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AIMS: This post hoc analysis assessed the efficacy and safety/tolerability of adjunctive perampanel in patients from China (aged ≥12 years) with focal seizures (FS), with/without focal to bilateral tonic-clonic seizures (FBTCS), or generalized tonic-clonic seizures (GTCS). METHODS: Study centers in China were identified using data from five double-blind, randomized, phase III studies of adjunctive perampanel (2-12 mg/day) and their open-label extensions (OLEx). Efficacy assessments included median percent reduction in seizure frequency per 28 days, and 50% and 75% responder and seizure-freedom rates. Safety/tolerability assessments included monitoring of treatment-emergent adverse events (TEAEs). RESULTS: Overall, 277 patients (placebo, n = 79; perampanel, n = 198) were included in the double-blind safety analysis set. The full analysis set comprised 274 patients (FS, n = 238 [placebo, n = 60; perampanel, n = 178]; FBTCS, n = 120 [placebo, n = 31; perampanel, n = 89]; GTCS, n = 36 [placebo, n = 18; perampanel, n = 18]). Median percent reductions in seizure frequency for placebo vs perampanel were as follows: 16.6% vs 32.4% (FS; P < 0.05) and 39.1% vs 48.2% (FBTCS; not significant [NS]) at 4-12 mg/day, and 37.9% vs 82.6% (GTCS; NS) at 8 mg/day; 50% responder rates were 31.7% vs 37.4% (FS; NS), 48.4% vs 51.9% (FBTCS; NS), and 33.3% vs 61.1% (GTCS; NS), respectively. Seizure-freedom rates were 1.7% vs 9.2%, 16.1% vs 25.3%, and 16.7% vs 44.4%, respectively (all NS). Overall, 262 patients entered the OLEx (FS, n = 228; GTCS, n = 34). Perampanel was efficacious for up to four years for FS and FBTCS and up to two years for GTCS. Across the double-blind and OLEx studies, TEAEs were reported in 65.7% and 81.3% of perampanel-treated patients, respectively; the most common was dizziness. Efficacy and safety/tolerability outcomes were generally similar between Chinese and non-Chinese patients. CONCLUSION: Adjunctive perampanel (up to 12 mg/day) may be a suitable treatment for Chinese patients with FS, with/without FBTCS, or GTCS, with similar efficacy and safety/tolerability compared to non-Chinese patients.

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Anticonvulsivantes/administración & dosificación , Nitrilos/administración & dosificación , Piridonas/administración & dosificación , Convulsiones/diagnóstico , Convulsiones/tratamiento farmacológico , Adolescente , Adulto , Anticonvulsivantes/efectos adversos , China/epidemiología , Método Doble Ciego , Quimioterapia Combinada , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Humanos , Masculino , Nitrilos/efectos adversos , Piridonas/efectos adversos , Convulsiones/epidemiología , Resultado del Tratamiento , Adulto Joven

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Epilepsies are disorders with highly phenotypic pleiotropy and genetic heterogeneity,and many problems and difficulties still exist in clinical teaching.In order to improve the quality of epilepsy teaching and train high-quality medical talents with innovative thinking,the concept of precision medicine is introduced into epilepsy teaching.Typical cases with epilepsy syndromes were collected and modified to form ideal epilepsy teaching cases.Based on the cases,specific situations and teaching plan were designed,in which the problem-based learning were applied to medical students in epilepsy teaching,in order to raise their ability of academic thinking and comprehensive analysis in the clinical practice of epilepsy.

