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OBJECTIVE: Seizure clusters require prompt medical treatment to minimize possible progression to status epilepticus, increased health care use, and disruptions to daily life. Isolated seizures may exhibit cyclical patterns, including circadian and longer rhythms. However, little is known about the cyclical patterns in seizure clusters. This post hoc analysis of data from a long-term, phase 3, open-label, repeat-dose safety study of diazepam nasal spray modeled the periodicity of treated seizure clusters. METHODS: Mixed-effects cosinor analysis evaluated circadian rhythmicity, and single component cosinors using 12 and 24 h were used to calculate cosinor parameters (e.g., midline statistic of rhythm, wave ampitude, and acrophase [peak]). Analysis was completed for the full cohort and a consistent cohort of participants with two or more seizure clusters in each of four, 3-month periods. The influence of epilepsy type on cosinor parameters was also analyzed. RESULTS: Seizure-cluster events plotted across 24 h showed a bimodal distribution with acrophases (peaks) at ~06:30 and ~18:30. A 12-h plot showed a single peak at ~06:30. Cosinor analyses of the full and consistent cohort aligned, with acrophases for both models predicting peak seizure activity at ~23:30 on a 24-h scale and ~07:30 on a 12-h scale. The consistent cohort was associated with increases in baseline and peak seizure-cluster activity. Analysis by epilepsy type identified distinct trends. Seizure clusters in the focal epilepsy group peaked in the evening (acrophase 19:19), whereas events in the generalized epilepsy group peaked in the morning (acrophase 04:46). Together they compose the bimodal clustering observed over 24 h. SIGNIFICANCE: This analysis of seizure clusters treated with diazepam nasal spray demonstrated that seizure clusters occur cyclically in 12- and 24-h time frames similar to that reported with isolated seizures. Further elucidation of these patterns may provide important information for patient care, ranging from improved patient-centered outcomes to seizure-cluster prediction.
Assuntos
Epilepsia Generalizada , Epilepsia , Humanos , Anticonvulsivantes/efeitos adversos , Ritmo Circadiano , Diazepam/efeitos adversos , Epilepsia/tratamento farmacológico , Epilepsia Generalizada/tratamento farmacológico , Sprays Nasais , Convulsões/tratamento farmacológicoRESUMO
OBJECTIVE: An epilepsy monitoring unit (EMU) is a specialized unit designed for capturing and characterizing seizures and other paroxysmal events with continuous video electroencephalography (vEEG). Nearly 260 epilepsy centers in the United States are accredited by the National Association of Epilepsy Centers (NAEC) based on adherence to specific clinical standards to improve epilepsy care, safety, and quality. This study examines EMU staffing, safety practices, and reported outcomes. METHOD: We analyzed NAEC annual report data and results from a supplemental survey specific to EMU practices reported in 2019 from 341 pediatric or adult center directors. Data on staffing, resources, safety practices and complications were collated with epilepsy center characteristics. We summarized using frequency (percentage) for categorical variables and median (inter-quartile range) for continuous variables. We used chi-square or Fisher's exact tests to compare staff responsibilities. RESULTS: The supplemental survey response rate was 100%. Spell classification (39%) and phase 1 testing (28%) were the most common goals of the 91,069 reported admissions. The goal ratio of EEG technologist to beds of 1:4 was the most common during the day (68%) and off-hours (43%). Compared to residents and fellows, advanced practice providers served more roles in the EMU at level 3 or pediatric-only centers. Status epilepticus (SE) was the most common reported complication (1.6% of admissions), while cardiac arrest occurred in 0.1% of admissions. SIGNIFICANCE: EMU staffing and safety practices vary across US epilepsy centers. Reported complications in EMUs are rare but could be further reduced, such as with more effective treatment or prevention of SE. These findings have potential implications for improving EMU safety and quality care.
