Expression of multidrug resistance 1 gene and C3435T genetic polymorphism in peripheral blood of patients with intractable epilepsy

BACKGROUND： Increased expression of multidrug resistance 1 （MDR1） mRNA in peripheral blood of patients with intractable epilepsy is not due to epilepsy drugs, but epilepsy behavior. Monitoring MDR1 expression in peripheral blood is a target for MDR1 gene evaluation. OBJECTIVE： To investigate the influence of antiepileptic drugs and seizures on MDR expression in intractable epilepsy, and to analyze the genetic polymorphisms of C3435T in the MDRl gene. DESIGN, TIME AND SETTING： Factorial designs and comparative observations at the experimental center of the Affiliated Hospital of Qingdao Medical College, Qingdao University between October 2003 and October 2004. PARTICIPANTS： A total of 120 subjects were recruited from the epilepsy clinical department of the Affiliated Hospital of Qingdao Medical College. Four groups （n = 30） were classified according to statistical factorial design： intractable epilepsy, treatment response, no treatment, and normal control groups. METHODS： One-step semi-quantitative reverse-transcription polymerase chain reaction technology was used to test expressions of the MDR1 gene in 120 subjects. C3435T polymorphisms in intractable epilepsy group and normal control groups were analyzed by polymerase chain reaction-restriction fragment length polymorphism. MAIN OUTCOME MEASURES： Expression of MDR1 mRNA in the four groups, and C3435T genetic polymorphisms in intractable epilepsy and normal control groups. RESULTS： MDRl gene expression was increased in the intractable epilepsy group, due to the factor seizures, but not the antiepileptic drugs. However, the interaction between the two factors was not statistically significant. Of the 30 subjects in the intractable epilepsy group, the following genotypes were exhibited： 3 （10%） C/C genotype, 9 （30%） C/T genotype, and 18 （60%） T/T genotype at the site of C3435T, while 4 （13%）, 10 （33%）, and 16 （53%） subjects were determined to express these genotypes in the normal control group, respectively. C and T allele frequency were 25% and 75% in the intractable epilepsy group, and 30% and 70% in the normal control group, respectively. However, there was no statistical difference between the groups. CONCLUSION： Results demonstrated that seizures, not antiepileptic drugs, induced MDR1 gene expression in intractable epilepsy. Genetic polymorphisms of C3435T in the MDR1 gene did not contribute to the development of multidrug resistance in patients with intractable epilepsy.

Preliminary analysis of the effect of vagus nerve stimulation in the treatment of children with intractable epilepsy

BACKGROUND Implant vagus nerve stimulation is an adjunctive treatment for intractable epilepsy when patients are not suitable for resective surgery.AIM To identify the safety and efficacy of vagus nerve stimulation in children with intractable epilepsy and analyze the effects on different epilepsy syndromes.METHODS Eligible children with intractable epilepsy were admitted to the study.We collected data from preoperative assessments as the baseline.During the followup time,we recorded the process of seizures(frequency,duration,and seizure type),the changes of drugs or parameters,the complications,etc.The mean reduction rate of seizures,response rate,and McHugh scale were chosen as the outcomes.RESULTS A total of 213 patients were implanted with Tsinghua Pins vagus nerve stimulators,and the average age was 6.6 years.In the follow-up time of postoperative 3 mo,6 mo,12 mo,18 mo,and 24 mo,the average reduction rate was 30.2%,49.5%,56.3%,59.4%,and 63.2%,while the response rate was 21.8%,62.5%,57.1%,69.2%,and 70.7%.In addition,implanted vagus nerve stimulation had different effects on epilepsy syndromes.The reduction rate of West syndrome increased from 36.4%(postoperative 6 m)to 74.3%(postoperative 24 m).The reduction rate of Lennox-Gastaut syndrome improved from 25.4%to 73.1%in 24 mo.The chi-square test of the five efficacy grades showed P<0.05.The comparison between the 3-mo follow-up and the 6-mo follow-up showed P<0.05,and the comparison between the 6-mo follow-up and the 24-mo follow-up showed P>0.05.CONCLUSION Vagus nerve stimulation is safe and effective in children with intractable epilepsy,and the seizure reduction occurred in a time-dependent manner.Moreover,patients with West syndrome may get the most benefits.

