAE Task Force on Nosology and Definitions
    Hirsch, E ; French, J ; Scheffer, IE ; Bogacz, A ; Alsaadi, T ; Sperling, MR ; Abdulla, F ; Zuberi, SM ; Trinka, E ; Specchio, N ; Somerville, E ; Samia, P ; Riney, K ; Nabbout, R ; Jain, S ; Wilmshurst, JM ; Auvin, S ; Wiebe, S ; Perucca, E ; Moshe, SL ; Tinuper, P ; Wirrell, EC (WILEY, 2022-05-03)
    In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the "genetic generalized epilepsies" (GGEs), which contained the "idiopathic generalized epilepsies" (IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE's Task Force on Nosology and Definitions (2017-2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic-clonic and myoclonic-tonic-clonic seizures, with 2.5-5.5 Hz generalized spike-wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications.
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    Dravet syndrome: A quick transition guide for the adult neurologist
    Andrade, DM ; Berg, AT ; Hood, V ; Knupp, KG ; Koh, S ; Laux, L ; Meskis, MA ; Miller, I ; Perry, MS ; Scheffer, IE ; Sullivan, J ; Villas, N ; Wirrell, E (ELSEVIER, 2021-10-05)
    INTRODUCTION: Dravet syndrome (DS) is still seen as a "pediatric disease", where patients receive excellent care in pediatric centers, but care is less than optimal in adult health care systems (HCS). This creates a barrier when young adults need to leave the family-centered pediatric system and enter the adult, patient-centered HCS. Here we create a guide to help with the transition from pediatric to adult for patients with DS. METHODS: Experts in Dravet syndrome flagged the main barriers in caring for adults with DS and created a 2-page transition summary guide based on their expertise and a literature review. RESULTS: The 2-page guide addresses: DS diagnosis in children and adults; clinical manifestations, including the differences in seizures types and frequencies between children and adults with DS; the natural history of intellectual disability, behavior, gait, motor disorders and dysautonomia; a review of optimal treatments (including medications not commonly used in adult epilepsy settings such as stiripentol and fenfluramine), as well as emergency seizure management; avoidance of triggers, preventive measures, and vaccine administration in adults with DS. CONCLUSION: Several young adults with DS are still followed by their child neurologist. This 2-page transition guide should help facilitate the transition of patients with DS to the adult HCS and should be given to families as well as adult health care providers that may not be familiar with DS.
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    The aetiologies of epilepsy
    Balestrini, S ; Arzimanoglou, A ; Bluemcke, I ; Scheffer, IE ; Wiebe, S ; Zelano, J ; Walker, MC (JOHN LIBBEY EUROTEXT LTD, 2021-02-01)
    The identification of the aetiology of a patient's epilepsy is instrumental in the diagnosis, prognostic counselling and management of the epilepsies. Indeed, the aetiology can be important for determining the recurrence risk of single seizures and so for making a diagnosis of epilepsy. Here, we divide the aetiologies into six categories: structural, genetic, infectious, metabolic, immune (all of which are part of the International League Against Epilepsy [ILAE] classification system) and neurodegenerative (which we have considered separately because of its growing importance in epilepsy). These are not mutually exclusive categories and many aetiologies fall into more than one category. Indeed, genetic factors probably play a role, to varying degrees, in the risk of seizures in all people with epilepsy. In each of the categories, we discuss what we regard as the most important aetiologies; importance being determined not only by prevalence but also by clinical significance. The introduction contains information suitable for level 1 competency (entry level), whilst the subsequent sections contain information aimed at level 2 competency (proficiency level) as part of the new ILAE competency-based curriculum. As we move towards precision medicine and targeted therapies, so aetiologies will play an even greater role in the management of epilepsy.
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    Climate change and epilepsy: Insights from clinical and basic science studies
    Gulcebi, M ; Bartolini, E ; Lee, O ; Lisgaras, CP ; Onat, F ; Mifsud, J ; Striano, P ; Vezzani, A ; Hildebrand, MS ; Jimenez-Jimenez, D ; Junck, L ; Lewis-Smith, D ; Scheffer, IE ; Thijs, RD ; Zuberi, SM ; Blenkinsop, S ; Fowler, HJ ; Foley, A ; Sisodiya, SM ; Balestrini, S ; Berkovic, S ; Cavalleri, G ; Correa, DJ ; Custodio, HM ; Galovic, M ; Guerrini, R ; Henshall, D ; Howard, O ; Hughes, K ; Katsarou, A ; Koeleman, BPC ; Krause, R ; Lowenstein, D ; Mandelenaki, D ; Marini, C ; O'Brien, TJ ; Pace, A ; De Palma, L ; Perucca, P ; Pitkanen, A ; Quinn, F ; Selmer, KK ; Steward, CA ; Swanborough, N ; Thijs, R ; Tittensor, P ; Trivisano, M ; Weckhuysen, S ; Zara, F (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-02-10)
    Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, complex, and often indirect, which makes predictions difficult. We need more data on possible climate-driven altered risks for seizures, epilepsy, and epileptogenesis, to identify underlying mechanisms at systems, cellular, and molecular levels for better understanding of the impact of climate change on epilepsy. Further focussed data would help us to develop evidence for mitigation methods to do more to protect people with epilepsy from the effects of climate change.
