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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 -
Pediatric Neurology Jun 2020Dravet syndrome is a debilitating epileptic encephalopathy of childhood with few treatment options available in the United States before 2018. In the modern era, new... (Review)
Review
Dravet syndrome is a debilitating epileptic encephalopathy of childhood with few treatment options available in the United States before 2018. In the modern era, new genetic testing options will allow diagnosis closer to disease onset. Three new medicines-stiripentol, cannabidiol, and fenfluramine-have documented efficacy and safety as adjunctive therapies for treating pharmacoresistant Dravet syndrome. Early diagnosis resulting in earlier treatment with these and other medications may improve prognosis of long-term outcomes, including less severity of cognitive, motor, and behavioral impairments. New rescue medication formulations can now manage acute seizures and help prevent status epilepticus via intranasal, buccal, and intramuscular routes as opposed to rectal administration. Preventing status epilepticus and generalized tonic-clonic seizures could potentially lower the risk of sudden unexpected death in epilepsy. With this changing landscape in diagnostic and treatment options comes questions and controversies for the practicing clinician, especially as diagnostic techniques outpace clinical treatment strategies. Critical decision points include when to start treatment, what pharmacotherapy combinations to try first, which rescue medication to recommend, and how to advise parents on controversial topics (e.g., immunizations). Given that most patients require polypharmacy, clinicians must be cognizant of drug-drug interactions between new medicines, existing anti-epileptic drugs, and other medications to manage comorbidities and must have an understanding of available therapeutic drug monitoring strategies and pharmacokinetic parameters. This review places new diagnostic, treatment and acute care options into the modern era and provides an overview of the challenges and opportunities facing the pediatric epileptologist in this rapidly changing landscape.
Topics: Anticonvulsants; Cannabidiol; Child; Dioxolanes; Epilepsies, Myoclonic; Fenfluramine; Genetic Testing; Humans
PubMed: 32165031
DOI: 10.1016/j.pediatrneurol.2020.01.005 -
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 -
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 -
Neurology Mar 2022Pathogenic variants in the neuronal sodium channel α1 subunit gene () are the most frequent monogenic cause of epilepsy. Phenotypes comprise a wide clinical spectrum,...
BACKGROUND AND OBJECTIVES
Pathogenic variants in the neuronal sodium channel α1 subunit gene () are the most frequent monogenic cause of epilepsy. Phenotypes comprise a wide clinical spectrum, including severe childhood epilepsy; Dravet syndrome, characterized by drug-resistant seizures, intellectual disability, and high mortality; and the milder genetic epilepsy with febrile seizures plus (GEFS+), characterized by normal cognition. Early recognition of a child's risk for developing Dravet syndrome vs GEFS+ is key for implementing disease-modifying therapies when available before cognitive impairment emerges. Our objective was to develop and validate a prediction model using clinical and genetic biomarkers for early diagnosis of -related epilepsies.
METHODS
We performed a retrospective multicenter cohort study comprising data from patients with -positive Dravet syndrome and patients with GEFS+ consecutively referred for genetic testing (March 2001-June 2020) including age at seizure onset and a newly developed genetic score. A training cohort was used to develop multiple prediction models that were validated using 2 independent blinded cohorts. Primary outcome was the discriminative accuracy of the model predicting Dravet syndrome vs other GEFS+ phenotypes.
RESULTS
A total of 1,018 participants were included. The frequency of Dravet syndrome was 616/743 (83%) in the training cohort, 147/203 (72%) in validation cohort 1, and 60/72 (83%) in validation cohort 2. A high genetic score (133.4 [SD 78.5] vs 52.0 [SD 57.5]; < 0.001) and young age at onset (6.0 [SD 3.0] vs 14.8 [SD 11.8] months; < 0.001) were each associated with Dravet syndrome vs GEFS+. A combined genetic score and seizure onset model separated Dravet syndrome from GEFS+ more effectively (area under the curve [AUC] 0.89 [95% CI 0.86-0.92]) and outperformed all other models (AUC 0.79-0.85; < 0.001). Model performance was replicated in both validation cohorts 1 (AUC 0.94 [95% CI 0.91-0.97]) and 2 (AUC 0.92 [95% CI 0.82-1.00]).
DISCUSSION
The prediction model allows objective estimation at disease onset whether a child will develop Dravet syndrome vs GEFS+, assisting clinicians with prognostic counseling and decisions on early institution of precision therapies (http://scn1a-prediction-model.broadinstitute.org/).
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that a combined genetic score and seizure onset model distinguishes Dravet syndrome from other GEFS+ phenotypes.
