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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 -
Epileptic Disorders : International... Feb 2020The growing interest in cannabidiol (CBD), specifically a pure form of CBD, as a treatment for epilepsy, among other conditions, is reflected in recent changes in... (Review)
Review
The growing interest in cannabidiol (CBD), specifically a pure form of CBD, as a treatment for epilepsy, among other conditions, is reflected in recent changes in legislation in some countries. Although there has been much speculation about the therapeutic value of cannabis-based products as an anti-seizure treatment for some time, it is only within the last two years that Class I evidence has been available for a pure form of CBD, based on placebo-controlled RCTs for patients with Lennox-Gastaut syndrome and Dravet syndrome. However, just as we are beginning to understand the significance of CBD as a treatment for epilepsy, in recent years, a broad spectrum of products advertised to contain CBD has emerged on the market. The effects of these products are fundamentally dependent on the purity, preparation, and concentration of CBD and other components, and consensus and standardisation are severely lacking regarding their preparation, composition, usage and effectiveness. This review aims to provide information to neurologists and epileptologists on the therapeutic value of CBD products, principally a purified form, in routine practice for patients with intractable epilepsy.
Topics: Cannabidiol; Cannabinoid Receptor Modulators; Drug Resistant Epilepsy; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Practice Guidelines as Topic
PubMed: 32096470
DOI: 10.1684/epd.2020.1141 -
Epilepsy & Behavior : E&B Jul 2022Dravet Syndrome is a genetic epileptic syndrome characterized by severe and intractable seizures associated with cognitive, motor, and behavioral impairments. The... (Review)
Review
Dravet Syndrome is a genetic epileptic syndrome characterized by severe and intractable seizures associated with cognitive, motor, and behavioral impairments. The disease is also linked with increased mortality mainly due to sudden unexpected death in epilepsy. Over 80% of cases are due to a de novo mutation in one allele of the SCN1A gene, which encodes the α-subunit of the voltage-gated ion channel Na1.1. Dravet Syndrome is usually refractory to antiepileptic drugs, which only alleviate seizures to a small extent. Viral, non-viral genetic therapy, and gene editing tools are rapidly enhancing and providing new platforms for more effective, alternative medicinal treatments for Dravet syndrome. These strategies include gene supplementation, CRISPR-mediated transcriptional activation, and the use of antisense oligonucleotides. In this review, we summarize our current knowledge of novel genetic therapies that are currently under development for Dravet syndrome.
Topics: Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Humans; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Seizures; Spasms, Infantile
PubMed: 35653814
DOI: 10.1016/j.yebeh.2022.108741 -
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 -
Genes Jul 2021The high pace of gene discovery has resulted in thrilling advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, or genomes... (Review)
Review
The high pace of gene discovery has resulted in thrilling advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, or genomes are now increasingly available and have led to a significant higher diagnostic yield in early-onset epilepsies and enabled precision medicine approaches. These have been instrumental in providing insights into the pathophysiology of both early-onset benign and self-limited syndromes and devastating developmental and epileptic encephalopathies (DEEs). Genetic heterogeneity is seen in many epilepsy syndromes such as West syndrome and epilepsy of infancy with migrating focal seizures (EIMFS), indicating that two or more genetic loci produce the same or similar phenotypes. At the same time, some genes such as can be associated with a wide range of epilepsy syndromes ranging from self-limited familial neonatal epilepsy at the mild end to Ohtahara syndrome, EIFMS, West syndrome, Lennox-Gastaut syndrome, or unclassifiable DEEs at the severe end of the spectrum. The aim of this study was to review the clinical and genetic heterogeneity associated with epilepsy syndromes starting in the first year of life including: Self-limited familial neonatal, neonatal-infantile or infantile epilepsies, genetic epilepsy with febrile seizures plus spectrum, myoclonic epilepsy in infancy, Ohtahara syndrome, early myoclonic encephalopathy, West syndrome, Dravet syndrome, EIMFS, and unclassifiable DEEs. We also elaborate on the advantages and pitfalls of genetic testing in such conditions. Finally, we describe how a genetic diagnosis can potentially enable precision therapy in monogenic epilepsies and emphasize that early genetic testing is a cornerstone for such therapeutic strategies.
Topics: Epileptic Syndromes; Genetic Testing; Humans; Infant; Phenotype
PubMed: 34356067
DOI: 10.3390/genes12071051 -
Brain : a Journal of Neurology Nov 2022Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with...
Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 × 10-7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.
Topics: Humans; Arthrogryposis; Epilepsies, Myoclonic; Epilepsy; Gain of Function Mutation; Migraine with Aura; Movement Disorders; NAV1.1 Voltage-Gated Sodium Channel; Phenotype; Spasms, Infantile; Infant, Newborn; Infant
PubMed: 35696452
DOI: 10.1093/brain/awac210 -
Epilepsia Jul 2022This study was undertaken to gain consensus from experienced physicians and caregivers regarding optimal diagnosis and management of Dravet syndrome (DS), in the context...
