The Gene Pathogenesis Of Epilepsy And Clinical Research Of Prevention And Treatment Of Epilepsy

PART ONE ABNORMAL EXPRESSION OF TRANSFORMING GROWTH FACTORβRECEPTOR IN BRAIN OF PATIENTS WITH INTRACTABLE EPILEPSYObjective: Studies showed that transforming growth factorβreceptors (TβRs) contributed to pathogenesis of epilepsy. However, it is still poor understood that the mechanism of TβRs involving in human epilepsy. The aim of the present study was to observe change of TβR in human patients with intractable temporal epilepsy.Methods: The tissues of temporal neocortices in 30 patients with intractable temporal epilepsy and in 30 controls were collected. TβRⅠwas detected using immunohistochemistry, immunofluorescence and western blot.Results: Increased expression of TβRⅠwas found in patients group compared to that in control group. TβRⅠwas expressed in astrocytes. Conclusion: TβRⅠprotein in patients with IE was significantly increased. Our study shows that TβRⅠmight contribute to the pathogenesis of intractable epilepsy.PART TWO GENETICS OF EPILEPSY: MUTATIONAL ANALYSIS OF CANDIDATE GENES AT 11Q 22.1-23.3 LOCUS IN A LARGE CHINESE HAN FAMILYMany studies indicate that epilepsy is a genetic disorder. To date, more than 20 genes associated with epilepsy have been identified in human epilepsy. However, disease-causing gene of epilepsy is rare reported in Asian population, especially in Chinese people.Our group identified a suggestive new locus on chromosome 11q22.1-23.3 (D11S898-D11S908) in a six-generational Chinese epileptic family with a rather homogenous seizure phenotype (generalized tonic-clonic seizure) and a high penetrance. Five genes at 11q22.1-23.3 locus were chosen as candidate genes for this family. We sequenced all exons of those genes using direct DNA sequence analysis in at least two affected family members. However, no mutation or novel polymorphisms have been detected. The possible reasons for the lack of disease-associated mutation at 11q22.1-23.3 locus include: (1) mutation might be in a region that was not sequenced in screened genes, such as introns, regulatory elements; (2) the mutation in our family might not be a simple small mutation detectable with direct DNA sequencing, which can only detect mutations within the sequenced region. If the mutation was larger, it could be undetectable by this method.In conclusion, SCN2B, SCN4B, GRIK4, HTR3B and HTR3A are not disease-causing genes responded to our large family. A further whole genome scan will be performed to exclude another shared region by the affected family members in our epileptic family.PART THREE CLINICAL OBSERVATIONAL STUDY ON TREATMENT IN PATIENTS WITH EPILEPSY§1 EFFICACY OF TOPIRAMATE IN ADULT PATIENTS WITH SYMPTOMATIC EPILEPSY: AN OPEN-LABEL, LONG-TERM, PROSPECTIVE OBSERVATIONObjective: The aim of the present study was to evaluate the efficacy of topiramate (TPM) in the treatment of adult patients with symptomatic epilepsy.Methods: This was an open-label, long-term, prospective observation. 227 patients with symptomatic epilepsy (110 male, 117 female) were enrolled into this study. The underlying etiologies included chronic tumors, trauma, cerebrovascular diseases, inflammation, diabetes, hydrocephalus, and parasitosis. TPM was titrated up to a target dosage of 200mg/day and maintained at least 12 months. TPM response was defined as the seizure frequency reducing at least 50% compared to the baseline phase. Seizure-free was defined as no seizure occurring in one year.Results: Hundred-fifty-nine (70.0%) patients showed TPM response and 126 (55.5%) patients were seizure-free with TPM administration. In different subgroups, the responders of TPM were 40 patients (74.0%) with chronic tumor, 32 (55.2%) with trauma, 30 (90.9%) with cerebrovascular diseases, 21 (55.3%) with infection, 18 (81.8%) with diabetes, 12 (85.7%) with parasitosis and 4 (50.0%) with hydrocephalus, respectively. The percentage of seizure freedom was 61.0% in brain tumors, 31.0% in trauma, 78.8% in cerebrovascular diseases, 44.7% in infection, 59.0% in diabetes, 85.7% in parasitosis, and 50.0% hydrocephalus, respectively. The incidence of side effects was 36.1%. The common reported side effects included weight loss, memory impairments, paraesthesia, headache and dizziness, and most of them were mild to moderate and transient. Sixty-eight (30.0%) patients withdraw TPM in this study. TPM was discontinued in 56 patients because of lack of efficacy and in 12 patients due to side effects.Conclusion: TPM is effective and well tolerated in adult patients with symptomatic epilepsy of various etiologies.