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Epilepsia , Estado Epiléptico , Adulto , Criança , Humanos , Eletroencefalografia/métodos , Epilepsia/epidemiologia , Epilepsia/tratamento farmacológico , Monitorização Fisiológica/métodos , Estudos Retrospectivos , Convulsões/diagnóstico , Convulsões/epidemiologia , Convulsões/tratamento farmacológico , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Focused ultrasound ablation (FUSA) is an emerging treatment for neurological and psychiatric diseases. We describe the initial experience from a pilot, open-label, single-center clinical trial of unilateral anterior nucleus of the thalamus (ANT) FUSA in patients with treatment-refractory epilepsy. METHODS: Two adult subjects with treatment-refractory, focal onset epilepsy were recruited. The subjects received ANT FUSA using the Exablate Neuro (Insightec) system. We determined the safety and feasibility (primary outcomes), and changes in seizure frequency (secondary outcome) at 3, 6, and 12 months. Safety was assessed by the absence of side effects, that is, new onset neurological deficits or performance deterioration on neuropsychological testing. Feasibility was defined as the ability to create a lesion within the anterior nucleus. The monthly seizure frequency was compared between baseline and postthalamotomy. RESULTS: The patients tolerated the procedure well, without neurological deficits or serious adverse events. One patient experienced a decline in verbal fluency, attention/working memory, and immediate verbal memory. Seizure frequency reduced significantly in both patients; one patient was seizure-free at 12 months, and in the second patient, the frequency reduced from 90-100 seizures per month to 3-6 seizures per month. SIGNIFICANCE: This is the first known clinical trial to assess the safety, feasibility, and preliminary efficacy of ANT FUSA in adult patients with treatment-refractory focal onset epilepsy.
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Núcleos Anteriores do Tálamo , Epilepsias Parciais , Adulto , Humanos , Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/cirurgia , Epilepsias Parciais/tratamento farmacológico , Convulsões/tratamento farmacológico , Atenção , Resultado do TratamentoRESUMO
Well-designed placebo-controlled clinical trials are critical to the development of novel treatments for epilepsy, but their design has not changed for decades. Patients, clinicians, regulators, and innovators all have concerns that recruiting for trials is challenging, in part, due to the static design of maintaining participants for long periods on add-on placebo when there are an increasing number of options for therapy. A traditional trial maintains participants on blinded treatment for a static period (e.g., 12 weeks of maintenance), during which participants on placebo have an elevated risk of sudden unexpected death in epilepsy compared to patients on an active treatment. Time-to-event trials observe participants on blinded treatment until a key event occurs (e.g., post-randomization seizure count matches pre-randomization monthly seizure count). In this article, we review the evidence for these designs based on re-analysis of prior trials, one published trial that used a time-to-second seizure design, and experience from an ongoing blinded trial. We also discuss remaining concerns regarding time-to-event trials. We conclude that, despite potential limitations, time-to-event trials are a potential promising mechanism to make trials more patient friendly and reduce placebo exposure, which are urgent needs to improve safety and increase recruitment to trials.
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Anticonvulsivantes , Epilepsia , Humanos , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Projetos de Pesquisa , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Ensaios Clínicos como AssuntoRESUMO
OBJECTIVE: The evaluation to determine candidacy and treatment for epilepsy surgery in persons with drug-resistant epilepsy (DRE) is not uniform. Many non-invasive and invasive tests are available to ascertain an appropriate treatment strategy. This study examines expert response to clinical vignettes of magnetic resonance imaging (MRI)-positive lesional focal cortical dysplasia in both temporal and extratemporal epilepsy to identify associations in evaluations and treatment choice. METHODS: We analyzed annual report data and a supplemental epilepsy practice survey reported in 2020 from 206 adult and 136 pediatric epilepsy center directors in the United States. Non-invasive and invasive testing and surgical treatment strategies were compiled for the two scenarios. We used chi-square tests to compare testing utilization between the two scenarios. Multivariable logistic regression modeling was performed to assess associations between variables. RESULTS: The supplemental survey response rate was 100% with 342 responses included in the analyses. Differing testing and treatment approaches were noted between the temporal and extratemporal scenarios such as chronic invasive monitoring selected in 60% of the temporal scenario versus 93% of the extratemporal scenario. Open resection was the most common treatment choice; however, overall treatment choices varied significantly (p < .001). Associations between non-invasive testing, invasive testing, and treatment choices were present in both scenarios. For example, in the temporal scenario stereo-electroencephalography (SEEG) was more commonly associated with fluorodeoxyglucose-positron emission tomography (FDG-PET) (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.06-3.29; p = .033), magnetoencephalography (MEG) (OR 2.90; 95% CI 1.60-5.28; p = <.001), high density (HD) EEG (OR 2.80; 95% CI 1.27-6.24; p = .011), functional MRI (fMRI) (OR 2.17; 95% CI 1.19-4.10; p = .014), and Wada (OR 2.16; 95% CI 1.28-3.66; p = .004). In the extratemporal scenario, choosing SEEG was associated with increased odds of neuromodulation over open resection (OR 3.13; 95% CI 1.24-7.89; p = .016). SIGNIFICANCE: In clinical vignettes of temporal and extratemporal lesional DRE, epilepsy center directors displayed varying patterns of non-invasive testing, invasive testing, and treatment choices. Differences in practice underscore the need for comparative trials for the surgical management of DRE.