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.
Topics: Consensus; Epilepsies, Myoclonic; Epileptic Syndromes; Humans; Infant; Seizures; Spasms, Infantile
PubMed: 35490361
DOI: 10.1111/epi.17274 -
Epilepsia Open Mar 2022Dravet 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... (Review)
Review
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.
Topics: Adult; Epilepsies, Myoclonic; Epilepsy; Epileptic Syndromes; Europe; Humans; Infant; Spasms, Infantile
PubMed: 34882995
DOI: 10.1002/epi4.12569 -
Seizure Oct 2019Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized epilepsy, and... (Review)
Review
Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized epilepsy, and neurological deterioration, including dementia and ataxia. PMEs may have infancy, childhood, juvenile or adult onset, but usually present in late childhood or adolescence, at variance from epileptic encephalopathies, which start with polymorphic seizures in early infancy. Neurophysiologic recordings are suited to describe faithfully the time course of the shock-like muscle contractions which characterize myoclonus. A combination of positive and negative myoclonus is typical of PMEs. The gene defects for most PMEs (Unverricht-Lundborg disease, Lafora disease, several forms of neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers [MERRF], and type 1 and 2 sialidoses) have been identified. PMEs are uncommon disorders, difficult to diagnose in the absence of extensive experience. Thus, aetiology is undetermined in many patients, despite the advance in molecular medicine. Treatment of PMEs remains essentially symptomaticof seizures and myoclonus, together with palliative, supportive, and rehabilitative measures. The response to therapy may initially be relatively favourable, afterwards however, seizures may become more frequent, and progressive neurologic decline occurs. The prognosis of a PME depends on the specific disease. The history of PMEs revealed that the international collaboration and sharing experience is the right way to proceed. This emerging picture and biological insights will allow us to find ways to provide the patients with meaningful treatment.
Topics: Humans; Myoclonic Epilepsies, Progressive; Precision Medicine
PubMed: 31476531
DOI: 10.1016/j.seizure.2019.08.012 -
Neurology Mar 2023We aimed to determine the population-based cumulative incidence and prevalence of developmental and epileptic encephalopathies (DEEs) and intellectual disability and...
BACKGROUND AND OBJECTIVES
We aimed to determine the population-based cumulative incidence and prevalence of developmental and epileptic encephalopathies (DEEs) and intellectual disability and epilepsy (ID+E) in children. We analyzed the cumulative incidence of specific epilepsy syndromes.
METHODS
Children younger than 16 years with a DEE or ID+E were ascertained using EEG records from 2000 to 2016 in the Wellington region of New Zealand. Epilepsy syndromes were diagnosed on medical record and EEG review. Point prevalence and cumulative incidence for children with epilepsy and developmental impairment, DEE and ID+E were calculated. Cumulative incidence for each epilepsy syndrome was calculated.
RESULTS
The cohort comprised 235 children (58% male) with developmental impairment and epilepsy, including 152 (65%) with DEE and 83 (35%) with ID+E. The median age of seizure onset was 15.4 months (range day 1-15 years). The median follow-up from seizure onset was 7.9 years (range 0-18.2 years). Point prevalence for the broad group of children with epilepsy and developmental impairment was 175/100,000 children (95% CI 149-203; DEE 112 and ID+E 63/100,000 children). Cumulative incidence for DEE was 169/100,000 children (95% CI 144-199) and that for ID+E was 125/100,000 children (95% CI 95.4-165). Cumulative incidence per 100,000 children was as follows: infantile epileptic spasms syndrome 58.2 (95% CI 45.0-75.3), epilepsy with myoclonic-atonic seizures 16.4 (95% CI 9.69-27.7), Lennox-Gastaut syndrome 13.2 (95% CI 4.1-41.9), and Dravet syndrome 5.1 (95% CI 2.1-12.2). Fifty/152 (33%) of children with DEE and 70/83 (84%) with ID+E could not be diagnosed with a known epilepsy syndrome.
DISCUSSION
Epilepsy and developmental impairment before the age of 16 years occurs in 1 in 340 children, with 1 in 590 having a DEE and 1 in 800 having ID+E. These individuals require significant health and community resources; therefore, these data will inform complex health service and education planning. Epidemiologic studies have focused on early childhood-onset DEEs. These do not fully reflect the burden of these disorders because 27% of DEEs and 70% of ID+E begin later, with seizure onset after the age of 3 years. Understanding the cumulative incidence of specific syndromes together with the broad group of DEEs is essential for the planning of therapeutic trials. Given trials focus on specific syndromes, there is a risk that effective therapies will not be developed for one-third of children with DEE.
Topics: Child; Humans; Child, Preschool; Male; Infant, Newborn; Adolescent; Female; Intellectual Disability; Lennox Gastaut Syndrome; Epilepsies, Myoclonic; Electroencephalography; Seizures
PubMed: 36581463
DOI: 10.1212/WNL.0000000000206758