Biomedical subjects
Publications and source records attributed to Dennis J Dlugos.
Presented is the case of a child with epilepsy with dramatic evolution between the ages of 18 months and 3 years. Initially, the case is one of treatment-responsive focal epilepsy, but then evolves to treatment-resistant focal epilepsy with an epileptic encephalopathy. The case demonstrates the poorly understood entities of age-related changes in seizure suspectibility, seizure types, and drug responsiveness.
Epilepsy is a heterogeneous group of multifactorial diseases, the vast majority determined by interactions between many genes and environmental factors; however, there are rare epilepsy syndromes that can be caused by a single gene mutation and are inherited according to classical mendelian genetic principles. Finding disease-causing genetic mutations in epilepsy has provided new opportunities for aiding diagnosis and developing therapies. Thus, the discovery of KCNQ2 mutations in benign familial neonatal convulsions, SCN1A mutations in severe myoclonic epilepsy of infancy and in generalized epilepsy with febrile seizures plus, and CHRA4 and CHRB2 mutations in autosomal-dominant nocturnal frontal lobe epilepsy, has led to the establishment of epilepsy as a disorder of ion channel function and, furthermore, has led to the introduction of genetic tests that are available clinically to aid in diagnosis and treatment. At the present time, clinical use of genetic testing in epilepsy is greatest in suspected cases of severe myoclonic epilepsy of infancy, generalized epilepsy with febrile seizures plus, atypical cases of benign familial neonatal convulsions and 'occult' cases of autosomal-dominant nocturnal frontal lobe epilepsy without a family history. Overall, clinical use is limited by the low number of documented disease-associated mutations and the uncertain clinical significance of many test results. Further elucidation of the relationship between gene mutations and channel function will add value to genetic testing in the future, as will better characterization of the association between gene mutations and clinical phenotypes.
The recent surge of interest in pharmacogenetics has provoked considerable thought regarding its relevance to antiepileptic drug (AED) therapy. Initial studies have focused on genes whose products play a putatively important role in AED pharmacology, particularly drug transporter proteins, drug metabolizing enzymes and ion channel subunits. However, there is a lack of good correspondence between results from different laboratories, and more recent findings are awaiting attempts at confirmation. Thus, there are currently no AED treatment guidelines that are informed by pharmacogenetic data. In order to begin to have clinical impact, standards specific to the conduct of future AED studies must be established. Of particular importance are the need for accurate epilepsy classification, appropriate AED selection and clear and objective assessment outcome measures. In addition, general standards for analysis and interpretation of genetic association data must be better codified and applied consistently across studies. Finally, extensive clinical research networks must be formulated and large numbers of well characterized patients must be recruited. Further development of these critical factors will optimize chances for overcoming current challenges posed by AED pharmacogenetic research and ultimately allow the realization of improved, more rational therapeutic strategies.
Selecting the optimal antiepileptic drug (AED) begins with accurate epilepsy classification, including seizure type and epilepsy syndrome if possible. Based on the available data, children with focal epilepsy, with or without secondary generalization, can be treated with a traditional or newer narrow-spectrum or broad-spectrum AED. Children with generalized convulsive epilepsy, mixed epilepsy, or seizures of an unknown type are best treated with a broad-spectrum AED. Children with childhood absence epilepsy can be treated with ethosuximide, valproate, or lamotrigine. In all cases, the best choice among the various AED options requires consideration of factors such as seizure frequency, seizure severity, AED adverse event profile, AED titration schedule, patient comorbidities, prescription plan coverage, and cost. Most children with epilepsy achieve the goal of "no seizures and no side effects" and most children eventually become seizure free without AEDs. If accurate epilepsy classification is made, clear differences in efficacy are not evident among the multiple available AEDs. Better comparative data emphasizing adverse event profiles, comorbidities and longer-term outcome are needed between the traditional and newer AEDs.
This study examined participation rates and reasons for refusal in a genetic study of human epilepsy. The study enrolled children with epilepsy and their parents, and required signing informed consent, verbalizing assent, and giving a peripheral blood sample. One hundred sixty-eight children met inclusion criteria; 137 agreed to enroll (82%), and 31 refused (18%). Sixteen of thirty-one patients (52%) who refused cited fear of phlebotomy as the reason for refusal. All patients refusing due to fear of phlebotomy did not require blood tests for clinical purposes. As fear of phlebotomy is the primary reason for study refusal, obtaining DNA samples from a buccal swab or mouthwash protocol may be an alternative for some studies, although there are limitations to these methods. Further analysis of the factors influencing decisions to decline study enrollment is warranted. These data will help in the design of future genetic studies and may increase future participation rates.
We developed a model to predict the outcome of treatment with carbamazepine in children with newly diagnosed focal epilepsy of presumed temporal lobe origin, using data available at the time of diagnosis. Eligible children observed at The Children's Hospital of Philadelphia during 1999 were identified. Data were abstracted on four potential predictor variables for carbamazepine success or failure. A total of 149 patients completed an adequate first antiepileptic trial. Carbamazepine was the initial drug used in 129 (87%) patients. Forty-one of these 129 patients (32%) had persistent seizures. Significant predictors of initial carbamazepine failure were as follows: early risk factor for epilepsy (risk ratio = 3.1 [95% confidence interval 1.6, 4.0]) and temporal lobe abnormality on magnetic resonance imaging scan (risk ratio = 3.1 [1.7, 4.2]). The outcome of the initial carbamazepine trial was correctly classified in up to 78% of patients. Accurate prediction of initial carbamazepine failure was as high as 0.67 (0.53, 0.79). Accurate prediction of initial carbamazepine success was as high as 0.87 (0.77, 0.94). In this study, standard clinical data were less than adequate for predicting response to the initial trial of carbamazepine, with prediction of carbamazepine failure being particularly difficult. Better markers of antiepileptic response and nonresponse are required to guide optimal therapy in patients with epilepsy.
Recently, an association between the C240T polymorphism in the brain-derived neurotrophic factor (BDNF) gene and partial epilepsy was demonstrated in a Japanese population. In this study we attempted to replicate the initial finding in a patient-control population of European ancestry and in addition tested whether the functional Val66Met polymorphism is associated with temporal lobe epilepsy (TLE). Genotypes of 151 TLE patients and 189 controls did not differ significantly for either of the variations. Results suggest that neither of the studied polymorphisms are strong susceptibility factors for TLE in this sample of individuals of European ancestry.