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1.
Epilepsia ; 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32141622

RESUMO

OBJECTIVE: Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). METHODS: A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set-based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. RESULTS: We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. SIGNIFICANCE: In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance.

2.
Lancet ; 394(10216): 2243-2254, 2020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31862249

RESUMO

BACKGROUND: Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. METHODS: In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. FINDINGS: Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7-72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2-52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. INTERPRETATION: In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. FUNDING: Zogenix.


Assuntos
Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Convulsões/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Administração Oral , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Fenfluramina/administração & dosagem , Fenfluramina/efeitos adversos , Humanos , Masculino , Estudos Observacionais como Assunto , Placebos , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/efeitos adversos , Resultado do Tratamento
3.
Epileptic Disord ; 21(S1): 15-21, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262717

RESUMO

Encephalopathy with continuous spike-waves during slow-wave sleep (CSWS) evolves over time, and three stages can be recognized: before the onset of CSWS, during CSWS, and after the CSWS period. Clinical seizures tend to remit spontaneously around puberty. This pattern is independent of the etiological lesion. The CSWS also disappears in all cases. Focal abnormalities instead, may persist for some time after the disappearance of CSWS. The disappearance of the clinical seizures and CSWS may be simultaneous or seizures may disappear before or after disappearance of the CSWS pattern on the EEG. Electroclinical parameters in the pre-CSWS period that have been proposed to predict a poor outcome are early-onset seizures, appearance of new seizures, and a significant increase in seizure frequency. From the electrical point of view, an increase in the frequency of the interictal EEG paroxysms while awake and during sleep and bilateral spike-and-wave paroxysms may also be predictive of a poor evolution in CSWS. When CSWS disappears, neurocognitive and behavioral status improve, but in most patients, residual moderate to severe neurocognitive impairments remain. In non-lesional epilepsy, cognitive recovery after cessation of the CSWS depends on the severity and duration of the initial regression. The duration of the CSWS seems to be the most important predictor of cognitive outcome. Early recognition and effective therapy to reduce the seizures and resolve the CSWS may be crucial to improve long-term prognosis. Cognitive recovery is observed in patients who respond well to AED treatment and outcome depends on the etiology.


Assuntos
Transtornos Cognitivos/psicologia , Epilepsia/psicologia , Convulsões/fisiopatologia , Sono/fisiologia , Encefalopatias/fisiopatologia , Transtornos Cognitivos/diagnóstico , Eletroencefalografia/métodos , Humanos , Estudos Longitudinais , Prognóstico , Convulsões/diagnóstico , Sono de Ondas Lentas
4.
Epilepsy Behav ; 97: 244-252, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31254844

RESUMO

OBJECTIVE: The objective of the study was to investigate electroclinical and neuropsychological features, genetic background, and evolution of children with idiopathic encephalopathy with status epilepticus during slow sleep (ESES), including Landau-Kleffner syndrome (LKS). MATERIAL AND METHODS: All children diagnosed with idiopathic ESES at the Danish Epilepsy Centre between March 2003 and December 2014 were retrospectively reviewed. Repeated 24-hour electroencephalography (24-h EEG) recordings, neuropsychological assessments, and clinical-neurological evaluation were performed throughout the follow-up in all patients. In 13 children, genetic investigations were performed. RESULTS: We collected 24 children (14 males and 10 females). Mean age at ESES diagnosis was 6 years, and mean ESES duration was 2 years and 7 months. Twenty-one children had epileptic seizures. Three children had LKS. Topography of sleep-related EEG epileptic abnormalities was diffuse in 3 subjects, hemispheric in 6, multifocal in 9, and focal in 6. During the active phase of ESES, all children presented with a heterogeneous combination of behavioral and cognitive disturbances. In 14 children, a parallel between severity of the clinical picture and spike-wave index (SWI) was observed. We could not find a strict correlation between the type and severity of neurobehavioral impairment and the side/topography of sleep-related EEG discharges during the active phase of ESES. At the last follow-up, 21 children were in remission from ESES. Complete recovery from neurobehavioral disorders was observed in 5 children. Genetic assessment, performed in 13 children, showed GRIN2A variant in two (15.4%). SIGNIFICANCE: Our patients with idiopathic ESES showed a heterogeneous pattern of epileptic seizures, neurobehavioral disorders, and sleep EEG features. Only one-fourth of children completely recovered from the neuropsychological disturbances after ESES remission. Lack of correlation between severity/type of cognitive derangement and SWI and/or topography of sleep EEG epileptic abnormalities may suggest the contribution of additional factors (including impaired sleep homeostasis due to epileptic activity) in the neurobehavioral derangement that characterize ESES.

