Early Identification of Refractory Epilepsy

Kwan, Patrick; Brodie, Martin J.

doi:10.1056/nejm200002033420503

Cited by 4,466 publications

(2,988 citation statements)

References 39 publications

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“…Medications are only able to fully protect about ⅔ of patients 2 from seizures, a number that has remained relatively stable for many years. Indeed, over 22 medications and two implanted devices have been approved by the FDA over the decades.…”

Section: Introductionmentioning

confidence: 99%

Monte Carlo simulations of randomized clinical trials in epilepsy

Goldenholz

Tharayil

Moss³

et al. 2017

Ann Clin Transl Neurol

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BackgroundThe placebo response in epilepsy randomized clinical trials (RCTs) has recently been shown to largely reflect underlying natural variability in seizure frequency. Based on this observation, we sought to explore the parameter space of RCT design to optimize trial efficiency and cost.MethodsWe used one of the world's largest patient reported seizure diary databases, SeizureTracker.com to derive virtual patients for simulated RCTs. We ran 1000 randomly generated simulated trials using bootstrapping (sampling with replacement) for each unique combination of trial parameters, sweeping a large set of parameters in durations of the baseline and test periods, number of patients, eligibility criteria, drug effect size, and patient dropout. We studied the resulting trial efficiency and cost.ResultsA total of 6,732,000 trials were simulated, drawing from 5097 patients in the database. We found that the strongest regression predictors of placebo response were durations of baseline and test periods. Drug effect size had a major impact on trial efficiency and cost. Dropout did not have a major impact on trial efficiency or cost. Eligibility requirements impacted trial efficiency to a limited extent. Cost was minimized while maintaining statistical integrity with very short RCT durations.DiscussionThis study suggests that RCT parameters can be improved over current practice to reduce costs while maintaining statistical power. In addition, use of a large‐scale population dataset in a massively parallel computing analysis allows exploration of the wider parameter space of RCT design prior to running a trial, which could help accelerate drug discovery and approval.

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Section: Introductionmentioning

confidence: 99%

Monte Carlo simulations of randomized clinical trials in epilepsy

Goldenholz

Tharayil

Moss³

et al. 2017

Ann Clin Transl Neurol

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“…Improvement in terms of clinical outcome, however, has fallen short of expectations, with up to one third of patients continuing to experience seizures or unacceptable medication-related side effects in spite of efforts to identify optimal treatment regimes with one or more drugs. 1,2 Since the landmark identification of the anticonvulsant properties of phenytoin in 1936 by virtue of its ability to protect against electroshock-induced convulsions in the cat, 3,4 the majority of novel AEDs have been identified through screening in animal models of epilepsy. The most widely used in vivo models have been the maximal electroshock (MES) test in normal mice and rats and the pentylenetetrazol (PTZ) test in normal mice.…”

Section: Introductionmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…Approximately 30−40% of patients with epilepsy fail medical treatment and are considered for epilepsy surgery [1][2][3]. Such decisions are made on the basis of ictal EEG recordings, with the results of other studies (imaging, neuropsychological testing, and intracarotid amobarbital procedure) providing outcome and neurological risk data to the patient before she or he decides whether to undergo the resective procedure.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive presurgical functional MRI language evaluation in adult patients with epilepsy

Szaflarski

Holland

Jacola

et al. 2008

Epilepsy & Behavior

113

137

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Functional magnetic resonance imaging (fMRI) has the potential to replace the intracarotid amobarbital procedure (IAP) in presurgical evaluation of patients with epilepsy patients. In this study, we compared fMRI verb generation (VG) and semantic decision/tone decision (SDTD) tasks and the IAP in their ability to localize language functions in patients with epilepsy undergoing presurgical evaluation. We enrolled 50 healthy controls to establish normal language activation patterns for VG and SDTD tasks at 3 or 4 T, and to design language regions of interest (ROIs) that were later applied to 38 patients with epilepsy (28 of 38 also underwent the IAP). We calculated laterality indices (LIs) for each task for each subject based on the ROIs, and we used general linear modeling to analyze the fMRI data. All healthy and epileptic subjects activated language areas with both fMRI tasks. We found significant correlations in language lateralization between the fMRI tasks (r = 0.495, P ≤ 0.001) and between VG and IAP (r = 0.652, P < 0.001) and SDTD and IAP (r = 0.735, P < 0.001). The differences in LIs between SDTD and VG tasks were small and not affected by age, gender, epilepsy status, handedness, or performance. SDTD and VG tasks combined explained approximately 58.4% in the variability of the IAP/language. In the general linear modeling, only the SDTD task significantly contributed to the determination of language lateralization in patients with epilepsy undergoing presurgical evaluation. Results indicate a moderate convergent validity between both fMRI language tasks and between IAP and fMRI tasks. The results of this study indicate that either of these fMRI tasks can be used for language lateralization in patients with epilepsy undergoing presurgical evaluation, but that the SDTD task is likely to provide more information regarding language lateralization than the VG task.

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Early Identification of Refractory Epilepsy

Abstract: Patients who have many seizures before therapy or who have an inadequate response to initial treatment with antiepileptic drugs are likely to have refractory epilepsy.

Cited by 4,466 publications

References 39 publications

Monte Carlo simulations of randomized clinical trials in epilepsy

Monte Carlo simulations of randomized clinical trials in epilepsy

Molecular Targets for Antiepileptic Drug Development

Comprehensive presurgical functional MRI language evaluation in adult patients with epilepsy

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