The "plus" side of epilepsy phenotyping

No abstract available

Genetics update: monogenetics, polygene disorders and the quest for modifying genes

The genetic channelopathies are a broad collection of diseases. Many ion channel genes demonstrate wide phenotypic pleiotropy, but nonetheless concerted efforts have been made to characterise genotype-phenotype relationships. In this review we give an overview of the factors that influence genotype-phenotype relationships across this group of diseases as a whole, using specific individual channelopathies as examples. We suggest reasons for the limitations observed in these relationships. We discuss the role of ion channel variation in polygenic disease and highlight research that has contributed to unravelling the complex aetiological nature of these conditions. We focus specifically on the quest for modifying genes in inherited channelopathies, using the voltage-gated sodium channels as an example. Epilepsy related to genetic channelopathy is one area in which precision medicine is showing promise. We will discuss the successes and limitations of precision medicine in these conditions

A clinical and genetic study of ion channel disorders in child neurology

Ion channels are macromolecular proteins in cell membranes that control the passage of charged particles including sodium, potassium and calcium ions in and out of cells. Rapid electrical signalling in the nervous system is mediated through the passage of ions through these channels. It is therefore not surprising that genetic mutations in the genes coding for these channels can result in neurological disease. Ion channel disorders or channelopathies have emerged in the last ten to fifteen years as an important new way of understanding neurological disease. Many of these conditions are paroxysmal in nature and include generalised and focal epilepsies, movement disorders and neuromuscular disorders. Some ofthese conditions follow simple Mendelian inheritance and are rare forms of common disorders such as epilepsy but they provide a useful model for more common neurological diseases with complex inheritance. Some conditions such as Dravet syndrome, a severe infantile onset epilepsy and sodium channelopathy produce devastating consequences for the affected child.In this thesis I will describe the clinical work I have undertaken defining phenotypes of this emerging group of disorders. Detailed phenotyping is the first essential step in characterising new aspects of these genetic disorders. I have collaborated closely with molecular geneticists and cell physiologists in units around the world exchanging ideas in order to better understand the mechanisms of disease and hopefully translate this into better care for patients. The main themes covered in the thesis are episodic ataxias type 1 and 2 (EA1 & 2), benign familial neonatal convulsions, autosomal dominant nocturnal frontal lobe epilepsy, and Dravet syndrome and other SCN1A related epileptic encephalopathies. In the course of this work I have described novel relationships between EA1 and EA2 and epilepsy, described a novel gene and phenotypes associated with frontal lobe epilepsy, a novel presentation of a potassium channelopathy, a family with a new genetic mechanism for their neonatal convulsions and epilepsy, and children with a novel mechanism for Startle disease (hyperekplexia). I have demonstrated the clinical utility of this translational research by establishing a molecular genetic diagnostic service for sodium channel (SCN1A) related infantile epilepsies. A study of the results from this national UK service shows that genetic diagnosis allows early diagnosis of these epilepsies. This can result in earlier focused treatment, and the hope for better epilepsy control and developmental outcome. I discuss the implications of this work and ongoing and future research projects

Progressive intellectual impairment in children with encephalopathy related to status epilepticus during slow sleep

We investigated whether Encephalopathy related to Status Epilepticus during slow Sleep (ESES) in childhood was associated with progressive intellectual decline. Participants were identified from the caseload of a single paediatric neurosciences centre and EEG department. A retrospective review of overnight sleep EEG reports (n=2200) over a five-year period identified twenty-two children as having the neurophysiological characteristics of ESES. All had repeat neuropsychological assessment using the WISC-III (UK) and/or WPPSI-R (UK). There was a statistically significant reduction in Full-Scale IQ and Performance IQ across a mean and median time interval of two years. Around a third of the participants showed a clinically significant regression in intellectual functioning evidenced by =>12-point reduction in IQ. These patients were not distinguishable from the rest of the cohort in terms of clinical history, imaging or duration of ESES. The reduction in IQ reflected reduced processing speed, working memory and overall cognitive efficiency. Children with a history of ESES require close monitoring in order to support educational planning and provide families with accurate information about prognosis

Response: Do all individuals with Dravet syndrome have intellectual disability?

No abstract available

ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions

The International League Against Epilepsy (ILAE) Task Force on Nosology andDefinitions proposes a classification and definition of epilepsy syndromes in theneonate and infant with seizure onset up to 2 years of age. The incidence of epi-lepsy is high in this age group and epilepsy is frequently associated with significantcomorbidities and mortality. The licensing of syndrome specific antiseizure medi-cations following randomized controlled trials and the development of precision,gene- related therapies are two of the drivers defining the electroclinical pheno-types of syndromes with onset in infancy. The principal aim of this proposal, con-sistent with the 2017 ILAE Classification of the Epilepsies, is to support epilepsydiagnosis and emphasize the importance of classifying epilepsy in an individualboth by syndrome and etiology. For each syndrome, we report epidemiology, clini-cal 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 epilep-tic encephalopathies, diseases where there is developmental impairment related toboth the underlying etiology independent of epileptiform activity and the epilep-tic encephalopathy. The emerging class of etiology- specific epilepsy syndromes,where there is a specific etiology for the epilepsy that is associated with a clearlydefined, relatively uniform, and distinct clinical phenotype in most affected in-dividuals as well as consistent EEG, neuroimaging, and/or genetic correlates, ispresented. The number of etiology- defined syndromes will continue to increase,and these newly described syndromes will in time be incorporated into this clas-sification. The tables summarize mandatory features, cautionary alerts, and exclu-sionary features for the common syndromes. Guidance is given on the criteria forsyndrome diagnosis in resource- limited regions where laboratory confirmation,including EEG, MRI, and genetic testing, might not be available

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

The 2017 International League Against Epilepsy classification has defined a three- tiersystem with epilepsy syndrome identification at the third level. Although a syndromecannot be determined in all children with epilepsy, identification of a specific syn-drome provides guidance on management and prognosis. In this paper, we describethe childhood onset epilepsy syndromes, most of which have both mandatory seizuretype(s) and interictal electroencephalographic (EEG) features. Based on the 2017Classification of Seizures and Epilepsies, some syndrome names have been updatedusing terms directly describing the seizure semiology. Epilepsy syndromes beginningin 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, andphotosensitive occipital lobe epilepsy; (2) generalized epilepsies, comprising three syn-dromes: childhood absence epilepsy, epilepsy with myoclonic absence, and epilepsywith eyelid myoclonia; and (3) developmental and/or epileptic encephalopathies,comprising five syndromes: epilepsy with myoclonic– atonic seizures, Lennox– Gastautsyndrome, developmental and/or epileptic encephalopathy with spike- and- wave acti-vation 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

Guidance on Dravet syndrome from infant to adult care: road map for treatment planning in Europe

Dravet syndrome (DS) is a severe, rare, and complex developmental and epileptic encephalopathy affecting 1 in 16 000 live births and characterized by a drug-resistant epilepsy, cognitive, psychomotor, and language impairment, and behavioral disorders. Evidence suggests that optimal treatment of seizures in DS may improve outcomes, even though neurodevelopmental impairments are the likely result of both the underlying genetic variant and the epilepsy. We present an updated guideline for DS diagnosis and treatment, taking into consideration care of the adult patient and nonpharmaceutical therapeutic options for this disease. This up-to-date guideline, which is based on an extensive review of the literature and culminates with a new treatment algorithm for DS, is a European consensus developed through a survey involving 29 European clinical experts in DS. This guideline will serve professionals in their clinical practice and, as a consequence, will benefit DS patients and their families

Neonatal Seizures: Is there a relationship between ictal electro-clinical features and etiology? – A critical appraisal based on a systematic literature review

Abstract The aim of this study was to evaluate whether specific etiologies of neonatal seizures have distinct ictal electro- clinical features. A systematic review of English articles using the PubMed database since 2004 (last update 9/26/16). Search terms included text words and MeSH terms related to neonatal seizures. Eligible articles included reports of neonates with seizures with a full description of seizure semiology and electroclinical findings. Independent extraction of data was performed by two authors using predefined data fields, including study quality indicators. Data was collected for every individual patient described in the articles. The dataset was analyzed with the Fisher?s exact test. The initial search led to 8507 titles; using filters, 2910 titles and abstracts were identified, with 177 full texts selected to be read. Fifty seven studies were included in the analysis with 151 neonates (37.7 male and 62.9% term). Genetic etiologies (51%) and sequential seizures (41.1%) predominated in this sample and hypoxic ischemic encephalopathy (HIE) accounted for only 4%. The low prevalence of HIE observed was probably due to a publication bias. A significant association was found between etiology and seizure type: hemorrhage with autonomic seizures (p=0.003), CNS infection and stroke with clonic seizures (p=0.042, pPeer reviewe

The ILAE classification of seizures and the epilepsies : Modification for seizures in the neonate. Position paper by the ILAE Task Force on Neonatal Seizures

Seizures are the most common neurological emergency in the neonatal period and in contrast to those in infancy and childhood, are often provoked seizures with an acute cause and may be electrographic-only. Hence, neonatal seizures may not fit easily into classification schemes for seizures and epilepsies primarily developed for older children and adults. A Neonatal Seizures Task Force was established by the International League Against Epilepsy (ILAE) to develop a modification of the 2017 ILAE Classification of Seizures and Epilepsies, relevant to neonates. The neonatal classification framework emphasizes the role of electroencephalography (EEG) in the diagnosis of seizures in the neonate and includes a classification of seizure types relevant to this age group. The seizure type is determined by the predominant clinical feature. Many neonatal seizures are electrographic-only with no evident clinical features; therefore, these are included in the proposed classification. Clinical events without an EEG correlate are not included. Because seizures in the neonatal period have been shown to have a focal onset, a division into focal and generalized is unnecessary. Seizures can have a motor (automatisms, clonic, epileptic spasms, myoclonic, tonic), non-motor (autonomic, behavior arrest), or sequential presentation. The classification allows the user to choose the level of detail when classifying seizures in this age group.Peer reviewe