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Seizure Mar 2021Juvenile myoclonic epilepsy (JME), like other forms of idiopathic generalized epilepsy, shows a marked female predominance. However, few studies have specifically... (Review)
Review
PURPOSE
Juvenile myoclonic epilepsy (JME), like other forms of idiopathic generalized epilepsy, shows a marked female predominance. However, few studies have specifically addressed the role of sex in its long-term prognosis. We performed a systematic review of the literature relevant to JME prognosis, focusing on sex-based differences in prognostic factors and outcome.
METHODS
A comprehensive literature search of the PubMed and Scopus databases was performed, considering all articles up to April 2020 in which long-term prognosis in JME had been explored and sex differences in outcome or prognostic factors were specified.
RESULTS
We included 25 articles published between 1984 and 2020. Sex differences in epilepsy outcome were explored by 21 of the 25 studies, but only three reported different outcomes in male vs female patients. All three found female sex to be associated with a later response to antiseizure medications, worse seizure control, and a higher risk of relapse in their entire study samples, which included JME patients. Eight studies found sex-based differences in possible predictors of long-term outcome: prolonged epileptiform EEG runs and the presence of eye closure sensitivity, both more frequent in women, were factors possibly linked to a poorer prognosis, as were praxis induction and generalized EEG asymmetric changes, which instead were more common in men. Valproate use, more frequent in men, was associated with a better outcome.
CONCLUSION
Most studies do not highlight sex differences in JME prognosis. However, some sex specificities do emerge, especially with regard to particular reflex traits and EEG abnormalities. Finally, sex may condition therapeutic choices, and thus have a possible impact on long-term outcome.
Topics: Electroencephalography; Female; Humans; Male; Myoclonic Epilepsy, Juvenile; Prognosis; Seizures; Sex Characteristics
PubMed: 33524768
DOI: 10.1016/j.seizure.2021.01.005 -
Genes Sep 2023Biallelic variants in the Golgi SNAP receptor complex member 2 gene () have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical...
Biallelic variants in the Golgi SNAP receptor complex member 2 gene () have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a -related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age of 8 years with partial response to clonazepam. The second patient, a female homozygous for the founder variant p.Gly144Trp, showed only mild fine motor developmental delay and generalized tonic-clonic seizures triggered by infections during adolescence, with seizure remission on levetiracetam. The associated movement disorder progressed atypically slowly during adolescence compared to its usual speed, from initial intention tremor and myoclonus to ataxia, hyporeflexia, dysmetria, and dystonia. These findings expand the genotype-phenotype spectrum of -related disorders and suggest that should be included in the consideration of monogenetic causes of dystonia, global developmental delay, and seizures.
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Male; Ataxia; Dystonia; Dystonic Disorders; Mutation; Myoclonic Epilepsies, Progressive; Myoclonus; Qb-SNARE Proteins; Seizures
PubMed: 37895210
DOI: 10.3390/genes14101860 -
Seizure Mar 2023
Topics: Humans; Epilepsy; Epilepsies, Myoclonic; Seizures; Electroencephalography; Epilepsy, Absence
PubMed: 36893512
DOI: 10.1016/j.seizure.2023.02.017 -
European Journal of Neurology Jun 2019Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome for which treatment response is generally assumed to be good. We aimed to determine the prevalence and... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND PURPOSE
Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome for which treatment response is generally assumed to be good. We aimed to determine the prevalence and prognostic risk factors for refractoriness of JME.
METHODS
We systematically searched PubMed and EMBASE and included 43 eligible studies, reporting seizure outcome after antiepileptic drug (AED) treatment in JME cohorts. We defined refractory JME as persistence of any seizure despite AED treatment and performed a random-effects meta-analysis to assess the prevalence of refractory JME and of seizure recurrence after AED withdrawal in individuals with well-controlled seizures. Studies reporting potential prognostic risk factors in relation to seizure outcome were included for subsequent meta-analysis of risk factors for refractoriness.
