| Epilepsy is one of the most common neurological disorders, characterized by sudden,recurrent and self-limited disturbance of cerebral fucnction caused by an abnormal neuronal discharge.Over 60%of epileptics had their childhood-onset initially.Approximately 70%～80%of children with childhood-onset eventually have a long-term remission by regular antiepileptic drug(AED) treatment.However,10%～30%of patients become refracroy epilepsy(RE) because of nonresponsive to drugs,which is also called pharmacoresistant epilepsy.Recurrent seizures could cause physical damage,as well as a series of psychosocial problems.In this regard,it is very important and necessary to do research on epilepsy,especially refracoty epilepsy.Sample size is not large in the domestic studies on RE as long as new classification was made by ILAE(2001).Pathogenisis has always been a hot part in the research on RE.The study on multidrug transporters and single nucleotide polymorphisms of candidate gene provide approaches to molecular genetics of RE.P-glycoprotein(P-gp),one of multidrug tansporters,has been implicated in the causation of refractory epilepsy.The expression and efflux efficiency of P-gp is influenced by some polymorphisms in the encoding gene(MDR1).We have investigated the clinical feature of refractory epilepsy.The prevalence of a single nucleotide polymorphism(SNP) of MDR1 in the patients and the association of this polymorphism with phamacoresistance by molecular epidemiology analysis.PART 1 Clinical analysis of Refractory Epilepsy in ChildrenObjective To analyse the frequency and principal features of refractory epilepsy(RE) and discuss the definition of RE in children.Methods Children with epilepsy(n=400,with 167 newly diagnosed) were retrospectively or prospectively identified from multiple sources in our hospital in Shanghai(2006-2008) and.followed-up for the occurrence of refractory epilepsy.Pharmacoresistance was defined as failure to control epilepsy by over two first-line antiepileptic drugs(AEDs),with a seizure frequency of at least one per month for 6 months' treatment,and collected data were examined by experts in neurology.We investigate the clinical feature of RE in aspects of age at onset,gender,seizure type, electroencephalogram,neuroimaging,development of central nervous system, etiology and prognosis et al.Multiple regression analysis is used to find risk factors of RE.ILAE definitions and classifications were used.Results 83 children(20.8%) met the criteria for RE(with 20 newly diagnosed,12.0%in all newly diagnosed patients),with the average follow-up of 1.17 years(±0.83),with the median follow-up of 0.96 year,and 33(39.8%) had been followed for more than 12 months.The study showed that:(1)The median age at onset was 0.93 year,and 43(51.8%) children started before 1 year old;male 55(66.3%),female 28(33.7%).(2)61(73.5%) children had high seizure frequency(with seizures per day or week),59(71.1%) had clustering and 43(51.8%) had multiple seizure types.(3)Epilepsy syndrome:31(37.3%) could be classified as some syndrome.The most common syndromes were West and Lennox-Castuat syndrome,with 13(41.9%) and 11(35.5%) respective.(4) Other aspects:Mental retardance was found in 74(89.8%) children.37(44.6%) had positive lesion in neuroimaging.26(74.3%,26/35) had slow EEG background. (5)Etiology classification:64(77.1%) were symtomatic,19(22.9%) cyptogenic. (6)Treatment:42.9%children used three AEDs,and 7.2%used four.Among the 83 patients,the markedly effective cases with seizure and frequency reduced to one forth amounted to 6(7.2%),and seizure frequency being reduced to less than half amounted to 40(48.2%) of the patients.As to 37(45.1%) patients, no response occurred,however,to 25(67.6%),seizure degree was reduced in a certain extent.(7)After multivariable analysis for age,gender, etiology,clustering and number of drugs,clustering was a risk factor of refractory epilepsy(OR=4.51,95%CI 1.84-11.04,p=0.001).Conclusion Approximately 20%of children met criteria for RE in the course of their epilepsy,the features of which were early age at onset,high initial.frequency,with or secondary with mental retardation(severe regression always suggests inherited metabolic disorders or neurological degenerative diseases),severe EEG change,neuroimaging abnormity,mostly symptomatic,and poor treatment effect using multiple AEDs.Clustering was a risk factor of refractory epilepsy.PART 2 Association of a MDR1 Gene Polymorphism with Refractory Epilepsy in ChildrenObjective We have investigated the frequecy of polymorphism at exon26 (C3435T) in multidrug-resistance gene(MDR1) and attempted to study the association of the single nucleotide polymophisms(SNPs) with pharmacoresistant epilepsy in children.Methods DNA samples were abtained from 132 patients with epilepsy and 62 health children by DNA Extraction kit.Genotype of the C3435T polymorphism was determined by DNA sequence analysis after traditonal polymerase chain reaction.Patients was divided into two group:refractory and responsive, with health children as normal contolled.The frequecy of genotypes and alleles among the three groups was compared by Chi-square test.Results In total,there were CC,CT and TT genetypes in all 194 objects, of which the frequecy was 38.1%,45.9%and 16.0%respective.In the patients, the frequecy was 37.0%,45.0%and 16.0%respective.Comparison of the total and the patients revealed no significant difference in genotype frequency (p=0.97).There were no significant difference in the genotype between the refractory group and responders or between the refractory group and the health controlled.Comparison of the refractory group and responders revealed no significant difference in allele frequency either.Conclusions There was no significant difference the patients and all the objects in genetypes(CC,CT,TT).This study failed to corroborate a previously reported association between the C3435T polymorphism in the human MDR1 gene and refractory epilepsy.And there was no association of C allele with pharmacoresistant epilepsy. |
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