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JAMA Neurology Mar 2020Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens.
OBJECTIVE
To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens.
DESIGN, SETTING, AND PARTICIPANTS
This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens.
INTERVENTIONS
Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients' assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary.
MAIN OUTCOMES AND MEASURES
The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline.
RESULTS
A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (≥50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension.
CONCLUSIONS AND RELEVANCE
Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT02926898.
Topics: Adolescent; Anticonvulsants; Child; Child, Preschool; Dioxolanes; Double-Blind Method; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsies, Myoclonic; Female; Fenfluramine; Humans; Male; Selective Serotonin Reuptake Inhibitors
PubMed: 31790543
DOI: 10.1001/jamaneurol.2019.4113 -
Molecules (Basel, Switzerland) Apr 2024It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat... (Review)
Review
It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat different types of seizures related to Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and more recently tuberous sclerosis complex (TSC). During this time, 39 randomized clinical trials (RCTs) and 13 meta-analyses on the efficacy and safety of CBD treatment have been published. Each of the meta-analyses had its own criteria for the RCTs' inclusion and, therefore, slightly different interpretations of the analyzed data. Each of them contributed in its own way to the understanding of CBD pharmacology, mechanisms of therapeutic action, development of adverse reactions, and drug-drug interactions. Hence, it seemed reasonable to gather the most relevant data in one article and present all the current knowledge on the use of CBD in epilepsy. The results of the 13 meta-analyses presented herein confirmed the effectiveness and safety of CBD in children and adolescents with DREs. In adults, reliable conclusions cannot be drawn due to insufficient data.
Topics: Humans; Cannabidiol; Epilepsy; Anticonvulsants; Randomized Controlled Trials as Topic; Lennox Gastaut Syndrome; Child; Treatment Outcome; Epilepsies, Myoclonic
PubMed: 38731471
DOI: 10.3390/molecules29091981 -
Paediatric Drugs Apr 2020The progressive myoclonic epilepsies (PMEs) represent a rare but devastating group of syndromes characterized by epileptic myoclonus, typically action-induced seizures,... (Review)
Review
The progressive myoclonic epilepsies (PMEs) represent a rare but devastating group of syndromes characterized by epileptic myoclonus, typically action-induced seizures, neurological regression, medically refractory epilepsy, and a variety of other signs and symptoms depending on the specific syndrome. Most of the PMEs begin in children who are developing as expected, with the onset of the disorder heralded by myoclonic and other seizure types. The conditions are considerably heterogenous, but medical intractability to epilepsy, particularly myoclonic seizures, is a core feature. With the increasing use of molecular genetic techniques, mutations and their abnormal protein products are being delineated, providing a basis for disease-based therapy. However, genetic and enzyme replacement or substrate removal are in the nascent stage, and the primary therapy is through antiepileptic drugs. Epilepsy in children with progressive myoclonic seizures is notoriously difficult to treat. The disorder is rare, so few double-blinded, placebo-controlled trials have been conducted in PME, and drugs are chosen based on small open-label trials or extrapolation of data from drug trials of other syndromes with myoclonic seizures. This review discusses the major PME syndromes and their neurogenetic basis, pathophysiological underpinning, electroencephalographic features, and currently available treatments.
Topics: Child; Humans; Myoclonic Epilepsies, Progressive; Research Design
PubMed: 31939107
DOI: 10.1007/s40272-019-00378-y -
Epilepsy Research Aug 2019Since 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which... (Clinical Trial)
Clinical Trial
BACKGROUND
Since 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which closely reflects clinical practice. We conducted an interim analysis of long-term efficacy and tolerability in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) who received CBD treatment through December 2016.
METHODS
Children and adults with LGS/DS taking stable doses of antiepileptic drugs (AEDs) at baseline were included from 25 EAP sites across the United States. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received a pharmaceutical formulation of highly purified CBD (Epidiolex®; 100 mg/mL) in oral solution at 2-10 mg/kg/day, titrated until tolerability limit or a maximum dose of 25-50 mg/kg/day. Patient visits were every 2-4 weeks. The percentage change from baseline in median monthly convulsive (ie, major motor) and total seizures was evaluated at 12-week intervals through 96 weeks. The percentages of patients who had ≥50%, ≥75%, and 100% reduction in monthly seizures relative to the baseline period were also evaluated. Adverse events (AEs) were monitored and summarized for the safety analysis set (SAS) through 144 weeks.
