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Epilepsia Jun 2022The International League Against Epilepsy (ILAE) Task Force on Nosology and Definitions proposes a classification and definition of epilepsy syndromes in the neonate and...
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.
Topics: Electroencephalography; Epilepsy; Epilepsy, Generalized; Epileptic Syndromes; Humans; Infant; Infant, Newborn; Seizures
PubMed: 35503712
DOI: 10.1111/epi.17239 -
Epilepsia Jun 2022The 2017 International League Against Epilepsy classification has defined a three-tier system with epilepsy syndrome identification at the third level. Although a...
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-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.
Topics: Child; Electroencephalography; Epilepsies, Myoclonic; Epilepsies, Partial; Epilepsy, Absence; Humans; Seizures
PubMed: 35503717
DOI: 10.1111/epi.17241 -
Neurotherapeutics : the Journal of the... Jul 2019The field of autoimmune epilepsy has evolved substantially in the last few decades with discovery of several neural autoantibodies and improved mechanistic understanding... (Review)
Review
The field of autoimmune epilepsy has evolved substantially in the last few decades with discovery of several neural autoantibodies and improved mechanistic understanding of these immune-mediated syndromes. A considerable proportion of patients with epilepsy of unknown etiology have been demonstrated to have an autoimmune cause. The majority of the patients with autoimmune epilepsy usually present with new-onset refractory seizures along with subacute progressive cognitive decline and behavioral or psychiatric dysfunction. Neural specific antibodies commonly associated with autoimmune epilepsy include leucine-rich glioma-inactivated protein 1 (LGI1), N-methyl-D-aspartate receptor (NMDA-R), and glutamic acid decarboxylase 65 (GAD65) IgG. Diagnosis of these cases depends on the identification of the clinical syndrome and ancillary studies including autoantibody evaluation. Predictive models (Antibody Prevalence in Epilepsy and Encephalopathy [APE2] and Response to Immunotherapy in Epilepsy and Encephalopathy [RITE2] scores) based on clinical features and initial neurological assessment may be utilized for selection of cases for autoimmune epilepsy evaluation and management. In this article, we will review the recent advances in autoimmune epilepsy and provide diagnostic and therapeutic algorithms for epilepsies with suspected autoimmune etiology.
Topics: Autoimmune Diseases of the Nervous System; Epilepsy; Humans; Immunotherapy
PubMed: 31240596
DOI: 10.1007/s13311-019-00750-3 -
Pharmacological Reviews Jul 2020Epilepsy is a chronic neurologic disorder that affects over 70 million people worldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for symptomatic... (Review)
Review
Epilepsy is a chronic neurologic disorder that affects over 70 million people worldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for symptomatic treatment of epileptic seizures, about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Patients with such drug-resistant epilepsy (DRE) have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life, so development of more effective therapies is an urgent clinical need. However, the various types of epilepsy and seizures and the complex temporal patterns of refractoriness complicate the issue. Furthermore, the underlying mechanisms of DRE are not fully understood, though recent work has begun to shape our understanding more clearly. Experimental models of DRE offer opportunities to discover, characterize, and challenge putative mechanisms of drug resistance. Furthermore, such preclinical models are important in developing therapies that may overcome drug resistance. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of ASD resistance and discuss how to overcome this problem. Encouragingly, better elucidation of the pathophysiological mechanisms underpinning epilepsies and drug resistance by concerted preclinical and clinical efforts have recently enabled a revised approach to the development of more promising therapies, including numerous potential etiology-specific drugs ("precision medicine") for severe pediatric (monogenetic) epilepsies and novel multitargeted ASDs for acquired partial epilepsies, suggesting that the long hoped-for breakthrough in therapy for as-yet ASD-resistant patients is a feasible goal. SIGNIFICANCE STATEMENT: Drug resistance provides a major challenge in epilepsy management. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of drug resistance in epilepsy and discuss how the problem might be overcome.
Topics: Animals; Anticonvulsants; Drug Resistance; Epilepsy; Humans; Randomized Controlled Trials as Topic
PubMed: 32540959
DOI: 10.1124/pr.120.019539 -
Neuropsychopharmacology Reports Sep 2021Antiseizure drugs (ASDs) are the primary therapy for epilepsy, with more than 20 drugs introduced into clinical practice to date. These drugs are typically grouped by... (Review)
Review
BACKGROUND
Antiseizure drugs (ASDs) are the primary therapy for epilepsy, with more than 20 drugs introduced into clinical practice to date. These drugs are typically grouped by their mechanisms of action and therapeutic spectrum. This article aims to educate non-neurologists and medical students about the new frontiers in the pharmacology of ASDs and presents the current state of the literature on the efficacy and tolerability of these agents.
METHODS
Randomized controlled trials, observational studies, and evidence-based meta-analyses of ASD efficacy and tolerability as initial monotherapy for epileptic seizures and syndromes were identified in PubMed, EMBASE, the Cochrane Library, and Elsevier Clinical Pharmacology.
