ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology.
University of Melbourne1, University of British Columbia2, New York University3, Federal University of São Paulo4, French Institute of Health and Medical Research5, University of California, Los Angeles6, Albert Einstein College of Medicine7, Children's Hospital Los Angeles8, University of Pavia9, Karolinska Institutet10, University of Calgary11, Peking University12, University of Glasgow13, Royal Hospital for Sick Children14
TL;DR: The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989 as mentioned in this paper.
Abstract: The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.
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TL;DR: Improved understanding of the gradual development of epilepsy, epigenetic determinants, and pharmacogenomics comes the hope for better, disease-modifying, or even curative, pharmacological and non-pharmacological treatment strategies.
762 citations
European Bioinformatics Institute1, Newcastle University2, Newcastle upon Tyne Hospitals NHS Foundation Trust3, Oregon Health & Science University4, University of Genoa5, Istituto Giannina Gaslini6, University of Western Australia7, King Edward Memorial Hospital8, American College of Medical Genetics9, Anschutz Medical Campus10, Johns Hopkins University11, Ludwig Maximilian University of Munich12, Children's Hospital of Philadelphia13, Austrian Academy of Sciences14, University of Connecticut15, French Institute of Health and Medical Research16, Lawrence Berkeley National Laboratory17, University of Michigan18, University of Freiburg19, University of Luxembourg20, Oregon State University21, Chestnut Hill College22, Medical University of Graz23, Queen Mary University of London24, Hebrew University of Jerusalem25, University of Pennsylvania26
TL;DR: Recent major extensions of the Human Phenotype Ontology for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas are presented and new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease are presented.
Abstract: The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems.
503 citations
TL;DR: Despite the decrease in the disease burden from 1990 to 2016, epilepsy is still an important cause of disability and mortality, and was similar among SDI quintiles.
Abstract: Summary Background Seizures and their consequences contribute to the burden of epilepsy because they can cause health loss (premature mortality and residual disability). Data on the burden of epilepsy are needed for health-care planning and resource allocation. The aim of this study was to quantify health loss due to epilepsy by age, sex, year, and location using data from the Global Burden of Diseases, Injuries, and Risk Factors Study. Methods We assessed the burden of epilepsy in 195 countries and territories from 1990 to 2016. Burden was measured as deaths, prevalence, and disability-adjusted life-years (DALYs; a summary measure of health loss defined by the sum of years of life lost [YLLs] for premature mortality and years lived with disability), by age, sex, year, location, and Socio-demographic Index (SDI; a compound measure of income per capita, education, and fertility). Vital registrations and verbal autopsies provided information about deaths, and data on the prevalence and severity of epilepsy largely came from population representative surveys. All estimates were calculated with 95% uncertainty intervals (UIs). Findings In 2016, there were 45·9 million (95% UI 39·9–54·6) patients with all-active epilepsy (both idiopathic and secondary epilepsy globally; age-standardised prevalence 621·5 per 100 000 population; 540·1–737·0). Of these patients, 24·0 million (20·4–27·7) had active idiopathic epilepsy (prevalence 326·7 per 100 000 population; 278·4–378·1). Prevalence of active epilepsy increased with age, with peaks at 5–9 years (374·8 [280·1–490·0]) and at older than 80 years of age (545·1 [444·2–652·0]). Age-standardised prevalence of active idiopathic epilepsy was 329·3 per 100 000 population (280·3–381·2) in men and 318·9 per 100 000 population (271·1–369·4) in women, and was similar among SDI quintiles. Global age-standardised mortality rates of idiopathic epilepsy were 1·74 per 100 000 population (1·64–1·87; 1·40 per 100 000 population [1·23–1·54] for women and 2·09 per 100 000 population [1·96–2·25] for men). Age-standardised DALYs were 182·6 per 100 000 population (149·0–223·5; 163·6 per 100 000 population [130·6–204·3] for women and 201·2 per 100 000 population [166·9–241·4] for men). The higher DALY rates in men were due to higher YLL rates compared with women. Between 1990 and 2016, there was a non-significant 6·0% (−4·0 to 16·7) change in the age-standardised prevalence of idiopathic epilepsy, but a significant decrease in age-standardised mortality rates (24·5% [10·8 to 31·8]) and age-standardised DALY rates (19·4% [9·0 to 27·6]). A third of the difference in age-standardised DALY rates between low and high SDI quintile countries was due to the greater severity of epilepsy in low-income settings, and two-thirds were due to a higher YLL rate in low SDI countries. Interpretation Despite the decrease in the disease burden from 1990 to 2016, epilepsy is still an important cause of disability and mortality. Standardised collection of data on epilepsy in population representative surveys will strengthen the estimates, particularly in countries for which we currently have no or sparse data and if additional data is collected on severity, causes, and treatment. Sizeable gains in reducing the burden of epilepsy might be expected from improved access to existing treatments in low-income countries and from the development of new effective drugs worldwide. Funding Bill & Melinda Gates Foundation.