RESULTS
Of the 607 patients in the SAS, 58 had DS and 94 had LGS (N = 152); 455 patients had other TREs. Twenty-eight percent of LGS/DS patients withdrew, primarily owing to lack of efficacy (20%). LGS/DS patients were taking a median of 3 (0-10) concomitant AEDs. Median treatment duration was 78.3 (range, 4.1-146.4) weeks. Between weeks 12 and 96, median CBD dose ranged from 21 to 25 mg/kg/day. At 12 weeks, add-on CBD reduced median monthly major motor seizures by 50% and total seizures by 44%, with consistent reductions in both seizure types through 96 weeks. At 12 weeks, the proportions of patients with ≥50%, ≥75%, and 100% reductions in major motor seizures were 53%, 23%, and 6%; the proportions with corresponding reductions in total seizures were 46%, 26%, and 5%. Responder rates for both seizure types were consistent through 96 weeks. CBD had an acceptable safety profile; the most common AEs were somnolence (30%) and diarrhea (24%).
CONCLUSIONS
Results from this interim analysis support add-on CBD as an effective long-term treatment option in LGS or DS.
Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Diarrhea; Drug Resistant Epilepsy; Duration of Therapy; Epilepsies, Myoclonic; Female; Humans; Infant; Lennox Gastaut Syndrome; Male; Middle Aged; Sleepiness; Treatment Outcome; Young Adult
PubMed: 31022635
DOI: 10.1016/j.eplepsyres.2019.03.015 -
Tremor and Other Hyperkinetic Movements... 2018Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal dominantly inherited disorder characterized by myoclonus, epilepsy, ataxia, and dementia. Diagnosis is... (Review)
Review
BACKGROUND
Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal dominantly inherited disorder characterized by myoclonus, epilepsy, ataxia, and dementia. Diagnosis is challenging due to the heterogeneous presentation and symptomatic overlap with other spinocerebellar ataxias. Symptoms vary according to age of onset, with a mean age at onset of 31 years. A CAG repeat expansion in the gene results in neuronal intranuclear inclusions, variable neuronal loss, and astrocytosis in the globus pallidus, dentate and red nuclei. No disease-modifying or curative treatments are currently available.
METHODS
We performed an online literature search using PubMed for all articles published in an English Language format on the topics of DRPLA or over the last 10 years. Where these articles cited other research as support for findings, or statements, these articles were also reviewed. Contemporary articles from related research fields (e.g., Huntington's Disease) were also included to support statements.
RESULTS
Forty-seven articles were identified, 10 were unobtainable and 10 provided no relevant information. The remaining 27 articles were then used for the review template: seven case reports, seven case series, six model system articles (one review article), four population clinical and genetic studies (one review article), two general review articles, and one human gene expression study. Other cited articles or research from related fields gave a further 42 articles, producing a total of 69 articles cited: 15 case series (including eight family studies), 14 model systems (one review article), 14 population clinical and genetic studies (two review articles), 10 case reports, eight clinical trials/guidelines, four genetic methodology articles, three general review articles, and one human gene expression study.
DISCUSSION
DRPLA remains an intractable, progressive, neurodegenerative disorder without effective treatment. Early recognition of the disorder may improve patient understanding, and access to services and treatments. Large-scale studies are lacking, but are required to characterize the full allelic architecture of the disorder in all populations and the heterogeneous phenotypic spectrum, including neuroimaging findings, possible biomarkers, and responses to treatment.
Topics: Adult; Animals; Brain; Child; Disease Management; Disease Models, Animal; Female; Humans; Male; Myoclonic Epilepsies, Progressive; Nerve Tissue Proteins; Peptides; PubMed
PubMed: 30410817
DOI: 10.7916/D81N9HST -
Human Gene Therapy Jun 2022Dravet syndrome (DS) is a developmental and epileptic encephalopathy caused by monoallelic loss-of-function variants in the gene. encodes for the alpha subunit of the...
Cell-Selective Adeno-Associated Virus-Mediated Gene Regulation Therapy Rescues Mortality and Seizure Phenotypes in a Dravet Syndrome Mouse Model and Is Well Tolerated in Nonhuman Primates.