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Objective To investigate the co-occurrence incidence,clinical features and risk predictors of autism and intellectual disability in patients with Lennox-Gastaut syndrome (LGS).Methods Sixty-four patients with LGS were recruited in our Epilepsy Center from June 2012 to June 2018.Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS) were performed to evaluate autism,while Chinese Wechsler Intelligence Scale for Children (C-WISC) and Gesell Developmental Scale were applied to estimate intelligence.The influences of different clinical factors in autism and intellectual disability were analyzed in patients with LGS.Results Among 64 patients with LGS,only three (4.7％) were diagnosed as having autism,and their average ABC and CARS scores were 80.0 and 40.0,respectively.The average ABC and CARS scores were 40.9±26.7 and 26.0±8.9 in thepatients with onset age＜one year,which were significantly higher than those in other two groups,respectively (P＜0.05).The average ABC and CARS scores in the patients accepted antiepileptic drugs (AEDs) ≥ 3 were 27.8±22.8 and 22.2±8.7,which were significantly higher than those in the patients accepted one or two kinds ofAEDs (P＜0.05).In addition,the ABC and CARS scores showed significant differences in the groups with different seizure frequency and in the groups with or without symptomatic etiologies (P＜0.05).Fifty patients (78.1％) presented different levels of intellectual disability;severe intellectual disability was the leading type,which accounted for 31.3％ (20/64);12(18.8％),7(10.9％),and 11 (17.2％) patients were with mild,moderate or profound intellectual disability,respectively.As compared with patients without intellectual disability,patients with intellectual disability had younger onset age,higher proportion of slow background activity on EEG and higher proportion of symptomatic etiologies,with significant differences (P＜0.05).Conclusion Patients are in higher risk of autism when they have earlier epilepsy onset age,higher frequency of epilepsy seizure attack,administration of AEDs ≥3 and symptomatic etiologies;early onset age is an independent risk predictor for intellectual disability of patients with LGS.

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Objective To study the influence of SCNIA intronic mutations in mRNA splicing in febrile seizures related epilepsy,and investigate the association between splicing changes and genotype-phenotype-inheritance pattern.Methods Molecular cloning of 5 SCN1A intronic mutations was performed in patients with partial epilepsy with antecedent febrile seizures plus (PEFS+) and Dravet syndrome (DS) through constructing mutant and wild-type plasmids of pTragetE2-3-4-5 and E24-25-26 by using Minigene splicing assay,and the in vitro expressions in HENK293 cells were detected.The mRNA splicing changes were analyzed qualitatively and quantitatively by reverse transcription (RT)-PCR and real time quantitative (q)-PCR.Results (1) Using RT-PCR,DS mutants presented a whole exon skipping without significant remain of normal mRNA transcripts,while PEFS+ mutants showed partial exon skipping or intronic insertion with coexistence of normal and aberrant mRNA transcripts.(2) Statistical differences were found between relative quantity (RQ) of aberrant and normal mRNA in PEFS+ mutant (c.473+5G＞A:4.92％±1.05％ and 6.10％±0.21％;c.473+5G＞C:7.97％±1.12％ and 3.94％ ±1.25％) and that in DS mutant (c.602+1G＞A:60.51％±1.81％ and 0.060％±0.022％,P＜0.05);similarly,there were statistical differences between relative RQ of normal and aberrant mRNA in PEFS+ mutant c.4853-25T＞A (71.22％±11.92％ and 7.38％±1.61％) and that in DS mutant c.4853-1G＞C (0.08％±0.01％ and 22.11％±2.83％,P＜0.05).Conclusion The position and difference of splicing patterns of SCNIA intronic mutations are potential molecular pathogenesis for phenotypic difference of febrile seizures related epilepsy.

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Objective To conduct mutation screening of SCN1A 3′ untranslated region (UTR) on Dravet syndrome (DS) patients without mutations in the SCN1A coding region and promoter region, and functional analysis of the variant from DS patients.Methods Twenty-eight DS patients without mutations in the SCN1A coding region and promoter region were screened for SCN1A 3′ UTR mutations using PCR and direct sequencing.Functional analysis of the detected mutation was done via luciferase assay, mRNA stability analysis and RNA electrophoretic mobility shift assay (RNA-EMSA).Results A novo variant (c.*20A>G) in SCN1A 3′ UTR was found in one DS patient.The variant (c.*20A>G) reduced the luciferase gene xpression by 30% through increasing the affinity of pluripotent embryonal carcinoma cell line NT2/cytoplasmic protein binding and reducing luciferase gene mRNA stability (t=8.5,P<0.01).Conclusions A functional variant was detected from one patient with DS.This variant negatively regulated the gene expression by increasing the affinity of pluripotent embryonal carcinoma cell line NT2/cytoplasmic protein binding and reducing mRNA stability.