RESULTS
Overall, 35% (95% confidence interval, 29-41%) of individuals (n = 3311) were refractory. There was marked heterogeneity between studies. Seizures recurred in 78% (95% confidence interval, 52-94%) of individuals who attempted to withdraw from treatment after a period of seizure freedom (n = 246). Seizure outcome by publication year suggested that prognosis did not improve over time. Meta-analysis suggested six variables as prognostic factors for refractoriness, i.e. having three seizure types, absence seizures, psychiatric comorbidities, earlier age at seizure onset, history of childhood absence epilepsy and praxis-induced seizures.
CONCLUSION
One-third of people with JME were refractory, which is a higher prevalence than expected. Risk factors were identified and can be used to guide treatment and counselling of people with JME.
Topics: Anticonvulsants; Humans; Myoclonic Epilepsy, Juvenile; Prevalence; Prognosis; Risk Factors
PubMed: 30223294
DOI: 10.1111/ene.13811 -
Seizure May 2020
Topics: Humans; Myoclonic Epilepsies, Progressive; Unverricht-Lundborg Syndrome
PubMed: 31740381
DOI: 10.1016/j.seizure.2019.09.008 -
Epilepsy & Behavior : E&B Jul 2022Dravet Syndrome (DS) is a severe, developmental epileptic encephalopathy (DEE) that begins in infancy and is characterized by pharmaco-resistant epilepsy and... (Review)
Review
INTRODUCTION
Dravet Syndrome (DS) is a severe, developmental epileptic encephalopathy (DEE) that begins in infancy and is characterized by pharmaco-resistant epilepsy and neurodevelopmental delay. Despite available antiseizure medications (ASMs), there is a need for new therapeutic options with greater efficacy in reducing seizure frequency and with adequate safety and tolerability profiles. Fenfluramine is a new ASM for the treatment of seizures associated with DS as add-on therapy to other ASMs for patients aged 2 years and older. Fenfluramine decreases seizure frequency, prolongs periods of seizure freedom potentially helping to reduce risk of Sudden Unexpected Death in Epilepsy (SUDEP) and improves patient cognitive abilities positively impacting on patients' Quality of Life (QoL). Reflective Multi-Criteria Decision Analysis (MCDA) methodology allows to determine what represents value in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner from the perspective of relevant stakeholders. The aim of this study was to determine the relative value contribution of fenfluramine for the treatment of DS in Spain using MCDA.
METHOD
A literature review was performed to populate an adapted a MCDA framework for orphan-drug evaluation in Spain. A panel of ten Spanish experts, including neurologists, hospital pharmacists, patient representatives and decision-makers, scored four comparative evidence matrices. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology.
RESULTS
Dravet syndrome is considered a severe, rare disease with significant unmet needs. Fenfluramine is perceived to have a higher efficacy profile than all available alternatives, with a better safety profile than stiripentol and topiramate and to provide improved QoL versus studied alternatives. Fenfluramine results in lower other medical costs in comparison with stiripentol and clobazam. Participants perceived that fenfluramine could lead to indirect costs savings compared to available alternatives due to its efficacy in controlling seizures. Overall, fenfluramine's therapeutic impact on patients with DS is considered high and supported by high-quality evidence.
CONCLUSIONS
Based on reflective MCDA, fenfluramine is considered to add greater benefit in terms of efficacy, safety and QoL when compared with available ASMs.