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Epilepsia Resistente a Medicamentos , Epilepsias Parciais , Epilepsia , Adulto , Criança , Humanos , Censos , Convulsões , Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/cirurgia , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/cirurgia , Eletroencefalografia/métodos , Imageamento por Ressonância Magnética , Resultado do Tratamento , Estudos RetrospectivosRESUMO
OBJECTIVE: Persons with drug-resistant epilepsy may benefit from epilepsy surgery and should undergo presurgical testing to determine potential candidacy and appropriate intervention. Institutional expertise can influence use and availability of evaluations and epilepsy surgery candidacy. This census survey study aims to examine the influence of geographic region and other center characteristics on presurgical testing for medically intractable epilepsy. METHODS: We analyzed annual report and supplemental survey data reported in 2020 from 206 adult epilepsy center directors and 136 pediatric epilepsy center directors in the United States. Test utilization data were compiled with annual center volumes, available resources, and US Census regional data. We used Wilcoxon rank-sum, Kruskal-Wallis, and chi-squared tests for univariate analysis of procedure utilization. Multivariable modeling was also performed to assign odds ratios (ORs) of significant variables. RESULTS: The response rate was 100% with individual element missingness < 11% across 342 observations undergoing univariate analysis. A total of 278 complete observations were included in the multivariable models, and significant regional differences were present. For instance, compared to centers in the South, those in the Midwest used neuropsychological testing (OR = 2.87, 95% confidence interval [CI] = 1.2-6.86; p = .018) and fluorodeoxyglucose-positron emission tomography (OR = 2.74, 95% CI = = 1.14-6.61; p = .025) more commonly. For centers in the Northeast (OR = .46, 95% CI = .23-.93; p = .031) and West (OR = .41, 95% CI = .19-.87; p = .022), odds of performing single-photon emission computerized tomography were lower by nearly 50% compared to those in the South. Center accreditation level, demographics, volume, and resources were also associated with varying individual testing rates. SIGNIFICANCE: Presurgical testing for drug-resistant epilepsy is influenced by US geographic region and other center characteristics. These findings have potential implications for comparing outcomes between US epilepsy centers and may inject disparities in access to surgical treatment.
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Epilepsia Resistente a Medicamentos , Epilepsia , Adulto , Criança , Humanos , Estados Unidos , Epilepsia/diagnóstico , Epilepsia/cirurgia , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/cirurgia , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia por Emissão de Pósitrons , Projetos de PesquisaRESUMO
2-deoxy-D-glucose (2DG) is a glucose analog differing from glucose only by removal of an oxygen atom at the 2 position, which prevents the isomerization of glucose-6-phosphate to fructose-6-phosphate, and thereby reversibly inhibits glycolysis. PET studies of regional brain glucose utilization positron-emitting 18F-2DG demonstrate that brain regions generating seizures have diminished glucose utilization during interictal conditions, but rapidly transition to markedly increased glucose delivery and utilization during seizures, particularly in status epilepticus (SE). 2-deoxy-D-glucose has acute antiseizure actions in multiple in vivo and in vitro seizure models, including models of SE induced by the chemo convulsants pilocarpine and kainic acid, suggesting that focal enhanced delivery of 2DG to ictal brain circuits is a potential novel anticonvulsant intervention for the treatment of SE.
