Clinical Trials for Treatment of Primary Generalized Epilepsies

Abstract

Summary:Purpose: To review the current state of knowledge of the treatment of primary (idiopathic) generalized epilepsy syndromes based on the efficacy results of clinical trials, to highlight obstacles in the design of these trials, and to suggest solutions for future research.Methods: Published reports of controlled clinical trials, as well as large or significant uncontrolled trials of treatments for these syndromes, were reviewed. Trials were selected for discussion based on their importance or their illustration of design issues.Results: Only a few randomized, controlled trials of therapy for these syndromes exist. Conclusions based on this Class I data include efficacy in absence epilepsies for ethosuximide, valproate, and lamotrigine, and for eight drugs for primary generalized tonic-clonic seizures. Many commonly accepted therapeutic strategies are not based on formal data. No controlled data exist for uncommon syndromes.Conclusions: More clinical trials of therapies for primary generalized epilepsies are needed. To overcome design obstacles, better funding, multicenter cooperation, inclusion of children, study designs requiring fewer patients, equivalent-control designs, use of EEG and video seizure counting, and better syndrome identification will be required. Key Words: Clinical trials-Generalized seizures-Primary generalized epilepsiesIdiopathic epilepsies-Antiepilepsy drugs.The design and interpretation of clinical trials for primary (idiopathic, genetic) generalized epilepsies involves consideration of several problems that differ from those encountered in clinical trials for localization-related epilepsies. Research in this area encounters some unique difficulties; consequently, data from well-controlled trials of therapies for these syndromes are sparse. There are fewer trials enrolling fewer patients, and very few data from Class I studies (randomized, controlled, blinded clinical trials) are available. We will review the problems associated with this endeavor, examine selected clinical trials for illustrative purposes, assign a quality level to therapeutic conclusions in the literature, then suggest possible solutions that may lead to better data and more confident therapeutic plans. This discussion is not a comprehensive review to support evidence-based guidelines. It includes only selected studies to illustrate problems and solutions, but includes most of those containing Class I evidence for efficacy. Choice of drug based on adverse effect profiles, ease of use, cost, and other variables is important, but this review focuses only on efficacy data.

Computational model of neuron-astrocyte interactions during focal seizure generation

“…The Ca 2+ increase due to a single spike is less than 100 nM and lasts for about half a second (inset in Figure 1A1). These results are compatible with experimental evidences (Pasti et al, 1997; James et al, 2011) and previous computational models (Jefferys, 2003; Nadkarni and Jung, 2004, 2007; Wade et al, 2011). The linear dependence of Ca 2+ increases as a function of simulated firing rate is reported in Figure 1B.…”

Evidence‐based Treatment of Idiopathic Generalized Epilepsies with Older Antiepileptic Drugs

“…There was no significant difference in seizure frequency between the two doses. This is consistent with the observation that some patients with IGE are very sensitive to a small dose of an effective medication (48).…”

Perampanel in routine clinical use in idiopathic generalized epilepsy: The 12‐month GENERAL study

“…• One hundred forty-nine people with IGE were treated with perampanel, and 83% remained on treatment after 1 year • Perampanel improved seizures in most patients, and was effective regardless of epilepsy syndrome (juvenile myoclonic epilepsy, GTCS only, and absence epilepsies) • All seizure types responded to perampanel: at 1 year, 62.6% were free of GTCS, 64.6% were free of myoclonic, and 51% of absence seizures • Few patients had worsening of any seizure type with perampanel treatment • The most common adverse events were irritability, somnolence, and dizziness small, as current treatments are effective in many patients. 4,5 Few AEDs are approved specifically for IGE, and the European Medical Association recently recommended that valproic acid-one of the most widely used drugs in IGE-should not be used in female patients once they reach childbearing age unless the conditions of the new pregnancy prevention program are met. 6 This highlights the limited drug options available and the need for new options supported with good data across all seizure types in IGE.…”

“…There are few randomized controlled trials of antiepileptic drugs (AEDs) in these patient populations, particularly for those with refractory seizures, and obstacles to trials include the often low frequency of GTCS, the complexity of syndrome diagnosis and classification, and difficulty counting some seizure types (such as frequent myoclonic or absence seizures). In addition, the refractory population from which trial subjects can be recruited is reasonably small, as current treatments are effective in many patients . Few AEDs are approved specifically for IGE, and the European Medical Association recently recommended that valproic acid—one of the most widely used drugs in IGE—should not be used in female patients once they reach childbearing age unless the conditions of the new pregnancy prevention program are met .…”