Topics: Anticonvulsants; Decision Support Techniques; Epilepsies, Myoclonic; Epileptic Syndromes; Fenfluramine; Humans; Quality of Life; Seizures; Spain; Spasms, Infantile
PubMed: 35588562
DOI: 10.1016/j.yebeh.2022.108711 -
Epileptic Disorders : International... Sep 2016The history of the progressive myoclonus epilepsies (PMEs) spans more than a century. However, the recent history of PMEs begins with a consensus statement published in... (Review)
Review
The history of the progressive myoclonus epilepsies (PMEs) spans more than a century. However, the recent history of PMEs begins with a consensus statement published in the wake of the Marseille PME workshop in 1989 (Marseille Consensus Group, 1990). This consensus helped define the various types of PME known at the time and set the agenda for a new era of genetic research which soon lead to the discovery of many PME genes. Prior to the Marseille meeting, and before the molecular era, there had been much confusion and controversy. Because investigators had but limited and biased experience with these rare disorders due to the uneven, skewed distribution of PMEs around the world, opinions and nosologies were based on local expertise which did not match well with the experiences of other researchers and clinicians. The three major areas of focus included: (1) the nature and limits of the concept of PME in varying scopes, which was greatly debated; (2) the description of discrete clinical entities by clinicians; and (3) the description of markers (pathological, biological, neurophysiological, etc.) which could lead to a precise diagnosis of a given PME type, with, in the best cases, a reliable correlation with clinical findings. In this article, we shall also examine the breakthroughs achieved in the wake of the 1989 Marseille meeting and recent history in the field, following the identification of several PME genes. As in other domains, the molecular and genetic approach has challenged some established concepts and has led to the description of new PME types. However, as may already be noted, this approach has also confirmed the existence of the major, established types of PME, which can now be considered as true diseases.
Topics: History, 19th Century; History, 20th Century; History, 21st Century; Humans; Myoclonic Epilepsies, Progressive
PubMed: 27621064
DOI: 10.1684/epd.2016.0834 -
International Journal of Molecular... Dec 2023Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy, is a rare and drug-resistant form of developmental and epileptic encephalopathies, which is... (Review)
Review
Dravet syndrome (DS), also known as severe myoclonic epilepsy of infancy, is a rare and drug-resistant form of developmental and epileptic encephalopathies, which is both debilitating and challenging to manage, typically arising during the first year of life, with seizures often triggered by fever, infections, or vaccinations. It is characterized by frequent and prolonged seizures, developmental delays, and various other neurological and behavioral impairments. Most cases result from pathogenic mutations in the sodium voltage-gated channel alpha subunit 1 () gene, which encodes a critical voltage-gated sodium channel subunit involved in neuronal excitability. Precision medicine offers significant potential for improving DS diagnosis and treatment. Early genetic testing enables timely and accurate diagnosis. Advances in our understanding of DS's underlying genetic mechanisms and neurobiology have enabled the development of targeted therapies, such as gene therapy, offering more effective and less invasive treatment options for patients with DS. Targeted and gene therapies provide hope for more effective and personalized treatments. However, research into novel approaches remains in its early stages, and their clinical application remains to be seen. This review addresses the current understanding of clinical DS features, genetic involvement in DS development, and outcomes of novel DS therapies.
Topics: Humans; Precision Medicine; Epilepsy; Epilepsies, Myoclonic; Epilepsy, Generalized; Seizures
PubMed: 38203200
DOI: 10.3390/ijms25010031 -
Epilepsia May 2023Loss-of-function variants in SCN1A cause Dravet syndrome, the most common genetic developmental and epileptic encephalopathy (DEE). However, emerging evidence suggests...
OBJECTIVE
Loss-of-function variants in SCN1A cause Dravet syndrome, the most common genetic developmental and epileptic encephalopathy (DEE). However, emerging evidence suggests separate entities of SCN1A-related disorders due to gain-of-function variants. Here, we aim to refine the clinical, genetic, and functional electrophysiological features of a recurrent p.R1636Q gain-of-function variant, identified in four individuals at a single center.
METHODS
Individuals carrying the recurrent SCN1A p.R1636Q variant were identified through diagnostic testing. Whole cell voltage-clamp electrophysiological recording in HEK-293 T cells was performed to compare the properties of sodium channels containing wild-type Na 1.1 or Na 1.1-R1636Q along with both Na β1 and Na β2 subunits, including response to oxcarbazepine. To delineate differences from other SCN1A-related epilepsies, we analyzed electronic medical records.