§2 TOLERABILITY AND SAFETY OF TOPIRAMATE IN CHINESE PATIENTS WITH EPILEPSY: AN OPEN-LABEL, LONG-TERM, PROSPECTIVE STUDYObjectives: This study focused on: (i) evaluating the long-term tolerability and safety of topiramate in Chinese patients with epilepsy, and (ii) comparing the tolerability and safety of topiramate monotherapy versus polytherapy in the same population.Methods: This was a prospective, open-label, long-term (36 months) clinical trial. 320 patients (275 adults and 45 children) with epilepsy were recruited into the study; of these, 156 patients had generalised seizures, 151 patients had partial seizures and 13 patients had unclassifiable seizures. All patients received topiramate ~200mg/day either as monotherapy or as adjunctive therapy. At each visit, physical examination and routine laboratory analysis were performed, and the adverse event (AE) profile was obtained by face to face interview.Results: 268 patients received topiramate <100mg/day and 52 patients received topiramate 100-200 mg/day. Topiramate-associated AEs occurred in 98 patients (30.6%). The most common AEs were weight loss in 18 patients (8.4%), paraesthesia in 17 (7.2%), poor memory in ten (3.8%), and dizziness in six (2.8%). Most AEs were mild to moderate and transitory; discontinuation of topiramate was observed in 13 patients (4.1%) as a result of AEs such as impaired memory (seven patients [54%]), paraesthesia (four patients [31%]), and weight loss and cutaneous reaction (each one patient [7.5% each]). The rate of AEs was significantly higher with use of topiramate as monotherapy than as adjunctive therapy (68 patients vs 30 patients, 47.8% vs 16.4%, respectively).Conclusion: Topiramate is well tolerated in Chinese patients with epilepsy in clinical practice.§3 NON-GENETIC ETIOLOGY OF EPILEPTIC SEIZURES IN TWO OTHERWISE HEALTHY CHINESE FAMILIES: TETRAMINE.– CASE PRESENTATION AND LITERATURE SURVEYTetramine, a banned rodenticide, is repeatedly reported to induce epileptic seizures in healthy people. Because both doctors and patients are often not aware of former tetramine contact, the occurrence of seizures is easily misdiagnosed as primary epilepsy. Here eight cases in two families with generalized tonic-clonic seizures are presented most probably induced by tetramine. The clinical manifestation, EEG characters, and treatment measures of tetramine poisoning are summarized. There is the possibility of tetramine-toxicity as a cause of epidemic epileptic seizures.§4 THREE NEW FAMILIAL EPILEPSY SYNDROMES IN THE PROPOSED DIAGNOSTIC SCHEME OF THE ILAE (2001): A CLINICAL EXPERIENCE IN SOUTHWEST CHINAObjective: This study aims to investigate clinical features of new familial epilepsy syndromes in Chinese patients with epilepsy according to the latest proposal for a diagnosed scheme by International League Against Epilepsy (ILAE).Methods: This is a retrospective survey. The clinical data of 5300 patients with epilepsy were reviewed using both computer and hand-work retrieval. When the manifestations of the patients were consistent with the 2001 proposed new epilepsy syndromes, the further interviews were performed to confirm them and improve medical records.Results: The survey finished in a total of 4894 patients. Hundred eight families with epilepsy have been identified. Two families with nine patients were diagnosed as familial mesial temporal lobe epilepsy, one family with five patients as familial focal epilepsy with variable foci, one family with three patients as generalized epilepsy with febrile seizure plus.Conclusion: The present findings have shown that three newly suggested familial epilepsy syndromes exist in Chinese patients with epilepsy. Our results provide more evidences for the future classification of epilepsy syndromes.