RESULTS
The choice of ASD varies primarily according to the seizure type. Practical guidelines for ASD selection in patients with new-onset and drug-resistant epilepsy were recently published. The guidelines have shown that the newer-generation drugs, which have unique mechanistic and pharmacokinetic properties, are better tolerated but have similar efficacy compared with the older drugs. Several ASDs are effective as first-line monotherapy in focal seizures, including lamotrigine, carbamazepine, phenytoin, levetiracetam, and zonisamide. Valproate remains the first-line drug for many patients with generalized and unclassified epilepsies. However, valproate should be avoided, if possible, in women of childbearing potential because of teratogenicity. Toxicity profile precludes several drugs from use as first-line treatment, for example, vigabatrin, felbamate, and rufinamide.
CONCLUSIONS
Antiseizure drugs have different pharmacologic profiles that should be considered when selecting and prescribing these agents for epilepsy. These include pharmacokinetic properties, propensity for drug-drug interactions, and adverse effects.
Topics: Anticonvulsants; Epilepsies, Partial; Epilepsy; Epilepsy, Generalized; Humans; Neuropharmacology; Pharmaceutical Preparations; Seizures; Valproic Acid
PubMed: 34296824
DOI: 10.1002/npr2.12196 -
Brain : a Journal of Neurology Oct 2022Epilepsy is well-recognized as a disorder of brain networks. There is a growing body of research to identify critical nodes within dynamic epileptic networks with the... (Review)
Review
Epilepsy is well-recognized as a disorder of brain networks. There is a growing body of research to identify critical nodes within dynamic epileptic networks with the aim to target therapies that halt the onset and propagation of seizures. In parallel, intracranial neuromodulation, including deep brain stimulation and responsive neurostimulation, are well-established and expanding as therapies to reduce seizures in adults with focal-onset epilepsy; and there is emerging evidence for their efficacy in children and generalized-onset seizure disorders. The convergence of these advancing fields is driving an era of 'network-guided neuromodulation' for epilepsy. In this review, we distil the current literature on network mechanisms underlying neurostimulation for epilepsy. We discuss the modulation of key 'propagation points' in the epileptogenic network, focusing primarily on thalamic nuclei targeted in current clinical practice. These include (i) the anterior nucleus of thalamus, now a clinically approved and targeted site for open loop stimulation, and increasingly targeted for responsive neurostimulation; and (ii) the centromedian nucleus of the thalamus, a target for both deep brain stimulation and responsive neurostimulation in generalized-onset epilepsies. We discuss briefly the networks associated with other emerging neuromodulation targets, such as the pulvinar of the thalamus, piriform cortex, septal area, subthalamic nucleus, cerebellum and others. We report synergistic findings garnered from multiple modalities of investigation that have revealed structural and functional networks associated with these propagation points - including scalp and invasive EEG, and diffusion and functional MRI. We also report on intracranial recordings from implanted devices which provide us data on the dynamic networks we are aiming to modulate. Finally, we review the continuing evolution of network-guided neuromodulation for epilepsy to accelerate progress towards two translational goals: (i) to use pre-surgical network analyses to determine patient candidacy for neurostimulation for epilepsy by providing network biomarkers that predict efficacy; and (ii) to deliver precise, personalized and effective antiepileptic stimulation to prevent and arrest seizure propagation through mapping and modulation of each patients' individual epileptogenic networks.
Topics: Adult; Child; Humans; Deep Brain Stimulation; Anticonvulsants; Epilepsy; Subthalamic Nucleus; Thalamus; Epilepsies, Partial
PubMed: 35771657
DOI: 10.1093/brain/awac234 -
Neurotherapeutics : the Journal of the... Apr 2020Epilepsy includes a number of medical conditions with recurrent seizures as common denominator. The large number of different syndromes and seizure types as well as the... (Review)
Review
Epilepsy includes a number of medical conditions with recurrent seizures as common denominator. The large number of different syndromes and seizure types as well as the highly variable inter-individual response to the therapies makes management of this condition often challenging. In the last two decades, a genetic etiology has been revealed in more than half of all epilepsies and single gene defects in ion channels or neurotransmitter receptors have been associated with most inherited forms of epilepsy, including some focal and lesional forms as well as specific epileptic developmental encephalopathies. Several genetic tests are now available, including targeted assays up to revolutionary tools that have made sequencing of all coding (whole exome) and non-coding (whole genome) regions of the human genome possible. These recent technological advances have also driven genetic discovery in epilepsy and increased our understanding of the molecular mechanisms of many epileptic disorders, eventually providing targets for precision medicine in some syndromes, such as Dravet syndrome, pyroxidine-dependent epilepsy, and glucose transporter 1 deficiency. However, these examples represent a relatively small subset of all types of epilepsy, and to date, precision medicine in epilepsy has primarily focused on seizure control, and other clinical aspects, such as neurodevelopmental and neuropsychiatric comorbidities, have yet been possible to address. We herein summarize the most recent advances in genetic testing and provide up-to-date approaches for the choice of the correct test for some epileptic disorders and tailored treatments that are already applicable in some monogenic epilepsies. In the next years, the most probably scenario is that epilepsy treatment will be very different from the currently almost empirical approach, eventually with a "precision medicine" approach applicable on a large scale.