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Objective To investigate the potential pathogenesis of Focal cortical dysplasia (FCD), we performed cDNA microarray analysis to obtain gene expression profile of FCD. Methods Three FCD samples and three normal controls were enrolled. Total RNA of the brain tissues were extracted. The difference gene expressions between FCD group and control group was detected using Affymetrix gene chip. The up and down-regulated genes were confirmed by Real-time PCR. Further, the related signal pathways involved in the pathogenic mechanisms of FCD were predicted by bioinformatics. Result In FCD, two up-regulated genes C21orF2 and AU152162 and 5 down-regulated genes ENPP2, ANLN, IP6K3, UGT8, and AZGP were found. Compared the FCD samples with the normal controls , there were significantly different in all down-regulated genes (P 0.05). Using bioinformatics analysis, the ENPP2 , UGT8 , and AZGP1 protein which located in the cell membrane or secreted into the extracellular matrix may be involved in the formation of the myelin sheath and the development of the nervous system by the lipid metabolism and LPA signaling pathway. Conclusion ENPP2, UGT8 and AZGP1 may be involved in pathogenesis of FCD through the process of myelin sheath formation and LPA signal pathway , which warrants further study to know their roles in the pathogenesis of FCD.

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Objective To analyze the causes of misdiagnosis and mistreatment of Dravet syndrome. Methods Patients with Dravet syndrome diagnosed according to clinical features and SCN1A gene mutation detection were recruited within recent 3 years. The patients were grouped into correct diagnosis-treatment group and misdiagnosis-mistreatment group according to whether the patients had ever been misdiagnosed and mistreated by sodium channel blockers. The clinical features were compared between two groups. Results Thirty-five cases with Dravet syndrome were collected and the rate of misdiagnosis reached 40%, Nine cases were misdiagnosed as symptomatic focal epilepsy, 4 as Lennox-Gastaut syndrome and 1 as Doose syndrome. The average age of onset in misdiagnosis-mistreatment group was (5.50 ± 3.56) months,and the age of confirmed diagnosis was (83.57 ± 105.62) months. The percentage of abnormal EEG, onset seizure with partial seizure, the seizure frequency within the first year from onset, onset with afebrile seizure, patients with status epilepticus or cluster seizures was higher in misdiagnosis-mistreatment group but it showed no significant statistical significance when compared with that of correct diagnosis-treatment group. The percentage of patients with mental retardation and focal neurological signs was significantly higher in misdiagnosis-mistreatment group (P=0.005 and 0.002, respectively). Conclusions Dravet syndrome is frequently misdiagnosed as symptomatic focal epilepsy. The appearance of focal neurological signs and mental retardation before confirmed diagnosis are important factors for misdiagnosis. Gene mutation screening will be helpful for differential diagnosis of Dravet syndrome.

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Objective To screen the fragilex mental retardation 1 (FMR1) gene mutations and explore the frequency of FMR1 gene mutation in the population with mental retardation in South China.Methods Seventy-two patients (65 males and 7 females) with suspected fragile X syndrome (FXS) in South China were enrolled in our hospitals from October 2009 to April 2014.The CGG trinucleotide repeats in 5'UTR of FMR1 gene and CCG trinucleotide repeats in FMR2 gene were screened respectively by PCR.Southern blotting and capillary electrophoresis sequencing were performed in male patients without normal target bands and suspected female patients;patients with normal CGG alleles were,then,performed exons and 3'-UTR ofFMR1 gene amplification and sequencing.The frequency of FMR1 gene mutation in patients with mental retardation in different countries and regions was compared with statistical analysis.Results Six pedigrees with full mutation (one female and five males being the probands),one pedigree (mother and son) with FMR1 gene deletion and one pedigree (mother and son) with mutation in the transition region were identified in 72 patients with mental retardation.The prevalence of total mutation was 9.7％ (7/72) and that in male patients was 9.2％ (6/65).These results showed significant differences in prevalence as compared with the results from different countries and areas (P＜0.05);there were no variations in 3'UTR ofFMR1 gene and FMR2 gene mutation in the patients with FXS-like phenotype.Conclusions FMR1 mutation frequency may be higher in mental retardation population in southem China as compared with that in developed countries or areas.Targeted screening on the unexplained mental retardation pedigrees (family history) can improve the diagnosis of FXS.Importantly,deletion mutations screening should also be performed in suspected FXS subjects with normal CGG repeats.