Topics: Child; Cohort Studies; Early Diagnosis; Epilepsies, Myoclonic; Epilepsy; Humans; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Retrospective Studies
PubMed: 35074891
DOI: 10.1212/WNL.0000000000200028 -
Epilepsia Jul 2021CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by...
CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.
Topics: Adolescent; Adult; Age of Onset; Child; Child, Preschool; Developmental Disabilities; Epilepsies, Myoclonic; Epilepsy, Generalized; Exome; Female; Genetic Variation; Humans; Infant; Intellectual Disability; Male; Mutation; Phenotype; Status Epilepticus; Young Adult
PubMed: 34041744
DOI: 10.1111/epi.16931 -
Epilepsy Research Dec 2022Dravet syndrome (DS) is a form of genetic refractory epilepsy. More than 80 % of DS patients carry pathogenic SCN1A mutations, and this percentage is actually higher... (Review)
Review
Dravet syndrome (DS) is a form of genetic refractory epilepsy. More than 80 % of DS patients carry pathogenic SCN1A mutations, and this percentage is actually higher due to false-negative results in gene testing. Potential genotype-phenotype correlations may exist but require further confirmation. "SCN1A mutation-mediated dysfunction of NaV1.1 affects GABAergic inhibitory interneurons" is currently the most accepted pathogenesis. Besides SCN1A, there are other genes associated with DS-like phenotypes, among which GABA-receptor subunit genes have recently received more attention. Most DS patients experience prolonged, hemiclonic or tonic-clonic seizures triggered by fever during the first year of life, followed by the gradual onset of other seizure types, including myoclonic, atypical absence, and focal seizures. Over time, seizures tend to become less frequent and severe but generalized tonic-clonic seizures remain. DS also has many comorbidities, including motor, cognitive, behavior, and sleep impairments, which cause poor quality of life and impact the long-term course. The electroencephalography and neuroimaging of DS lack specificity, but the evolution of electroencephalography may help to identify DS. Current treatments for DS are symptomatic and difficult to control seizures. The combination of valproic acid, clobazam and stiripentol is a commonly used clinical treatment option, fenfluramine and cannabidiol have been used as second- and third-line drugs, respectively. Later therapeutic options include other anti-seizure medications, the ketogenic diet, and vagus nerve stimulation, whereas sodium channel blockers should be avoided in DS. Furthermore, several promising drugs including soticlestat are in development, and genetic therapies are beginning to emerge, representing future treatment directions.
Topics: Humans; NAV1.1 Voltage-Gated Sodium Channel; Quality of Life; Epilepsies, Myoclonic; Piperidines
PubMed: 36368227
DOI: 10.1016/j.eplepsyres.2022.107041 -
Journal of General Internal Medicine Jul 2021Cannabidiol, a non-intoxicating phytocannabinoid, has potential therapeutic effects over a broad range of disorders. Recently, there has been increased interest in CBD,... (Review)
Review
Cannabidiol, a non-intoxicating phytocannabinoid, has potential therapeutic effects over a broad range of disorders. Recently, there has been increased interest in CBD, as several studies showed promising anticonvulsant efficacy with few side effects. In 2018, a CBD-based oral solution, Epidiolex®, was approved by the FDA to treat two severe forms of pediatric epilepsy, Dravet syndrome, and Lennox-Gastaut syndrome. Although only these two syndromes are recognized indications for CBD, it has been consumed in an unregulated fashion for a variety of indications including chronic pain, muscle stiffness, inflammation, anxiety, smoking cessation, and even cancer. While CBD legislation in the USA is confusing due to the differences in state and federal laws, CBD has proliferated in the US market in several forms such as CBD oil or capsules, hemp oil/extract, and also as an ingredient in several dietary supplements, syrups, teas, and creams. With the ever-increasing use of CBD and its widespread availability to the general public, it is important to examine and report on possible drug-drug interactions between CBD and other therapeutic agents as well as addictive substances such as alcohol and tobacco. A detailed literature search for CBD's possible interactions was conducted using online databases. As expected, CBD has been reported to interact with anti-epileptic drugs, antidepressants, opioid analgesics, and THC, but surprisingly, it interacts with several other common medications, e.g. acetaminophen, and substances including alcohol. This review provides a comprehensive list of interacting drugs. The possible mechanisms for these drug-drug interactions are presented in table format. Given the growing popularity of CBD as a medication and the dearth of available information on CBD drug-drug interactions, it is critical to be aware of current drug-drug interactions and it will be important to investigate the impact of CBD upon concomitant medication use in future randomized, controlled trials.