5.
Epileptic Disord ; 21(S1): 76-81, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31172954

RESUMO

The major goal of therapy in patients with Encephalopathy related to Status Epilepticus during slow Sleep (ESES) is to prevent or reduce associated cognitive deficits. Whether or not the EEG pattern of ESES should be completely suppressed to improve cognition is unknown. In clinical practice, there are two major challenges: to establish the optimal treatment strategy in patients with ESES, and to identify the patients who will benefit most from therapy, including atypical cases. Here, we provide a comprehensive overview of the current literature on treatment efficacy in patients with ESES.


Assuntos
Encefalopatias/tratamento farmacológico , Transtornos Cognitivos/fisiopatologia , Sono/fisiologia , Estado Epiléptico/tratamento farmacológico , Encefalopatias/fisiopatologia , Criança , Eletroencefalografia/métodos , Humanos , Estado Epiléptico/fisiopatologia , Resultado do Tratamento
6.
Ther Drug Monit ; 41(3): 340-347, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30688870

RESUMO

BACKGROUND: The indication for the antiepileptic drug lacosamide (LCM) was recently extended to include children from the age of 4 years. Real-life data on the use and serum concentrations of LCM in children and adolescents are limited. The purpose of this study was to investigate the use of LCM in this patient group in relation to age, comedication, dose, serum concentrations and duration of treatment, and to examine pharmacokinetic variability. METHODS: Children and adolescents (<18 years) who had serum concentrations of LCM measured from January 2012 to June 2018 were retrospectively identified from the therapeutic drug monitoring databases at 2 national epilepsy centers in Norway and Denmark. Clinical data were collected from request forms and medical records. RESULTS: Data from 124 patients were included, 61 girls/63 boys. Weight was available for 76 patients. Median age was 15 years (range 2-17 years), dose of LCM 300 mg/d (76-600 mg/d), and serum concentration 18 µmol/L (5-138 µmol/L) [4.5 mg/L (1.3-34.5 mg/L)]. Pharmacokinetic variability was demonstrated as the concentration/(dose/kg) ratio ranged from 1.3 to 9.4 (µmol/L)/(mg/kg) and was affected by age. Polytherapy with 1-3 other antiepileptic drugs was noted in 107 patients (86%). Treatment was continued beyond 1 year in 71% (n = 45) of the 63 patients where such information was available, and all of these 45 patients had serum concentrations within the defined reference range. The 1-year retention rate was higher in patients not concomitantly using other sodium channel-blocking drugs (82% versus 56%). CONCLUSIONS: The study demonstrates pharmacokinetic variability in and between age groups, which indicates usefulness of therapeutic drug monitoring. More than two-thirds of patients continued treatment beyond 1 year, suggesting reasonable effectiveness.


Assuntos
Anticonvulsivantes/farmacocinética , Lacosamida/farmacocinética , Adolescente , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Dinamarca , Monitoramento de Medicamentos/métodos , Quimioterapia Combinada/métodos , Epilepsia/tratamento farmacológico , Feminino , Humanos , Lacosamida/uso terapêutico , Masculino , Noruega , Estudos Retrospectivos
7.
Epilepsy Behav ; 76: 63-70, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28927712

RESUMO

INTRODUCTION: Rufinamide is approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged ≥4years. The objective of this study was to provide real-world, long-term data on patients with LGS initiating rufinamide as add-on therapy and patients with LGS receiving other antiepileptic drugs (AEDs). METHODS: A Phase IV, noninterventional, multicenter registry study was conducted in patients with LGS aged ≥4years requiring modification to any AED treatment, including initiation of add-on rufinamide therapy. Safety/tolerability was assessed by evaluating treatment-emergent adverse events (TEAEs), and efficacy was assessed using a generic seizure frequency scale. RESULTS: A total of 111 patients from 64 sites in 8 European countries were included, of whom 64 initiated rufinamide ("rufinamide" group) and 21 did not receive rufinamide at any time during the study ("no-rufinamide" group). Mean ages were 16.1years (rufinamide) and 15.0years (no rufinamide). The median duration of follow-up was >2years (range: 1.3-46.4months). Antiepileptic drug-related TEAEs were reported for 40.6% (rufinamide) and 33.3% (no rufinamide) of patients and led to discontinuation of 7.8% and 4.8%, respectively. The most frequently reported rufinamide-related TEAEs (≥5% patients) were somnolence (7.8%) and decreased appetite (6.3%). There were no unexpected safety/tolerability findings. At month 12, the proportion of patients with improvement in all seizures ("much improved" or "very much improved") was 28.6% (12/42) for the rufinamide group and 14.3% (2/14) for the no-rufinamide group. CONCLUSION: The study provided valuable information on LGS and its management, and evidence that rufinamide has a consistent and generally favorable safety/tolerability profile when used in routine clinical practice. CLINICALTRIALS. GOV IDENTIFIER: NCT01991041.