457 citations
TL;DR: The overall prognosis of epilepsy is favorable in the majority of patients when measured by seizure freedom, and reports from low/middle-income countries (LMIC; where patients with epilepsy are largely untreated) give prevalence and remission rates that overlap those of HICs.
Abstract: Epilepsy is a chronic disease of the brain characterized by an enduring (i.e., persisting) predisposition to generate seizures, unprovoked by any immediate central nervous system insult, and by the neurobiologic, cognitive, psychological, and social consequences of seizure recurrences. Epilepsy affects both sexes and all ages with worldwide distribution. The prevalence and the incidence of epilepsy are slightly higher in men compared to women and tend to peak in the elderly, reflecting the higher frequency of stroke, neurodegenerative diseases, and tumors in this age-group. Focal seizures are more common than generalized seizures both in children and in adults. The etiology of epilepsy varies according to the sociodemographic characteristics of the affected populations and the extent of the diagnostic workup, but a documented cause is still lacking in about 50% of cases from high-income countries (HIC). The overall prognosis of epilepsy is favorable in the majority of patients when measured by seizure freedom. Reports from low/middle-income countries (LMIC; where patients with epilepsy are largely untreated) give prevalence and remission rates that overlap those of HICs. As the incidence of epilepsy appears higher in most LMICs, the overlapping prevalence can be explained by misdiagnosis, acute symptomatic seizures and premature mortality. Studies have consistently shown that about one-half of cases tend to achieve prolonged seizure remission. However, more recent reports on the long-term prognosis of epilepsy have identified differing prognostic patterns, including early and late remission, a relapsing-remitting course, and even a worsening course (characterized by remission followed by relapse and unremitting seizures). Epilepsy per se carries a low mortality risk, but significant differences in mortality rates are expected when comparing incidence and prevalence studies, children and adults, and persons with idiopathic and symptomatic seizures. Sudden unexplained death is most frequent in people with generalized tonic-clonic seizures, nocturnal seizures, and drug refractory epilepsy.
405 citations
TL;DR: Understanding is focused on the IL-1 receptor–Toll-like receptor 4 axis, the arachidonic acid–prostaglandin cascade, oxidative stress and transforming growth factor-β signalling associated with blood–brain barrier dysfunction, all of which are pathways that are activated in pharmacoresistant epilepsy in humans and that can be modulated in animal models to produce therapeutic effects on seizures.
Abstract: Epilepsy is a chronic neurological disease characterized by an enduring propensity for generation of seizures. The pathogenic processes of seizure generation and recurrence are the subject of intensive preclinical and clinical investigations as their identification would enable development of novel treatments that prevent epileptic seizures and reduce seizure burden. Such treatments are particularly needed for pharmacoresistant epilepsies, which affect ~30% of patients. Neuroinflammation is commonly activated in epileptogenic brain regions in humans and is clearly involved in animal models of epilepsy. An increased understanding of neuroinflammatory mechanisms in epilepsy has identified cellular and molecular targets for new mechanistic therapies or existing anti-inflammatory drugs that could overcome the limitations of current medications, which provide only symptomatic control of seizures. Moreover, inflammatory mediators in the blood and molecular imaging of neuroinflammation could provide diagnostic, prognostic and predictive biomarkers for epilepsy, which will be instrumental for patient stratification in future clinical studies. In this Review, we focus on our understanding of the IL-1 receptor-Toll-like receptor 4 axis, the arachidonic acid-prostaglandin cascade, oxidative stress and transforming growth factor-β signalling associated with blood-brain barrier dysfunction, all of which are pathways that are activated in pharmacoresistant epilepsy in humans and that can be modulated in animal models to produce therapeutic effects on seizures, neuronal cell loss and neurological comorbidities.