Evaluation of P-glycoprotein-targeting circulating microRNAs as peripheral biomarkers for medically intractable epilepsy

Background Early diagnosis of medically intractable epilepsy is challenging in clinical work.P-glycoprotein(P-gp)is one of the most important multidrug efux transporters,which has been demonstrated to contribute to the drug resistance of intractable epilepsy.The present study was aimed to explore the diagnostic value of microRNAs(miRNAs)targeting P-gp for medically intractable epilepsy.Methods Thirty-six patients with intractable epilepsy and 36 epilepsy patients responsive to anti-epilepsy drugs,who visited Jinshan Hospital of Fudan University from September 2014 to September 2016,were enrolled in this study.Clinical information of the patients was obtained by retrospectively reviewing medical records.MiRNAs with diferential serum expression between the two groups of patients were detected by microarray assay.Meanwhile,miRNAs that were confrmed to regulate P-gp in vitro by western blot were selected for further validation.In the validation phase,reverse transcription quantitative PCR(RT-qPCR)was conducted to confrm the diferential expression of the candidate miRNAs in the epilepsy cohorts.Receiver operating characteristic(ROC)curve analysis was carried out to evaluate the diagnostic value of the miRNAs for intractable epilepsy.Results Three miRNAs including miR-6514-3p,miR-6076-5p,and miR-6855-3p were identifed to be candidate miRNAs by microarray assay.The results of western blotting validated that miR-146a-5p and miR-138-5p could regulate P-gp expression in vitro,so they were included in the candidate miRNAs for further validation.In the validation phase,the results of RT-qPCR indicated that compared with drug-responsive patients,the patients with intractable epilepsy showed decreased level of miR-138-5p and increased level of miR-146a-5p.The results of ROC curve analysis indicated that miR-138-5p(AUC=0.877)and miR-146a-5p(AUC=0.866)had high diagnostic value for intractable epilepsy.In addition,the miR-panel composed of miR-138-5p and miR-146a-5p showed higher diagnostic value(AUC=0.926)than the miRNAs selected by microarray assay.Conclusions Our results indicated that the dysregulated miR-138-5p and miR-146a-5p which target P-gp expression have high potential as peripheral biomarkers for medically intractable epilepsy.

MULTIPLE SUBPIAL TRANSECTION FOR TREATMENT OF INTRACTABLE EPILEPSY

On the basis of experimental study, we applied multiple subpial transection (MST) to treat 50 patients with intractable epilepsy in which epileptigenic lesion involved functional areas such as pericentral gyms, postcentral gyrus, Broca's area, Wernicke's area, visual cortex, etc. They were followed up for 6 to 40 months. Complete control of seizures was obtained in 32 patients, significant reduction of seizure (more than 50%) in 13, reduction (less than 50%) in 3, and no effect in 2. The total effective rate was 96%. No functional defect was found in all patients. The mechanism of the disease and surgical technique were discussed in detail. We consider that MST could replace some standard excisional therapy for local epilepsy.

Treatment of epilepsy in China Formal or informal?

Antiepileptic drugs are the preferred treatment approach for epileptic patients. However, informal treatment is important for intractable epilepsy. In this study, 500 epileptic patients were recruited from the General Hospital of Beijing Military Area Command of Chinese PLA during the period of October 2009 to January 2012. These involved patients that had been medically treated for at least 1 year. Information on the initial treatment and changes to treatment regimens for each patient was collected through questionnaires. The survey results showed that 52.3% of the epileptic patients searched for treatment after the first seizure, and the mean numbers of seizures was 12.8; 59.8% of the epileptic patients were diagnosed at the first visit, and the mean onset time was 17 months after the first seizure. After diagnosis, patients were treated for an average of 20 days, and the median time was 1 day. Formal anti-epileptic drugs were selected as the first treatment regimen by 67.8% of patients, and 77.5% of these drugs were monotherapies. The mean and median numbers of seizure were respectively 36.9 and 3.0 times before the first regimen was changed. The regimen was changed within the first 6 months by 46.6% of patients, and after the first and second years of treatment, the proportions increased to 54.0% and 71.8%, respectively. In total, 78.5% of the regi- mens were changed to informal treatments. The informal treatment of epilepsy in China is common, being initiated by either patients or physicians. Enhancing epileptic treatment services in hospital, improving physicians＇ professional quality, and strengthening health propaganda may promote the normalization of drug treatment of epilepsy in China.