Assuntos
Anticonvulsivantes/uso terapêutico , Síndrome de Lennox Gastaut/tratamento farmacológico , Triazóis/uso terapêutico , Adolescente , Criança , Pré-Escolar , Grupos Étnicos , Europa (Continente) , União Europeia , Feminino , Humanos , Masculino , Sistema de Registros , Convulsões/tratamento farmacológico , Fases do Sono/efeitos dos fármacos , Resultado do Tratamento , Triazóis/efeitos adversos
8.
Curr Pharm Des ; 23(37): 5639-5648, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28950817

RESUMO

BACKGROUND: Patient features, apart from the type of seizures/epilepsy, affect markedly antiepileptic drug (AED) choice and dosage. The present review focuses on gender, age and psychiatric comorbidities which play a leading role in influencing antiepileptic treatment. METHODS: Reviews with large population of patients, controlled clinical trials, observational investigations, experimental studies and experimental reviews of experimental data, where appropriated, were analysed and illustrated to produce the most homogeneous indications possible. Different and also contradictory observations have been highlighted to stimulate a critical approach to specific aspects. RESULTS: Women of childbearing age should avoid valproic (VPA), acid, since this drug doubles the risk of major malformations and causes in the exposed offspring reduced intellectual development and disorders of autistic spectrum. The drug is also associated with hormonal disorders, polycystic ovary and reduced fertility. Children treated with valproic acid or phenobarbital can exhibit hyperactivity, nervousness and attention disorders. As a consequence of increased drug elimination, younger children require higher doses as compared to adults and older patients. Elderly patients treated with phenobarbital may face the risk of cognitive disorders and/or falls resulting in bone fractures. Fractures are also facilitated by carbamazepine-induced osteoporosis. Psychiatric disorders are frequently associated with epilepsy and evidence has been gained that common pathological steps underlie these conditions. Depressed patients should avoid drugs like phenobarbital, topiramate, levetiracetam, zonisamide and perampanel since these drugs can induce mood disorders. Although not conclusive, literature data indicate that topiramate and levetiracetam and also tiagabine and vigabatrin, are associated with suicidal thought/behaviour. Conversely, lamotrigine, carbamazepine, VPA and oxcarbazepine exert beneficial effects on mood. Bupropion, clomipramine, amoxapine and maprotyline among antidepressants, and clozapine, olanzapine and quietapine among antipsychotics have been observed to lower seizure threshold. Serum AED concentration monitoring is of help in dosage adjustments, especially in very young children, in patients with cognitive decline and in patients with psychiatric comorbidities. CONCLUSIONS: A careful evaluation of the patient variables analysed in the present review is useful to personalize and optimize AED therapy.


Assuntos
Anticonvulsivantes/uso terapêutico , Antipsicóticos/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/patologia , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/patologia , Fatores Etários , Comorbidade , Epilepsia/complicações , Humanos , Transtornos Mentais/complicações , Fatores Sexuais
9.
Epileptic Disord ; 19(2): 226-230, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28637637

RESUMO

We describe a case of a child suffering from alternating hemiplegia with a heterozygous p. E815K pathogenic variant of ATP1A3. The patient started to present abnormal eye movements in the first days of life, followed by the appearance at 2 months of dystonic episodes, and later on, by recurrent episodes of alternating hemiplegia more often on the right side. A severe epilepsy started at the age of 2 years with episodes of status epilepticus since the onset which frequently recurred, requiring admission to the intensive care unit. MRI showed bilateral mesial temporal sclerosis and a left-sided ischaemic lesion. Interictal EEG showed bilateral abnormalities, whereas postictal EEG after status epilepticus showed overt slowing on the left side, suggesting a predominant involvement of ictal activity of the left hemisphere. We hypothesize that in our patient, the left hemisphere might have been more prominently affected by the pathogenetic abnormalities underlying alternating hemiplegia of childhood, rendering it more prone to early ischaemic lesions and recurrent unilateral status epilepticus. We speculate whether alternating hemiplegia of childhood shares some common pathophysiological mechanisms with familial hemiplegic migraine that may be associated with a pathogenic variant of ATP1A2.


