The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant ...seizures in the Dravet syndrome.
In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.
The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, -22.8 percentage points; 95% confidence interval CI, -41.1 to -5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient's overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.
Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375 .).
Summary Epileptic encephalopathies of infancy and childhood comprise a large, heterogeneous group of severe epilepsies characterised by several seizure types, frequent epileptiform activity on EEG, ...and developmental slowing or regression. The encephalopathies include many age-related electroclinical syndromes with specific seizure types and EEG features. With the molecular revolution, the number of known monogenic determinants underlying the epileptic encephalopathies has grown rapidly. De-novo dominant mutations are frequently identified; somatic mosaicism and recessive disorders are also seen. Several genes can cause one electroclinical syndrome, and, conversely, one gene might be associated with phenotypic pleiotropy. Diverse genetic causes and molecular pathways have been implicated, involving ion channels, and proteins needed for synaptic, regulatory, and developmental functions. Gene discovery provides the basis for neurobiological insights, often showing convergence of mechanistic pathways. These findings underpin the development of targeted therapies, which are essential to improve the outcome of these devastating disorders.
Epilepsy surgery in children and adults Ryvlin, Philippe, Prof; Cross, J Helen, Prof; Rheims, Sylvain, MD
Lancet neurology,
11/2014, Volume:
13, Issue:
11
Journal Article
Peer reviewed
Summary Epilepsy surgery is the most effective way to control seizures in patients with drug-resistant focal epilepsy, often leading to improvements in cognition, behaviour, and quality of life. ...Risks of serious adverse events and deterioration of clinical status can be minimised in carefully selected patients. Accordingly, guidelines recommend earlier and more systematic assessment of patients' eligibility for surgery than is seen at present. The effectiveness of surgical treatment depends on epilepsy type, underlying pathology, and accurate localisation of the epileptogenic brain region by various clinical, neuroimaging, and neurophysiological investigations. Substantial progress has been made in the methods of presurgical assessment, particularly in patients with normal features on MRI, but evidence is scarce for the indication and effect of most presurgical investigations, with no biomarker precisely delineating the epileptogenic zone. A priority for the development of epilepsy surgery is the generation of high-level evidence to promote the harmonisation and dissemination of best practices.
Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional ...antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy.
In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period.
A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations.
Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560 .).
High-fat, low-carbohydrate diets, known as ketogenic diets, have been used as a non-pharmacological treatment for refractory epilepsy. A key mechanism of this treatment is thought to be the ...generation of ketones, which provide brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose, resulting in beneficial downstream metabolic changes, such as increasing adenosine levels, which might have effects on seizure control. However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis. Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise seizure threshold. The mechanisms underlying the ketogenic diet might also have roles in other disorders, such as preventing neurodegeneration in Alzheimer's disease, the proliferation and spread of cancer, and insulin resistance in type 2 diabetes. Analysing medium-chain fatty acids in future ketogenic diet studies will provide further insights into their importance in modified forms of the diet. Moreover, the results of these studies could facilitate the development of new pharmacological and dietary therapies for epilepsy and other disorders.
Summary
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.
Summary Rasmussen's encephalitis is a rare chronic neurological disorder, characterised by unilateral inflammation of the cerebral cortex, drug-resistant epilepsy, and progressive neurological and ...cognitive deterioration. Neuropathological and immunological studies support the notion that Rasmussen's encephalitis is probably driven by a T-cell response to one or more antigenic epitopes, with potential additional contribution by autoantibodies. Careful analysis of the association between histopathology and clinical presentation suggests that initial damage to the brain is mediated by T cells and microglia, suggesting a window for treatment if Rasmussen's encephalitis can be diagnosed early. Advances in neuroimaging suggest that progression of the inflammatory process seen with MRI might be a good biomarker in Rasmussen's encephalitis. For many patients, families, and doctors, choosing the right time to move from medical management to surgery is a real therapeutic dilemma. Cerebral hemispherectomy remains the only cure for seizures, but there are inevitable functional compromises. Decisions of whether or when surgery should be undertaken are challenging in the absence of a dense neurological deficit, and vary by institutional experience. Further, the optimum time for surgery, to give the best language and cognitive outcome, is not yet well understood. Immunomodulatory treatments seem to slow rather than halt disease progression in Rasmussen's encephalitis, without changing the eventual outcome.
Aim
To assess the prevalence and risk factors for autism spectrum disorder (ASD) in epilepsy, and to better understand the relationship and comorbidity between these disorders.
Method
PsychINFO and ...PubMed were searched for articles published in the past 15 years that examined the prevalence of ASD in individuals with epilepsy.