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Desoxiglucose , Estado Epiléptico , Humanos , Desoxiglucose/uso terapêutico , Desoxiglucose/farmacologia , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Convulsões/tratamento farmacológico , Glucose , Glicólise , Pilocarpina/toxicidadeRESUMO
BACKGROUND AND OBJECTIVES: Neuropsychological research on mesial temporal lobe epilepsy (MTLE) often highlights material-specific memory deficits, but a lesion-focused model may not accurately reflect the underlying networks that support episodic memory in these patients. Our study evaluated the pathophysiology behind verbal learning/memory deficits as revealed by hypometabolism quantified through 18-fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS: This retrospective study included thirty presurgical patients with intractable unilateral MTLE who underwent interictal FDG-PET and verbal memory assessment (12 females, mean age: 38.73 years). Fluorodeoxyglucose-positron emission tomography mapping was performed with voxel-based mapping of glucose utilization to a database of age-matched controls to derive regional Z-scores. Neuropsychological outcome variables included scores on learning and recall trials of two distinct verbal memory measures validated for use in epilepsy research. Pearson's correlations evaluated relationships between clinical variables and verbal memory. Linear regression was used to relate regional hypometabolism and verbal memory assessment. Post hoc analyses assessed areas of FDG-PET hypometabolism (threshold Z ≤ -1.645 below mean) where verbal memory was impaired. RESULTS: Verbal memory deficits correlated with hypometabolism in limbic structures ipsilateral to language dominance but also correlated with hypometabolism in networks involving the ipsilateral perisylvian cortex and contralateral limbic and nonlimbic structures. DISCUSSION: We conclude that traditional models of verbal memory may not adequately capture cognitive deficits in a broader sample of patients with MTLE. This study has important implications for epilepsy surgery protocols that use neuropsychological data and FDG-PET to draw conclusions about surgical risks.
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Epilepsia do Lobo Temporal , Memória Episódica , Feminino , Humanos , Adulto , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/psicologia , Fluordesoxiglucose F18 , Estudos Retrospectivos , Tomografia por Emissão de Pósitrons/métodos , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/etiologiaRESUMO
BACKGROUND: Improved understanding of physical activity barriersand preferences in people with epilepsyis needed to successfully design and perform larger, more robust effectivenesstrials. METHODS: Adult patients at a single tertiary epilepsy center between January and April 2020 were surveyed. The survey included a validated physical activity questionnaire (Physical Activity Scale for the Elderly) plus 15 items aimed to address 1) perceptions and beliefs regarding physical activity, 2) barriers to routine physical activity, and 3) willingness and ability to participate in a physical activity intervention and 4) current physical abilities, activities, and preferences. RESULTS: 95 participants with epilepsy (age 42 ± 16.2, 59 % female) completed the survey. Sixty-five participants (68.4 %) reported that they believe that physical activity could improve their seizure frequency. However, 40 % of those surveyed said their neurologist had never talked to them about physical activity. The most commonly reported barriers to physical activity were lack of time (24.7 %) and fear of having a seizure (19.7 %), while barriers to intervention participation included being unable to come to in-person sessions (53 % of those willing to participate),living far away (39.3 %), time constraints (28.6 %), and lack of transportation (21.4 %). CONCLUSION: Future physical activity studies in people with epilepsy should focus on using tailored interventions that accommodate their unique beliefs and barriers.
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Epilepsia , Adulto , Humanos , Feminino , Idoso , Masculino , Convulsões , Exercício Físico , Inquéritos e Questionários , MedoRESUMO
BACKGROUND: The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied. METHODS: In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death. RESULTS: A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant. CONCLUSIONS: In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).