Assuntos
Epilepsia/genética , Hemiplegia/genética , ATPase Trocadora de Sódio-Potássio/genética , Pré-Escolar , Epilepsia/fisiopatologia , Hemiplegia/fisiopatologia , Humanos , Masculino
10.
Neurology ; 88(5): 483-492, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28053010

RESUMO

OBJECTIVE: To examine the role of mutations in GABRB3 encoding the ß3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. METHODS: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. RESULTS: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant ß3, together with α5 and γ2s subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations. CONCLUSIONS: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism.


Assuntos
Epilepsia/genética , Mutação , Receptores de GABA-A/genética , Animais , Automação Laboratorial , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/fisiopatologia , Feminino , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Potenciais da Membrana/fisiologia , Oócitos , Técnicas de Patch-Clamp , Fenótipo , Receptores de GABA-A/metabolismo , Xenopus laevis
11.
Brain Behav ; 6(9): e00505, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27688936

RESUMO

AIM: To assess the clinical trial and real-world data for adjunctive perampanel in adolescents and develop consensus recommendations to guide the use of perampanel in this population in clinical practice. METHODS: In May 2015, 15 epilepsy experts attended a Consensus Development Meeting to assess the clinical trial data for perampanel, specific to the adolescent age group (12-17 years) and develop consensus treatment recommendations. RESULTS AND DISCUSSION: Analysis of the adolescent subgroup data of three pivotal placebo-controlled, double-blind, phase 3 trials investigating perampanel in patients with ongoing focal epileptic seizures despite receiving one to three antiepileptic drugs found that perampanel 4-12 mg was superior to placebo. The tolerability profile of perampanel was generally acceptable. Adolescent patients receiving long-term treatment with perampanel in an open-label extension study maintained improvements in seizure control compared with baseline, with a favorable risk-benefit profile. A phase 2 study showed that perampanel had no clinically important effects on cognitive function, growth, and development. CONCLUSION: Perampanel is a welcome addition to the armamentarium of existing antiepileptic drugs as it represents a new approach in the management of epilepsy, with a novel mechanism of action, and the potential to have a considerable impact on the treatment of adolescents with epilepsy.

12.
Mol Syndromol ; 7(4): 210-219, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27781031

RESUMO

In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including SCN1A, STXBP1, CDKL5, SCN2A, SCN8A, GABRA1, KCNA2, and STX1B. Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.

13.
Neurology ; 86(10): 954-62, 2016 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-26865513

RESUMO

OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. RESULTS: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. CONCLUSION: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Proteínas Munc18/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Adulto , Encefalopatias/diagnóstico , Encefalopatias/epidemiologia , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , Adulto Jovem
14.
Seizure ; 35: 106-10, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26820223

RESUMO

PURPOSE: PCDH19 mutations cause epilepsy and mental retardation limited to females (EFMR) or Dravet-like syndromes. Especially in the first years of life, epilepsy is known to be highly pharmacoresistant. The aim of our study was to evaluate the effectiveness of antiepileptic therapy in patients with PCDH19 mutations. METHODS: We report a retrospective multicenter study of antiepileptic therapy in 58 female patients with PCDH19 mutations and epilepsy aged 2-27 years (mean age 10.6 years). RESULTS: The most effective drugs after 3 months were clobazam and bromide, with a responder rate of 68% and 67%, respectively, where response was defined as seizure reduction of at least 50%. Defining long-term response as the proportion of responders after 12 months of treatment with a given drug in relation to the number of patients treated for at least 3 months, the most effective drugs after 12 months were again bromide and clobazam, with a long-term response of 50% and 43%, respectively. Seventy-four percent of the patients became seizure-free for at least 3 months, 47% for at least one year. SIGNIFICANCE: The most effective drugs in patients with PCDH19 mutations were bromide and clobazam. Although epilepsy in PCDH19 mutations is often pharmacoresistant, three quarters of the patients became seizure-free for at least for 3 months and half of them for at least one year. However, assessing the effectiveness of the drugs is difficult because a possible age-dependent spontaneous seizure remission must be considered.