Results
A total of 19 studies were found with a pooled ASD prevalence of 6.3% in epilepsy. When divided by type, the risks of ASD for general epilepsy, infantile spasms, focal seizures, and Dravet syndrome were 4.7%, 19.9%, 41.9%, and 47.4% respectively. Studies with populations under 18 years showed a 13.2 times greater risk of ASD than study populations over 18 years, and samples with most (>50%) individuals with intellectual disability showed a greater risk 4.9 times higher than study populations with a minority of individuals with intellectual disability. The main risk factors for ASD reported in the 19 studies included presence of intellectual disability, sex, age, and symptomatic aetiology of epilepsy.
Interpretation
Current research supports a high prevalence of ASD in epilepsy. This study helps to define the clinical profile of patients with epilepsy who are at risk for ASD, which may help clinicians in early screening and diagnosis of ASD in this population.
What this paper adds
Critical evaluation of previous studies examining the prevalence of autism spectrum disorder (ASD) in individuals with epilepsy.
A meta‐analysis of 19 studies showed a pooled ASD prevalence of 6.3% in individuals with epilepsy.
Studies that included a majority of individuals with intellectual disability or younger population age had a higher prevalence of autism.
Risk factors reported in studies included presence of intellectual disability, sex, age, and symptomatic epilepsy origin.
Resumen
Prevalencia y factores de riesgo para trastornos del espectro autista en epilepsia: una revisión sistemática y meta‐ análisis
Objetivos
Evaluar la prevalencia y los factores de riesgo para el trastorno del espectro autista (TEA) en epilepsia, y comprender mejor la relación y comorbilidad entre estos 2 trastornos.
Metodos
A través de PsychINFO y Pubmed se realizó la búsqueda de artículos publicados en los últimos 15 años que evaluaron la prevalencia de TEA en individuos con epilepsia.
Resultados
Se encontraron un total de 19 artículos con una prevalencia de TEA en epilepsia del 6,3%. Cuando se divide en tipos, los riesgos de TEA para epilepsia general, espasmos de la infancia, convulsiones focales y Dravet fueron de 4,7%, 19,9%, 41,9% y 47,4% respectivamente. Los estudios con poblaciones menores de 18 años de edad mostraron un riesgo para TEA 13.2% mayor que los estudios con poblaciones mayores de 18 años de edad, y las muestras con la mayoría de los individuos (> 50%) con discapacidad intelectual mostró un riesgo de 4.9 mayor que los estudios con poblaciones con minoría de individuos con discapacidad intelectual. Los principales factores de riesgo reportados para TEA en los 19 estudios incluyeron: discapacidad intelectual, sexo, edad y epilepsia sintomática.
Interpretacion
Los estudios actuales apoyan una mayor prevalencia de TEA en epilepsia. Este estudio ayuda a definir el perfil clínico de los pacientes con epilepsia que se encuentran en riesgo para TEA, pudiendo ayudar al clínico para una pesquisa y diagnóstico temprano de TEA en esta población.
Resumo
Prevalência e fatores de risco para transtorno do espectro autista na epilepsia: uma revisão sistemática e metanálise
Objetivo
Determinar a prevalência e fatores de risco para transtorno do espectro autista (TEA) na epilesia, e entender melhor a relação e comorbidade entre essas duas desordens.
Mëtodos
Foram pesquisados artigos publicados nos últimos 15 anos no PsychINFO e PubMed e analisada a prevalência de TEA em indivíduos com epilepsia.
Resultados
Foi encontrado um total de 19 estudos, com uma prevalência agrupada de autismo de 6,3% na epilepsia. Quando dividido por tipo, o risco de TEA para epilepsia generalizada, espasmos infantis, crises focais e síndrome de Dravet foi de 4,7%, 19,9%, 41,9 e 47,4% respectivamente. Estudos com populações menores de 18 anos mostrou um risco 13,2 vezes maior de TEA do que estudos com populações maiores de 18 anos, e amostras com maioria (>50%) de indivíduos com deficiência intelectual mostrou um risco 4,9 vezes maior que estudos com populações com uma minoria de indivíduos com deficiência intelectual. Os maiores fatores de risco para TEA reportados nos 19 estudos foram presença de deficiência intelectual, sexo, idade e etiologia sintomática da epilepsia.
Interpretação
Estudos atuais confirmam uma alta prevalência de TEA na epilepsia. Este estudo ajuda a definir o perfil clínico de pacientes com epilepsia que estão em risco para TEA, que pode ajudar clínicos no rastreio e diagnóstico precoces de TEA nesta população.
What this paper adds
Critical evaluation of previous studies examining the prevalence of autism spectrum disorder (ASD) in individuals with epilepsy.
A meta‐analysis of 19 studies showed a pooled ASD prevalence of 6.3% in individuals with epilepsy.
Studies that included a majority of individuals with intellectual disability or younger population age had a higher prevalence of autism.
Risk factors reported in studies included presence of intellectual disability, sex, age, and symptomatic epilepsy origin.
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