Topics: Epilepsy; Genetic Testing; Humans; Precision Medicine
PubMed: 31981099
DOI: 10.1007/s13311-020-00835-4 -
Epilepsia Mar 2021Precision medicine in the epilepsies has gathered much attention, especially with gene discovery pushing forward new understanding of disease biology. Several targeted... (Review)
Review
Precision medicine in the epilepsies has gathered much attention, especially with gene discovery pushing forward new understanding of disease biology. Several targeted treatments are emerging, some with considerable sophistication and individual-level tailoring. There have been rare achievements in improving short-term outcomes in a few very select patients with epilepsy. The prospects for further targeted, repurposed, or novel treatments seem promising. Along with much-needed success, difficulties are also arising. Precision treatments do not always work, and sometimes are inaccessible or do not yet exist. Failures of precision medicine may not find their way to broader scrutiny. Precision medicine is not a new concept: It has been boosted by genetics and is often focused on genetically determined epilepsies, typically considered to be driven in an individual by a single genetic variant. Often the mechanisms generating the full clinical phenotype from such a perceived single cause are incompletely understood. The impact of additional genetic variation and other factors that might influence the clinical presentation represent complexities that are not usually considered. Precision success and precision failure are usually equally incompletely explained. There is a need for more comprehensive evaluation and a more rigorous framework, bringing together information that is both necessary and sufficient to explain clinical presentation and clinical responses to precision treatment in a precision approach that considers the full picture not only of the effects of a single variant, but also of its genomic and other measurable environment, within the context of the whole person. As we may be on the brink of a treatment revolution, progress must be considered and reasoned: One possible framework is proposed for the evaluation of precision treatments.
Topics: Epilepsy; Forecasting; Genetic Variation; Humans; Mutation; Pedigree; Precision Medicine
PubMed: 32776321
DOI: 10.1111/epi.16539 -
Journal of Sleep Research Aug 2022Sleep and epilepsy have a reciprocal relationship, and have been recognized as bedfellows since antiquity. However, research on this topic has made a big step forward... (Review)
Review
Sleep and epilepsy have a reciprocal relationship, and have been recognized as bedfellows since antiquity. However, research on this topic has made a big step forward only in recent years. In this narrative review we summarize the most stimulating discoveries and insights reached by the "European school." In particular, different aspects concerning the sleep-epilepsy interactions are analysed: (a) the effects of sleep on epilepsy; (b) the effects of epilepsy on sleep structure; (c) the relationship between epilepsy, sleep and epileptogenesis; (d) the impact of epileptic activity during sleep on cognition; (e) the relationship between epilepsy and the circadian rhythm; (f) the history and features of sleep hypermotor epilepsy and its differential diagnosis; (g) the relationship between epilepsy and sleep disorders.
Topics: Circadian Rhythm; Electroencephalography; Epilepsy; Humans; Sleep; Sleep Wake Disorders
PubMed: 35487880
DOI: 10.1111/jsr.13622 -
Clinical Drug Investigation Mar 2021Anecdotal reports addressing the successful seizure treatment of severe epilepsies with cannabidiol (CBD) have increased both public interest and academic research.... (Review)
Review
Anecdotal reports addressing the successful seizure treatment of severe epilepsies with cannabidiol (CBD) have increased both public interest and academic research. Placebo-controlled, randomized, controlled trials proved the efficacy of pharmaceutical-grade CBD in epilepsy treatment, thus leading to pharmaceutical-grade CBD approval by the US Food and Drug Administration and the European Medicines Agency for the treatment of seizures in Dravet syndrome and Lennox-Gastaut syndrome as well as for tuberous complex syndrome by the Food and Drug Administration only. However, the CBD market is confusing because an array of products of different origins, purity, and concentration is available. Additionally, the results from the pivotal studies with plant-derived, pharmaceutical-grade CBD cannot simply be transferred to other epilepsy types or CBD of any origin. Because of the high demands and expectations that patients with epilepsy and their caregivers have regarding CBD, information outlining the proven facts and potential risks is essential. The aim of this article is to thoroughly review available research data and practical recommendations to provide the treating physician with the necessary information for counseling patients with epilepsy.
Topics: Anticonvulsants; Cannabidiol; Epilepsies, Myoclonic; Epilepsy; Humans; Lennox Gastaut Syndrome; Randomized Controlled Trials as Topic; Seizures; United States; United States Food and Drug Administration
PubMed: 33559102
DOI: 10.1007/s40261-021-01003-y