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Objectives: Stiripentol, fenfluramine, and cannabidiol are licensed add-on therapies to treat seizures in Dravet Syndrome (DS). There are no direct or indirect comparisons assessing their full licensed dose regimens, across different jurisdictions, as first-line add-on therapies in DS., Methods: We conducted a systematic review and frequentist network meta-analysis (NMA) of randomized controlled trial (RCT) data for licensed add-on DS therapies. We compared the proportions of patients experiencing: reductions from baseline in monthly convulsive seizure frequency (MCSF) of ≥50% (clinically meaningful), ≥75% (profound), and 100% (seizure-free); serious adverse events (SAEs); discontinuations due to AEs., Results: We identified relevant data from two placebo-controlled RCTs for each drug. Stiripentol 50 mg/kg/day and fenfluramine 0.7 mg/kg/day had similar efficacy in achieving ≥50% (clinically meaningful) and ≥75% (profound) reductions from baseline in MCSF (absolute risk difference [RD] for stiripentol versus fenfluramine 1% [95% confidence interval: -20% to 22%; p = 0.93] and 6% [-15% to 27%; p = 0.59], respectively), and both were statistically superior (p < 0.05) to licensed dose regimens of cannabidiol (10 or 20 mg/kg/day, with/irrespective of clobazam) for these outcomes. Stiripentol was statistically superior in achieving seizure-free intervals compared to fenfluramine (RD = 26% [CI: 8% to 44%; p < 0.01]) and licensed dose regimens of cannabidiol. There were no significant differences in the proportions of patients experiencing SAEs. The risk of discontinuations due to AEs was lower for stiripentol, although the stiripentol trials were shorter., Significance: This NMA of RCT data indicates stiripentol, as a first-line add-on therapy in DS, is at least as effective as fenfluramine and both are more effective than cannabidiol in reducing convulsive seizures. No significant difference in the incidence of SAEs between the three add-on agents was observed, but stiripentol may have a lower risk of discontinuations due to AEs. These results may inform clinical decision-making and the continued development of guidelines for the treatment of people with DS., Plain Language Summary: This study compared three drugs (stiripentol, fenfluramine, and cannabidiol) used alongside other medications for managing seizures in a severe type of epilepsy called DS. The study found that stiripentol and fenfluramine were similarly effective in reducing seizures and both were more effective than cannabidiol. Stiripentol was the best drug for stopping seizures completely based on the available clinical trial data. All three drugs had similar rates of serious side effects, but stiripentol had a lower chance of being stopped due to side effects. This information can help guide treatment choices for people with DS., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Double-blind, randomized, and placebo-controlled trial SP0967 (NCT02477839/2013-000717-20) did not demonstrate superior efficacy of lacosamide versus placebo in patients aged ≥1 month to <4 years with uncontrolled focal seizures, per ≤72 h video-electroencephalogram (video-EEG)-based primary endpoints (reduction in average daily frequency of focal seizures at end-of-maintenance [EOM] versus end-of-baseline [EOB], patients with ≥50% response). This was unexpected because randomized controlled trial SP0969 (NCT01921205) showed efficacy of lacosamide in patients aged ≥4 to <17 years with uncontrolled focal seizures. SP0969's primary endpoint was based on seizure diary instead of video-EEG, an issue with the latter being inter-reader variability. We evaluated inter-reader agreement in video-EEG interpretation in SP0967, which to our knowledge, are the first such data for very young children with focal seizures from a placebo-controlled trial., Methods: Local investigator and central reader agreement in video-EEG interpretation was analyzed post hoc., Results: Analysis included 105 EOB and 98 EOM video-EEGs. Local investigators and central reader showed poor agreement based on ≥2 focal seizures at EOB (Kappa = 0.01), and fair agreement based on ≥2 focal seizures at EOM (Kappa = 0.23). Local investigator and central reader seizure count interpretations varied substantially, particularly for focal seizures, but also primary generalized and unclassified epileptic seizures, at both timepoints., Interpretation: High inter-reader variability and low inter-reader reliability of the interpretation of seizure types and counts prevent confident conclusion regarding the lack of efficacy of lacosamide in this population. We recommend studies in very young children do not employ video-EEGs exclusively for accurate study inclusion or as an efficacy measure., (© 2024 UCB Biopharma SRL. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Epilepsy is one of the main symptoms affecting the lives of individuals with tuberous sclerosis complex (TSC), causing a high rate of morbidity. Individuals with TSC can present with various types of seizures, epilepsies, and epilepsy syndromes that can coexist or appear in relation to age. Focal epilepsy is the most frequent epilepsy type with two developmental and epileptic encephalopathies: infantile spasms syndrome and Lennox-Gastaut syndrome. Active screening and early management of epilepsy is recommended in individuals with TSC to limit its consequences and its impact on quality of life, cognitive outcome and the economic burden of the disease. The progress in the knowledge of the mechanisms underlying epilepsy in TSC has paved the way for new concepts in the management of epilepsy related to TSC. In addition, we are moving from traditional "reactive" and therapeutic choices with current antiseizure medications used after the onset of seizures, to a proactive approach, aimed at predicting and preventing epileptogenesis and the onset of epilepsy with vigabatrin, and to personalized treatments with mechanistic therapies, namely mechanistic/mammalian target of rapamycin inhibitors. Indeed, epilepsy linked to TSC is one of the only epilepsies for which a predictive and preventive approach can delay seizure onset and improve seizure response. However, the efficacy of such interventions on long-term cognitive and psychiatric outcomes is still under investigation., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction : Management of individuals with Dravet Syndrome has evolved significantly over the past 10 years. Progress has been made in understanding the pathophysiology, the long-term outcome and possible consequences of inappropriate therapies, new drugs have been approved by the regulatory authorities and patients and families expressed their needs beyond seizures' control. Areas covered : The authors aimed at providing an overview of the main antiseizure medications used in Dravet syndrome with a particular focus on safety considerations. As the highly active phase of seizures takes place before the age of 5 years, the characteristics of antiseizure medications in infancy and childhood have also been considered due to their impact on antiseizure medication safety. Expert opinion : Recent treatments, evaluated via randomized clinical trials, are promising in terms of efficacy and safety in individuals with DS. However, the balance between expected benefits and risks taken must be accurately assessed on an individual basis. There is a lack of data to understand the needs of patients and families, a major point particularly in this population, where the evaluation of efficacy and safety beyond seizures is difficult due to cognitive delay and behavioral disorders and where this evaluation is coming almost exclusively from caregivers.

Introduction: Stiripentol is an orphan drug approved for the treatment of seizures associated with Dravet syndrome (since 2007 in Europe). Therapeutic options recently grew in this rare and severe early-onset epilepsy with the approval of stiripentol and cannabidiol in 2018 in the US and the positive trials just completed with fenfluramine. Areas covered: First, the short-term efficacy of stiripentol as adjunctive therapy to clobazam and valproate, which was discovered by serendipity thanks to a basket study and then confirmed in 1998 despite the small number of samples in phase III trials. Second, the further observational series worldwide, which showed sustained efficacy and satisfactory tolerability for up to 20 year exposure. Third, why it took more than 20 years for stiripentol be approved in a number of countries despite these extensive data: drug-drug interactions between stiripentol and comedication will be addressed, as well as the experimental and pharmacogenetic data which support the anticonvulsant effect of stiripentol per se. Expert opinion: Considering current and future competitors (cannabidiol and fenfluramine), efficacy seems lower for cannabidiol and seizure freedom seems occasionally be obtained with fenfluramine. Additionally, stiripentol could be especially useful in two critical conditions of the disease, very young age (<2 years) and convulsive status epilepticus.

