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Epileptic Disorders : International... Apr 2022Although epilepsy as a comorbidity in neurodegenerative disorders is increasingly recognized, its incidence is still underestimated and the features of epilepsy in the... (Review)
Review
Although epilepsy as a comorbidity in neurodegenerative disorders is increasingly recognized, its incidence is still underestimated and the features of epilepsy in the different neurodegenerative conditions are still poorly defined. Improved health care, resulting in increased longevity, will unavoidably lead to an increment of epilepsy cases in the elderly. Thus, it is conceivable to expect that neurologists will have to deal with these comorbid conditions to a growing extent in the future. In this seminar, we provide an updated overview of the clinical features, pathophysiological mechanisms and diagnostic and treatment approaches of epilepsy in the most common neurodegenerative disorders (such as Alzheimer disease and other types of dementia, Parkinson disease, Down syndrome, prion diseases, and progressive myoclonus epilepsies), aiming to provide a tool that can help epileptologists and neurologists in the diagnosis and management of this increasingly reported comorbidity.
Topics: Aged; Down Syndrome; Electroencephalography; Epilepsies, Myoclonic; Epilepsy; Humans; Neurodegenerative Diseases
PubMed: 35596580
DOI: 10.1684/epd.2021.1406 -
Current Opinion in Neurology Apr 2023Epilepsy affects 70 million people worldwide and is a significant cause of morbidity and early mortality. The mainstay of therapy is oral medications. Epilepsy drug... (Review)
Review
PURPOSE OF REVIEW
Epilepsy affects 70 million people worldwide and is a significant cause of morbidity and early mortality. The mainstay of therapy is oral medications. Epilepsy drug development is escalating, driven by continued drug resistance in up to a third of epilepsy patients. Treatment development now focuses on discovery of novel mechanisms of action and syndrome-specific therapies.
RECENT FINDINGS
Difficult-to-treat epilepsy related to conditions including tuberous sclerosis complex (TSC), Lennox Gastaut syndrome (LGS) and Dravet syndrome (DS) have been the target of recent developments. Disease-modifying therapy for epilepsy related to TSC with vigabatrin at onset of first electroencephalographic epileptiform changes, rather than after first clinical seizure, has demonstrated strongly positive seizure and developmental outcomes. Fenfluramine, approved for DS and, more recently, LGS, has robust data supporting efficacy, safety/tolerability, as well as mortality, quality of life and cognitive function. Rescue therapy has expanded to include better tolerated benzodiazepines in the form of nasal midazolam and valium. Cenobamate, a first-in-class inactivator of the persistent voltage-gated sodium channel and approved for adult partial onset epilepsy, has exceptional efficacy and tolerability and will be expanded to children and to generalized onset epilepsy in adults.
SUMMARY
The repertoire of available and developmental therapies for epilepsy is rapidly expanding, and now includes disease-modifying vigabatrin in TSC and agents with extraordinary efficacy, fenfluramine and cenobamate.
Topics: Child; Adult; Humans; Anticonvulsants; Vigabatrin; Quality of Life; Epilepsy; Lennox Gastaut Syndrome; Seizures; Epilepsies, Myoclonic; Epilepsies, Partial; Fenfluramine
PubMed: 36762638
DOI: 10.1097/WCO.0000000000001144 -
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 -
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 -
Current Opinion in Neurology Apr 2021This review will illustrate the electroclinical description of Dravet syndrome, highlighting the difficulty to understand the correlation between the SCN1A mutation and... (Review)
Review
PURPOSE OF REVIEW
This review will illustrate the electroclinical description of Dravet syndrome, highlighting the difficulty to understand the correlation between the SCN1A mutation and clinical characteristics, including the frequent comorbidities. Therefore, the efficacy of the new treatment options, which now become available, should not only focus on seizure frequency reduction but also on the long-term effects on these comorbidities, such as intellectual disability, motor and sleep problems.
RECENT FINDINGS
Comprehensive guidelines for a more standardized treatment in children with Dravet syndrome have been published. First-line and second-line treatments actually include only a few antiseizure medications, such as valproate, clobazam, stiripentol, topiramate and bromide. Cannabidiol and fenfluramine were shown to be very effective drugs and will become standard second-line drugs in Dravet syndrome. There are preliminary data showing that both drugs also have a positive effect on quality of life and on cognitive functioning. Genetic treatments in Dravet syndrome most likely will dramatically change the natural course of this refractory epilepsy syndrome.
SUMMARY
A better understanding of the full clinical picture is necessary to understand the potential value of new treatment options in Dravet syndrome. Treatment nowadays with the newer drugs becomes much more standardized and effective, and this will have a positive effect on long-term overall outcome.
