This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis 1: A single anticonvulsant can be identified as the optimum initial monotherapy among the three anticonvulsants that have Level one evidence of short-term efficacy (ETX, LTG and VPA). Hypothesis 2: The variability observed in AED effic acy in patients with CAE results i) from identifiable pharmacogenetic (pG) factors effecting drug response (seizure control) and drug exposure and ii) from identifiable non-heritable host factors. Hypothesis 3: The variability observed in AED tolerability in patients with CAE results i) from identifiable pG factors effecting drug response (toxicity) and drug exposure and ii) from identifiable non-heritable host factors. Primary Objective Identify the most effective initial monotherapy (among ethosuximide, lamotrigine and valproic acid) for children with Childhood Absence Epilepsy using the freedom from failure rate in the double blind portion of the clinical trial. We hypothesize that a single anticonvulsant will be at least 20% more effective than either of the other two anticonvulsants. Treatment failure during the double blind portion will be defined as either i) a generalized tonic clonic seizure of any duration, ii) persistence or relapse of absence seizures (clinical, hyperventilation induced seizures or electrographic seizures), iii) drug related systemic toxicity (e.g., drug related rash or a =15% increase in BMI) or iv) patient/parent/guardian or physician desire for patient to withdraw (Grant Specific Aim 1a). Secondary Objectives There will be multiple secondary objectives including: 1. Assess the effects of monotherapy on cognition (attention) using omission errors and the overall index (OI) of the Conners Continuous Performance Test and the Kiddie Continuous Performance Test (Grant Specific Aim 1b). 2. Assess the effects of monotherapy on behavior and quality of life using t-scores from the Child Behavior Check List, and results from the Quality of Life in Childhood Epilepsy questionnaire (Grant Specific Aim 1b). 3. Assess the effects of common polymorphic variations in T type calcium channel AED binding subunit genes or the AED-efflux transporter ABCB1 gene on AED efficacy using the seizure free rate at the 16 week double blind visit (Grant Specific Aim 2a). 4. Assess the effects of AED systemic exposure on AED efficacy using the seizure free rate at the 16 week double blind visit (Grant Specific Aim 2b). 5. Assess the predictive power of clinical factors on AED efficacy using the seizure free rate at the 16 week double blind visit (Grant Specific Aim 2c). 6. Assess the effect of common polymorphic variations in the CYP 3A4/5 gene on ethosuximide exposure and gastrointestinal side effect using ethosuximide exposure measured either a) at the time of a gastrointestinal side effect or b) at the 16 week double blind visit for patients who did not have gastrointestinal side effect (Grant Specific Aim 3a). 7. Assess the effect of common polymorphic variations (in the UGT1A4 gene) on lamotrigine exposure and lamotrigine related rash using lamotrigine exposure measured either a) at the time of a rash or b) at the 16 week double blind visit for patients who did not have a rash (Grant Specific Aim 3b). 8. Assess the effect of common polymorphic variations in genes coding for valproic acid drug metabolizing enzymes, valproic acid metabolite profiles, and clinical factors on valproic acid-associated excessive weight gain using either percentage of patients meeting study exit criteria for weight gain (a =15% increase in BMI) or BMI percentiles as a measure of weight gain (Grant Specific Aim 3c). Childhood Absence Epilepsy (CAE) is a common, clinically homogenous, well-characterized, childhood-onset syndrome that accounts for 10-15% of all childhood epilepsies. Childhood Absence Epilepsy (pyknolepsy) is characterized by very frequent (several to many per day) absences seizures in an otherwise normal child with an EEG usually demonstrating 3 Hz bilateral, synchronous, symmetrical spike-waves pattern with normal background activity (3-5). Commonly misperceived as a """"""""benign"""""""" epilepsy syndrome, patients with CAE demonstrate variable response to therapy, exhibit cognitive deficits, encounter elevated rates of accidental injury, demonstrate long-term psychosocial difficulties, and have variable remission rates. Similar to other epilepsies, the current therapeutic approach for children with CAE is empiric: an antiepileptic drug (AED) is selected based on limited clinical trial data, then titrated to an acceptable balance of seizure control and side effects. Based on short-term clinical trials, three AEDs -- ethosuximide (ETX), lamotrigine (LTG), valproic acid (VPA) - are efficacious against absence seizures. However, their long term efficacy is unknown, their toxicity profiles are distinct, and their long-term effects on the developing nervous system of children have not been well studied. A randomized, clinical trial comparing these AEDs, focusing not only upon seizure control but also on tolerability, neuropsychological functioning and quality of life, can bridge our gap in knowledge as to the optimum initial therapy for children with CAE. Such a trial