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Objective To explore the possible role of Nav 1.1 in the pathogenesis of increased susceptibility to epileptic seizures in FMR1 knockout (FMR1 KO) mice.Methods FVB strain FMR1 KO mice and wild type (WT) controls at ages of 2 and 4 weeks old were chosen;immunohistochemistry was used to determine the expression of Nav 1.1 in different brain regions (striate cortex,temporal cortex,piriform cortex,hippocampus CA1,CA3 and dentate gyrus),and Western blotting was used to determine the Nav1.1 level in the cerebral acustici cortex and hippocampus.Results The mean optical density of Nav1.1 was significantly increased in the striate cortex,temporal acustici cortex,piriform cortex,regions of CA1 and dentate gyrus in FMR1 KO mice at ages of 2 and 4 weeks (2 weeks:0.058±0.006,0.054± 0.006,0.130±0.015,0.090±0.009 and 0.142±0.010;4 weeks:0.066±0.007,0.060±0.007,0.159±0.018,0.102±0.015 and 0.192±0.025) as compared with the age-matched WT mice (2 weeks:0.049±0.007,0.046±0.007,0.118±0.012,0.080±0.009 and 0.133±0.010;4 weeks:0.051±0.007,0.048±0.005,0.127± 0.012,0.089±0.012 and 0.175±0.024,P＜0.05).The levels of Nav1.1 in the cerebra1 cortex and hippocampus in FMR1 KO mice at ages of 2 and 4 weeks (2 weeks:0.635±0.082 and 0.954±0.111;4 weeks:0.819 ±0.064 and 1.145 ±0.159) were also significantly increased as compared with the age-matched WT mice (2 weeks:0.382±0.025 and 0.555±0.056;4 weeks:0.550±0.040 and 0.847±0.127,P＜0.05).Conclusion Increased expression of Nav1.1 might play an important role in the increased susceptibility to epileptic seizures in FMR1 KO mice.

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Objective To observe the efficacy and side effect of Chinese style modified Atkins diet as add-on therapy in Chinese patients with intractable epilepsy to provide an easier operational choice for these patients.Methods A prospective study was performed on the clinical data of 15 patients with intractable epilepsy,admitted to our hospital from January 2010 to May 2013.On the basis of Johns Hopkins hospital operation method,other three measures were added:recommending calories and protein restriction,guaranteeing lowest fat intake,and choosing 1 g carbohydrate as one serving.All the patients were implemented with this method on the base of drugs.The efficacy,retention rate and side effect after this diet were observed.Results These patients were followed-up for 6 months to 3 years.Three patients (20％) had no attack,4 (26％) had reduced onset of ＞90％ attacks,6 (40％) had reduced 50％ -90％ of their attacks,and the other two did not enjoy good effect.The retention rate at 6 months was 66％; 33％ patients (5/15) had elevated blood lipids (including triglyceride and cholesterol).Conclusion As compared with ketogenic diet,Chinese style modified Atkins diet achieves similar effect,enjoying higher retention rate and fewer side effect,which is worth for clinical promotion.

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Objective To study the clinical characteristics of autism in febrile seizures plus (FS+) and the relationship between autism and SCN1A mutation. Methods Clinical data of 103 patients with FS+ treated in epilepsy centre of the Second Affiliated Hospital of Guangzhou Medical University were collected and analyzed. According to the international criteria, generalized epilepsy with febrile seizures plus (GEFS+), partial seizures with febrile seizures plus (PEFS+), Dravet syndrome (DS) and autism were diagnosed. Genomic DNA was obtained from blood samples. SCN1A were PCR amplified and mutations were detected by DHPLC and sequencing. Result Mental retardation was found in 53.8%of patients with GEFS+, 69.2%of patients with PEFS+, and all patients with DS, respectively. One in GEFS+, one in PEFS+and nine in DS patients were accompanied with autism (P<0.01). Among FS+patients with autism, one SCN1A mutation was found in PEFS+patients, while six SCN1A mutations were found in DS patients. Conclusions Majority of GEFS+and PEFS+patients showed mental retardation, while all the DS patients were accompanied with retardation. The occurrence of autism with DS is higher than GEFS+and PEFS+. No definite relationship between autism and SCN1A mutation was indicated.

