Antiepileptic drug treatment of generalized tonic-clonic seizures: An evaluation of regulatory data and five criteria for drug selection

BACKGROUND: A generalized tonic–clonic seizure (GTCS) is the most severe form of common epileptic seizure and carries the greatest risk of harm. The aim of this review is to provide an evidence-based guide for the selection of antiepileptic drugs (AEDs) for patients with GTCSs. Eight AEDs are approved in Europe and the USA for the treatment of both primarily GTCSs (PGTCSs) and secondarily GTCSs (SGTCSs) and are considered in this paper. METHODS: Each AED is evaluated using five criteria: (1) efficacy, by seizure type (a: PGTCSs and b: SGTCSs); (2) adverse effects; (3) interactions; (4) adherence and dosing; and (5) mechanism of action (MOA). To ensure the inclusions of robust data, only efficacy data accepted by regulatory authorities were considered, and data related to adverse effects, interactions, adherence, and MOA were all extracted from UK Summaries of Product Characteristics (SPCs). RESULTS: (1a) There is class 1 evidence of the efficacy of only four AEDs in controlling PGTCSs (lamotrigine, levetiracetam, perampanel, and topiramate). (1b) There is no class 1 evidence of the efficacy of any AED in SGTCSs although some evidence from pooled/subgroup analyses or meta-analyses supports the use of the four AEDs (levetiracetam, perampanel, topiramate, and with less robust data for lamotrigine). (2) AEDs are associated with different, but to some extent overlapping, common adverse effect profiles but have differing idiosyncratic adverse effects. (3) Pharmacokinetic interactions are seen with most, but not all, AEDs and are most common with carbamazepine and phenytoin. (4) Good adherence is important for seizure control and is influenced by frequency of dosing, among other factors. (5) Mechanism of action is also a consideration in rationalising AED selection when switching or combining AEDs. CONCLUSION: Ultimately, the choice of AED depends on all these factors but particularly on efficacy and adverse effects. Different patients will weigh the various factors differently, and the role of the treating physician is to provide accurate information to allow patients to make informed choices

Predictors of hospital and one-year mortality in intensive care patients with refractory status epilepticus : a populationbased study

Background: The aim was to determine predictors of hospital and 1-year mortality in patients with intensive care unit (ICU)-treated refractory status epilepticus (RSE) in a population-based study. Methods: This was a retrospective study of the Finnish Intensive Care Consortium (FICC) database of adult patients (16 years of age or older) with ICU-treated RSE in Finland during a 3-year period (2010-2012). The database consists of admissions to all 20 Finnish hospitals treating RSE in the ICU. All five university hospitals and 11 out of 15 central hospitals participated in the present study. The total adult referral population in the study hospitals was 3.92 million, representing 91% of the adult population of Finland. Patients whose condition had a post-anoxic aetiological basis were excluded. Results: We identified 395 patients with ICU-treated RSE, corresponding to an annual incidence of 3.4/100,000 (95% confidence interval (CI) 3.04-3.71). Hospital mortality was 7.4% (95% CI 0-16.9%), and 1-year mortality was 25. 4% (95% CI 21.2-29.8%). Mortality at hospital discharge was associated with severity of organ dysfunction. Mortality at 1 year was associated with older age (adjusted odds ratio (aOR) 1.033, 95% CI 1.104-1.051, p = 0.001), sequential organ failure assessment (SOFA) score (aOR 1.156, CI 1.051-1.271, p = 0.003), super-refractory status epilepticus (SRSE) (aOR 2.215, 95% CI 1.20-3.84, p = 0.010) and dependence in activities of daily living (ADL) (aOR 2.553, 95% CI 1.537-4.243, p <0.0001). Conclusions: Despite low hospital mortality, 25% of ICU-treated RSE patients die within a year. Super-refractoriness, dependence in ADL functions, severity of organ dysfunction at ICU admission and older age predict long-term mortality.Peer reviewe

Predictors of hospital and one-year mortality in intensive care patients with refractory status epilepticus: a populationbased study

Background: The aim was to determine predictors of hospital and 1-year mortality in patients with intensive care unit (ICU)-treated refractory status epilepticus (RSE) in a population-based study.Methods: This was a retrospective study of the Finnish Intensive Care Consortium (FICC) database of adult patients (16 years of age or older) with ICU-treated RSE in Finland during a 3-year period (2010-2012). The database consists of admissions to all 20 Finnish hospitals treating RSE in the ICU. All five university hospitals and 11 out of 15 central hospitals participated in the present study. The total adult referral population in the study hospitals was 3.92 million, representing 91% of the adult population of Finland. Patients whose condition had a post-anoxic aetiological basis were excluded.Results: We identified 395 patients with ICU-treated RSE, corresponding to an annual incidence of 3.4/100,000 (95% confidence interval (CI) 3.04-3.71). Hospital mortality was 7.4% (95% CI 0-16.9%), and 1-year mortality was 25. 4% (95% CI 21.2-29.8%). Mortality at hospital discharge was associated with severity of organ dysfunction. Mortality at 1 year was associated with older age (adjusted odds ratio (aOR) 1.033, 95% CI 1.104-1.051, p = 0.001), sequential organ failure assessment (SOFA) score (aOR 1.156, CI 1.051-1.271, p = 0.003), super-refractory status epilepticus (SRSE) (aOR 2.215, 95% CI 1.20-3.84, p = 0.010) and dependence in activities of daily living (ADL) (aOR 2.553, 95% CI 1.537-4.243, p < 0.0001).Conclusions: Despite low hospital mortality, 25% of ICU-treated RSE patients die within a year. Super-refractoriness, dependence in ADL functions, severity of organ dysfunction at ICU admission and older age predict long-term mortality

Current practices in long-term video-EEG monitoring services: A survey among partners of the E-PILEPSY pilot network of reference for refractory epilepsy and epilepsy surgery.