Vigabatrin is indicated as adjunctive therapy for refractory focal seizures. For children, European recommendations indicate maintenance doses varying from 30 to 100 mg/kg/day for this indication. Since cumulated dose was associated with retinal toxicity, it is essential to administrate the lowest effective dose to patients. This work was conducted with the purpose to determine the pediatric doses of vigabatrin that allow a similar exposure than effective doses in adults (2-3 g/day) through a pharmacokinetic (PK) study, using both pediatric and adult data. For this study, we focused on the active S(+) enantiomer of vigabatrin. First, the adult effective exposition range of vigabatrin-S was determined from an adult PK model. Then, this same model was scaled to the pediatric population using allometry and maturation principles to account for growth and development. The ability of the model to predict pediatric data was assessed by comparing population predictions with observed pediatric data. Finally, the extrapolated pediatric model was used to simulate pediatric expositions which were compared to the adult exposition range (36.5-77.9 mg.h/L). From those simulations, we determined that, for children aged between 3 months and 18 years, doses between 40 and 50 mg/kg/day allow vigabatrin-S expositions similar to those found in adults at the recommended posology. We proposed those doses as optimal maintenance doses that may be increased, if necessary, by slow titration., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Vigabatrin is an antiepileptic drug indicated as monotherapy in infantile spasms. However, the pharmacokinetic profile of this compound in infants and young children is still poorly understood, as is the minimal effective dose, critical information given the risk of exposure-related retinal toxicity with vigabatrin. A reasonable approach to determining this minimal dose would be to identify the lowest dose providing a low risk of exposure overlap with the 36-mg/kg dose, which is the highest dose associated with an increased risk for treatment failure, based on randomized dose-ranging data. A population pharmacokinetic model was consequently developed from 28 children (aged 0.4-5.7 years) for the active S(+)-enantiomer, using Monolix software. In parallel, a population model was developed from published adult data and scaled to children using theoretical allometry and maturation of the renal function. A one-compartment model with zero-order absorption and first-order elimination described the pediatric data. Mean population estimates (percentage interindividual variability) for the apparent clearance, apparent distribution volume, and absorption duration were 2.36 L/h (24.5%), 17 L (38%), and 0.682 hours, respectively. Apparent clearance and apparent distribution volume were related to body weight by empirical allometric equations. Monte Carlo simulations evidenced that a daily dose of 80 mg/kg should minimize exposure overlap with the 36-mg/kg dose. Similar results were obtained for the adult model scaled to children. Consequently, a minimal effective dose of 80 mg/kg/day could be considered for patients with infantile spasms., (© 2018, The American College of Clinical Pharmacology.)

Objective: To evaluate continuing stiripentol treatment in adulthood in Dravet syndrome (DS)., Method: Longitudinal data were collected from the last visit prior to age 15 years (V 15 y ) to the last visit in adulthood (V adult ) in the 40 DS patients (32 typical, eight atypical) of a French historical cohort (Paris) of subjects who continued stiripentol from childhood or adolescence to adulthood., Results: At V adult (18-40 years, median = 23 years), all the patients were still receiving stiripentol (exposure = 3-24 years, median = 18 years), associated with clobazam (40/40), valproate (39/40), and topiramate (21/40). Between V 15 y and V adult , stiripentol was interrupted in five patients (two for adverse events) but reintroduced following seizure aggravation. Loss of appetite affected 15 of 40 patients but resolved after reducing the dose of stiripentol or valproate; no other new stiripentol-related adverse events were reported. Mean stiripentol dose was progressively decreased from 39 to 25 mg/kg/d (P = 0.0002), whereas clobazam (0.27 mg/kg/d) and valproate (14 mg/kg/d) remained stable. At V adult , 37 of 40 patients still had generalized tonic-clonic seizures, but none still had status epilepticus (vs three at V 15 y ) and only one had myoclonia. During adulthood, generalized tonic-clonic seizure frequency and duration continued to decrease (P = 0.02, P = 0.008) and 10 patients experienced seizure-free periods ≥ 1 years (up to 5 years). All patients already had intellectual disability at V 15 y , but retardation was more severe at V adult (P = 0.03). Furthermore, neurological/gait condition had declined (two patients became bedridden) and behavior had worsened (P < 0.0002). Nevertheless, the 33 patients on stiripentol from infancy/childhood (<15 years) tended to have better seizure outcome in midadulthood than the seven treated from adolescence (>15 years) and the DS patients treated from adult age or stiripentol-naive subjects reported in the literature., Significance: The efficacy and safety of the stiripentol/valproate/clobazam combination started at pediatric age are maintained at very long term during adulthood. Such prolonged stiripentol therapy tends to positively impact the late prognosis of epilepsy, especially when initiated before adolescence., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Aim: The aim of this study was to describe the pharmacokinetics of stiripentol in children with Dravet syndrome and to determine the concentrations of stiripentol achieved in this population for the usual 25 mg/kg twice-daily dose., Methods: Thirty-five children with epilepsy were included in a prospective population pharmacokinetic study (using MONOLIX software). Four blood samples were drawn per patient. Stiripentol area under the plasma concentration-time curve (AUC) values and trough concentrations were simulated for 7000 theoretical children weighing between 10 and 70 kg for the 25 mg/kg twice-daily dose., Results: The pharmacokinetics of stiripentol was described using a one-compartment model with zero-order absorption and first-order elimination. The apparent clearance (CL/F) and apparent volume of distribution (V d /F) of stiripentol were related to body weight by allometric equations. A dose-dependent non-linearity was also observed with an allometric model relating CL/F to the weight-normalised dose. Mean population estimates (% inter-individual variability) were 4.2 L/h (21%) for CL/F and 82 L (25%) for V d /F. The AUC of stiripentol increased by 300% when body weight increased from 10 to 70 kg., Conclusion: This population pharmacokinetic model of stiripentol in children with Dravet syndrome confirmed the dose-dependent non-linearity that has been evidenced in adults. It also supported that a 25 mg/kg twice-daily dose might lead to excessive exposure in children >30 kg, suggesting an eventual dose adjustment during adolescence., Clinical Trial Identifier: This study is part of the STIPOP study (EUDRACT number: 2007-001784-30).

Purpose: The objective of this work was to develop a population pharmacokinetic model for a prolonged-release granule formulation of valproic acid (VPA) in children with epilepsy and to determine the doses providing a VPA trough concentration (C trough ) within the target range (50-100 mg/L)., Methods: Ninety-eight children (1-17.6 years, 325 plasma samples) were included in the study. The model was built with NONMEM 7.3. The probability to obtain C trough between 50 and 100 mg/L was determined by the Monte Carlo simulations for doses of 20, 30, 40, and 60 mg/kg/day and body weights between 10 and 70 kg., Results: A one compartment model, with first-order absorption and flip-flop parameterization and linear elimination, but taking protein binding into account, was used to describe the data. Typical values for unbound VPA clearance and distribution volume were 6.24 L/h/70 kg and 130 L/h/70 kg respectively. Both parameters were related to body weight via allometric models. The highest probability to obtain a C trough within the target range for 10-kg children was obtained with a 40 mg/kg daily dose, whereas daily doses of 30 and 20 mg/kg were found appropriate for 20 to 30- and ≥ 40-kg children respectively. However, for these same doses, the exposure to unbound VPA could differ by 40%., Conclusions: If the present study supports the current dose recommendations of 20-30 mg/kg/day, except for children under 20 kg, who may need higher doses, it also highlights the need for further research on the pharmacokinetics/pharmacodynamic profile of unbound VPA.