RESULTS
All four individuals had an early onset DEE characterized by focal tonic seizures and additional seizure types starting in the first few weeks of life. Electrophysiological analysis showed a mixed gain-of-function effect with normal current density, a leftward (hyperpolarized) shift of steady-state inactivation, and slower inactivation kinetics leading to a prominent late sodium current. The observed functional changes closely paralleled effects of pathogenic variants in SCN3A and SCN8A at corresponding positions. Both wild type and variant exhibited sensitivity to block by oxcarbazepine, partially correcting electrophysiological abnormalities of the SCN1A p.R1636Q variant. Clinically, a single individual responded to treatment with oxcarbazepine. Across 51 individuals with SCN1A-related epilepsies, those with the recurrent p.R1636Q variants had the earliest ages at onset.
SIGNIFICANCE
The recurrent SCN1A p.R1636Q variant causes a clinical entity with a wider clinical spectrum than previously reported, characterized by neonatal onset epilepsy and absence of prominent movement disorder. Functional consequences of this variant lead to mixed loss and gain of function that is partially corrected by oxcarbazepine. The recurrent p.R1636Q variant represents one of the most common causes of early onset SCN1A-related epilepsies with separate treatment and prognosis implications.
Topics: Humans; Infant, Newborn; Epilepsies, Myoclonic; Epilepsy; Gain of Function Mutation; HEK293 Cells; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Oxcarbazepine
PubMed: 36287100
DOI: 10.1111/epi.17444 -
Epilepsy & Behavior : E&B May 2024A pathogenic variant in SCN1A can result in a spectrum of phenotypes, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS + )...
BACKGROUND
A pathogenic variant in SCN1A can result in a spectrum of phenotypes, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS + ) syndrome. Dravet syndrome (DS) is associated with refractory seizures, developmental delay, intellectual disability (ID), motor impairment, and challenging behavior(1,2). GEFS + is a less severe phenotype in which cognition is often normal and seizures are less severe. Challenging behavior largely affects quality of life of patients and their families. This study describes the profile and course of the behavioral phenotype in patients with SCN1A-related epilepsy syndromes, explores correlations between behavioral difficulties and potential risk factors.
METHODS
Data were collected from questionnaires, medical records, and semi-structured interviews. Behavior difficulties were measured using the Adult/Child Behavior Checklist (C/ABCL) and Adult self-report (ASR). Other questionnaires included the Pediatric Quality of Life Inventory (PedsQL), the Functional Mobility Scale (FMS) and the Sleep Behavior Questionnaire by Simonds & Parraga (SQ-SP). To determine differences in behavioral difficulties longitudinally, paired T-tests were used. Pearson correlation and Spearman rank test were used in correlation analyses and multivariable regression analyses were employed to identify potential risk factors.
RESULTS
A cohort of 147 participants, including 107 participants with DS and 40 with genetic epilepsy with febrile seizures plus (GEFS + ), was evaluated. Forty-six DS participants (43.0 %) and three GEFS + participants (7.5 %) showed behavioral problems in the clinical range on the A/CBCL total problems scale. The behavioral profile in DS exists out of withdrawn behavior, aggressive behavior, and attention problems. In DS patients, sleep disturbances (β = 1.15, p < 0.001) and a lower age (β = -0.21, p = 0.001) were significantly associated with behavioral difficulties. Between 2015 and 2022, behavioral difficulties significantly decreased with age (t = -2.24, CI = -6.10 - -0.15, p = 0.04) in DS participants aging from adolescence into adulthood. A decrease in intellectual functioning (β = 3.37, p = 0.02) and using less antiseizure medications in 2022 than in 2015, (β = -1.96, p = 0.04), were identified as possible risk factors for developing (more) behavioral difficulties.
CONCLUSIONS
These findings suggest that, in addition to epilepsy, behavioral difficulties are a core feature of the DS phenotype. Behavioral problems require personalized management and treatment strategies. Further research is needed to identify effective interventions.
Topics: Humans; Male; Female; NAV1.1 Voltage-Gated Sodium Channel; Adult; Child; Adolescent; Young Adult; Child, Preschool; Epilepsies, Myoclonic; Quality of Life; Epileptic Syndromes; Neurodevelopmental Disorders; Seizures, Febrile; Problem Behavior; Epilepsy
PubMed: 38513571
DOI: 10.1016/j.yebeh.2024.109726