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Despite the approval of ~20 additional antiseizure medications (ASMs) since the 1980s, one‐third of epilepsy patients experience seizures despite therapy. Drug‐resistant epilepsy (DRE) is associated with cognitive and psychiatric comorbidities, socioeconomic impairment, injuries, and a 9.3–13.4 times higher mortality rate than in seizure‐free patients. Improved seizure control can reduce morbidity and mortality. Two new ASMs were launched in the United States in 2020: cenobamate for focal epilepsy in adults and fenfluramine for Dravet syndrome (DS). They offer markedly improved efficacy. Cenobamate achieved 21% seizure freedom with the highest dose and decreased tonic–clonic seizures by 93% during maintenance treatment in a randomized clinical trial (RCT). In long‐term, open‐label studies, 10%–36% of patients were seizure‐free for a median duration of ~30–45 months. Fenfluramine treatment in DS reduced convulsive seizure frequency by 56% over placebo at the highest dose, with 8% of patients free of convulsive seizures, and 25% with only one convulsive seizure over 14 weeks. These results were sustained for up to 3 years in open‐label extension studies. Mortality was reduced 5‐fold. These results are superior to all other approved ASMs, placing these two drugs among the most effective antiseizure therapies. The adverse event profiles resemble those of other ASMs. Despite greater efficacy and similar toxicity, these medications are infrequently used. Two years after US market entry, < 5% of either adults with focal DRE or patients with DS were treated with either cenobamate or fenfluramine. We believe this is a failure of our medical system, resulting from limited knowledge about these drugs stemming partly from the separation of academia from industry; restrictions to access created by health care payors, hospitals, and regulatory agencies; and insufficient post‐launch information about the efficacy and safety of these ASMs. [ABSTRACT FROM AUTHOR]

A reduction in seizures means fewer preseizure migraines and frightening prodromal symptoms, less time spent in bed recovering from a seizure, and a reduced risk of having a seizure in public. Keywords: drug resistant; epilepsy; minimal clinically important difference; patient outcome assessment EN drug resistant epilepsy minimal clinically important difference patient outcome assessment 1469 1471 3 06/06/23 20230601 NES 230601 I am a researcher. [Extracted from the article]

Summary: Objective: The definition of drug‐resistant epilepsy (DRE) affects case identification and treatment, and impacts prevalence or incidence estimates and health burden estimation in epidemiology. The objective of this systematic review is to evaluate the consistency between definitions of DRE in the literature and the official definition in the International League Against Epilepsy (ILAE) guidelines, and to estimate the incidence, prevalence, and risk factors for DRE. Methods: MEDLINE and EMBASE were searched for observational studies of DRE published between January 1980 and July 2015. The definitions of DRE in these studies were compared with the definition in the ILAE guidelines. Random‐effect model meta‐analyses were used to generate pooled estimates of prevalence or incidence and pooled odds ratios of the association with risk factors. Results: Thirty‐five studies met inclusion criteria, including 13 080 epilepsy patients and 3941 patients with DRE. The definition of DRE varied widely across studies, with only 12% meeting the requirements of the ILAE definition. The pooled prevalence proportion of DRE among epilepsy patients was 0.30 (95% confidence interval [CI] 0.19‐0.42), and the pooled incidence proportion was 0.15 (95% CI 0.11‐0.19). Age at onset, symptomatic epilepsy, abnormal neuroimaging findings, abnormal electroencephalography results, history of mental retardation, neuropsychiatric disorders, febrile seizure, and status epilepticus increased risk for DRE. Significance: There are limited high‐quality data available on DRE. Lack of consistency in definitions limits the ability to obtain robust estimates on the burden of DRE. More data based on the ILAE definition from well‐designed epidemiologic studies are needed to generate accurate and reliable results. [ABSTRACT FROM AUTHOR]

Seizures cannot be medically controlled in approximately 40% of people with epilepsy. Although we are beginning to understand how to better treat certain seizure types, we still do not know the regulatory events that determine antiepileptic drug resistance. Proposed pathoetiologic mechanisms include altered expression of drug targets (i.e., receptor or ion channel modifications), endothelial drug transporter activation (i.e., increasing drug clearance), or intrinsic severity factors. The latter hypothesis results from an often confirmed clinical observation, that seizure severity is a reliable predictor for the development of pharmacoresistance ( PR) in epilepsy. Herein, we propose, that genome modifications that do not involve changes to the DNA sequence per se (i.e., epigenetic changes) could confer PR in patients with epilepsy. Seizures cause excessive neuronal membrane depolarization, which can influence the cellular nucleus; we thus hypothesize that seizures can mediate epigenetic modifications that result in persistent genomic methylation, histone density, and posttranslational modifications, as well as noncoding RNA-based changes. Although experimental evidence is lacking in epilepsy, such mechanisms are well characterized in cancer, either as a result of anticancer drugs themselves or cancer-related intrinsic signals (i.e., noncoding RNAs). We suggest that similar mechanisms also play a role in PR epilepsies. Addressing such epigenetic mechanisms may be a successful strategy to increase the brain's sensitivity to antiepileptic drugs and may even act as disease-modifying treatment. [ABSTRACT FROM AUTHOR]