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Anticonvulsivantes/uso terapêutico , Levetiracetam/uso terapêutico , Fenitoína/análogos & derivados , Estado Epiléptico/tratamento farmacológico , Ácido Valproico/uso terapêutico , Adolescente , Adulto , Anticonvulsivantes/efeitos adversos , Benzodiazepinas/uso terapêutico , Criança , Pré-Escolar , Método Duplo-Cego , Resistência a Medicamentos , Feminino , Humanos , Hipotensão/induzido quimicamente , Infusões Intravenosas , Injeções Intramusculares , Levetiracetam/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fenitoína/efeitos adversos , Fenitoína/uso terapêutico , Ácido Valproico/efeitos adversos , Adulto JovemRESUMO
OBJECTIVES: Drug treatment for children with epilepsy should, ideally, be governed by evidence from adequate and well-controlled clinical studies. However, these studies are difficult to conduct, and so direct evidence supporting the informed use of specific drugs is often lacking. The Research Roundtable for Epilepsy (RRE) met in 2020 to align on an approach to therapy development for focal seizures in children age 1 month <2 years of age. METHODS: The RRE reviewed the regulatory landscape, epidemiology, seizure semiology, antiseizure medicine pharmacology, and safety issues applicable to this population. RESULTS: After reviewing evidence, the conclusion was that pediatric efficacy trials would be impracticable to conduct but a waiver of the regulatory requirement to conduct any study would lead to an absence of information to guide dosing in a critical population. Review of available data and discussion of RRE attendees led to the conclusion that the requirements for extrapolation of efficacy from older children down to infants from age 1 month to <2 years old appeared to be met. After the RRE, the US Food and Drug Administration (FDA) approved brivaracetam for use in children with focal epilepsy above the age of 1 month in August 2021 and lacosamide in October 2021, both based on the principle of extrapolation from data in older children. SIGNIFICANCE: These recommendations should result in more rapid accessibility of antiseizure medications for infants.
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Epilepsias Parciais , Epilepsia , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Epilepsias Parciais/tratamento farmacológico , Epilepsia/tratamento farmacológico , Humanos , Lactente , Lacosamida/uso terapêutico , Convulsões/tratamento farmacológicoRESUMO
BACKGROUND: Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups. METHODS: In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075. FINDINGS: Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group. INTERPRETATION: Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus. FUNDING: National Institute of Neurological Disorders and Stroke, National Institutes of Health.
Assuntos
Anticonvulsivantes/administração & dosagem , Levetiracetam/administração & dosagem , Fenitoína/análogos & derivados , Estado Epiléptico/tratamento farmacológico , Ácido Valproico/administração & dosagem , Adolescente , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anticonvulsivantes/efeitos adversos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Lactente , Levetiracetam/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fenitoína/administração & dosagem , Fenitoína/efeitos adversos , Ácido Valproico/efeitos adversos , Adulto JovemRESUMO
OBJECTIVE: This study was undertaken to describe patterns of benzodiazepine use as first-line treatment of status epilepticus (SE) and test the association of benzodiazepine doses with response to second-line agents in patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT). METHODS: Patients refractory to an adequate dose of benzodiazepines for the treatment of SE were enrolled in ESETT. Choice of benzodiazepine, doses given prior to administration of second-line agent, route of administration, setting, and patient weight were characterized. These were compared with guideline-recommended dosing. Logistic regression was used to determine the association of the first dose of benzodiazepine and the cumulative benzodiazepine dose with the response to second-line agent. RESULTS: Four hundred sixty patients were administered 1170 doses of benzodiazepines (669 lorazepam, 398 midazolam, 103 diazepam). Lorazepam was most frequently administered intravenously in the emergency department, midazolam intramuscularly or intravenously by the emergency medical services personnel, and diazepam rectally prior to ambulance arrival. The first dose of the first benzodiazepine (N = 460) was lower than guideline recommendations in 76% of midazolam administrations and 81% of lorazepam administrations. Among all administrations, >85% of midazolam and >76% of lorazepam administrations were lower than recommended. Higher first or cumulative benzodiazepine doses were not associated with better outcomes or clinical seizure cessation in response to second-line medications in these benzodiazepine-refractory seizures. SIGNIFICANCE: Benzodiazepines as first-line treatment of SE, particularly midazolam and lorazepam, are frequently underdosed throughout the United States. This broad and generalizable cohort confirms prior single site reports that underdosing is both pervasive and difficult to remediate. (ESETT ClinicalTrials.gov identifier: NCT01960075.).