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Objective To screen and analyze nucleotide variants in 5'-untranslated region(5'-UTR)in voltage-gated sodium channel α1-subunit gene(SCN1A)in patients with Dravet syndrome and to evaluate the association of the variants with disease.Methods Peripheral blood of 24 patients with Dravet syndrome and 100 unrelated normal persons were collected and genomic DNA was extracted.PCR-sequencing of SCN1 A 5'-UTR in these DNA was performed.To evaluate the possibility of mutation inducing disease,bioinformatics analysis was applied to analyze the conservation of the sequences around the mutation site and predict the potential transcription elements.Results The nucleotide variant of 166.642.520G→A in exon 2 was identified in two patients,but not in normal controls.The mutation was a de novo mutation in a patient with early-onset.In the second proband,the mutation was also carried by his clinically asymptomatic mother.The nucleotide site 166.642.520 was moderately conserved in mammals(62.5%).The average nucleotide identity rate between human and other mammals species in the region adjacent to 166.642.520 was 88.5%.Two potential transcription regulatory elements were predicted on the sequence with the mutation of 166.642.520G>A,and only one on the sequence with wild-type.Conclusions The mutation 166.642.520G>A may be associated with Dravet syndrome and further studied should be performed to verify it and demonstrate its pathogenic mechanisms.

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@#Objective To investigate the neuroprotective effect of extraction of gastrodia elata on status epilepticus induced by Li-pilocarpine in rats. Methods 144 SD rats were randomly divided into 4 groups: saline control (5 ml/kg twice daily), small dose gastrodia group (5 ml/kg twice daily), large dose gastrodia group (10 ml/kg twice daily) and lamotrigine group (20 mg/kg twice daily). The status epilepticus was induced 3 d after treatment. The duration of status epilepticus, neuron loss, the rate of spontaneous seizure and the score of mossy fiber sprouting were analyzed. Results Large dose gastrodia or lamotrigine administration can shorten the duration of status epilepticus and decrease the neuron loss compared with the small dose gastrodia and control administration. But all treatments cannot prevent mossy fiber sprouting and spontaneous seizures. Conclusion 20 ml/kg gastrodia or 40 mg/kg lamotrigine administration can shorten the duration of status epilepticus induced by Li-pilocarpine, and decrease the neuron loss of CA1, CA3 of hippocampus and hilus of dentate gyrus, but cannot prevent epileptogenesis after brain insult.

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Objective To explore the inheritance characteristics of SCN1A gene in familial severe myoclome epilepsy in infancy.Methods The clinical information and blood of the patients and their relatives who had febrile seizure(FS)or epilepsy history were collected.Blood genome DNA were extracted.All exons of SeN1A gene were PCR amplified and screened with denaturing high Performance liquid chromatography(DHPLC)technology,and sequence analysis was performed.Results Fourteen SME patients had FS or epilepsy family history.Five were found positive history in first class relatives and 2 of them had inherited mutations of SCN1A(C.4284+2T>C and e.1216G>T):Other9 were found positive history in second class relatives and 2 of them had de novo mutations of SCN1A.Condusions SCN1A is the pathogenic gene for SME.The same muatation of SCN1A gene can be related to different clinical phenotypes.SME patients whose first class relatives with FS or epilepsy history should be taken as the focus of SCN1A inherited mutation screening.

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Objective To study the sodium channel α1-subunit (SCN1A) gene in a pair of monozygotic twins with borderland severe myoclonic epilepsy in infancy (SMEB) and its characteristic of clinical manifestations. Methods The clinical features of 2 monozygotic twins were summarized. All 26 exons of SCNIA genes were screened with denaturing high performance liquid chromatography (DHPLC), and direct sequence analysis was performed on those with abnormal elution peak. Results The proband and her sister showed typical clinical features of SMEB. The same heterozygous mutations on exon 26 which caused the related amino acid change were found among them (c. 5348C > T, A1783E). Conclusion Monozygotic twins with similar clinical phenotype of SMEB have same SCN1A gene mutation.