provides an ideal framework to study the biologic basis for efficacy and toxicity of AEDs using advanced genetic, pharmacokinetic and clinical phenotyping techniques, providing an important opportunity to move from empiric -based therapeutic strategies, to biologically rational disease/syndrome specific treatment strategies. The goals of this proposal are a) to identify the optimal (i.e., highest rate of seizure control, lowest incidence of treatment limiting toxicity) initial AED for pediatric patients with CAE, and b) to determine the pharmacogenetic and other nonheritable factors underlying the inter-individual variation in AED response. A randomized, double blind comparative trial of ETX, LTG, and VPA as initial monotherapy will be performed utilizing freedom from failure rate as the primary endpoint. Patients will be extensively genotyped and phenotyped. Determination Of Optimal Therapy For CAE (Specific Aim 1) The definitions of absence seizures, generalized tonic clonic seizure (grand mal), and CAE are widely accepted and each has an easily recognizable phenotype, minimizing the potential for misdiagnosis. This pediatric epilepsy syndrome is regularly diagnosed and treated by pediatric neurologists. Children with CAE have multiple medical and psychosocial issues that have not been well studied. Incomplete seizure control may have significant sequelae, adverse effects of AEDs can aggravate comorbidities. Ethosuximide (ETX), lamotrigine (LTG), valproic acid (VPA) were selected for study because these are the only antiepileptic drugs (AEDs) with controlled clinical trial evidence of efficacy in absence seizures. No study to date, however, has examined the long-term efficacy and tolerability of these AEDs in a prospective randomized controlled clinical trial. Prior studies of ETX, LTG, and VPA had significant methodological flaws limiting the ability to identify the optimum initial treatment of CAE. Our proposed clinical trial is based on the current syndrome definition for CAE and employs a long duration freedom from failure design that considers i) a stringent definition of freedom from seizures as the definition of treatment success along with ii) short and long term treatment limiting drug toxicities in order to identify the optimal therapy for CAE (Specific Aim 1a). Overall, to date, clinical trials in CAE have not adequately incorporated assessment of AED effect on cognition (especially attention), behavior, or quality of life. Our proposed clinical trial will serially assess each AED's impact on cognition (specifically attention), behavior and epilepsy specific HRQOL to identify differences between AEDs that clinicians can use in selecting optimal therapy for CAE patients. (Specific Aim 1b) Pharmacogenetic, Pharmacokinetic, And Clinical Factors That Impact AED Efficacy (Specific Aim 2) Understanding the relationship between pharmacogenetic, pharmacokinetic and clinical factors and therapeutic response will bridge our gap in knowledge of how best to use AEDs for the treatment of children with CAE, and will form the foundation for the future individualization of therapy. Our proposed study of the relationship between polymorphisms in the CACNA1G, CACNA1H, and CACNA1I genes (that code for the a1G, a1H and a1I subunits of the T-type calcium channel) and the response to AED therapy is based on the basic pharmacology of AED action on T-type calcium channels. This study will bridge our gap in knowledge of the molecular basis for differential response to AEDs in CAE. Population pharmacokinetic models for ETX, VPA and LTG will provide a comprehensive understanding of the interpatient variability in drug disposition and its impact on drug response and toxicity. The models will allow for defining important pharmacogenetic and pharmacodynamic correlations. Although CAE has an easily recognizable phenotype, multiple subtypes of absence seizures exist along with recognizable differences in baseline interictal and ictal EEG patterns. A comprehensive analysis of subtypes, response to treatment and prognosis has not been performed. Pharmacogenetic, Pharmacokinetic And Clinical Factors That Limit Treatment (Specific Aim 3) ? As 20%-33% of children ultimately experience gastrointestinal side effects with ethosuximide (ETX), the identification of genetic factors predisposing to decreased drug clearance and higher systemic exposures that may be associated with gastrointestinal side effects would permit rational individualization of AED selection. ? Since 10%-12% of children may develop a treatment limiting rash on lamotrigine (LTG) therapy, the identification of an association between rate of systemic LTG exposure increase and rash may allow for a pharmacokinetically guided dose escalation. ? Since 9%-44% of children develop treatment limiting weight gain associated with valproic acid (VPA), the identification of clinical factors (nutritional or exercise) metabolic (patterns of valproic acid metabolites) or genetic factors (polymorphisms in genes coding for VPA metabolizing enzymes or albumin) associated with the occurrence of weight gain would permit for rational AED selection and individualization of therapy.
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