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Benzodiazepinas/administração & dosagem , Estado Epiléptico/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Benzodiazepinas/uso terapêutico , Criança , Diazepam/administração & dosagem , Diazepam/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Lorazepam/administração & dosagem , Lorazepam/uso terapêutico , Midazolam/administração & dosagem , Midazolam/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
Epilepsy surgery remains underutilized, in part because non-invasive methods of potential seizure foci localization are inadequate. We used high-resolution, parametric quantification from dynamic 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography (dFDG-PET) imaging to locate hypometabolic foci in patients whose standard clinical static PET images were normal. We obtained dFDG-PET brain images with simultaneous EEG in a one-hour acquisition on seven patients with no MRI evidence of focal epilepsy to record uptake and focal radiation decay. Images were attenuation- and motion-corrected and co-registered with high-resolution T1-weighted patient MRI and segmented into 18 regions of interest (ROI) per hemisphere. Tracer uptake was calibrated with a model corrected blood input function with partial volume (PV) corrections to generate tracer parametric maps compared between mean radiation values between hemispheres with z-scores. We identified ROI with the lowest negative z scores (<-1.65 SD) as hypometabolic. Dynamic 2-[18F] fluoro-2-deoxy-d-glucose positron emission tomography ( found focal regions of altered metabolism in all cases in which standard clinical FDG-PET found no abnormalities. This pilot study of dynamic FDG-PET suggests that further research is merited to evaluate whether glucose dynamics offer improved clinical utility for localization of epileptic foci over standard static techniques.
Assuntos
Epilepsias Parciais , Fluordesoxiglucose F18 , Eletroencefalografia , Epilepsias Parciais/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Projetos Piloto , Tomografia por Emissão de PósitronsRESUMO
The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings.
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Anticonvulsivantes/administração & dosagem , Peso Corporal/efeitos dos fármacos , Levetiracetam/administração & dosagem , Fenitoína/análogos & derivados , Estado Epiléptico/tratamento farmacológico , Ácido Valproico/administração & dosagem , Adolescente , Adulto , Peso Corporal/fisiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Fenitoína/administração & dosagem , Método Simples-Cego , Estado Epiléptico/fisiopatologia , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: There is scant evidence to quantify the risk of contact sports such as football to patients with epilepsy. This retrospective review was performed to evaluate the incidence of injuries or seizure exacerbation related to football participation in patients with epilepsy. METHODS: Between the years 1994 and 2004, 157,709 consecutive clinic notes were searched for mention of "football" and "epilepsy" or "seizure". Resulting notes were reviewed to quantify the number of seizure exacerbations and the number of injuries in this cohort. RESULTS: Seven of 44 subjects with epilepsy (15.9%) experienced injury while playing football. Four of 32 (12.5%) patients experienced seizure exacerbation during a time when they were concurrently participating in football though 3 of these patients stopped taking or were weaned off of their antiepileptic drugs (AEDs). One in 32 patients with epilepsy (3.1%) had an exacerbation of seizures while playing football and consistently taking AEDs. CONCLUSION: The risk of injury and seizure exacerbation due to participation in football for patients with epilepsy is low. Clinicians should use their best judgment in deciding whether contact sports increase risks for a particular patient based on individual seizure frequency, concurrent neurological and medical issues, and medication adverse effects.
Assuntos
Epilepsia/diagnóstico , Epilepsia/epidemiologia , Futebol Americano/lesões , Convulsões/diagnóstico , Convulsões/epidemiologia , Adulto , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Futebol Americano/tendências , Humanos , Incidência , Masculino , Estudos Retrospectivos , Medição de Risco , Convulsões/tratamento farmacológico , Serviços de Saúde para Estudantes/tendências , Adulto JovemRESUMO
OBJECTIVE: To determine whether a less-invasive approach to surgery for medically refractory temporal lobe epilepsy is associated with lower health care costs and costs of lost productivity over time, compared to open surgery. METHODS: We compared direct medical costs and indirect productivity costs associated with treatment with stereotactic radiosurgery (SRS) or anterior temporal lobectomy (ATL) in the ROSE (Radiosurgery or Open Surgery for Epilepsy) trial. Health care use was abstracted from hospital bills, the study database, and diaries in which participants recorded health care use and time lost from work while seeking care. Costs of use were calculated using a Medicare costing approach used in a prior study of the costs of ATL. The power of many analyses was limited by the sample size and data skewing. RESULTS: Combined treatment and follow-up costs (in thousands of US dollars) did not differ between SRS (n = 20, mean = $76.6, 95% confidence interval [CI] = 50.7-115.6) and ATL (n = 18, mean = $79.0, 95% CI = 60.09-103.8). Indirect costs also did not differ. More ATL than SRS participants were free of consciousness-impairing seizures in each year of follow-up (all P < 0.05). Costs declined following ATL (P = 0.005). Costs tended to increase over the first 18 months following SRS (P = 0.17) and declined thereafter (P = 0.06). This mostly reflected hospitalizations for SRS-related adverse events in the second year of follow-up. SIGNIFICANCE: Lower initial costs of SRS for medial temporal lobe epilepsy were largely offset by hospitalization costs related to adverse events later in the course of follow-up. Future studies of less-invasive alternatives to ATL will need to assess adverse events and major costs systematically and prospectively to understand the economic implications of adopting these technologies.