Synaptic Vesicle Protein2A Decreases in Amygdaloid-kindling Pharmcoresistant Epileptic Rats

Synaptic vesicle protein 2A（SV2A） involvement has been reported in the animal models of epilepsy and in human intractable epilepsy. The difference between pharmacosensitive epilepsy and pharmacoresistant epilepsy remains poorly understood. The present study aimed to observe the hippocampus SV2 A protein expression in amygdale-kindling pharmacoresistant epileptic rats. The pharmacosensitive epileptic rats served as control. Amygdaloid-kindling model of epilepsy was established in 100 healthy adult male Sprague-Dawley rats. The kindled rat model of epilepsy was used to select pharmacoresistance by testing their seizure response to phenytoin and phenobarbital. The selected pharmacoresistant rats were assigned to a pharmacoresistant epileptic group（PRE group）. Another 12 pharmacosensitive epileptic rats（PSE group） served as control. Immunohistochemistry,real-time PCR and Western blotting were used to determine SV2 A expression in the hippocampus tissue samples from both the PRE and the PSE rats. Immunohistochemistry staining showed that SV2 A was mainly accumulated in the cytoplasm of the neurons,as well as along their dendrites throughout all subfields of the hippocampus. Immunoreactive staining level of SV2A-positive cells was 0.483±0.304 in the PRE group and 0.866±0.090 in the PSE group（P〈0.05）. Real-time PCR analysis demonstrated that 2-ΔΔCt value of SV2 A m RNA was 0.30±0.43 in the PRE group and 0.76±0.18 in the PSE group（P〈0.05）. Western blotting analysis obtained the similar findings（0.27±0.21 versus 1.12±0.21,P〈0.05）. PRE rats displayed a significant decrease of SV2 A in the brain. SV2 A may be associated with the pathogenesis of intractable epilepsy of the amygdaloid-kindling rats.

Study on hippocampal volume with quantitative 3T magnetic resonance imaging in Chinese patients with epilepsy

Background It was still rare for the quantitative magnetic resonance imaging （MRI） research of regional changes in hippocampus sclerosis （HS） in Chinese patients with epilepsy. This study aimed to study the hippocampal volumes （HVs） with quantitative MRI measurement in Chinese patients with epilepsy. Methods Forty-six Chinese patients with epilepsy （intractable epilepsy （IE）, n=21; non-intractable epilepsy （NIE）, n=25） and 25 normal controls were collected between July 2007 and March 2008. All of the subjects underwent a 3T high-resolution MRI with oblique coronal thin sections oriented perpendicular to the hippocampal long axis. Hippocampal structures were assessed by visual detection, and HVs were quantitatively studied with a Picture Archiving and Communication System （PACS）. Results Our study suggested that there was no significant difference in gender （P 〉0.05） while the right hippocampal head volume （HHV）, hippocampal body volume （HBV）, and the whole hippocampal volume （HCV） were greater than the left one （P 〈0.05）, but no significant difference was found in bilateral hippocampal tail volume （HTV） （P 〉0.05） in normal controls. That unilateral/diffuse （64%/21%） and bilateral/focal （86%/20%） hippocampal atrophy （HA） were significant in IE and NIE patients, respectively. Anterior hippocampus, especially HHV （26% in IE and 20% in NIE） and HBV （29% in IE and 12% in NIE）, had more significant atrophy than the HTV （5% in IE and 0% in NIE） in patients with epilepsy.

Epilepsy surgery for tuberous sclerosis complex： a case report and literature review

Tuberous sclerosis complex （TSC） is a multisystem genetic disorder with variable phenotypic expression.Epilepsy is the most common neurological complication and up to 80%-90% of the individuals with TSC suffer from epilepsy at some point in their lifetime. Developmental delay, intellectual impairment, autism, behavioral problems, and neuropsychiatric disorders occur commonly in individuals with TSC and may be associated with poorly controlled epilepsy.~ In this paper we reported a case report of TSC, focusing on the patient＇s clinical symptom, surgical aspects and neuropathology through a comprehensive analysis.

Why patients with refractory epilepsy reject surgery in China

EPilepsy is a common neurological disorder among all age groups and socioeconomic classes. Epilepsy surgery has been demonstrated to be a safe and effective treatment for drug-refractory epilepsy.Despite this success, many potential surgical candidates refuse surgery. On average, there is a 20-year delay between the diagnosis of epilepsy and surgical treatment,1 suggesting that epilepsy surgery is underutilized. The prevalence of active epilepsy is even higher in developing countries due to the limited availability and high cost of medication. To date, however, few studies have addressed the reasons for delayed surgical treatment in developing countries such as China. To address these issues, we conducted a cross- sectional survey to document potential barriers limiting patients access to the surgical treatment of epilepsy.