Efficacy and safety of adjunctive perampanel 4 mg/d for the treatment of focal seizures: A pooled post hoc analysis of four randomized, double‐blind, phase III studies

Abstract

Objective

This post hoc analysis evaluated the efficacy and safety of adjunctive perampanel 4 mg/d received as modal dose, which may have differed from randomized dose, for treatment of focal seizures.

Methods

Data were pooled from four randomized, double‐blind, placebo‐controlled, phase III studies of adjunctive perampanel in patients (aged ≥12 years) with focal seizures, with/without focal to bilateral tonic‐clonic (FBTC) seizures: studies 304 (NCT00699972), 305 (NCT00699582), 306 (NCT00700310), and 335 (NCT01618695). Efficacy assessments included median percentage reductions in seizure frequency per 28 days and seizure‐freedom rates for ...

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Seizures induce obstructive apnea in DBA/2J audiogenic seizure‐prone mice: Lifesaving impact of tracheal implants

Abstract

The mechanism(s) for sudden death in epilepsy (SUDEP) remain(s) unknown, but seizure spread to brainstem areas serving autonomic and respiratory function is critical. In a rat model, we established a mechanism for SUDEP that involves seizure‐induced laryngospasm and obstructive apnea lasting until respiratory arrest. We hypothesized that DBA/2J mice, which display lethal audiogenic seizures, would be protected from death by implanting a tracheal T‐tube as a surrogate airway. In a 2 × 2 design, mice were implanted with either open or closed ...

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Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

Abstract

Owing to the complexity of the pathophysiological mechanisms driving epileptogenesis following traumatic brain injury (TBI), effective preventive treatment approaches are not yet available for posttraumatic epilepsy (PTE). Neuroinflammation appears to play a critical role in the pathogenesis of the acquired epilepsies, including PTE, but despite a large preclinical literature demonstrating the ability of anti‐inflammatory treatments to suppress epileptogenesis and chronic seizures, no anti‐inflammatory treatment approaches have been clinically proven to date. TBI triggers robust inflammatory cascades, suggesting that they may ...

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Phase‐dependent modulation of cortical and thalamic sensory responses during spike‐and‐wave discharges

Abstract

Objective

The neuronal underpinnings of impaired consciousness during absence seizures remain largely unknown. Spike‐and‐wave (SW) activity associated with absences imposes two extremely different states in cortical neurons, which transition from suprathreshold synaptic depolarizations during spike phases to membrane hyperpolarization and electrical silence during wave phases. To investigate whether this rhythmic alternation of neuronal states affects the processing of sensory information during seizures, we examined cortical and thalamic responsiveness to brief sensory stimuli in the different phases of the epileptic cycle.

Methods

Electrocorticographic (ECoG) ...

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Open‐label study to investigate the safety and efficacy of adjunctive perampanel in pediatric patients (4 to <12 years) with inadequately controlled focal seizures or generalized tonic‐clonic seizures

Abstract

Objective

Study 311 (NCT02849626) was a global, multicenter, open‐label, single‐arm study that assessed safety, tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics of once‐daily adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12 years) with focal seizures (FS) (with/without focal to bilateral tonic‐clonic seizures [FBTCS]) or generalized tonic‐clonic seizures (GTCS).

Methods

In the 311 Core Study, a 4‐week Pre‐treatment Period (Screening/Baseline) preceded a 23‐week Treatment Period (11‐week Titration; 12‐week Maintenance) and 4‐week Follow‐up. Endpoints included safety/tolerability (primary endpoint), median percent change in seizure frequency per 28 days ...

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Hyperlipidemia in patients newly treated with anticonvulsants: A population study

Abstract

Objective

To determine the incidence of hyperlipidemia after first anticonvulsant treatment for seizures, using a large US administrative claims database.

Methods

We obtained data from the MarketScan Commercial and Medicare databases for 2005‐2009 for all adult patients newly treated with an anticonvulsant for seizures who had no previous history of hyperlipidemia or treatment with a lipid‐lowering agent. We divided the population based upon whether they were treated with an enzyme‐inducing anticonvulsant (phenytoin, carbamazepine, phenobarbital, primidone) or a noninducing anticonvulsant (all others). The primary ...

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Phenotypic spectrum and genetics of SCN2A‐related disorders, treatment options, and outcomes in epilepsy and beyond

Abstract

Pathogenic variants in the SCN2A gene are associated with a variety of neurodevelopmental phenotypes, defined in recent years through multicenter collaboration. Phenotypes include benign (self‐limited) neonatal and infantile epilepsy and more severe developmental and epileptic encephalopathies also presenting in early infancy. There is increasing evidence that an important phenotype linked to the gene is autism and intellectual disability without epilepsy or with rare seizures in later childhood. Other associations of SCN2A include the movement disorders chorea and episodic ataxia. It ...

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Dravet syndrome as part of the clinical and genetic spectrum of sodium channel epilepsies and encephalopathies

Abstract

Dravet syndrome is the most studied form of genetic epilepsy. It has now been clarified that the clinical spectrum of the syndrome does not have firmly established boundaries. The core phenotype is characterized by intractable, mainly clonic, seizures precipitated by increased body temperature with onset in the first year of life and subsequent appearance of multiple seizures types still precipitated by, but not confined to, hyperthermia. Cognitive impairment is invariably present when the full syndrome is manifested. This complex of ...

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SCN1A‐related phenotypes: Epilepsy and beyond

Abstract

SCN1A, encoding the alpha 1 subunit of the sodium channel, is associated with several epilepsy syndromes and a range of other diseases. SCN1A represents the archetypal channelopathy associated with a wide phenotypic spectrum of epilepsies ranging from genetic epilepsy with febrile seizures plus (GEFS+), to developmental and epileptic encephalopathies (DEEs). SCN1A disorders also result in other diseases such as hemiplegic migraine and autism spectrum disorder (ASD). Dravet syndrome (DS) is the prototypic DEE with an early onset of febrile status ...

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SCN2A channelopathies: Mechanisms and models

Summary

Variants in the SCN2A gene, encoding the voltage‐gated sodium channel NaV1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self‐limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype‐phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain‐of‐function variants. Here, we sum up the functional mechanisms underlying ...

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