Assuntos
Epilepsia do Lobo Temporal/cirurgia , Custos de Cuidados de Saúde/estatística & dados numéricos , Radiocirurgia/economia , Adulto , Custos e Análise de Custo , Epilepsia do Lobo Temporal/economia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricosRESUMO
Convulsive status epilepticus (SE) is a relatively common emergency condition affecting individuals of all ages. The primary goal of treatment is prompt termination of seizures. Where first-line treatment with benzodiazepine has failed to achieve this, a condition known as established SE (ESE), there is uncertainty about which agent to use next. The Established Status Epilepticus Treatment Trial (ESETT) is a 3-arm (valproate (VPA), fosphenytoin (FOS), levetiracetam (LEV)), phase III, double-blind randomized comparative effectiveness study in patients aged 2â¯years and above with established convulsive SE. Enrollment was completed in January 2019, and the results are expected later this year. We discuss lessons learnt during the conduct of the study in relation to the following: ethical considerations; trial design and practical implementation in emergency settings, including pediatric and adult populations; quality assurance; and outcome determination where treating emergency clinicians may lack specialist expertise. We consider that the ESETT is already informing both clinical practice and future trial design. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".
Assuntos
Anticonvulsivantes/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Serviço Hospitalar de Emergência/normas , Estado Epiléptico/tratamento farmacológico , Adulto , Benzodiazepinas/uso terapêutico , Pré-Escolar , Testes Diagnósticos de Rotina/métodos , Testes Diagnósticos de Rotina/normas , Método Duplo-Cego , Feminino , Humanos , Levetiracetam/uso terapêutico , Masculino , Estado Epiléptico/diagnóstico , Resultado do Tratamento , Ácido Valproico/uso terapêuticoRESUMO
Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the â¼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.
Assuntos
Deficiência Intelectual/genética , Mutação/genética , Espasmos Infantis/genética , Transtornos Globais do Desenvolvimento Infantil , Estudos de Coortes , Exoma/genética , Feminino , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Predisposição Genética para Doença/genética , Humanos , Lactente , Deficiência Intelectual/fisiopatologia , Síndrome de Lennox-Gastaut , Masculino , Taxa de Mutação , N-Acetilglucosaminiltransferases/genética , Probabilidade , Receptores de GABA-A/genética , Espasmos Infantis/fisiopatologiaRESUMO
Although the epilepsy and neurology communities have position papers on a number of topics pertaining to epilepsy diagnosis and management, no current paper exists for the rationale and appropriate indications for epilepsy monitoring unit (EMU) evaluation. General neurologists, hospital administrators, and insurers also have yet to fully understand the role this type of testing has in the diagnosis and management of individuals with paroxysmal neurologic symptoms. This review outlines the indications for long-term video-electroencephalography (VEEG) for typical elective admissions to a specialized inpatient setting. The common techniques used in EMUs to obtain diagnostic information are reviewed. The added benefit of safety measures and clinical testing above that available for routine or long-term ambulatory electroencephalography is also discussed. The indications for admission to the EMU include differential diagnosis of paroxysmal spells, characterization of seizure types, presurgical epilepsy evaluations, seizure quantification, monitoring medication adjustment in a safe setting, and differentiation between seizures and side effects. We conclude that the appropriate use of this specialized testing can lead to an early and correct diagnosis in a variety of clinical circumstances. The EMU evaluation is considered the gold standard test for the definitive diagnosis of epilepsy and seizure-like spells.