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Topiramate in the Treatment of Generalized Convulsive Status Epilepticus in Adults: A Systematic Review with Individual Patient Data Analysis.

ABSTRACT: Generalized convulsive status epilepticus (GCSE) is a medical emergency associated with high morbidity and mortality that requires prompt medical intervention. Topiramate (TPM) is an antiepileptic drug effective against a broad spectrum of seizure types, and has been proposed as a possible therapeutic option for super-refractory status epilepticus (SRSE), the most severe form of GCSE.This review aimed to evaluate the role of TPM in GCSE, including SRSE.MEDLINE, CENTRAL, ClinicalTrials.gov, LILACS, Google Scholar, and Opengrey.eu were systematically searched. We compared: (1) patients who did and who did not receive TPM as their last drug; (2) patients receiving TPM as the last drug and achieving SE control and patients receiving TPM as the last drug but without termination of SE.The literature search yielded 1164 results, with individual data available for 35 patients (six with SRSE) from four studies. SE was controlled in 68.6% of patients receiving TPM either as the last drug (20) or not (15), and in 14 of the 20 patients receiving TPM as the last drug (70%). Only six patients received TPM for SRSE; in five of them, TPM was administered as the last drug with resolution of SE in four. When comparing patients who did and did not receive TPM as the last drug, no statistically significant difference was found for any of the variables considered; similarly, no difference was found comparing patients receiving TPM as the last drug and achieving SE control with those receiving TPM as the last drug but without termination of SE.The lack of a statistically significant difference is likely to be due to the small sample size. In only a few patients was TPM used for SRSE. There is an unmet need for high-quality studies to evaluate the role of TPM in GCSE.

SUBMITTER: Brigo F

PROVIDER: S-EPMC5216088 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Topiramate in the Treatment of Generalized Convulsive Status Epilepticus in Adults: A Systematic Review with Individual Patient Data Analysis.

Brigo Francesco F Bragazzi Nicola Luigi NL Igwe Stanley C SC Nardone Raffaele R Trinka Eugen E

Drugs 20170101 1

<h4>Background</h4>Generalized convulsive status epilepticus (GCSE) is a medical emergency associated with high morbidity and mortality that requires prompt medical intervention. Topiramate (TPM) is an antiepileptic drug effective against a broad spectrum of seizure types, and has been proposed as a possible therapeutic option for super-refractory status epilepticus (SRSE), the most severe form of GCSE.<h4>Aim</h4>This review aimed to evaluate the role of TPM in GCSE, including SRSE.<h4>Methods< ...[more]

PMID: 28004305

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Project description:ImportanceStatus epilepticus (SE) is associated with significant morbidity and mortality. Since the late 1990s, a more aggressive management of prolonged convulsive seizures lasting longer than 5 minutes has been advocated.ObjectiveTo determine if convulsive SE mortality has decreased during a time of increasing advocacy for out-of-hospital treatment and escalating and earlier treatment protocols for prolonged seizures and SE.Data sourceThis systemic review and meta-analysis on studies focused on the mortality of convulsive status epilepticus was conducted by searching MEDLINE, Embase, PsychINFO, CINAHL Plus, and the Cochrane Database of Systematic Reviews between January 1, 1990, and June 30, 2017.Study selectionStudies were excluded if they had fewer than 30 participants (<20 for refractory SE), were limited to SE of single specific etiology or an evaluation of a single treatment modality, or were studies of nonconvulsive SE.Data extraction and synthesisData were abstracted and their quality was assessed via a modified Newcastle-Ottawa scale independently by 2 reviewers (A.N. and T.D.G.) using the Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. Data were pooled using a random-effects model.Main outcomes and measuresThe main outcome measure was in-hospital mortality or 30-day case fatality expressed as proportional mortality.ResultsSixty-one studies were included in the analysis. The pooled mortality ratios were 15.9% (95% CI, 12.7-19.2) for adult studies, 13.0% (95% CI, 7.2-19.0) for all-age population studies, 3.6% (95% CI, 2.0%-5.2%) for pediatric studies, and 17.3% (95% CI, 9.8-24.7) for refractory SE studies, with very high between-study heterogeneity. We found no evidence of a change in prognosis over time nor by the definition of SE used.Conclusions and relevanceThe mortality of convulsive SE is higher in adults than in children and there was no evidence for improved survival over time. Although there are many explanations for these findings, they can be explained by aetiology of SE being the major determinant of mortality. However, there are potential confounders, including differences in case ascertainment and study heterogeneity. This meta-analysis highlights the need for strict international guidelines for the study of this condition.