The European Union-funded E-PILEPSY network aims to improve awareness of, and accessibility to, epilepsy surgery across Europe. In this study we assessed current clinical practices in epilepsy monitoring units (EMUs) in the participating centers. A 60-item web-based survey was distributed to 25 centers (27 EMUs) of the E-PILEPSY network across 22 European countries. The questionnaire was designed to evaluate the characteristics of EMUs, including organizational aspects, admission, and observation of patients, procedures performed, safety issues, cost, and reimbursement. Complete responses were received from all (100%) EMUs surveyed. Continuous observation of patients was performed in 22 (81%) EMUs during regular working hours, and in 17 EMUs (63%) outside of regular working hours. Fifteen (56%) EMUs requested a signed informed consent before admission. All EMUs performed tapering/withdrawal of antiepileptic drugs, 14 (52%) prior to admission to an EMU. Specific protocols on antiepileptic drugs (AED) tapering were available in four (15%) EMUs. Standardized Operating Procedures (SOP) for the treatment of seizure clusters and status epilepticus were available in 16 (59%). Safety measures implemented by EMUs were: alarm seizure buttons in 21 (78%), restricted patient's ambulation in 19 (70%), guard rails in 16 (59%), and specially designated bathrooms in 7 (26%). Average costs for one inpatient day in EMU ranged between 100 and 2200 Euros. This study shows a considerable diversity in the organization and practice patterns across European epilepsy monitoring units. The collected data may contribute to the development and implementation of evidence-based recommended practices in LTM services across Europe

Lacosamide adjunctive therapy for partial-onset seizures: a meta-analysis

Background. The relative efficacy and safety of lacosamide as adjunctive therapy compared to other antiepileptic drugs has not been well established.Objective. To determine if lacosamide provides improved efficacy and safety, reduced length of hospital stay and improved quality of life compared with other anti-epileptic therapies for adults with partial-onset seizures.Data Sources. A systematic review of the medical literature using Medline (1946–Week 4, 2012), EMBASE (1980–Week 3, 2012), Cochrane Central Register of Controlled Trials (Issue 1 of 12, January 2012). Additional studies were identified (through to February 7, 2012) by searching bibliographies, the FDA drug approval files, clinical trial registries and major national and international neurology meeting abstracts. No restrictions on publication status or language were applied.Study Selection. Randomized controlled trials of lacosamide in adults with partial-onset seizures were included.Data Extraction. Study selection, extraction and risk of bias assessment were performed independently by two authors. Authors of studies were contacted for missing data.Data Synthesis. All pooled analyses used the random effects model.Results. Three trials (1311 patients) met inclusion criteria. Lacosamide increased the 50% responder rate compared to placebo (RR 1.68 [95% CI 1.36 to 2.08]; I2 = 0%). Discontinuation due to adverse events was statistically significantly higher in the lacosamide arm (RR3.13 [95% CI 1.94 to 5.06]; I2 = 0%). Individual adverse events (ataxia, dizziness, fatigue, and nausea) were also significantly higher in the lacosamide group.Limitations. All dosage arms from the included studies were pooled to make a single pair-wise comparison to placebo. Selective reporting of outcomes was found in all of the included RCTs.Conclusions. Lacosamide as adjunctive therapy in patients with partial-onset seizures increases the 50% responder rate but with significantly more adverse events compared to the placebo

Association of Human Herpesvirus-6B with Mesial Temporal Lobe Epilepsy

Steve Jacobson and colleagues report finding human herpesvirus-6B DNA in brain resections from 11 of 16 patients with mesial temporal lobe epilepsy, strengthening the evidence for a role for this virus in this condition

Emergence of spatially heterogeneous burst suppression in a neural field model of electrocortical activity

Burst suppression in the electroencephalogram (EEG) is a well-described phenomenon that occurs during deep anesthesia, as well as in a variety of congenital and acquired brain insults. Classically it is thought of as spatially synchronous, quasi-periodic bursts of high amplitude EEG separated by low amplitude activity. However, its characterization as a “global brain state” has been challenged by recent results obtained with intracranial electrocortigraphy. Not only does it appear that burst suppression activity is highly asynchronous across cortex, but also that it may occur in isolated regions of circumscribed spatial extent. Here we outline a realistic neural field model for burst suppression by adding a slow process of synaptic resource depletion and recovery, which is able to reproduce qualitatively the empirically observed features during general anesthesia at the whole cortex level. Simulations reveal heterogeneous bursting over the model cortex and complex spatiotemporal dynamics during simulated anesthetic action, and provide forward predictions of neuroimaging signals for subsequent empirical comparisons and more detailed characterization. Because burst suppression corresponds to a dynamical end-point of brain activity, theoretically accounting for its spatiotemporal emergence will vitally contribute to efforts aimed at clarifying whether a common physiological trajectory is induced by the actions of general anesthetic agents. We have taken a first step in this direction by showing that a neural field model can qualitatively match recent experimental data that indicate spatial differentiation of burst suppression activity across cortex

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods: Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease. Results: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.info:eu-repo/semantics/publishedVersio

A survey of the European Reference Network EpiCARE on clinical practice for selected rare epilepsies

Objective: Clinical care of rare and complex epilepsies is challenging, because evidence‐based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. / Methods: Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web‐based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht‐like diseases. A consensus‐based questionnaire was generated for each disease. / Results: Twenty‐six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht‐like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. / Significance: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers