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1.
JAMA Neurol ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31790543

RESUMO

Importance: Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. Objective: To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens. Design, Setting, and Participants: This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. Interventions: Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients' assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. Main Outcomes and Measures: The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. Results: A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (≥50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension. Conclusions and Relevance: Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome. Trial Registration: ClinicalTrials.gov identifier: NCT02926898.

2.
CNS Drugs ; 33(9): 867-881, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31549357

RESUMO

Dravet syndrome is a rare but severe epilepsy syndrome that begins in the first year of life with recurrent seizures triggered by fever that are typically prolonged and hemiclonic. The epilepsy is highly drug resistant. Although development is normal at onset, over time, most patients develop moderate-to-severe intellectual disability, behavior disorders, and a characteristic crouch gait. There is a significant mortality, predominantly owing to sudden unexpected death in epilepsy. Complete seizure control is rarely attainable. Initial therapy includes valproic acid and clobazam, but response is typically inadequate. The results of new drugs for Dravet syndrome, including stiripentol, cannabidiol, and fenfluramine, are very promising. Stiripentol was associated with a greater than 50% reduction in convulsive seizure frequency in 71% of cases, when added to valproic acid and clobazam, and also markedly reduced status epilepticus. Pharmaceutical-grade cannabidiol resulted in a median change in monthly motor seizures from baseline of - 36.5%. Fenfluramine was associated with a greater than 50% reduction in seizures of 70%, with one quarter of cases achieving near seizure freedom over the duration of the trial. These agents are generally well tolerated, with few patients discontinuing for adverse effects. There is limited evidence to date regarding improvement in cognition with these newer agents; however, a meaningful change is challenging to assess over short trial periods and requires longer follow-up studies. While current treatments focus predominantly on seizure control, newer therapies including genetic treatments and antisense oligonucleotides can target the SCN1A channelopathy, and thus, may also significantly impact the important co-morbidities associated with this syndrome.

3.
Hum Mutat ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31513310

RESUMO

Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage-dependent potassium channel Kv 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of Kv 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less-severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.

4.
Brain ; 142(10): 2996-3008, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31532509

RESUMO

Epilepsy of infancy with migrating focal seizures was first described in 1995. Fifteen years later, KCNT1 gene mutations were identified as the major disease-causing gene of this disease. Currently, the data on epilepsy of infancy with migrating focal seizures associated with KCNT1 mutations are heterogeneous and many questions remain unanswered including the prognosis and the long-term outcome especially regarding epilepsy, neurological and developmental status and the presence of microcephaly. The aim of this study was to assess data from patients with epilepsy in infancy with migrating focal seizures with KCNT1 mutations to refine the phenotype spectrum and the outcome. We used mind maps based on medical reports of children followed in the network of the French reference centre for rare epilepsies and we developed family surveys to assess the long-term outcome. Seventeen patients were included [age: median (25th-75th percentile): 4 (2-15) years, sex ratio: 1.4, length of follow-up: 4 (2-15) years]. Seventy-one per cent started at 6 (1-52) days with sporadic motor seizures (n = 12), increasing up to a stormy phase with long lasting migrating seizures at 57 (30-89) days. The others entered this stormy phase directly at 1 (1-23) day. Ten patients entered a consecutive phase at 1.3 (1-2.8) years where seizures persisted at least daily (n = 8), but presented different semiology: brief and hypertonic with a nocturnal (n = 6) and clustered (n = 6) aspects. Suppression interictal patterns were identified on the EEG in 71% of patients (n = 12) sometimes from the first EEG (n = 6). Three patients received quinidine without reported efficacy. Long-term outcome was poor with neurological sequelae and active epilepsy except for one patient who had an early and long-lasting seizure-free period. Extracerebral symptoms probably linked with KCNT1 mutation were present, including arteriovenous fistula, dilated cardiomyopathy and precocious puberty. Eight patients (47%) had died at 3 (1.5-15.4) years including three from suspected sudden unexpected death in epilepsy. Refining the electro-clinical characteristics and the temporal sequence of epilepsy in infancy with migrating focal seizures should help diagnosis of this epilepsy. A better knowledge of the outcome allows one to advise families and to define the appropriate follow-up and therapies. Extracerebral involvement should be investigated, in particular the cardiac system, as it may be involved in the high prevalence of sudden unexpected death in epilepsy in these cases.

5.
Epilepsy Behav ; 99: 106482, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31461681

RESUMO

PURPOSE: Executive functions (EF) are high-order cognitive skills that have a major influence on quality of life, social skills, and school achievement. We aimed to screen EF daily life abilities in young patients with myoclonic-atonic epilepsy (MAE) using an ecological questionnaire and to correlate EF to epilepsy characteristics. METHODS: Behavioral Rating Inventory of Executive Functions - Preschool (BRIEF-P) and BRIEF - for school-aged patients - parental questionnaires were proposed to patients with MAE and typically developing children (TDC) including Inhibit, Shift, Emotional control, Working memory (WM), Plan/Organize, Initiate, Organization of materials, and Monitor subscales. We included prospectively 12 patients with MAE and 44 TDC aged 3 to 5 years and seven patients with MAE and 21 TDC aged 6-7 years. We performed in addition for all patients an intellectual efficiency evaluation using WPPSI-IV (Wechsler intelligence scale for preschool children version IV) and collected demographics, age at onset of epilepsy, epilepsy duration, response to treatment, number and type of treatments including AEDs (antiepileptic drugs), and ketogenic diet. RESULTS: Four out of 12 patients for BRIEF-P and 6/7 patients for BRIEF had pathological scores for at least one domain. Behavioral Rating Inventory of Executive Functions' questionnaires showed higher pathological scores for WM, Plan/Organize, Initiate, Monitor, and Metacognition Index in patients with MAE compared to TDC suggesting higher problems reported by parents. Working memory scores were higher in the group with MAE than TDC for both BRIEF-P and BRIEF. Response to treatment is a predictor of multiple BRIEF-P domains. Epilepsy duration predicts Shift and WM domains while age at onset predicts WM domain on BRIEF in this syndrome. CONCLUSIONS: This study is the first to assess prospectively EF in young patients with MAE. We show everyday deficits in EF reported by parents. Metacognition and more specifically WM, appear to be a core deficit. Early evaluation of EF using both questionnaires and standardized tools is necessary for early detection of EF deficit and initiating tailored rehabilitation. Given the normal development before seizure onset and the absence of cerebral lesion in MAE, these results are in favor of the impact of epilepsy on EF.

6.
Clin Genet ; 96(3): 254-260, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31170314

RESUMO

Myoclonic-atonic epilepsy (MAE) is thought to have a genetic etiology. Mutations in CHD2, SLC2A1 and SLC6A1 genes have been reported in few patients showing often intellectual disability prior to MAE onset. We aimed to explore putative causal genetic factors in MAE. We performed array-CGH and whole-exome sequencing in 27 patients. We considered non-synonymous variants, splice acceptor, donor site mutations, and coding insertions/deletions. A gene was causal when its mutations have been already linked to epilepsy or other brain diseases or when it has a putative function in neuronal excitability or brain development. We identified candidate disease-causing variants in 11 patients (41%). Single variants were found in some known epilepsy-associated genes (namely CHD2, KCNT1, KCNA2 and STXBP1) but not in others (SLC2A1 and SLC6A1). One new candidate gene SUN1 requires further validation. MAE shows underlying genetic heterogeneity with only few cases linked to mutations in genes reported in developmental and epileptic encephalopathies.

7.
Dev Med Child Neurol ; 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31050360

RESUMO

AIM: We aimed to evaluate the contribution of early magnetic resonance imaging (MRI) for the presymptomatic diagnosis of Sturge-Weber syndrome (SWS) in infants with a facial port-wine birthmark (PWB). METHOD: Asymptomatic infants with a facial PWB who performed a first MRI scan before 3 months and a second MRI scan after 9 months were included in this study. Leptomeningeal enhancement on T1-weighted imaging and four indirect signs of leptomeningeal angioma (choroid plexus enlargement, cerebral atrophy, signal inversion of the white matter with T2 hyposignal, and T1 hypersignal) were screened on the first MRI scan and correlated with clinical and/or radiological diagnosis of SWS. RESULTS: Thirteen of 30 included patients had SWS with leptomeningeal angioma. Eleven had a leptomeningeal enhancement on the first MRI scan and 10 had associated indirect signs. The presence of a direct or at least one indirect sign of leptomeningeal angioma on the first MRI scan confirmed the diagnosis of SWS with a sensitivity of 100 per cent (95% confidence interval 75-100%) and a specificity of 94 per cent (71-100%). INTERPRETATION: Early diagnosis of SWS is possible on contrast-enhanced MRI performed in asymptomatic infants with a facial PWB before the age of 3 months. This early detection would help to select patients who may benefit from early neuroprotective intervention. WHAT THIS PAPER ADDS: Specific magnetic resonance imaging markers provide early diagnosis of leptomeningeal angioma in Sturge-Weber syndrome (SWS). Presymptomatic diagnosis of SWS should help to select patients for early therapy intervention.

8.
Epilepsy Behav ; 96: 23-27, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31077938

RESUMO

INTRODUCTION: Tuberous sclerosis complex (TSC) is a multisystemic genetic disease with high clinical variability and age-related manifestations. These characteristics add to the complexity of transition to adulthood. This study aimed to explore the perception of medical follow-up and transition experience in a large group of patients with TSC who presented epilepsy in childhood. METHOD: This multicenter French study included patients with TSC aged 18 years or older who developed epilepsy before the age of 16 years. A questionnaire specifically designed for the study explored patients' opinion through 270 questions covering different aspects of their social, familial, professional, and medical courses. RESULTS: The questionnaire was sent to 72 patients, and 60 patients were included in the study (83% response rate) with a mean age of 32 years (18-55 years). Cognitive impairment was present in 80% of patients, and half of questionnaires were completed by the family. Pediatric care was coordinated by the child neurologist and was more regular and multidisciplinary than adult care. Epilepsy had the best follow-up followed by renal issues. Unmet needs were identified for psychiatric and behavioral disorders, both in children and adults. Respondents considered the help in achieving autonomy better in adult care. Only 50% of patients with a normal intellectual development had clear knowledge about their disease and the need for a regular monitoring. Two-thirds of respondents estimated that they had a transition experience between 16.5 and 21-year-old, considered as good in 60% of them. Seventy percent felt continuity between pediatric and adult care, and only 3% of respondents felt that their care would have been better if they were still followed in pediatric healthcare system. The change of care structure and/or caregivers was the most stressful factor during transition and transfer. CONCLUSION: This study highlights persistent issues in the regularity and coordination of the follow-up of patients with TSC despite established international guidelines. Although most patients had a positive transition experience, there is still an urgent need to optimize transition programs. This would be essential to maintain care continuity between pediatric and adult health systems, especially for patients with TSC with epilepsy and high rate of cognitive and psychiatric impairments.

10.
J Clin Invest ; 129(6): 2571-2577, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946030

RESUMO

Increased urinary oxalate excretion (hyperoxaluria) promotes the formation of calcium oxalate crystals. Monogenic diseases due to hepatic enzymes deficiency result in chronic hyperoxaluria, promoting end-stage renal disease in children and young adults. Ethylene glycol poisoning also results in hyperoxaluria promoting acute renal failure and frequently death. Stiripentol is an antiepileptic drug used to treat children affected by Dravet syndrome, possibly by inhibiting neuronal lactate dehydrogenase 5 isoenzyme. As this isoenzyme is also the last step of hepatic oxalate production, we hypothesized that Stiripentol would potentially reduce hepatic oxalate production and urine oxalate excretion. In vitro, Stiripentol decreased in a dose-dependent manner the synthesis of oxalate by hepatocytes. In vivo, Stiripentol oral administration reduced significantly urine oxalate excretion in rats. Stiripentol protected kidneys against calcium oxalate crystal deposits in acute ethylene glycol intoxication and chronic calcium oxalate nephropathy models. In both models, Stiripentol improved significantly renal function. Patients affected by Dravet syndrome and treated with Stiripentol had a lower urine oxalate excretion than control patients. A young girl affected by severe type I hyperoxaluria received Stiripentol for several weeks: urine oxalate excretion decreased by two-thirds. Stiripentol is a promising potential therapy against genetic hyperoxaluria and ethylene glycol poisoning.

11.
Dev Med Child Neurol ; 61(10): 1229-1236, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30828793

RESUMO

AIM: To assess the relevance and generalizability across countries of concepts of the impact of Dravet syndrome beyond seizures, as recognized by families. METHOD: Caregivers of children with Dravet syndrome in four countries (Australia [n=8]; USA, UK, and Italy [all n=4]) participated in 1-hour qualitative telephone interviews, identifying key Dravet syndrome concepts. Interviews were recorded, transcribed, and, where necessary, translated into English for thematic analysis. Conceptual saturation was assessed and findings compared to the previously developed French conceptual disease model. RESULTS: The most common seizure types reported by caregivers were tonic-clonic, absence, or focal-impaired awareness (localized/partial). Fever and physical activity were the most commonly reported triggers. Patient-relevant impacts included impairment in cognition, motor skills, communication, social skills, and behavioural functioning. Caregivers consistently reported negative social, physical, and family impacts. Concepts identified in the interviews showed similarity with the French conceptual model. Minor differences between countries are likely to reflect variations in health care systems. INTERPRETATION: Findings in Italy, Australia, UK, and USA confirm that the key impacts of Dravet syndrome on children and caregivers identified in France are generalizable across countries. Key symptom and impact concepts relevant to children and parents should be targeted as critical outcomes in new therapy evaluations. WHAT THIS PAPER ADDS: Relevance of the impact of Dravet syndrome on children and caregivers was confirmed across countries. Patient and caregiver-relevant Dravet syndrome impacts contribute to poorer health-related quality of life. Indirect seizure impacts were reported to be as important as direct impacts. Country-specific differences in concepts probably reflect differences in health care systems.

12.
Epilepsy Behav ; 93: 133-137, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30626546

RESUMO

There is limited information about the effectiveness of transition programs for youth moving from pediatric to adult care with any chronic disease. Two Delphi studies and National Institute for Health and Care Excellence (NICE) guidelines about transition for epilepsy have suggested few critical outcome measures for transition. A single large prospective study found that the most important transition program elements were appropriate parent involvement, promotion of health self-efficacy, and meeting the adult team before transfer. Two Cochrane reviews of the value of transition for epilepsy found insufficient evidence to establish or refute the value of various programs, although evaluation of a few programs suggested a great deal of family/patient satisfaction. The cost of transition programs and their cost effectiveness have also not been established except for renal transplantation where transition programs were associated with fewer losses of the transplanted kidneys, a cost-effective outcome. Published data on the overall cost of care for children and adults with epilepsy may be helpful to establish a business plan for a transition program, and are briefly reviewed. Establishing cost effectiveness of transition programs for epilepsy would promote their establishment and viability. However, a number of studies will be needed based on the nature of the program, the healthcare system where it is carried out, and the type of epilepsy. In fee-for-service health systems, the reevaluation of patients with epilepsy prior to transfer may be sufficient to cover the costs of the transition program, whereas in single payer systems, there may be positive downstream health or societal benefits that justify the costs. A theoretical framework for comprehensive evaluation of epilepsy transition programs is needed. The Triple Aim Framework seems applicable with focus on population health, patient experiences, and cost and has the potential to assess transition interventions in the context of system-wide improvements in healthcare. Transition programs in general have not been well evaluated, and very little evaluation data exist regarding transition programs for epilepsy. We recommend more evaluative research using rigorous methodology to comprehensively assess these programs.

13.
Epilepsy Behav ; 93: 138-147, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30642688

RESUMO

Objective evidence is limited for the value of transition programs for youth with chronic illness moving from pediatric to adult care; however, such programs intuitively "make sense". We describe the strengths and weaknesses of a variety of transition programs from around the world for adolescents with epilepsy. Consequences of poorly organized transition beyond suboptimal seizure control may include an increased risk of sudden unexpected death in epilepsy (SUDEP), poor psychological and social outcome, and inadequate management of comorbidities. The content of transition programs for those with normal intelligence differs from those with intellectual disability, but both groups may benefit from an emphasis on sporting activities. Concerns that may interfere with optimal transition include lack of nursing or social work services, limited numbers of adult neurologists/epileptologists confident in the treatment of complex pediatric epilepsy problems, institutional financial support, and time constraints for pediatric and adult physicians who treat epilepsy and the provision of multidisciplinary care. Successful programs eventually need to rely on a several adult physicians, nurses, and other key healthcare providers and use novel approaches to complex care. More research is needed to document the value and effectiveness of transition programs for youth with epilepsy to persuade institutions and healthcare professionals to support these ventures.

14.
Ann Neurol ; 85(2): 204-217, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30597612

RESUMO

OBJECTIVE: Dysregulation of γ-aminobutyric acidergic (GABAergic) transmission has been reported in lesional acquired epilepsies (gliomas, hippocampal sclerosis). We investigated its involvement in a developmental disorder, human focal cortical dysplasia (FCD), focusing on chloride regulation driving GABAergic signals. METHODS: In vitro recordings of 47 human cortical acute slices from 11 pediatric patients who received operations for FCD were performed on multielectrode arrays. GABAergic receptors and chloride regulators were pharmacologically modulated. Immunostaining for chloride cotransporter KCC2 and interneurons were performed on recorded slices to correlate electrophysiology and expression patterns. RESULTS: FCD slices retain intrinsic epileptogenicity. Thirty-six of 47 slices displayed spontaneous interictal discharges, along with a pattern specific to the histological subtypes. Ictal discharges were induced in proepileptic conditions in 6 of 8 slices in the areas generating spontaneous interictal discharges, with a transition to seizure involving the emergence of preictal discharges. Interictal discharges were sustained by GABAergic signaling, as a GABAA receptor blocker stopped them in 2 of 3 slices. Blockade of NKCC1 Cl- cotransporters further controlled interictal discharges in 9 of 12 cases, revealing a Cl- dysregulation affecting actions of GABA. Immunohistochemistry highlighted decreased expression and changes in KCC2 subcellular localization and a decrease in the number of GAD67-positive interneurons in regions generating interictal discharges. INTERPRETATION: Altered chloride cotransporter expression and changes in interneuron density in FCD may lead to paradoxical depolarization of pyramidal cells. Spontaneous interictal discharges are consequently mediated by GABAergic signals, and targeting chloride regulation in neurons may be considered for the development of new antiepileptic drugs. Ann Neurol 2019; 1-14 ANN NEUROL 2019;85:204-217.


Assuntos
Córtex Cerebral/metabolismo , Epilepsias Parciais/metabolismo , Malformações do Desenvolvimento Cortical/metabolismo , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo , Adolescente , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia/métodos , Epilepsias Parciais/diagnóstico por imagem , Epilepsias Parciais/fisiopatologia , Feminino , Humanos , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/fisiopatologia
15.
Epilepsy Res ; 150: 38-45, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30639958

RESUMO

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.


Assuntos
Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Convulsões/tratamento farmacológico , Vigabatrina/farmacocinética , Vigabatrina/uso terapêutico , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Masculino , Método de Monte Carlo
16.
Dev Med Child Neurol ; 61(8): 891-898, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30680721

RESUMO

The aim of this study was to disentangle mechanisms of epileptogenesis in monogenic epilepsies in children. We reviewed paediatric monogenic epilepsies excluding brain malformation or an inborn error of metabolism, but including the gene function whether there is loss-of-function or gain-of-function, age at gene expression when available, and associated epilepsy syndrome. Genes for which at least five patients with similar epilepsy phenotype had been reported were selected. Three mechanisms are shared by most monogenic epilepsies: (1) excess of N-methyl-d-aspartate (NMDA) transmission activation (NMDA-pathies); (2) abnormal gamma-aminobutyric acid (GABA) transmission with reduced inhibition (phasic GABA-pathies); and (3) tonic activation of extrasynaptic GABAA receptors by extracellular GABA (tonic GABA-pathies). NMDA-pathies comprise early epileptic encephalopathy with suppression-burst, neonatal/infantile benign seizures, West and Lennox-Gastaut syndromes, and encephalopathy with continuous spike waves in slow sleep, thus brief seizures with major interictal spiking. Phasic GABA-pathies comprise mostly generalized epilepsy with febrile seizures plus and Dravet syndrome, thus long-lasting seizures with mild interictal spiking. Tonic GABA-pathies cause epilepsy with myoclonic-atonic seizures and Angelman syndrome, thus major high-amplitude slow-wave activity. This pathophysiological approach to monogenic epilepsies provides diagnostic clues and helps to guide treatment strategy. WHAT THIS PAPER ADDS: In paediatric monogenic epilepsies, electroclinical patterns point to three main mechanisms: NMDA-pathies, and phasic and tonic GABA-pathies. Antiepileptic treatment choice could be guided by each of these mechanisms.


Assuntos
Encéfalo/metabolismo , Epilepsia/genética , Mutação , N-Metilaspartato/metabolismo , Ácido gama-Aminobutírico/metabolismo , Criança , Epilepsia/metabolismo , Humanos
17.
Epilepsia ; 60(2): 294-302, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30582156

RESUMO

OBJECTIVE: Add-on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double-blind, placebo-controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo-controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5. METHODS: Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d. RESULTS: By November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open-label extension. Median treatment duration was 274 days (range 1-512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty-two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE: This trial shows that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.

18.
Epilepsia ; 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30525185

RESUMO

OBJECTIVE: We aimed to characterize epilepsy of infancy with migrating focal seizures (EIMFS), a rare, severe early onset developmental epilepsy related to KCNT1 mutation, and to define specific electroencephalography (EEG) markers using EEG quantitative analysis. The ultimate goal would be to improve early diagnosis and to better understand seizure onset and propagation of EIMFS as compared to other early onset developmental epilepsy. METHODS: EEG of 7 EIMFS patients with KCNT1 mutations (115 seizures) and 17 patients with other early onset epilepsies (30 seizures) was included in this study. After detection of seizure onset and termination, spatiotemporal characteristics were quantified. Seizure propagation dynamics were analyzed using chronograms and phase coherence. RESULTS: In patients with EIMFS, seizures started and were localized predominantly in temporal and occipital areas, and evolved with a stable frequency (4-10 Hz). Inter- and intrahemispheric migrations were present in 60% of EIMFS seizures with high intraindividual reproducibility of temporospatial dynamics. Interhemispheric migrating seizures spread in 71% from temporal or occipital channels to the homologous contralateral ones, whereas intrahemispheric seizures involved mainly frontotemporal, temporal, and occipital channels. Causality links were present between ictal activities detected under different channels during migrating seizures. Finally, time delay index (based on delays between the different ictal onsets) and phase correlation index (based on coherence of ictal activities) allowed discrimination of EIMFS and non-EIMFS seizures with a specificity of 91.2% and a sensitivity of 84.4%. SIGNIFICANCE: We showed that the migrating pattern in EIMFS is not a random process, as suggested previously, and that it is a particular propagation pattern that follows the classical propagation pathways. It is notable that this study reveals specific EEG markers (time delay and phase correlation) accessible to visual evaluation, which will improve EIMFS diagnosis.