Objectives: Little is known about off-label use and manipulations to achieve the prescribed dose of antiepileptic drugs (AEDs) in outpatient prescriptions. This study aimed to evaluate this practice in a tertiary center for child epilepsy., Methods: We reviewed off-label use and manipulations of AEDs delivered to the outpatient's epilepsy clinic. Multivariate logistic regressions were used to determine the factors associated with off-label and manipulated uses., Results: Five hundred eleven consultations generated 897 AED deliveries (1.75/consultation). Off-label use involved 182 (20.3%) of prescribed AEDs. Factors associated with off-label use were polytherapy and new AEDs while increase of age and nondevelopmental and structural-metabolic etiologies have a protective effect. Among the 1725 doses of AEDs prescribed per day, 33.5% generated manipulations (n=582): 40% inadequate (n=237) and 60% adequate (203 syrups, 112 scored tablets, 30 drops medicine). Polytherapy (p<10 -4 ) and the absence of market authorization significantly favored manipulations whereas the increase in age restricted them., Conclusion: Off-label use and manipulations of AEDs remain an important problem in home care of children with epilepsy. This is mainly a concern for the most vulnerable groups, i.e., young patients, patients undergoing polytherapy, and patients with developmental and epileptic encephalopathy (DEE). International initiatives have been launched to improve the availability of labeled and adapted drugs in this population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: Oxcarbazepine is an antiepileptic drug with an activity mostly due to its monohydroxy derivative metabolite (MHD). A parent-metabolite population pharmacokinetic model in children was developed to evaluate the consistency between the recommended paediatric doses and the reference range for trough concentration (C trough ) of MHD (3-35 mg l -1 )., Methods: A total of 279 plasma samples were obtained from 31 epileptic children (age 2-12 years) after a single dose of oxcarbazepine. Concentration-time data were analysed with Monolix 4.3.2. The probability to obtain C trough between 3-35 mg l -1 was determined by Monte Carlo simulations for doses ranging from 10 to 90 mg kg -1  day -1 ., Results: A parent-metabolite model with two compartments for oxcarbazepine and one compartment for MHD best described the data. Typical values for oxcarbazepine clearance, central and peripheral distribution volume and distribution clearance were 140 l h -1  70 kg -1 , 337 l 70 kg -1 , 60.7 l and 62.5 l h -1 , respectively. Typical values for MHD clearance and distribution volume were 4.11 l h -1  70 kg -1 and 54.8 l 70 kg -1 respectively. Clearances and distribution volumes of oxcarbazepine and MHD were related to body weight via empirical allometric models. Enzyme-inducing antiepileptic drugs (EIAEDs) increased MHD clearance by 29.3%. Fifty-kg children without EIAEDs may need 20-30 mg kg -1  day -1 instead of the recommended target maintenance dose (30-45 mg kg -1  day -1 ) to obtain C trough within the reference range. By contrast, 10-kg children with EIAEDs would need 90 mg kg -1  day -1 instead of the maximum recommended dose of 60 mg kg -1  day -1 ., Conclusion: This population pharmacokinetic model of oxcarbazepine supports current dose recommendations, except for 10-kg children with concomitant EIAEDs and 50-kg children without EIAEDs., (© 2017 The British Pharmacological Society.)

Objective: The aim of this study was to assess outcome and seizure response to treatment with stiripentol (STP) associated to valproate (VPA) and clobazam (CLB), which we have used in our center since the 1990s, in patients with Dravet syndrome (DS)., Methods: We performed a cross-sectional study of all DS patients with SCN1A mutations who had at least one visit to our center in 2013. A total of 54 patients were included (32 males, 22 females), whose ages ranged from 2.5 to 22 years., Results: Seizure onset ranged from 2 to 9 months (mean 5 months). Treatment started at a mean age of 7 months with valproate (VPA) as first therapy in 83% of patients. STP was prescribed in 96% at an average age of 20 months. At last follow-up (up to 22 years, median 8 years), 96% were still receiving STP, with VPA and clobazam (CLB) in 91%. Additional therapies were prescribed in 72% of patients. Most patients (96%) continued to have clonic or tonic-clonic seizures but they were brief (<5min, with last status epilepticus (SE) episode being before 4 years of age). Seizures occurred weekly (>3/month) in 38% of patients, monthly (1-3/month) in 40%, and yearly in the remaining patients. None presented with daily seizures. Seizure frequency at last visit was related to the age of treatment initiation, the age of last SE, and SCN1A mutation type., Conclusions: Triple therapy with STP, VPA, and CLB was maintained long-term by 96% of this large DS cohort because the reduced frequency and severity of seizures STP provided when added to CLB and VPA was durable. Nevertheless, only a few patients achieved seizure freedom and persisting seizures remains a concern in the majority of patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Stiripentol and vigabatrin are the two anticonvulsant drugs currently approved in severe infantile-onset epilepsies, respectively Dravet syndrome and infantile spasms., Areas Covered: For both, the indication was discovered by chance thanks to an exploratory study. Both demonstrated indisputable efficacy through randomized-controlled trials. Stiripentol as adjunctive therapy to clobazam and valproate performed better than placebo, and vigabatrin as first-line monotherapy better than the reference steroid therapy in spasms due to tuberous sclerosis. At one-year treatment vigabatrin and steroids were equally efficient in the other etiologies of spasms. However, it took more than 20 years for both drugs to be approved world-wide., Expert Opinion: Stiripentol suffered from pharmacokinetic potentiation of clobazam, thus raising the question whether it was efficient per se. Finally, animal models and pharmacogenetic data on CYP2C19 confirmed its specific anticonvulsant effect. Stiripentol (in comedication with clobazam and valproate) is therefore to be recommended for Dravet patients. Vigabatrin was found to have a frequent and irreversible retinal toxicity, which required an alternative visual testing to be detected in young children. Today the benefit/risk ratio of vigabatrin as first-line is considered to be positive in infantile spasms, given the severity of this epilepsy and the lack of a safer alternative therapy.

Aim: The aim of this study was to describe the pharmacokinetics of clobazam and its active metabolite N-desmethylclobazam (N-CLB) in children with Dravet syndrome receiving the stiripentol/valproic acid/clobazam combination therapy of reference and to determine the concentrations of clobazam and N-CLB obtained in this population for the usual 0.2 mg/kg twice-daily dose., Methods: Thirty-five children with epilepsy were included in a prospective population pharmacokinetic study (using NONMEM(®) software). Four blood samples were drawn per patient. Area under the plasma concentration-time curve (AUC) and trough concentration (C trough) values for clobazam and N-CLB were simulated for 12,000 theoretical children weighing between 10 and 60 kg., Results: The pharmacokinetics of clobazam were described by a one-compartment model with first-order absorption, and elimination, formation and elimination of N-CLB were also first-order processes. The apparent total clearance (CL/F) and distribution volume (V CLB/F) of clobazam and the elimination rate constant of N-CLB (Kem) were related to body weight by allometric equations. Mean population estimates (% inter-individual variability) were 1.23 L/h (29%) for CL/F, 39.1 L (18%) for V CLB/F and 0.0706 h(-1) (26%) for Kem. The AUC values for clobazam and N-CLB were found to increase by 100% when bodyweight increased from 10 to 60 kg, and the simulated C trough values were higher than the currently accepted target values (0.03-0.3 mg/L for clobazam and 0.3-3 mg/L for N-CLB)., Conclusion: This is the first simultaneous pharmacokinetic model for clobazam and N-CLB in epileptic children. Indicative values for the routine therapeutic drug monitoring of clobazam in children with Dravet syndrome treated by stiripentol are provided. The possible consequences of the weight-related changes on clobazam and N-CLB exposures should be further evaluated.

Contrary to the treatment concerns regarding drug compliance or pregnancy at transition to adulthood, those directly related to epilepsy remain poorly documented. As an initial step to answer this problem, we reviewed the controlled trials of antiepileptic drugs (AEDs) independently performed in adults and children for a given syndrome. Then we reviewed the longitudinal long-term course in the various epilepsy syndromes. Optimizing AED treatment at adulthood might be beneficial, even after many years of pharmacoresistance. Finally we retrospectively reviewed our personal series of 39 patients with specific pharmacoresistant epilepsy syndromes, who transferred from pediatric to adult care between 2005 and 2012. In 26 of the patients, AEDs were modified and, we reduced seizure frequency in 62% of them, including highly refractory patients. By contrast, AED changes in six controlled patients (for pregnancy anticipation or vigabatrin-related retinal toxicity) led to severe seizure relapse. Further studies are needed to elaborate guidelines in pharmacoresistant syndromes during transition and after transfer to adult care., (Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.)

Because children who have been receiving stiripentol for the treatment of Dravet syndrome for more than 10 years are now becoming young adults, it is important to accurately characterize stiripentol pharmacokinetics in this age range. A double-blind placebo-controlled dose ranging study was therefore conducted to investigate the pharmacokinetics and tolerability of stiripentol in 12 healthy volunteers. Each subject received 3 single doses of stiripentol (500, 1000, and 2000 mg) separated by a wash-out period of 1 week. Pharmacokinetics of stiripentol was analyzed for each dose by non-compartmental analysis. Median area under the curve (AUC), terminal elimination half-life (t1/2,z) and maximal concentration (Cmax) were calculated for between-dose comparison. Safety was evaluated based on both clinical and biological criteria. Oppositely to previous results, there was no concentration rebounds in the elimination phase, which could be the consequence of the food intake. A more than proportional increase in the AUC was observed, associated with a significant increase in the t1/2,z, for increasing doses (median AUC of 8.3, 31 and 88 mgh/L, and median t1/2,z of 2, 7.7 and 10h for the 500, 1000, and 2000 mg doses respectively), which confirmed the Michaelis-Menten pharmacokinetics of Stiripentol. However, dose-normalized Cmax did not significantly vary between doses. Median Michaelis-Menten parameters were 117 mg/h for Vmax and 1.9 mg/L for Km. No safety concern was observed during the study. The present study allowed a better characterization of the disposition phase of stiripentol and confirmed its non-linear pharmacokinetic behaviour. Further pharmacokinetic/pharmacodynamic studies would be useful to determine the optimal dose of stiripentol for the treatment of Dravet patients in adulthood., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Randomized controlled trials (RCTs) in refractory paediatric epilepsy usually involve the two main types of epilepsy shared by children and adults, focal epilepsy and Lennox-Gastaut syndrome (LGS). Most other epilepsy syndromes, specifically paediatric, are excluded from drug development. In order to identify among them the candidate(s) for dedicated RCTs with a new drug, the European Medicine Agency (EMA) recently recommended proceeding in two steps: (1) an exploratory (prospective-observational) trial (POT) including a large variety of paediatric epilepsy syndromes and (2) a subsequent RCT in each of those that disclose a signal for possible efficacy., Objective: Our objective was to address the three following issues that have not been addressed by the EMA: (1) to determine a minimal threshold for this signal; (2) to establish a list of epilepsies to evaluate; and (3) to estimate the number of patients to include in such POTs., Methods: We extensively reviewed the POTs (including various syndromes) and RCTs reported in paediatric patients with uncontrolled epilepsy using MEDLINE (from 1990 to 2011) and the Cochrane library. We determined the threshold as the lowest percentage of responders observed in a POT with a positive corresponding RCT. The syndromes that reached this threshold in a POT were those to evaluate in an RCT. The minimal number of patients to include for each syndrome for a POT with a new antiepileptic drug was estimated in order to reach at least this threshold of responders with a 95 % confidence interval., Results: We found the minimal responder threshold to be 25 %. We identified eight epilepsy types/syndromes reaching this threshold and estimated for each of them the minimal sample needed: refractory focal epilepsy (n = 40), Lennox-Gastaut syndrome (n = 32), infantile spasms (n = 50), Dravet syndrome (n = 32), childhood absence epilepsy (n = 12), other symptomatic generalized epilepsy (n = 38), epileptic encephalopathy with continuous spikes and waves during sleep (n = 7) and epilepsy with myoclonic-astatic seizures (n = 4) [the two last samples may be underestimated due to the lack of RCTs in these conditions]., Conclusion: Among the eight epilepsy types/syndromes that we recommend to systematically include in exploratory trials using the POT procedure, we assume that, for the minimal sample given above, a responder threshold of 25 % will provide a reliable efficacy signal, to be confirmed by a dedicated RCT. This strategy should avoid missing new therapeutic possibilities for children with epilepsy and reduce the off-label use of drugs in paediatric neurology.

There has been important progress in the identification of antiepileptic compounds and their indications in children over the past 15 years: their number has doubled and specific pediatric trials are being performed to document their effect according to seizures and syndromes as well as their tolerability in pediatrics. The improved understanding of pharmacokinetics and drug-drug interactions has helped to optimize treatment. Specific issues specific of infants have also been studied although new antiepileptic drugs are still dramatically lacking for this age group. Before reaching a syndromic diagnosis, the choice of a first- line agent goes to compounds with the largest range of efficacy and least identified risks. Subsequent choices are mainly based on the epilepsy syndrome and seizure type in addition to good clinical practice to determine dose, adverse effect profile, risk of aggravating seizures and drug interactions, clinician's experience, cultural habits, and availability of drugs. If there are several options, preference is given to the compound that exhibits the best risk/benefit ratio, or the most rapid titration when seizure frequency is the major issue. For new antiepileptic compounds, price is often a limiting factor in countries with poor insurance coverage. Third generation anti-epileptic drugs are emerging which also seem to be promising., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The aim of the medical treatment of childhood epilepsy is to control seizures as best as possible without any significant adverse event. Treatment includes classical and new antiepileptic drugs and ketogenic diet as well The drug(s) selected is dependent on the epilepsy syndrome: the same drug may completely control seizures in a given syndrome, but aggravate them in another one. Drug-drug interact ons must be taken into account when polytherapy is needed because doses need to be modified. The treatment of childhood epilepsy is different from that of adult epilepsy because many epilepsy syndromes are specifically paediatric and maturational process requires to prescribe these drugs according to age and weight.

The efficacy of stiripentol (STP) in Dravet Syndrome (DS) was discovered first in an exploratory study in pediatric pharmacoresistant epilepsies. This efficacy signal, used as a proof of concept, led to - two independent multicenter randomized, double-blind, placebo-controlled trials in DS patients: STICLO-France and STICLO-Italy. In adjunction to valproate and clobazam, STP demonstrated marked efficacy and these trials became the basis for the registration of STP as an orphan drug for DS. Although STP had previously shown antiepileptic activity, since it inhibits cytochromes P450, the increased plasma levels of clobazam (CLB), norclobazam (NCLB), and NCLB/CLB ratio reported in STICLO studies brought into question the activity of STP per se. Recent pharmacological studies demonstrated that (i) STP is a direct allosteric modulator of the GABA receptors at a site distinct from benzodiazepines; (ii) STP and CLB/NCLB act independently at GABA(A) receptors; (iii) their combination increases the maximum response beyond that of either drug alone. All these effects are independent of considerations of changes in metabolism. Some responders in STICLO studies failed to display any increase of plasmatic concentrations of NCLB/CLB ratio as STP could not inhibit CYP2C19 because of its inhibition by progabide or due to an inactivating CYP polymorphism. The responder rate proved to be in the same range whether the NCLB/CLB ratio increased or not. These analyses confirmed that the effects of STP cannot result from a simple pharmacokinetic interaction. We propose that the success of STP should serve as a model for AED development in rare pediatric epileptic syndromes., (Copyright © 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Recent data have reported the effectiveness of levetiracetam (LVT) on generalized seizures. Among them, it seems that LVT can be successfully used to treat absence seizures. Many antiepileptic drugs (AEDs) have been occasionally reported to paradoxically aggravate some seizures. We retrospectively identified patients with aggravation of absence seizures using LVT from the databases of 2 pediatric neurology departments (Robert-Debré, Paris and Amiens; France). We also used the prospective data from an open-label clinical trial performed in a third pediatric neurology department (Necker, Paris; France). We included 6 patients: n = 2 childhood absence epilepsy, n = 3 juvenile absence epilepsy and n = 1 epilepsy with myoclonic absences. All of them have had an aggravation of the absences with a causal and temporal relationship between introduction of the drug and the detrimental effect. The aggravation disappeared when LVT was decreased or was withdrawn. This report highlights that LVT may aggravate epilepsy with absence seizures., (Copyright © 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

We aimed to test the efficacy of ketogenic diet (KD) in patients with Dravet syndrome (DS) not satisfactorily controlled by antiepileptic drugs (AEDs). We included prospectively 15 DS patients aged >3 years with partial response to AEDs including stiripentol. All patients had a seizure diary and clinical examination with Conners and Achenbach scales before KD, at 1 month following onset and every 3 months thereafter. At 1 month, 10 patients (66%) had a decrease of seizure frequency ≥75%. Efficacy was maintained in eight responders at 3 and 6 months and in six responders at 9 months. Five patients (33%) remained on KD over 12 months, and one was seizure-free. In addition to efficacy on seizure frequency, KD was beneficial on behavior disturbances including hyperactivity. This effect was reported in all responders and in a few nonresponders. KD might have a double effect, on seizure control and on hyperactivity and behavior disturbances in patients with DS., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Although LVT is currently extensively prescribed in childhood epilepsy, its effect on the panel of refractory epilepsy syndromes has not been entirely evaluated prospectively. In order to study the efficacy and safety of LVT as adjunctive therapy according to syndromes, we included 102 patients with refractory seizures (6 months to 15 years) in a prospective open-labeled trial. The responder rate was respectively 36% and 32% at 3 and 6 months with 6% and 7% patients becoming seizure free. Among the responders at 6 months (n=33), seizure frequency decreased by 66% and 79% at 3 and 6 months LVT compared to baseline. The highest benefit was for CSWS patients with 2/3 responders, 50% seizure free and no aggravation. LVT provided respectively 39% and 42% responders in focal and absence epilepsies. Infantile spasms and Dravet syndrome experienced the lowest efficacy. No patient with myoclonic-astatic epilepsy or Lennox-Gastaut syndrome was aggravated. LVT dose over 40 mg/kg/d was associated with a lower response rate. Tolerability was excellent. In spite of a small sample, we assume that CSWS is a good candidate for a randomized-controlled trial with LVT., (Copyright © 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Dravet syndrome (DS) is one of the most pharmacoresistant epilepsy syndromes. Valproate is used as a first-line agent to prevent the recurrence of febrile seizures and oral/nasal/rectal benzodiazepine is used for any long-lasting seizures, but these agents are most often insufficient. Lamotrigine, carbamazepine, and high doses of intravenous phenobarbital should be avoided because they may worsen seizures. Topiramate, levetiracetam, bromide, and the ketogenic diet may provide substantial efficacy as adjunctive therapy/procedure. Stiripentol is the only compound that proved its efficacy in DS through two independent randomized placebo-controlled trials, when combined with valproate and clobazam. Their dose has to be decreased to minimize the side effects (mostly loss of appetite) resulting from pharmacokinetic interactions of stiripentol powerfully inhibiting cytochromes P450. Stiripentol acts as a γ-aminobutyric acid (GABA)ergic agent, mainly via the α3 subunit of GABA(A) receptors. Stiripentol (Diacomit) was approved as an orphan drug in 2007 in Europe for adjunctive therapy in DS. Up to now, >500 children have been safely treated, and recent experiment in Japan confirmed stiripentol benefit in DS children with comedications other than valproate and clobazam. Because early status epilepticus is likely to negatively impact cognitive outcome, we recommend the introduction of stiripentol as soon as the diagnosis of DS is clinically confirmed. Topiramate and the ketogenic diet are alternatives in pharmacoresistant cases., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Dravet syndrome is a highly pharmaco-resistant form of epilepsy. Valproate and benzodiazepines are the first-line treatment but are usually insufficient therapeutic options. Lamotrigine, carbamazepine and high doses of intravenous phenobarbital can aggravate seizures and should be avoided. Topiramate, levetiracetam, bromide and ketogenic diet also provide substantial efficacy as adjunctive therapy and procedures. Stiripentol is the only new drug to demonstrate efficacy when combined with valproate and clobazam, as shown in two independent double-blind controlled trials dedicated to Dravet children. In order to avoid side effects (mainly loss of appetite and loss of weight) resulting from the inhibition of cytochromes P450 by stiripentol, the prescribed doses of valproate and clobazam should be reduced. Stiripentol has a proper antiepileptic effect and enhances GABAergic neurotransmission by acting on the alpha-3 subunit of GABA(A) receptors. Stiripentol was approved as an orphan drug in Europe in 2007 for adjunctive therapy in Dravet syndrome. More than 500 Dravet patients have currently been satisfactorily treated and recent experiments in Japan have confirmed stiripentol's benefit. In practice, valproate should be initiated at the first onset of complicated febrile seizure in Dravet patients. Relapses justify the addition of clobazam and stiripentol when available. Topiramate and a ketogenic diet are alternatives in pharmaco-resistant cases., (© 2011 The Author. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.)

Purpose: To determine the range of topiramate (TPM) concentrations obtained in children under 4 with the recommended dosage regimen (3-9 mg/kg/day) and to compare them to adult target ranges., Methods: The population pharmacokinetic model developed for TPM, with/without enzyme inducer antiepileptic drugs (EIAEDs) in children was used to determine dosage regimens providing AUC and trough concentrations (C(trough)s) within the adult ranges., Results: TPM pharmacokinetics was described by a one-compartment model. EIAEDs increased the apparent clearance (CL/F) and age and body weight increased the apparent distribution volume (Vd/F). Mean population estimates (% CV interindividual variability) were 0.608/1.15 L/h (13%) for CL/F without/with EIAEDs, 28.6L (0.2%) for Vd/F and 1.4h(-1) (124%) for the absorption rate constant. Mean AUC(0-12h) reached with a 2mg/kg/day dosing regimen was within described range. A 6-16 mg/kg/day dose depending on age allowed reaching target C(trough) range with the highest probability. Combined EIAEDs led to a 2- and 3-fold decrease in AUC and C(trough), respectively., Conclusion: TPM dosage of 2/4 mg/kg/day (without/with EIEADs, respectively) provides the AUC reported in adults. In children under 4, alternative dosing regimen should be considered mainly when associated to EIAED to reach C(trough) comparable to adult values., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Use of the antiepileptic drug vigabatrin is associated with an elevated risk of visual field loss., Objective: To determine the frequency of, and risk factors for, vigabatrin-attributed visual field loss (VAVFL) in the setting of a large-scale, multinational, prospective, observational study., Study Design: A comparative, open-label, parallel-group, multicentre study., Setting: Hospital outpatient clinics at 46 centres in five countries., Patients: 734 patients with refractory partial epilepsy, divided into three groups and stratified by age (8-12 years; >12 years) and exposure to vigabatrin. Group I comprised patients treated with vigabatrin for > or =6 months. Group II comprised patients previously treated with vigabatrin for > or =6 months who had withdrawn from the drug for > or =6 months. Group III comprised patients never treated with vigabatrin. Patients underwent perimetry at either 4- or 6-month intervals, for up to 36 months. Visual field outcome was evaluated masked to drug exposure., Intervention: Perimetry., Main Outcome Measure: The visual field outcome at each of four analysis points: (i) at enrolment (i.e. baseline, all patients); (ii) for patients exhibiting a conclusive outcome at the initial visual field examination; (iii) for patients exhibiting at least one conclusive outcome to the visual field examinations; and (iv) at the last conclusive outcome to the visual field examinations., Results: Of the 734 patients, 524 yielded one or more conclusive visual field examinations. For Group I, the frequency of VAVFL at the last conclusive examination was 10/38 (26.3%) for those aged 8-12 years and 65/150 (43.3%) for those aged >12 years. For Group II, the respective frequencies were 7/47 (14.9%) and 37/151 (24.5%). One case resembling VAVFL was present amongst the 186 patients in Group III at the last conclusive examination. The frequency of VAVFL in Groups I and II combined was 20.0% for those aged 8-12 years and 33.9% for those aged >12 years. VAVFL was associated with duration of vigabatrin therapy (odds ratio [OR] up to 15.2; 95% CI 4.4, 51.7), mean daily dose of vigabatrin (OR up to 26.4; 95% CI 2.4, 291.7) and male gender (OR 2.51; 95% CI 1.5, 4.1). VAVFL was more frequently detected with static than with kinetic perimetry (OR up to 0.43; 95% CI 0.24, 0.75)., Conclusions: Since the probability of VAVFL is positively associated with treatment duration, careful assessment of the risk-benefit ratio of continuing treatment with vigabatrin is recommended in patients currently receiving this drug. All patients continuing to receive vigabatrin should undergo visual field examination at least every 6 months for the duration of treatment. We recommend two-level (three-zone), gradient-adapted, suprathreshold static perimetry of the peripheral field together with threshold perimetry of the central field out to 30 degrees from fixation. The frequency of ophthalmological and perimetric examinations should be increased in the presence of VAVFL.

Purpose: To develop a population pharmacokinetic model to evaluate the demographic and physiologic determinants of levetiracetam (LEV) pharmacokinetics (PK) and to suggest recommended doses of LEV in children., Methods: LEV PK were investigated in a prospective open trial of LEV as adjunctive therapy using a population approach performed with NONMEM (Nonlinear Mixed Effects Model) on 170 LEV concentration-time records and covariate information from 44 children between 4 and 16 years of age. Possible associations between pharmacokinetic parameters and age, gender, body weight, creatinine clearance, and concomitant antiepileptic drugs (AEDs) were assessed. The final model was used to perform Monte Carlo simulations in order to identify the dosing regimens that should achieve the same nominal target concentration range as in adults., Results: LEV PK were well described by a one-compartment model with first-order absorption and elimination. Both LEV apparent clearance and distribution volume were related to body weight, and no pharmacokinetic interaction was observed. Monte Carlo simulations showed that a 10mg/kg twice daily (b.i.d.) regimen provides a plasma concentration similar to that obtained in adults for the recommended 500 mg b.i.d. starting dose, and that a 20 mg/kg b.i.d. regimen would achieve the previously described 6-20 mg/L target range for the trough concentration., Discussion: Our results support the use of a weight-based LEV dosing regimen and provide a basis for a recommended pediatric dosage regimen. The relationship between LEV plasma concentrations and clinical effect has not been evaluated fully and could differ between adults and children. Clinical studies should be able to validate these dosing recommendations.