Topics: Anticonvulsants; Cannabidiol; Child; Epilepsies, Myoclonic; Humans; Lennox Gastaut Syndrome; Spasms, Infantile
PubMed: 33515191
DOI: 10.1007/s11606-020-06504-8 -
Epileptic Disorders : International... Dec 2019Benign spasms of infancy (BSI), previously described as benign non-epileptic infantile spasms or benign myoclonus of early infancy, are non-epileptic movements...
Benign spasms of infancy (BSI), previously described as benign non-epileptic infantile spasms or benign myoclonus of early infancy, are non-epileptic movements manifesting during the first year of life and spontaneously resolving in the second year of life. BSI are characterized by spasms typically lasting 1-2 seconds, involving, to varying degrees, the head, neck, trunk, shoulders and upper extremities. Ictal and interictal EEG recordings are normal. BSI are not associated with developmental regression and do not require treatment. Distinction between BSI and infantile epileptic disorders, such as epileptic spasms or myoclonic epilepsy of infancy, can be challenging given the clinical similarities. Moreover, interictal EEGs can be normal in all conditions. Epileptic spasms and myoclonic epilepsy require timely treatment to improve neurodevelopmental outcomes. We describe a six-month-old infant presenting with spasm-like movements. His paroxysms as well as a positive family history for epileptic spasms were in keeping with a likely diagnosis of West syndrome. Surprisingly, ictal video-EEG did not reveal epileptiform activity, and suggested a diagnosis of BSI. We emphasize that ictal video-EEG is the gold standard for classification of infantile paroxysms as epileptic or non-epileptic, thereby avoiding over-treatment for BSI and facilitating timely targeted treatment of infantile epilepsies. [Published with video sequences].
Topics: Diagnosis, Differential; Epilepsies, Myoclonic; Humans; Infant; Male; Spasms, Infantile
PubMed: 31843733
DOI: 10.1684/epd.2019.1116 -
Epilepsia Oct 2022Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare treatment-resistant childhood epilepsies classed as developmental and epileptic encephalopathies. ELEKTRA... (Randomized Controlled Trial)
Randomized Controlled Trial
A phase 2, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox-Gastaut syndrome (ELEKTRA).
OBJECTIVE
Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare treatment-resistant childhood epilepsies classed as developmental and epileptic encephalopathies. ELEKTRA investigated the efficacy and safety of soticlestat (TAK-935) as adjunctive therapy in children with DS or LGS (NCT03650452).
METHODS
ELEKTRA was a phase 2, randomized, double-blind, placebo-controlled study of soticlestat (≤300 mg twice daily, weight-adjusted) in children (aged 2-17 years) with DS, demonstrating three or more convulsive seizures/month, or with LGS, demonstrating four or more drop seizures/month at baseline. The 20-week treatment period comprised an 8-week dose-optimization period and a 12-week maintenance period. Efficacy endpoints included change from baseline in seizure frequency versus placebo. Safety assessments included incidence of treatment-emergent adverse events (TEAEs).
RESULTS
ELEKTRA enrolled 141 participants; 126 (89%) completed the study. The modified intent-to-treat population included 139 participants who received one or more doses of study drug and had one or more efficacy assessments (DS, n = 51; LGS, n = 88). ELEKTRA achieved its primary endpoint: the combined soticlestat-treated population demonstrated a placebo-adjusted median reduction in seizure frequency of 30.21% during the maintenance period (p = .0008, n = 139). During this period, placebo-adjusted median reductions in convulsive and drop seizure frequencies of 50.00% (p = .0002; patients with DS) and 17.08% (p = .1160; patients with LGS), respectively, were observed. TEAE incidences were similar between the soticlestat (80.3%) and placebo (74.3%) groups and were mostly mild or moderate in severity. Serious TEAEs were reported by 15.5% and 18.6% of participants receiving soticlestat and placebo, respectively. TEAEs reported in soticlestat-treated patients with ≥5% difference from placebo were lethargy and constipation. No deaths were reported.
SIGNIFICANCE
Soticlestat treatment resulted in statistically significant, clinically meaningful reductions from baseline in median seizure frequency (combined patient population) and in convulsive seizure frequency (DS cohort). Drop seizure frequency showed a nonstatistically significant numerical reduction in children with LGS. Soticlestat had a safety profile consistent with previous studies.
Topics: Anticonvulsants; Child; Double-Blind Method; Epilepsies, Myoclonic; Epileptic Syndromes; Humans; Lennox Gastaut Syndrome; Piperidines; Pyridines; Seizures; Spasms, Infantile; Treatment Outcome
PubMed: 35841234
DOI: 10.1111/epi.17367