19.
Epileptic Disord ; 20(6): 457-467, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30530412

RESUMO

Protocadherin 19 (PCDH19) mutations have been identified in epilepsy in females with mental retardation as well as patients with a "Dravet-like" phenotype. We aimed to elucidate the electroclinical phenotype associated with PCDH19 mutation, which is currently difficult to identify at onset leading to a delay in diagnosis. We retrospectively reviewed clinical and EEG data for 13 consecutive patients with PCDH19 mutations or deletions diagnosed at our centers from 2009 to 2011, and followed these patients into adolescence and adulthood. We identified a specific temporal sequence of electroclinical manifestations, identified as three main stages. During the first two years of life, previously healthy girls presented with clusters of afebrile focal seizures. Early seizures were recorded on video-EEG in 10/13 patients, and were focal (n=8) with temporo-occipital and frontal onset. Three patients with strictly stereotyped focal seizures underwent a pre-surgical work-up. Two patients started with generalized seizures, one presenting with early-onset atypical absences and the other generalized tonic-clonic seizures. During the course of the disease, from two to 10 years, seizures became fever-sensitive and continued to recur in clusters, although these were less frequent. Seizures were mainly described by eyewitnesses as generalized tonic-clonic, even though three of five seizures, recorded on EEG, showed a focal onset with fast bilateral spread. Atypical absences and fever-induced tonic-clonic seizures remained frequent in only one patient until the age of 16 years. No specific treatment or combination appeared to be more effective over another. Various degrees of cognitive or behavioural impairment were reported for all patients, but it was in the second decade that behavioural disturbances prevailed with hetero-aggressiveness and behaviour associated with frontal lobe abnormalities leading to psychosis in two. Early recognition of the above features should improve early diagnosis and long-term management of patients with epilepsy and PCDH19 mutations.


Assuntos
Encéfalo/fisiopatologia , Caderinas/genética , Epilepsia/fisiopatologia , Adolescente , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia/genética , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Mutação , Fenótipo , Estudos Retrospectivos , Adulto Jovem
20.
J Clin Pharmacol ; 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30412268

RESUMO

Valproate is an old-generation antiepileptic drug often used in children. The pharmacokinetics of valproate are noteworthy for a large and difficult to predict interindividual variability in measured serum concentrations and for saturable protein binding. A model-based approach to personalize valproate treatment could be relevant in pediatric patients. The aims of this study were to review all published valproate population pharmacokinetic models in children and assess them by external validation to determine their predictive performance. Through simulations with the best model, we evaluated dosing regimen. A validation data set included valproate serum concentrations assayed during routine therapeutic drug monitoring of epileptic children. We applied to our population 11 published pediatric population pharmacokinetic models. For each model, predictive performance was assessed by external validation, using bias and precision calculations as well as goodness-of-fit plots. Dose simulations were conducted with the best predictive model to evaluate dosing regimen. The validation data set contained 178 valproate concentrations ranging from 13.4 to 128 mg/L from 114 patients. The best model exhibited a mean prediction error of 6.6 mg/L and a root mean squared error of 25.1 mg/L, with no model misspecification evidenced by visual predictive check. In our cohort, half the patients had a trough concentration <50 mg/L. Simulations suggested increasing doses, especially for children ≤40 kg. External evaluation of published valproate pharmacokinetic models enabled us to identify a suitable model for simulations and Bayesian forecasting. Dosing regimen should be adjusted to weight, with decreasing doses with increasing weight.

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