Purpose: Vigabatrin used to treat infantile spasms (IS) has been associated with transient magnetic resonance imaging (MRI) abnormalities. We carried out a retrospective review to better characterize the frequency of those abnormalities in IS and in children and adults treated with vigabatrin for refractory complex partial seizures (CPS)., Methods: Medical records and 332 cranial MRIs from 205 infants (aged 16 years) with CPS were re-reviewed. Prespecified MRI abnormalities were defined as any hyperintensity on T(2)-weighted or fluid-attenuated inversion-recovery (FLAIR) sequences with or without diffusion restriction not readily explained by a radiographically well-characterized pathology. MRIs were read by two neuroradiologists blinded to treatment group. The incidence and prevalence of MRI abnormalities associated with vigabatrin were estimated., Results: Among infants with IS, the prevalence of prespecified MRI abnormalities was significantly higher among vigabatrin-treated versus vigabatrin-naive subjects (22% vs. 4%; p < 0.001). Of nine subjects in the prevalence population with at least one subsequent determinate MRI, resolution of MRI abnormalities occurred in six (66.7%)-vigabatrin was discontinued in four. Among adults and children treated with vigabatrin for CPS, there was no statistically significant difference in the incidence or prevalence of prespecified MRI abnormalities between vigabatrin-exposed and vigabatrin-naive subjects., Discussion: Vigabatrin is associated with transient, asymptomatic MRI abnormalities in infants treated for IS. The majority of these MRI abnormalities resolved, even in subjects who remained on vigabatrin therapy.

Severe myoclonic epilepsy in infancy (SMEI) is a rare, but severe disorder with seizures typically resistant to conventional antiepileptic drugs. The objective of the present study was to systematically review the literature on the available treatments for SMEI. Databases searched included Medline, Embase, and Cochrane. We used a fixed effect model to summarize the odds ratio of seizures rates and a logistic model to evaluate the influence of patient characteristics on treatment effect. We found 23 uncontrolled studies and 2 randomized controlled trials (RCTs) that compared stiripentol with placebo. Overall, 64 children aged between 3 and 20 years were included in the two RCTs. The odds ratio of responding to stiripentol relative to placebo was 32 (CI: 6.2, 161) and stiripentol reduced seizure rate by 70% (93%; 47%). The multivariate analysis does not suggest any differences within subgroups of participants and cotherapy. Results of uncontrolled studies in children with SMEI are potentially biased and do not provide valid information on the benefits and harms of treatments. The two RCTs identified, however, were performed with the same objectives and design and showed that seizure frequency is greatly reduced by stiripentol in children with SMEI after 2 months of treatment.

The European Commission and the European Parliament have acknowledged the specific need for a proper evaluation of new drugs in children. The evaluation of the antiepileptic drugs (AEDs) available on the market illustrates the deficit in therapeutic trials for childhood epilepsy syndromes. Currently, the development of AEDs is mainly performed in children with focal epilepsy, whereas infants and the specific age-related epilepsy syndromes, particularly epileptic encephalopathies, are neglected. Infantile epilepsies remain 'therapeutic orphans', although they are the most frequent and deleterious disorders in the area of epilepsy. In order to circumvent the difficulties faced when conducting AED trials in children, we addressed the question of improving feasibility without decreasing quality, while optimally taking into account paediatric ethical requirements. For this review, we first raise the issues of paediatric epilepsies that require special considerations for randomized controlled trials (RCTs) in children. Then, we attempt to determine to what extent adult data could be extrapolated to children. Finally, we review innovative approaches that could be used in the evaluation of AEDs in children. The main specificities of paediatric epilepsies (heterogeneity, severity, cognitive impact, pharmacoresistance, syndrome-specific efficacy profile) are related to brain development and should be taken into consideration when establishing specific guidelines for the evaluation of AEDs in children. Extrapolating efficacy data from adults to children may be possible in focal epilepsy except in infants who need age-specific trials. Epileptic encephalopathies do not exist in adults and require specific trials. Pharmacokinetic data are required below a lower age limit for extrapolation of adult data to be determined in a case-to-case approach. Safety data are required at any paediatric age. RCTs in small but homogeneous populations in each paediatric-specific epileptic syndrome, the use of sequential or responder-enrichment designs, and population pharmacokinetics represent potentially promising approaches to evaluate drugs in children in an efficient way.

Purpose: The risk factors for visual field loss attributable to vigabatrin (VAVFL) are equivocal. This multinational, prospective, observational study aimed to clarify the principal/major factors for VAVFL., Methods: Interim analysis of three groups with refractory partial epilepsy, stratified by age (8-12 years; >12 years) and exposure to vigabatrin (VGB). Group I comprised participants treated with VGB for >or=6 months, Group II participants previously treated with VGB for >or=6 months who had discontinued the drug for >or=6 months and Group III those never treated with VGB. Perimetry was undertaken at least every six months, for up to 36 months; results were evaluated masked to drug exposure., Results: Based upon 563 participants in the locked data set, 432 yielded one or more Conclusive visual field examinations. For Group I, the frequency of VAVFL at the last Conclusive examination was 10/32 (31.2%) for those aged 8-12 years and 52/125 (41.6%) for those aged >12 years. For Group II, the proportions were 4/39 (10.3%) and 31/129 (24.0%). No cases resembling VAVFL manifested in Group III. VAVFL was associated with duration of VGB therapy (Odds ratio [OR] 14.2; 95% CI 5.0 to 40.5); mean dose of VGB (OR 8.5; 95% CI 2.2 to 33.2); and male gender (OR 2.1; 95% CI 1.2 to 3.7). VAVFL was more common with static than kinetic perimetry (OR 2.3, 95% CI 1.3 to 4.2)., Conclusions: The therapeutic benefit of VGB is counteracted by the progressive accrual of the risk of VAVFL with continued exposure and with increase in mean dose.

Stiripentol (STP) is a new antiepileptic compound made by Biocodex. It recently proved to increase the GABAergic transmission in vitro in an experimental model of immature rat. Clinical studies were based on the fact that STP also acts as an inhibitor of CYP3A4, CYP1A2, and CYP2C19 in vivo in epileptic patients. Whereas the studies in adult patients were disappointing, the trials conducted in pediatric populations demonstrated a specific efficacy of STP in severe myoclonic epilepsy in infancy, Dravet syndrome, when combined with valproate and clobazam. Based on these results, STP was granted orphan drug status in the European Union for the treatment of Dravet syndrome. The French experience in compassionate use suggests that STP might also be of benefit when combined with carbamazepine in pediatric patients with pharmacoresistant partial epilepsy. The interactions of STP with a large number of drugs need to be carefully taken into account, with doses of the combined antiepileptic drugs adjusted to improve the tolerability of the therapeutic association.

The purpose of this study was to assess the effectiveness and tolerability of topiramate (TPM) as add-on therapy in children with Dravet syndrome and considered unsatisfactorily controlled using stiripentol. All the 36 patients having been treated with TPM in our centre in 2001 were retrospectively evaluated. Seventy percent of them still received stiripentol when TPM was introduced. The association of both drugs did not need any particular adaptation of dosages. The mean TPM follow-up was 13.3 months (4-25 months) and the mean optimal TPM dose was 3.2 mg/kg/d (0.6-9.2 mg/kg/d). Twenty eight children (78 %) showed more than 50 % reduction in the frequency of generalized tonic-clonic seizures and status epilepticus (SE), whereas 8 % had more than 50 % increase. Six patients (17 %) remained seizure-free for at least 4 months. The most frequently reported side-effects were gastrointestinal and behavioural disturbances. TPM had to be stopped in 17 % of patients, because of poor tolerability and/or lack of efficacy. Topiramate seems therefore to be helpful in Dravet syndrome, even in patients not satisfactorily controlled by stiripentol. Both drugs can be easily and safely associated.