Assuntos
Anticonvulsivantes/uso terapêutico , Caderinas/genética , Epilepsia/tratamento farmacológico , Epilepsia/genética , Mutação/genética , Farmacogenética , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Cruz Vermelha , Estudos Retrospectivos , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
15.
Epilepsia ; 56(12): e203-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26537434

RESUMO

The first mutations identified in SLC2A1, encoding the glucose transporter type 1 (GLUT1) protein of the blood-brain barrier, were associated with severe epileptic encephalopathy. Recently, dominant SLC2A1 mutations were found in rare autosomal dominant families with various forms of epilepsy including early onset absence epilepsy (EOAE), myoclonic astatic epilepsy (MAE), and genetic generalized epilepsy (GGE). Our study aimed to investigate the possible role of SLC2A1 in various forms of epilepsy including MAE and absence epilepsy with early onset. We also aimed to estimate the frequency of GLUT1 deficiency syndrome in the Danish population. One hundred twenty patients with MAE, 50 patients with absence epilepsy, and 37 patients with unselected epilepsies, intellectual disability (ID), and/or various movement disorders were screened for mutations in SLC2A1. Mutations in SLC2A1 were detected in 5 (10%) of 50 patients with absence epilepsy, and in one (2.7%) of 37 patient with unselected epilepsies, ID, and/or various movement disorders. None of the 120 MAE patients harbored SLC2A1 mutations. We estimated the frequency of SLC2A1 mutations in the Danish population to be approximately 1:83,000. Our study confirmed the role of SLC2A1 mutations in absence epilepsy with early onset. However, our study failed to support the notion that SLC2A1 aberrations are a cause of MAE without associated features such as movement disorders.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/epidemiologia , Epilepsias Mioclônicas/genética , Epilepsia Tipo Ausência/genética , Transportador de Glucose Tipo 1/genética , Proteínas de Transporte de Monossacarídeos/deficiência , Erros Inatos do Metabolismo dos Carboidratos/genética , Pré-Escolar , Dinamarca/epidemiologia , Epilepsia Generalizada/genética , Transportador de Glucose Tipo 1/deficiência , Transportador de Glucose Tipo 1/fisiologia , Humanos , Lactente , Proteínas de Transporte de Monossacarídeos/genética , Mutação , Síndrome
16.
Funct Neurol ; 30(2): 139-41, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26415787

RESUMO

Encephalopathy with status epilepticus during sleep (ESES) is an age-related disorder characterized by neuropsychological regression, epilepsy and a typical EEG pattern of continuous epileptiform activity (> 85%) during NREM sleep. Cases of worsening or induction of ESES with phenytoin, carbamazepine and phenobarbital have been reported. We describe a child with benign epilepsy with centrotemporal spikes (BECTS) in whom treatment with oxcarbazepine (OXC) induced ESES. The patient was studied through repeated clinical-neuropsychological evaluations and 24-hour EEG recordings. He was treated with OXC two months after epilepsy onset. One month after starting OXC, he developed an abrupt and severe cognitive deterioration. A 24-hour EEG and neuropsychological tests showed an electroclinical picture compatible with ESES. Withdrawal of OXC and introduction of other drugs were followed by a prompt improvement. Five months after ESES onset, a 24-hour EEG was normal. Our report indicates that OXC can induce ESES in BECTS.


Assuntos
Encefalopatias/induzido quimicamente , Carbamazepina/análogos & derivados , Córtex Cerebral/fisiopatologia , Epilepsias Parciais/complicações , Sono/fisiologia , Estado Epiléptico/induzido quimicamente , Encefalopatias/complicações , Carbamazepina/efeitos adversos , Criança , Eletroencefalografia , Humanos , Masculino , Testes Neuropsicológicos , Oxcarbazepina , Estado Epiléptico/complicações
17.
Epilepsia ; 56(9): e114-20, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26122718

RESUMO

Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype-phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances.


