Epilepsia
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Approximately one-third of people living with epilepsy are unable to obtain seizure control with the currently marketed antiseizure medications (ASMs), creating a need for novel therapeutics with new mechanisms of action. Cenobamate (CBM) is a tetrazole alkyl carbamate derivative that received US Food and Drug Administration approval in 2019 for the treatment of adult partial onset (focal) seizures. Although CBM displayed impressive seizure reduction in clinical trials across all seizure types, including focal aware motor, focal impaired awareness, and focal to bilateral tonic-clonic seizures, the precise mechanism(s) through which CBM exerts its broad-spectrum antiseizure effects is not known. ⋯ CBM's preclinical performance in tests, including the mouse 6-Hz model of treatment-resistant seizures, the chemoconvulsant seizure models of generalized epilepsy, and the rat hippocampal kindling model of focal epilepsy, was distinct from other voltage-gated sodium channel blockers and GABAA modulators. This distinction, in light of its proposed mechanism(s) of action, provides insight into the impressive clinical efficacy of CBM in the adult patient with focal onset epilepsy. The results of this comparative reverse translational analysis suggest that CBM is a mechanistically distinct ASM that offers an important advancement in drug development for treatment of therapy-resistant epilepsy.
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The rapid spread of the SARS-CoV-2 pandemic poses particular challenges to the management of persons with chronic disease. Reports of a possible neuroinvasiveness of SARS-CoV-2 as well as pathophysiological mechanisms and indirect consequences in severe COVID-19 cases raise the question of whether the infection can be associated with an increased risk of seizure recurrence or the development of new onset and acute symptomatic seizures. Although the literature does not provide relevant evidence for seizure worsening in persons with epilepsy during the course of a SARS-CoV-2 infection, there are theoretical risks, for example, seizures triggered by fever. ⋯ This is further confirmed by reports of occasional seizures in COVID-19 patients. Although the low number of reports so far suggests that the risk may be relatively low, the reports indicate that an early neurological manifestation with seizures should not be ruled out. In the context of these cases, we discuss possible pathophysiological mechanisms that may trigger ictogenesis in patients with SARS-CoV-2 infection.
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Four pivotal randomized placebo-controlled trials have demonstrated that adjunctive therapy with cannabidiol (CBD) improves seizure control in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). Between 47% and 68% of patients allocated to CBD treatment in these trials were receiving clobazam (CLB), which shows complex interactions with CBD resulting, in particular, in a 3.4- to 5-fold increase in plasma concentration of the active metabolite norclobazam. This raises concern as to the role played by these interactions in determining the reduction in seizure frequency in CBD-treated patients, and the question of whether CBD per se has clinically evident antiseizure effects. ⋯ Stronger evidence for an antiseizure effect of CBD independent of an interaction with CLB emerges from meta-analyses of seizure outcomes in the pooled population of LGS and DS patients not receiving CLB comedication. Although these results need to be interpreted taking into account methodological limitations, they provide the best clinical evidence to date that CBD exerts therapeutic effects in patients with epilepsy that are independent of its interaction with CLB. Greater antiseizure effects, and a greater burden of adverse effects, are observed when CBD is combined with CLB.
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To evaluate the potential impact of concomitant clobazam (CLB) use on the efficacy of cannabidiol (CBD) treatment in patients with Dravet syndrome and Lennox-Gastaut syndrome using meta-analytical techniques. ⋯ CBD was associated with a higher rate of seizure response in comparison to placebo when added to the existing antiepileptic regimen both in patients taking and in those not taking concomitant CLB. The lack of randomization for CLB status and the limited sample size need to be considered in the interpretation of the findings.
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To identify and appraise published evidence of the measurement properties for epilepsy-specific patient-reported outcome measures (PROMs) of children's health-related quality of life (HRQoL). ⋯ This review identified two leading candidate epilepsy-specific PROMs for measuring health-related quality of life in children. Establishing evidence of the responsiveness of PROMs is a priority to help the interpretation of meaningful change scores.