Dravet syndrome (DS) is a developmental and epileptic encephalopathy caused by monoallelic loss-of-function variants in the gene. encodes for the alpha subunit of the voltage-gated type I sodium channel (Na1.1), the primary voltage-gated sodium channel responsible for generation of action potentials in GABAergic inhibitory interneurons. In these studies, we tested the efficacy of an adeno-associated virus serotype 9 (AAV9) gene regulation therapy, AAV9-RE-eTF, designed to target transgene expression to GABAergic inhibitory neurons and reduce off-target expression within excitatory cells, in the mouse model of DS. Biodistribution and preliminary safety were evaluated in nonhuman primates (NHPs). AAV9-RE-eTF was engineered to upregulate expression levels within GABAergic inhibitory interneurons to correct the underlying haploinsufficiency and circuit dysfunction. A single bilateral intracerebroventricular (ICV) injection of AAV9-RE-eTF in postnatal day 1 mice led to increased mRNA transcripts, specifically within GABAergic inhibitory interneurons, and Na1.1 protein levels in the brain. This was associated with a significant decrease in the occurrence of spontaneous and hyperthermia-induced seizures, and prolonged survival for over a year. In NHPs, delivery of AAV9-RE-eTF by unilateral ICV injection led to widespread vector biodistribution and transgene expression throughout the brain, including key structures involved in epilepsy and cognitive behaviors, such as hippocampus and cortex. AAV9-RE-eTF was well tolerated, with no adverse events during administration, no detectable changes in clinical observations, no adverse findings in histopathology, and no dorsal root ganglion-related toxicity. Our results support the clinical development of AAV9-RE-eTF (ETX101) as an effective and targeted disease-modifying approach to SCN1A DS.
Topics: Animals; Dependovirus; Disease Models, Animal; Epilepsies, Myoclonic; Epileptic Syndromes; Mice; NAV1.1 Voltage-Gated Sodium Channel; Phenotype; Primates; Seizures; Spasms, Infantile; Tissue Distribution; gamma-Aminobutyric Acid
PubMed: 35435735
DOI: 10.1089/hum.2022.037 -
Seizure Jul 2023The endophenotype of Idiopathic Generalized Epilepsies (IGE) comprises distinct neuropsychological deficits compared to normal controls. It is unknown if the severity of...
PURPOSE
The endophenotype of Idiopathic Generalized Epilepsies (IGE) comprises distinct neuropsychological deficits compared to normal controls. It is unknown if the severity of features of the endophenotype correlates with resistance to anti-seizure medication. Therefore, we here studied the association of neuropsychological profiles with treatment response.
METHODS
We evaluated 106 Danish patients aged ≥18 and diagnosed with IGE using a neuropsychological test battery comprising tests for executive dysfunction, visual attention, episodic memory, and verbal comprehension. Tests were complemented by the Purdue Pegboard test. Patients with suspected ongoing psychogenic non-epileptic seizures were excluded.
RESULTS
At testing, 72 patients were seizure free, and 34 patients had recent seizures despite anti-seizure medication. As compared to age corrected Danish normative values, IGE patients showed significant impairments in semantic fluency and performed significantly worse in the Purdue Pegboard test. The vocabulary subtest of the WAIS-IV suggested lower verbal comprehension in IGE patients. We found no signs of memory impairment. Comparisons between results of the test battery, drug resistance, and the different IGE subsyndromes revealed consistent null-associations in various predefined and exploratory univariate and multivariate analyses.
CONCLUSION
We here found and confirmed the distinct neuropsychological profile comprising impaired executive functions, reduced psychomotor speed, and normal memory previously described in juvenile myoclonic epilepsy. This profile was, however, not restricted to juvenile myoclonic epilepsy but equally affected all IGE patients. The neuropsychological deficits were not significantly associated with drug treatment outcome.