Project description:Status epilepticus has been shown to activate the proliferation of neural stem cells in the hippocampus of the brain, while also causing a large amount of neuronal death, especially in the subgranular zone of the dentate gyrus and the subventricular zone. Simultaneously, proliferating stem cells tend to migrate to areas with obvious damage. Our previous studies have clearly confirmed the effect of sodium valproate on cognitive function in rats with convulsive status epilepticus. However, whether neurogenesis can play a role in the antiepileptic effect of sodium valproate remains unknown. A model of convulsive status epilepticus was established in Wistar rats by intraperitoneal injection of 3 mEq/kg lithium chloride, and intraperitoneal injection of pilocarpine 40 mg/kg after 18-20 hours. Sodium valproate (100, 200, 300, 400, 500, or 600 mg/kg) was intragastrically administered six times every day (4-hour intervals) for 5 days. To determine the best dosage, sodium valproate concentration was measured from the plasma. The effective concentration of sodium valproate in the plasma of the rats that received the 300-mg/kg intervention was 82.26 ± 11.23 μg/mL. Thus, 300 mg/kg was subsequently used as the intervention concentration of sodium valproate. The following changes were seen: Recording excitatory postsynaptic potentials in the CA1 region revealed high-frequency stimulation-induced long-term potentiation. Immunohistochemical staining for BrdU-positive cells in the brain revealed that sodium valproate intervention markedly increased the success rate and the duration of induced long-term potentiation in rats with convulsive status epilepticus. The intervention also reduced the number of newborn neurons in the subgranular area of the hippocampus and subventricular zone and inhibited the migration of newborn neurons to the dentate gyrus. These results indicate that sodium valproate can effectively inhibit the abnormal proliferation and migration of neural stem cells and newborn neurons after convulsive status epilepticus, and improve learning and memory ability.

Project description:BackgroundGeneralized convulsive status epilepticus (GCSE) is a frequent medical emergency. GCSE treatment focuses on the administration of benzodiazepines followed by a second-line antiepileptic drug (AED). Despite this stepwise strategy, GCSE is not controlled in one-quarter of patients and is associated with protracted hospitalization, high mortality, and long-term disability. Valproic acid (VPA) is an AED with good tolerability and neuroprotective properties.ObjectiveThis study aims to demonstrate that administration of VPA as an adjuvant for first- and second-line treatment in GCSE can improve outcomes.MethodsA multicenter, double-blind, randomized controlled trial was conducted, comparing VPA with a placebo in adults admitted to intensive care units (ICUs) for GCSE in France. GCSE was diagnosed by specifically trained ICU physicians according to standard criteria. All patients received standard of care, including a benzodiazepine and a second-line AED (not VPA), at the discretion of the treating medical team. In the intervention arm, VPA was administered intravenously at a loading dose of 30 mg/kg over 15 minutes, followed by a continuous infusion of 1 mg/kg/hour over the next 12 hours. In the placebo group, an identical intravenous administration of 0.9% saline was used. The primary outcome was the proportion of patients discharged alive from the hospital by day 15. Secondary outcomes were frequency of refractory and super refractory GCSE, ICU-related morbidity, adverse events related to VPA, and cognitive dysfunction at 3 months. Statistical analyses will be performed according to the intent-to-treat principle.ResultsThe first patient was randomized on February 18, 2013, and the last patient was randomized on July 7, 2018. Of 248 planned patients, 98.7% (245/248) were enrolled across 20 ICUs. At present, data management is still ongoing, and all parties involved in the trial remain blinded.ConclusionsThe Valproic Acid as an Adjuvant Treatment for Generalized Convulsive Status Epilepticus (VALSE) trial will evaluate whether the use of VPA as an adjuvant for first- and second-line treatment in GCSE improves outcomes.Trial registrationClinicalTrials.gov NCT01791868; https://clinicaltrials.gov/ct2/show/NCT01791868.International registered report identifier (irrid)DERR1-10.2196/22511.

Dataset Information

Topiramate in the Treatment of Generalized Convulsive Status Epilepticus in Adults: A Systematic Review with Individual Patient Data Analysis.

Publications

Topiramate in the Treatment of Generalized Convulsive Status Epilepticus in Adults: A Systematic Review with Individual Patient Data Analysis.

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