399 citations
References
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Children's Memorial Hospital1, Northern Illinois University2, University of Melbourne3, Western Infirmary4, Boston Children's Hospital5, UCL Institute of Child Health6, Bosch7, University of California, Los Angeles8, New York University9, Cincinnati Children's Hospital Medical Center10, Albert Einstein College of Medicine11, University of Paris12
TL;DR: The International League Against Epilepsy (ILAE) Commission on Classification and Terminology has revised concepts, terminology, and approaches for classifying seizures and forms of epilepsy.
Abstract: The International League Against Epilepsy (ILAE) Commission on Classification and Terminology has revised concepts, terminology, and approaches for classifying seizures and forms of epilepsy. Generalized and focal are redefined for seizures as occurring in and rapidly engaging bilaterally distributed networks (generalized) and within networks limited to one hemisphere and either discretely localized or more widely distributed (focal). Classification of generalized seizures is simplified. No natural classification for focal seizures exists; focal seizures should be described according to their manifestations (e. g., dyscognitive, focal motor). The concepts of generalized and focal do not apply to electroclinical syndromes. Genetic, structural-metabolic, and unknown represent modified concepts to replace idiopathic, symptomatic, and cryptogenic. Not all epilepsies are recognized as electroclinical syndromes. Organization of forms of epilepsy is first by specificity: electroclinical syndromes, nonsyndromic epilepsies with structural-metabolic causes, and epilepsies of unknown cause. Further organization within these divisions can be accomplished in a flexible manner depending on purpose. Natural classes (e. g., specific underlying cause, age at onset, associated seizure type), or pragmatic groupings (e. g., epileptic encephalopathies, self-limited electroclinical syndromes) may serve as the basis for organizing knowledge about recognized forms of epilepsy and facilitate identification of new forms.
3,775 citations
Stanford University1, HCL Technologies2, Universidad Mayor3, UCL Institute of Child Health4, University of Bonn5, University of California, Los Angeles6, Umeå University7, New York University8, Columbia University9, Yonsei University10, Albert Einstein College of Medicine11, University of Pavia12, University of Melbourne13, Karolinska Institutet14, University of Calgary15
TL;DR: A revised definition of epilepsy brings the term in concordance with common use for individuals who either had an age‐dependent epilepsy syndrome but are now past the applicable age or who have remained seizure‐free for the last 10 years and off antiseizure medicines for at least the last 5 years.
Abstract: Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy (ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. "Resolved" is not necessarily identical to the conventional view of "remission or "cure." Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
3,491 citations
TL;DR: A diagnostic scheme that makes use of standardized terminology and concepts to describe individual patients is proposed, and a variety of approaches to classification are possible, and some are presented here by way of example only.
Abstract: The International League Against Epilepsy (ILAE) made a major contribution when it established standardized classifications and terminology for epileptic seizures and syndromes. This provided a universal vocabulary that not only facilitated communication among clinicians, but also established a taxonomic foundation for performing quantitative clinical and basic research on epilepsy. Much, however, has changed since the adoption of the currently used Classification of Epileptic Seizures in 1981 (1) and the Classification of Epilepsies and Epileptic Syndromes in 1989 (2). Consequently, the Executive Committee of the ILAE, which took office in July 1997, agreed that review and revision of the current classification system would be a priority for this Executive term. A Task Force on Classification and Terminology was appointed, which divided itself into four working groups concerned with Descriptive Terminology for Ictal Events; Seizures; Syndromes and Diseases; and Impairment. During the course of several meetings and vigorous e-mail discussions, the Task Force agreed that it would not be possible to replace the current international classifications with similar revised and updated classifications that would be universally accepted and meet all the clinical and research needs such a formal organizational system would be expected to provide. Rather, the Task Force is proposing a diagnostic scheme that makes use of standardized terminology and concepts to describe individual patients (Table 1). Within this diagnostic scheme, a variety of approaches to classification are possible, and some are presented here by way of example only. The Task Force views the development of specific classifications as a continuing work in progress. Flexible and dynamic classifications will be revised periodically based not only on rapidly emerging new information, but also on the resolution of problems that will inevitably be identified through use. At this point, the proposal does include several definitive changes in concepts and terminology (Table 2), and classifications are presented as examples of what could be devised in the future.
2,106 citations
Stanford University1, UCL Institute of Child Health2, University of York3, Jikei University School of Medicine4, Utrecht University5, Katholieke Universiteit Leuven6, Albert Einstein College of Medicine7, University Hospital of Lausanne8, Royal Children's Hospital9, University of Glasgow10, Royal Hospital for Sick Children11
TL;DR: The International League Against Epilepsy presents a revised operational classification of seizure types to recognize that some seizure types can have either a focal or generalized onset, to allow classification when the onset is unobserved, to include some missing seizure types, and to adopt more transparent names.
Abstract: The International League Against Epilepsy (ILAE) presents a revised operational classification of seizure types. The purpose of such a revision is to recognize that some seizure types can have either a focal or generalized onset, to allow classification when the onset is unobserved, to include some missing seizure types, and to adopt more transparent names. Because current knowledge is insufficient to form a scientifically based classification, the 2017 Classification is operational (practical) and based on the 1981 Classification, extended in 2010. Changes include the following: (1) "partial" becomes "focal"; (2) awareness is used as a classifier of focal seizures; (3) the terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized are eliminated; (4) new focal seizure types include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive, and emotional; (5) atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be of either focal or generalized onset; (6) focal to bilateral tonic-clonic seizure replaces secondarily generalized seizure; (7) new generalized seizure types are absence with eyelid myoclonia, myoclonic absence, myoclonic-atonic, myoclonic-tonic-clonic; and (8) seizures of unknown onset may have features that can still be classified. The new classification does not represent a fundamental change, but allows greater flexibility and transparency in naming seizure types.
2,011 citations
Journal Article•
TL;DR: Results of a clinico-encephalographic study using proposal for classification of epilepsies and epileptic syndromes (1989 ILAE) showed that in 17 cases seizures could not be controlled in 6 of them, and an agreement is necessary for these problems.
Abstract: We reported results of a clinico-encephalographic study using proposal for classification of epilepsies and epileptic syndromes (1989 ILAE). Fifty-three patients belonged to localization-related epilepsies (LE) and syndromes; forty-one patients belonged to generalized epilepsies and syndromes (GE); one patient belonged to epilepsies and syndromes undetermined, focal or generalized; and we could not classify 4 patients. No patients with the onset after 2 years of age belonged to idiopathic LE and no patients with the onset after 10 years of age belonged to symptomatic LE and GE. The rate of patients who had a past history of febrile convulsions was 38% in idiopathic LE and 35% in idiopathic GE. The rate of patients whose epileptic seizures were well controlled by medication was 83%. It was almost 100% in idiopathic LE, cryptogenic LE and idiopathic GE, but it was 60-70% in the other three groups. In seventeen patients their seizures were difficult to control. Six cases in this group had had frontal focus at least once. Although the patients who had had frontal foci at least once were 17 cases seizures could not be controlled in 6 of them. International Classification of Epilepsies and Epileptic Syndromes is convenient to clinicians, but some problems exist. One is unclearness of a definition differentiating cryptogenic from symptomatic LE. The other is the classification of patients with generalized seizures and interictal focal cortical epileptiform EEG activities. An agreement is necessary for these problems.
1,733 citations