Assuntos
Epilepsias Parciais/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Canais de Potássio/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Morte Súbita do Lactente/genética
18.
Am J Hum Genet ; 96(5): 808-15, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25865495

RESUMO

GAT-1, encoded by SLC6A1, is one of the major gamma-aminobutyric acid (GABA) transporters in the brain and is responsible for re-uptake of GABA from the synapse. In this study, targeted resequencing of 644 individuals with epileptic encephalopathies led to the identification of six SLC6A1 mutations in seven individuals, all of whom have epilepsy with myoclonic-atonic seizures (MAE). We describe two truncations and four missense alterations, all of which most likely lead to loss of function of GAT-1 and thus reduced GABA re-uptake from the synapse. These individuals share many of the electrophysiological properties of Gat1-deficient mice, including spontaneous spike-wave discharges. Overall, pathogenic mutations occurred in 6/160 individuals with MAE, accounting for ~4% of unsolved MAE cases.


Assuntos
Epilepsias Mioclônicas/genética , Epilepsia Generalizada/genética , Proteínas da Membrana Plasmática de Transporte de GABA/genética , Animais , Epilepsias Mioclônicas/patologia , Epilepsia Generalizada/patologia , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Camundongos , Mutação
19.
Neuropediatrics ; 46(2): 110-6, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25730374

RESUMO

OBJECTIVE: This article aims to report the first clinical experiences concerning effectiveness and tolerability of perampanel (PER) in a pediatric population with refractory epilepsies. PATIENTS AND METHODS: This nonsponsored, observational, retrospective survey was conducted through collaboration with multiple centers in Europe. The clinical course of the first pediatric patients treated in these centers with PER was documented with the help of a questionnaire completed by the treating physicians. Effectiveness and adverse effects were evaluated. The study population consisted of 58 patients (mean age, 10.5 years; range, 2-17 years), suffering from various refractory epilepsies, classified as focal epilepsy (n = 36), unclassified generalized epilepsy (n = 12), Lennox-Gastaut syndrome (n = 5), West syndrome (n = 3), and Dravet syndrome (n = 2). RESULTS: The response rate (≥ 50% seizure reduction) after the first 3 months of therapy was 31% (18/58 patients) in total. Complete seizure control was achieved in five patients (9% overall). Aggravation of seizures occurred in five cases (9%). The most frequently occurring adverse effects were reduced vigilance or fatigue (n = 16) and behavioral changes (n = 14). DISCUSSION: PER seems to be effective also in children and adolescents with pharmaco-refractory epilepsies. Tolerability was acceptable.


Assuntos
Epilepsia Resistente a Medicamentos/tratamento farmacológico , Piridonas/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Piridonas/efeitos adversos , Receptores de AMPA/antagonistas & inibidores , Estudos Retrospectivos , Resultado do Tratamento
20.
Eur J Paediatr Neurol ; 18(6): 685-90, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24929673

RESUMO

PURPOSE: The literature on the efficacy and safety of rufinamide in childhood-onset epilepsy syndromes currently includes approximately 600 paediatric patients. This paper summarizes the views of a panel of experienced European epileptologists with regard to the current role of rufinamide in the treatment of childhood epilepsies. RESULTS: Rufinamide is effective in decreasing the seizure frequency in the Lennox-Gastaut syndrome (LGS), especially tonic and atonic seizures. It might consequently be preferred to other drugs as a second-line treatment for LGS when drop-attacks are frequent. The mean responder rate in the published studies is 38% with seizure freedom achieved in 2.4% of patients. Rufinamide has shown some efficacy in epileptic encephalopathies other than LGS. It can be also effective as adjunctive therapy in children and adolescents with drug-resistant partial seizures. The available data suggest that rufinamide has an acceptable risk/benefit ratio with quite a low risk of aggravating seizures. Common adverse effects (somnolence, nausea and vomiting) are usually mild and self-limiting; they are more frequently observed during titration than in the maintenance phase, suggesting that low escalation rates might be associated with fewer adverse effects. Rufinamide appears to have a favourable cognitive profile compared with other antiepileptic drugs. CONCLUSION: Rufinamide is only approved for adjunctive treatment of seizures associated with LGS in children 4 years of age and older. There are very few data on rufinamide treatment at the onset of LGS or early in the course of the disorder; whether early treatment will improve outcome has yet to be determined.


Assuntos
Anticonvulsivantes/normas , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Guias como Assunto , Triazóis/normas , Triazóis/uso terapêutico , Anticonvulsivantes/farmacocinética , Feminino , Humanos , Masculino , Triazóis/farmacocinética
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