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    International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions
    Specchio, N ; Wirrell, EC ; Scheffer, IE ; Nabbout, R ; Riney, K ; Samia, P ; Guerreiro, M ; Gwer, S ; Zuberi, SM ; Wilmshurst, JM ; Yozawitz, E ; Pressler, R ; Hirsch, E ; Wiebe, S ; Cross, HJ ; Perucca, E ; Moshe, SL ; Tinuper, P ; Auvin, S (WILEY, 2022-05-03)
    The 2017 International League Against Epilepsy classification has defined a three-tier system with epilepsy syndrome identification at the third level. Although a syndrome cannot be determined in all children with epilepsy, identification of a specific syndrome provides guidance on management and prognosis. In this paper, we describe the childhood onset epilepsy syndromes, most of which have both mandatory seizure type(s) and interictal electroencephalographic (EEG) features. Based on the 2017 Classification of Seizures and Epilepsies, some syndrome names have been updated using terms directly describing the seizure semiology. Epilepsy syndromes beginning in childhood have been divided into three categories: (1) self-limited focal epilepsies, comprising four syndromes: self-limited epilepsy with centrotemporal spikes, self-limited epilepsy with autonomic seizures, childhood occipital visual epilepsy, and photosensitive occipital lobe epilepsy; (2) generalized epilepsies, comprising three syndromes: childhood absence epilepsy, epilepsy with myoclonic absence, and epilepsy with eyelid myoclonia; and (3) developmental and/or epileptic encephalopathies, comprising five syndromes: epilepsy with myoclonic-atonic seizures, Lennox-Gastaut syndrome, developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep, hemiconvulsion-hemiplegia-epilepsy syndrome, and febrile infection-related epilepsy syndrome. We define each, highlighting the mandatory seizure(s), EEG features, phenotypic variations, and findings from key investigations.
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    International consensus on diagnosis and management of Dravet syndrome
    Wirrell, EC ; Hood, V ; Knupp, KG ; Meskis, MA ; Nabbout, R ; Scheffer, IE ; Wilmshurst, J ; Sullivan, J (WILEY, 2022-05-12)
    OBJECTIVE: This study was undertaken to gain consensus from experienced physicians and caregivers regarding optimal diagnosis and management of Dravet syndrome (DS), in the context of recently approved, DS-specific therapies and emerging disease-modifying treatments. METHODS: A core working group was convened consisting of six physicians with recognized expertise in DS and two representatives of the Dravet Syndrome Foundation. This core group summarized the current literature (focused on clinical presentation, comorbidities, maintenance and rescue therapies, and evolving disease-modifying therapies) and nominated the 31-member expert panel (ensuring international representation), which participated in two rounds of a Delphi process to gain consensus on diagnosis and management of DS. RESULTS: There was strong consensus that infants 2-15 months old, presenting with either a first prolonged hemiclonic seizure or first convulsive status epilepticus with fever or following vaccination, in the absence of another cause, should undergo genetic testing for DS. Panelists agreed on evolution of specific comorbidities with time, but less agreement was achieved on optimal management. There was also agreement on appropriate first- to third-line maintenance therapies, which included the newly approved agents. Whereas there was agreement for recommendation of disease-modifying therapies, if they are proven safe and efficacious for seizures and/or reduction of comorbidities, there was less consensus for when these should be started, with caregivers being more conservative than physicians. SIGNIFICANCE: This International DS Consensus, informed by both experienced global caregiver and physician voices, provides a strong overview of the impact of DS, therapeutic goals and optimal management strategies incorporating the recent therapeutic advances in DS, and evolving disease-modifying therapies.
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    A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam
    Campbell, C ; McCormack, M ; Patel, S ; Stapleton, C ; Bobbili, D ; Krause, R ; Depondt, C ; Sills, GJ ; Koeleman, BP ; Striano, P ; Zara, F ; Sander, JW ; Lerche, H ; Kunz, WS ; Stefansson, K ; Stefansson, H ; Doherty, CP ; Heinzen, EL ; Scheffer, IE ; Goldstein, DB ; O'Brien, T ; Cotter, D ; Berkovic, SF ; Sisodiya, SM ; Delanty, N ; Cavalleri, GL (WILEY, 2022-04-01)
    OBJECTIVE: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. METHODS: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). RESULTS: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. SIGNIFICANCE: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.