Stiripentol, a new antiepileptic drug inhibiting cytochrome P450-enzymes, suggested some efficacy when combined with carbamazepine in an open trial in refractory partial epilepsy of childhood. Our objective was to test these results in a placebo-controlled trial. To limit the number of patients included, we used an enrichment and withdrawal design. Among the 67 children entered in a 4-month open add-on stiripentol study following a 1-month single-blind placebo baseline, the 32 responders were randomized for 2 months either to continue stiripentol (n = 17) or to withdraw to placebo (n = 15). If seizures increased by at least 50% after randomization compared with baseline, the patients dropped out (primary end point): there were six patients on stiripentol and eight patients on placebo (not significant). However, a decrease in seizure frequency compared with baseline (secondary end point) was greater on stiripentol (-75%) than on placebo (-22%) (P < .025). Twelve patients experienced at least one adverse event on stiripentol (71%) compared with four patients on placebo (27%); none were reported as severe. The combination of stiripentol and carbamazepine proved to reduce seizure frequency in children with refractory partial epilepsy, although it failed to show a significant impact according to the escape criteria selected as the primary end point in the present study, for ethical reasons.

Purpose: Stiripentol (STP) is currently an efficient drug for add-on therapy in infantile epilepsies because it improves the efficacy of antiepileptic drugs (AEDs) through its potent inhibition of liver cytochromes P450. In addition, STP directly reduces seizures in several animal models of epilepsy, suggesting that it might also have anticonvulsive effects of its own. However, its underlying mechanisms of action are unknown., Methods: We examined the interactions of STP with gamma-aminobutyric acid (GABA) transmission by using patch-clamp methods in CA3 pyramidal neurons in the neonatal rat., Results: STP markedly increased miniature inhibitory postsynaptic current (mIPSC) decay-time constant in a concentration-dependent manner. The prolongation of mIPSC duration does not result from an interaction with GABA transporters because it persisted in the presence of GAT-1 inhibitors (SKF-89976A and NO-711). An interaction with benzodiazepine or neurosteroid binding sites also was excluded because STP-mediated increase of decay time was still observed when these sites were initially saturated (by clobazam, zolpidem, or pregnanolone) or blocked (by flumazenil or dehydroepiandrosterone sulfate), respectively. In contrast, saturating barbiturate sites with pentobarbital clearly occluded this effect of STP, suggesting that STP and barbiturates interact at the same locus. This was directly confirmed by using outside-out patches, because STP increased the duration and not the frequency of opening of GABAA channels., Conclusions: At clinically relevant concentrations, STP enhances central GABA transmission through a barbiturate-like effect, suggesting that STP should possess an antiepileptic effect by itself.

A metabolic interaction between stiripentol (STP), an anticonvulsant agent that inhibits the activity of several cytochromes P450 (P450s), and clobazam (CLB), a 1,5-benzodiazepine, used in association with STP in severe myoclonic epilepsy in infancy was observed in vivo. This interaction was characterized in vitro using cDNA-expressed CYP3A4 and CYP2C19 (main P450 involved in CLB metabolism) to calculate K(i) and IC(50) of stiripentol in comparison with ketoconazole (CYP3A4 inhibitor) and omeprazole (CYP2C19 inhibitor). STP inhibited N-demethylation of CLB to N-desmethylclobazam (NCLB) mediated by CYP3A4 (noncompetitively) and CYP2C19 (competitively) with K(i) = 1.59 +/- 0.07 and 0.516 +/- 0.065 microM and IC(50) = 1.58 microM [95% confidence interval (CI95%) = 1.20-2.08] and 3.29 microM (CI95% = 1.87-5.79), respectively. STP inhibited also more strongly the 4'-hydroxylation of NCLB to 4'-hydroxy-N-desmethylclobazam by CYP2C19 [competitive interaction with K(i) = 0.139 +/- 0.025 microM and IC(50) = 0.276 microM (CI95% = 0.206-0.371)]. The inhibitory effect of STP on CLB demethylation by CYP3A4 was much weaker than that of ketoconazole [IC(50) = 0.023 microM (CI95% = 0.016-0.033)], whereas its effect on NCLB hydroxylation by CYP2C19 was much higher than that of omeprazole [IC(50) = 2.99 microM (CI95% = 2.11-4.24)]. The major in vitro inhibitory effect of STP on CLB metabolism and mostly on NCLB biotransformation is consistent with the changes in vivo in CLB and NCLB plasma concentrations in children treated by the association CLB/STP.

Electrical status epilepticus during sleep syndrome and its variants are age-dependent epileptic encephalopathies associated with a sleep-related electroencephalographic pattern of continuous spike-waves, combined with motor or cognitive impairment. These epileptic encephalopathies are usually not responsive to conventional antiepileptic drugs. This report describes two children in whom clonazepam had no effect on cognitive and motor disorders but controlled spike activity, preventing a proper diagnosis. Withdrawal of clonazepam was accompanied by the recurrence of continuous spike-waves in slow sleep, permitting the diagnosis of electrical status epilepticus during sleep syndrome and appropriate therapeutic decisions. These two cases of the misleading effect of clonazepam in electrical status epilepticus during sleep syndrome illustrate the puzzling situation that can occur when therapeutic options only consider the electroencephalographic features without prior syndromic diagnosis.

Unlabelled: Sodium valproate (VPA) is an anti-epileptic drug which was until now administered to children as drinkable or injectable form. A new galenic form of this compound has been developed as microgranules with prolonged release (Micropakine)LP; MPK). This new galenic form of VPA allows a greater stability of the plasmatic rates, thus limiting the risk of amount-dependent adverse effects at the time of the peaks, and of less effectiveness at the time of the fall of the circulating rates. The main objective of this study was to evaluate the acceptability of the new galenic form of VPA, in monotherapy, for epileptic children with >or=3 years old. The evaluation was performed at day (D)90 by the patients using a hedonic visual scale. The secondary objectives were to evaluate the acceptability by the parents, the treatment compliance, the percentage of patients free of seizure at D 90, and the tolerance. Finally, the authors compared all these data to those recovered at the baseline in patients already treated by the previous drinkable VPA. A total of 307 patients were involved by 76 hospital neuropediatric physicians. The population was constituted by 110 children <5 years old and 197 children from 5 to 14 years old. MPK was well accepted for total population at D 90 (<5 years old: 83.3%; >or=5 years old: 80%). For patients previously treated by drinkable form of VPA (N=199), MPK was significantly better accepted than the drinkable form at D1 (<5 years, P=0.0189; >or=5 years, P<0.0001). Less difficulties were experienced by the parents to administrate MPK when compared to the drinkable form (P<0.001), mainly due to his neutral taste. Patients free of seizure at D 90 were 77% [70,3; 82,5]. Specially, fewer epileptic seizures were evidenced for all children previously treated at D1 by drinkable form of VPA. The treatment was well respected by the patients, which were compliant in 80% of the cases. The adherence to treatment was good since the treatment compliance was 87%. MPK was well tolerated., Conclusion: MPK in the microgranule form significantly improves the treatment acceptability with a good tolerance. Two daily intakes and neutral taste are two major advantages to favour the compliance in children, thus contributing to the efficacy of the antiepileptic treatment.

Stiripentol (STP) is a new antiepileptic compound produced by Biocodex. It is not structurally related to any of the other currently marketed antiepileptic products as it belongs to the group of aromatic allylic alcohols. It has recently been proved to increase GABAergic transmission in experimental models. It has been studied and used in France and Canada for > 10 years, but its clinical development was delayed due to the inhibitory effect of STP on hepatic cytochrome P450 (CYP). Clinical studies were based on the fact that STP also acts as an inhibitor of CYP3A4, CYP1A2 and CYP2C19 in vivo in epileptic patients. Although the studies in adult patients were disappointing, the trials conducted in paediatric populations demonstrated a specific efficacy of STP in a severe form of early childhood epilepsy, Dravet syndrome (severe myoclonic epilepsy in infancy), when combined with valproate and clobazam. Based on these results, STP was granted orphan drug status in the European Union for the treatment of Dravet syndrome. The French experience in compassionate use suggests that STP might also be of benefit when combined with carbamazepine in paediatric patients with pharmacoresistant partial epilepsy. Nevertheless, two controlled adjunctive-therapy trials were recently completed in paediatric populations with epilepsy. The interactions of STP with a large number of drugs need to be carefully taken into account by adjusting the doses of the combined antiepileptic drugs in order to improve the tolerability of the therapeutic association.