Topics: Humans; Myoclonic Epilepsy, Juvenile; Executive Function; Neuropsychological Tests; Epilepsy, Generalized; Immunoglobulin E
PubMed: 37178660
DOI: 10.1016/j.seizure.2023.04.021 -
Medicina 2019Epileptic encephalopathies is a group of epileptic syndromes characterized by progressive cognitive impairment beyond the expected for the epilepsy activity. They are... (Review)
Review
Epileptic encephalopathies is a group of epileptic syndromes characterized by progressive cognitive impairment beyond the expected for the epilepsy activity. They are characterized by severe pharmaco-resistant epilepsy, severely abnormal electroencephalograms, early-age onset, neurocognitve impairment, variable phenotype and usually normal brain MRI. These syndromes are usually genetically determined. A correct and timely diagnosis could help and guide the medical counselling and the correct therapeutic approach improving the short, medium and long term outcomes. In this article we review the electroencephalographic and genetic findings along with the most recommended therapeutic options facilitating the clinical management. We include the following epileptic encephalopathy syndromes: Ohtahara, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West, Dravet, non-progressive myoclonic status, Doose, Lennox-Gastaut, Landau-Kleffner and continuous spike-wave during sleep epilepsy.
Topics: Anticonvulsants; Brain Diseases; Electroencephalography; Epilepsies, Myoclonic; Humans; Spasms, Infantile; Syndrome
PubMed: 31603843
DOI: No ID Found -
Seizure Aug 2021Epileptic syndromes are well-defined conditions comprising particular clinical features [seizure types, age of onset, response to treatment] and characteristic... (Review)
Review
Epileptic syndromes are well-defined conditions comprising particular clinical features [seizure types, age of onset, response to treatment] and characteristic electroencephalographic changes, while their etiology and subsequent prognosis may vary. The recognition of these syndromes is fundamental for pediatric neurology practice, representing an essential learning topic in this field. Nevertheless, many epileptic syndromes are still quite unfamiliar to students, residents and even neurologists, because of their low incidence and their minimal representation in the literature. This narrative review discusses the concept of epileptic syndromes and revisits seven lesser-known or uncommon syndromes in order to summarize their core clinical features, which can become important clues for daily neurological practice, namely epilepsy of infancy with migrating focal seizures, myoclonic epilepsy of infancy, self-limited infantile epilepsy, myoclonic encephalopathy in nonprogressive disorders, Jeavons syndrome, and epilepsy with myoclonic absences.
Topics: Child; Electroencephalography; Epilepsies, Myoclonic; Epilepsy, Reflex; Epileptic Syndromes; Humans; Incidence
PubMed: 34023208
DOI: 10.1016/j.seizure.2021.05.005 -
Arquivos de Neuro-psiquiatria May 2022Cannabidiol (CBD) has become a promising therapeutic option in the treatment of epilepsy. Recent studies provide robust evidence that CBD is effective and safe.... (Review)
Review
BACKGROUND
Cannabidiol (CBD) has become a promising therapeutic option in the treatment of epilepsy. Recent studies provide robust evidence that CBD is effective and safe. Limitations in current knowledge and regulatory issues still limit CBD use. CBD use regarding epilepsy types still lacks clear guidelines.
OBJECTIVE
To critically review the main current pharmacological features and clinical issues regarding CBD use in epilepsy, to provide current regulatory background regarding CBD use in Brazil, and to suggest a practical CBD therapeutic guide in Brazil.
METHODS
Non-systematic literature review (up to February 2022) of current concepts of CBD and epilepsy, including the authors' personal experience.
RESULTS
Five pivotal trials have led to CBD approval as an adjunctive treatment for Dravet and Lennox-Gastaut syndromes, and for the tuberous sclerosis complex. Efficacy of CBD in other drug-resistant epilepsies remains not completely understood. CBD adverse event profile and drug interactions are better understood. CBD is well tolerated. In Brazil, CBD is not classified as a medication, but as a product subject to a distinct regulatory legislation. CBD is still not offered by the National Brazilian health system, but can be purchased in authorized pharmacies or imported under prescription and signed informed consent.
CONCLUSION
CBD is a recognized novel treatment for epilepsy. Future well-designed studies and public health strategies are needed to offer widespread access to CBD, and to improve the quality of life of people living with epilepsy in Brazil.
Topics: Anticonvulsants; Brazil; Cannabidiol; Epilepsies, Myoclonic; Epilepsy; Humans; Quality of Life
PubMed: 35976327
DOI: 10.1590/0004-282X-ANP-2022-S137