Topics: Anticonvulsants; Child; Epilepsies, Myoclonic; Humans; Quality of Life; Seizures; Spasms, Infantile
PubMed: 33395108
DOI: 10.1097/WCO.0000000000000902 -
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 -
European Journal of Paediatric... Jan 2022The aim of this review is to propose the updated diagnostic criteria of epilepsy with myoclonic-atonic seizures (EMAS), which is a recent subject of genetic studies.... (Review)
Review
The aim of this review is to propose the updated diagnostic criteria of epilepsy with myoclonic-atonic seizures (EMAS), which is a recent subject of genetic studies. Although EMAS has been well known as Doose syndrome, it is often difficult to diagnose due to a lack of consensus regarding some of the inclusion criteria. Along with progress in molecular genetic study on the syndrome, it becomes important to recruit electroclinical homogeneous EMAS patients, hence the validity of the clinical criteria should be verified based on recent clinical researches. At present, the most updated ILAE diagnostic manual of EMAS includes: (1) normal development and cognition before the onset of epilepsy; (2) onset of epilepsy between 6 months and 6 years of age (peak: 2-4 years); (3) myoclonic-atonic seizures (MAS) are mandatory (4) presence of generalized spike-wave discharges at 2-3 Hz without persistent focal spike discharges; and (5) exclusion of other myoclonic epilepsy syndromes. In the criteria, we should emphasize that the age at onset of MAS is between 2-5 years in (2), presence of myoclonic-atonic, atonic or myoclonic-flexor seizures (MASs) causing drop attacks associated with generalized spike-wave discharges is mandatory in (3), and epileptic spasms causing drop attacks must be excluded in (5). In the modified criteria, I propose that EMAS is redesignated as genetic generalized epilepsy with MASs, consistent with the familial genetic study conducted by Doose and the recent identification of candidate genes. It should also be noted that EMASs evolves to transient or long-lasting epileptic encephalopathy.
Topics: Child; Child, Preschool; Electroencephalography; Epilepsies, Myoclonic; Epilepsy; Epilepsy, Generalized; Humans; Infant; Seizures
PubMed: 34883415
DOI: 10.1016/j.ejpn.2021.11.009 -
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 -
Epilepsia Jan 2021Epilepsy with myoclonic-atonic seizures (EMAS) is a rare childhood onset epileptic encephalopathy. There is no clear consensus for recommended treatments, and...
OBJECTIVE
Epilepsy with myoclonic-atonic seizures (EMAS) is a rare childhood onset epileptic encephalopathy. There is no clear consensus for recommended treatments, and pharmacoresistance is common. To better assess the clinical phenotype, most effective treatment, and determinants of cognitive and seizure outcomes, three major pediatric epilepsy centers combined data, creating the largest cohort of patients with EMAS ever studied to date.
METHODS
Authors performed a retrospective chart review of patients with EMAS who received care at the authors' institutions.
RESULTS
A total of 166 children were identified. Global developmental delay (>1 domain) was present in 2% of children at onset and 49% during the course of the disease. Afebrile seizures occurred after the age of 2 years in 88%, generalized tonic-clonic seizures in 60%, and drop attack or myoclonic seizures in 30%. At onset, electroencephalography (EEG) found 28% normal, background slowing in 20%, and epileptiform discharges or seizures in 69%. Subsequent EEG found slowing in 62% and discharges or seizures in 90%. Response (>50% seizure reduction) to the first three antiseizure drugs (ASDs) was 26% (levetiracetam, 17%; valproic acid, 31%; other ASDs combined, 26%). Diet therapy was used as a second or third therapy in 19% and ultimately used in 57%; response was 79%, significantly greater than the first three ASDs (P = .005, χ ). Seizure freedom occurred in 57% and was less likely in the case of persistent global developmental delays (P < .001), seizure recorded on subsequent EEGs (P = .027), and failure to respond to diet therapy (P = .005). Development was normal in 47%, and 12% had delays in one domain, which was less likely in the case of global developmental delay after epilepsy onset (P < .001) and failure to achieve seizure freedom (P < .001).
SIGNIFICANCE
This large cohort of children with EMAS clarifies areas of variability in practice. Diet therapy is by far the most effective treatment; failure to respond was associated with failure to attain seizure freedom. This therapy should be used early in the treatment in EMAS. This study also identified a bidirectional link between cognitive and seizure outcomes.
Topics: Anticonvulsants; Child; Child, Preschool; Cohort Studies; Developmental Disabilities; Diet, Ketogenic; Electroencephalography; Epilepsies, Myoclonic; Female; Humans; Infant; Levetiracetam; Male; Retrospective Studies; Treatment Outcome; Valproic Acid
PubMed: 33190223
DOI: 10.1111/epi.16752 -
Seminars in Neurology Apr 2020Epilepsy is a common disorder in children and adults that causes significant morbidity and affects many aspects of a patient's lives. Two-thirds of patients with... (Review)
Review
Epilepsy is a common disorder in children and adults that causes significant morbidity and affects many aspects of a patient's lives. Two-thirds of patients with epilepsy are controlled with established antiseizure medications, leaving a significant number of patients searching for other options. The purpose of this review is to provide an overview of recent advancements in the management of treatment-resistant epilepsy in pediatric patients. Recent publications have shown the efficacy of new pharmaceutical options such as fenfluramine and cannabidiol, some of which have been tested specifically in patients with childhood-onset epilepsy syndromes such as Dravet's syndrome and Lennox-Gastaut's syndrome. Furthermore, recent approval by the U.S. Food and Drug Administration of stiripentol has made available a previously difficult-to-obtain option for patients with Dravet's syndrome. Finally, implanted responsive neurostimulation devices for direct cortical stimulation and deep brain stimulation have shown efficacy in adult patients and may represent a thrilling new horizon for pediatric patients.
Topics: Anticonvulsants; Child; Drug Resistant Epilepsy; Electric Stimulation Therapy; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome
PubMed: 32185791
DOI: 10.1055/s-0040-1702941