Purpose: To study the pharmacokinetics of topiramate (TPM) at steady state in children younger than 4 years comedicated with other antiepileptic drugs (AEDs)., Methods: Twenty-two children aged 6 months to 4 years with pharmacoresistant partial or generalized epilepsy were enrolled in an open-label prospective study. Children were assigned to different groups according to comedication with enzyme-inducing AEDs (n = 8), valproic acid (VPA) (n = 6), or other AEDs not known to affect drug metabolism (neutral AEDs, n = 7). One child was receiving treatment with both enzyme-inducing AEDs and VPA. After dose titration, blood samples were collected at steady state just before and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 h after the morning dose of TPM. Pharmacokinetic parameters were determined by a noncompartmental method., Results: TPM apparent oral clearance (CL/F) was significantly higher in children taking enzyme-inducing AEDs (85.4 +/- 34.0 ml/h/kg) than in those receiving VPA (49.6 +/- 13.6 ml/h/kg) or neutral AEDs (46.5 +/- 12.8 ml/h/kg). Conversely, dose-normalized areas under the plasma TPM concentration curves (0-12 h) were significantly lower in enzyme-induced patients than in patients receiving VPA or other AEDs., Conclusions: Compared with children not receiving enzyme inducers, children younger than 4 years who receive concomitant enzyme-inducing AEDs need higher doses (milligrams per kilogram) to achieve comparable plasma TPM concentrations.

The treatment of status epilepticus (SE) in children with epilepsy depends on the epilepsy syndrome, in order to avoid worsening drugs such as IV barbiturates in severe myoclonic epilepsy in infancy (SMEI) (Dravet's syndrome) or IV benzodiazepam in tonic SE of Lennox-Gastaut syndrome. Intensive care procedures should not be systematical in convulsive SE (CSE) and are not indicated in non-convulsive SE (NCSE). Generalized CSE mostly involve SMEI before 3 years of age, symptomatic generalized epilepsy and partial lesional epilepsy. Treatment is an emergency and relies on IV benzodiazepines and, if necessary, IV phenytoine using plasmatic concentrations for an optimal management. The partial CSE of partial lesional epilepsy can result in focal deficit and need the same treatment as generalized CSE. NCSE consist in absence and/or myoclonic SE and are often unrecognised during a long time until EEG is performed. They mostly involve myoclonic epilepsies and can be controlled by IV benzodiazepines. The frequency of partial NCSE is underestimated, particularly in infants. Diagnosis relies on video EEG and treatment is the same as that used in partial CSE.

Long-term treatment of children with drug-resistant epilepsy has not been addressed in detail in the literature. Contraindications for surgery must be reassessed periodically. The epileptic nature and the focal characteristic of seizures must be verified, the absence of tumor, malformation or another indication for surgery (i.e. obstructed valve.), the choice of anti-epileptic drugs depending on the epilepsy syndrome, even following callosotomy, and the dose, that is often over-estimated, must also be re-evaluated.

Purpose: We developed a new in vitro preparation of immature rats, in which intact corticohippocampal formations (CHFs) depleted in magnesium ions become progressively epileptic. The better to characterize this model, we examined the effects of 14 antiepileptic drugs (AEDs) currently used in clinical practice., Methods: Recurrent ictal-like seizures (ILEs, four per hour) were generated in intact CHFs of P7-8 rats, and extracellular recordings were performed in the hippocampus and neocortex. AEDs were applied at clinically relevant concentrations (at least two), during 30 min after the third ILE. Their ability to prevent or to delay the next ILE was examined., Results: Valproic acid and benzodiazepines (clobazam and midazolam) but also phenobarbital and levetiracetam prevent the occurrence of seizures. In contrast, usual concentrations of carbamazepine (CBZ), phenytoin, vigabatrin, tiagabine, gabapentin, lamotrigine (LTG), topiramate, felbamate, and ethosuximide did not suppress ILEs. In addition, LTG and CBZ aggravate seizures in one third of the cases., Conclusions: This intact in vitro preparation in immature animals appears to be quite resistant to most AEDs. Blockade of seizures was achieved with drugs acting mainly at the gamma-aminobutyric acid (GABA)A-receptor site but not with those that increase the amount of GABA. Drugs with a broad spectrum of activity are efficient but not those preferentially used in partial seizures or absences. We suggest that this preparation may correspond to a model of epilepsy with generalized convulsive seizures and could be helpful to develop new AEDs for refractory infantile epilepsies.

To investigate the impact of treatment lag in infantile spasms (IS) on treatment response, occurrence of later epilepsy, and long-term cognition and behavior in patients with one single etiological entity, we examined 18 patients with Down syndrome (DS) and earlier IS retrospectively (follow-up period of 32-180 months with a mean of 85.1 months), and determined their history and present condition, in terms of previously mentioned items. There was a statistically significant correlation between treatment lag and lag to cessation of spasms (R=0.55, P=0.02), developmental quotient (DQ) (R=-0.75, P=0.003), and score of autistic features (AF) (R=0.57, P=0.04). Moreover we found that the later the response to treatment of IS, the lower was the DQ (R=-0.86, P=0.001) and the higher was the score of autistic features (R=0.5, P=0.06). A long duration of spasms also determined a low DQ (R=-0.93, P<0.0001) and a high score of autistic features (R=0.66, P<0.01). All patients with persistent epilepsy (n=5) had had a treatment lag of over 2 months. Conversely, for all children treated within 2 months (n=8) spasms ceased within 3 months of treatment and none of them had later epilepsy. This group of patients with a treatment lag of less than 2 months had earlier treatment response (P=0.002), higher DQ (P=0.004) and lower score of autistic features (P=0.006). The data stress the importance of a short treatment lag in view of mental development and prevention of later epilepsy and autistic features, and raise the question of antiepileptogenic effect in this specific condition.

To evaluate the efficacy and tolerability of topiramate (TPM) as add-on therapy in children less than 12 years of age with refractory epilepsy, according to epilepsy syndromes, we conducted an open, prospective, pragmatic and multicenter study in France. Efficacy was assessed, especially according to epilepsy syndromes, as well as tolerability. We included 207 children (41 of whom were less than 4 years of age). TPM was effective (responders with >50% decrease in seizure frequency) in 50% of 128 patients with partial epilepsy, and in 44% of 79 patients with generalized epilepsy. In case of generalized epilepsy, responders more frequently had generalized symptomatic epilepsy, severe myoclonic epilepsy and myoclono-astatic epilepsy, whereas response rate was mild in both infantile spasms and Lennox-Gastaut syndrome (LGS). Improvement was well maintained in all patients during the treatment period (median 5.6 months). Seizure frequency/severity increased (worsening) in 13% of patients with partial epilepsy and 17% with generalized epilepsy (particularly in those with infantile spasms), and resulted in withdrawal of TPM for 8%. The most frequently reported adverse events were moderate neurobehavioral and gastrointestinal disorders. Adverse events led to withdrawal of TPM from 13.5% of patients. Children less than 4 years of age had particularly good tolerability. Results confirm that TPM is effective and well tolerated in children under 12 years of age in a broad range of epilepsy syndromes, including refractory partial epilepsy, and symptomatic and myoclonic generalized epilepsy. Use of TPM should be considered in children under 4 years of age, and slow and progressive titration is important.

Objective: To describe the long term efficacy and tolerance of stiripentol associated with valproate and clobazam in an exhaustive cohort of patients with severe myoclonic epilepsy of infancy (Dravet's syndrome), in which short term efficacy of such a treatment has recently been demonstrated in a placebo-controlled trial., Results: In 46 patients the frequency and the duration of seizures was significantly reduced (p < 0.001) as well as the number of convulsive status at a median of three-year follow-up. Ten patients were dramatically improved (seizures significantly decreased in number [p = 0.002] and duration [p = 0.002] and status epilepticus disappeared), 20 were moderately improved (seizures significantly decreased in duration [p = 0.001] and status were less numerous), four had no response and efficacy was non evaluable in 12 mainly because of adverse events. Efficacy was better in the youngest patients. The most frequent adverse events were loss of appetite and loss of weight. They could be so severe in patients over 12 years of age that the stiripentol dosage could not be increased to 50 mg kg-1 j-1., Conclusion: This follow-up study shows that stiripentol added to valproate and clobazam maintains its efficacy at long term in children with severe myoclonic epilepsy of infancy and suggests that the tritherapy should be introduced as early as possible in these patients in order to suppress the convulsive status epilepticus.