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Objective To study the SCN1A gene in a family with partial epilepsy with febrile seizures plus ( PEFS+ ) and its characteristics of inheritance. Methods The clinical features of the 2 patients and their father were summarized. All 26 exons of SCN1A gene were screened with denaturing high performance liquid chromatography (DHPLC), and direct sequence analysis was pedormed on those with abnormal elution peak. Pyrosequencing was subsequently performed in those without abnormality in direct sequence analysis. Results The proband and his sister had the phenotype of PEFS+ . The same heterozygous mutations (AS768G) on exon 26 which caused the related amino acid change (Q1923R) were found among them. Their father had frequent febrile seizures (FS) in childhood, and seizures stopped spontaneously. No abnormality was found in direct sequence but mosaic mutation in the same site was discovered with pyrosequencing (mutation quantity was 25% ). Conclusions The mutatin of SCN1A could cause partial epilepsy. PEFS+ could be inherited, the relatives carrying the affected gene may have mild clinical symptoms, possibly resulting from the low concentration of the mutated gene due to mosaic mutation.

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@#Objective To explore the role of Kv channel interacting protein 1(KChIP1)in the process of epileptic seizure and the relationship between KChIP1 and gamma-aminobutyric acid-(GABA)ergic neurons.Methods Normal female Sprague-Dawley rats were treated with pentylenetetrazole to make acute pentylenetetrazole models of epilepsy.Laser Scanning Confocal Microscope(LSCM)combined with double-labeled immunohistochemical technique was applied to observe the expression of the KChIP1 and the GABAergic neurons in the hippocampus of rats.Results The number of KChIP1-postive neurons in the hippocampus was significantly increased in the acute pentylenetetrazole model rats(P<0.05).There was no significant difference in the number of double-labled neurons(P>0.05),nor of the GABA-postive neurons between the model rats and the controls.The ratio of double-labeled neurons/total positive neurons was 63.9% in the hippocampus.Conclusion The KChIP1 might be involved in epileptogenesis of pentylenetetrazole induced seizure.The KChIP1 was associated with GABAergic neurons,whereas it may be functionally different from GABA.

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In order to improve the quality of epilepsy teaching,the appropriate version of the international classification of epilepsy and epileptic syndrome were selected to teach in the different level students by the way of PBL and clinical case analysis.The clinical thoughts and enthusiasm were improved.The classification of epilepsy could be grasped and easily used in their clinical work.

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Generalized epilepsy with febrile seizures plus is a novel and common generalized epilepsy syndromes, with significant genetic and phenotypic heterogeneity. Research on genetic position and mutant of generalized epilepsy with febrile seizures plus has been a hot spot, which has importance in clarifying epilepsy syndrome as a kind of channelopathy.

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Objectives To evaluate the valproate plasma l ev els,the clinical efficacy and adverse effects in patients with epilepsy treated with the conventional preparations and the sustained-release preparations of sodium valproate (VPA-Na?SR).Methods 33 patients received oral conventional formul ation of sodium valproate for over six months and a similar dosage of VPA-Na?SR for 4 weeks.After 12 or 24 hours,the valproate plasma concentr ations of the two formulations were measured respectively before taking drugs in the early mor ning.The valproate plasma concentrations and the clinical efficacy of the VPA-N a?SR were assessed by comparing with that of conventional valproate.The adverse effects were recorded.Results The average valproate plasma trough concentration was s ignificantly higher in patients receiving VPA-Na?SR than that of those receiving conventional valproate.Seizure free in patients was achi eved by 76%(n=25) with VPA-Na?SR and by 45%(n=15) with conventional valproate resp ectively.There was statistical difference between the two formulations.The seizu re frequency was significantly reduced in 5 patients treated with VPA-Na?SR.A dverse ef fects were observed in 2 patients with conventional valproate,5 patients with V PA-Na?SR whose valproate plasma levels were higher than that of conventional p reparations.Adverse effects were related to increased valproate plasm a levels and individual drugtolerance. Conclusions The advantage of VPA-Na?SR is that serum valproa te con centrations may increase smoothly and minimize fluctuation in serum dr ug concentrations during a dosing interval. It is a more effective and more convenient antiepileptic agent.