: The optimal treatment for Childhood Absence Epilepsy (CAE), a common pediatric epilepsy syndrome affecting 10-15% of all children with epilepsy, and the basis for the inter-individual variation in response to therapy, has not been defined. Commonly misperceived as a benign epilepsy syndrome, patients with CAE demonstrate variable response to therapy, exhibit cognitive deficits, and demonstrate long-term psychosocial difficulties. The objectives of this proposal are: 1) to identify the anti-epileptic drug (AED) that produces and sustains the highest rate of seizure control coupled with the lowest incidence of treatment limiting toxicity for children with CAE, and 2) to determine the pharmacogenetic and non-heritable factors underlying the inter-individual variation in AED efficacy and toxicity. A randomized, double-blind comparative trial of Ethosuximide (ETX), lamotrigi_ (LTG) and valproate (VPA) as initial monotherapy will be performed in children with CAE utilizing freedom from failure rate as the primary endpoint. Twenty sites in the U.S. will enroll 473 children, 2- 13 years of age, over a 3-year period. Treatment success will be defined as a composite of seizure control and short and long-term tolerability. Each AED's impact on cognition (especially attention), behavior, and quality of life will be studied. Each patient's epilepsy syndrome will be extensively phenotyped with video EEGs. Individual systemic drug exposures, determined using a population pharmacokinetic (pK) approach, will define the impact of interpatient variability in drug disposition on AED efficacy and toxicity, and will be utilized in pharmacogenetic (pG) correlative studies of select drug metabolizing enzymes. The role of polymorphic variation in the genes coding for the alpha1G, alpha1H, alpha1I subunits of the T type calcium channels in response to therapy will be investigated. Factors potentially predictive for the most common treatment limitations of each AED will be studied, including the pG, pK and clinical profiles of patients developing LTG associated rash, VPA induced weight gain or evidence of impaired neurocognitive skills (potential limitation of all AEDs). This study will determine the AED that provides for the greatest likelihood of seizure control coupled with the best short and long term tolerability. By comprehensively defining the phenotypic spectrum of absence seizures along with pG and non-heritable factors that underlie interpatient variability in AED response, this proposal will form the foundation of a pharmacologically rational approach to syndrome based AED therapy. Knowledge gained by this study will lead to individualized treatment for children with CAE that may in part be generalizable to other pediatric and adult seizure disorders.
| Nariai, Hiroki; Duberstein, Susan; Shinnar, Shlomo (2018) Treatment of Epileptic Encephalopathies: Current State of the Art. J Child Neurol 33:41-54 |
| Arya, Ravindra; Peariso, Katrina; Gaínza-Lein, Marina et al. (2018) Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus. Epilepsy Res 144:1-6 |
| Knox, Andrew T; Glauser, Tracy; Tenney, Jeffrey et al. (2018) Modeling pathogenesis and treatment response in childhood absence epilepsy. Epilepsia 59:135-145 |
| Glauser, Tracy A; Holland, Katherine; O'Brien, Valerie P et al. (2017) Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy. Ann Neurol 81:444-453 |
| Garcia-Ramos, Camille; Bobholz, Sam; Dabbs, Kevin et al. (2017) Brain structure and organization five decades after childhood onset epilepsy. Hum Brain Mapp 38:3289-3299 |
| Shinnar, Ruth C; Shinnar, Shlomo; Cnaan, Avital et al. (2017) Pretreatment behavior and subsequent medication effects in childhood absence epilepsy. Neurology 89:1698-1706 |
| Nariai, Hiroki; Beal, Jules; Galanopoulou, Aristea S et al. (2017) Scalp EEG Ictal gamma and beta activity during infantile spasms: Evidence of focality. Epilepsia 58:882-892 |
| Kessler, Sudha Kilaru; Shinnar, Shlomo; Cnaan, Avital et al. (2017) Pretreatment seizure semiology in childhood absence epilepsy. Neurology 89:673-679 |
| Galanopoulou, Aristea S; Mowrey, Wenzhu B; Liu, Wei et al. (2017) Preclinical Screening for Treatments for Infantile Spasms in the Multiple Hit Rat Model of Infantile Spasms: An Update. Neurochem Res 42:1949-1961 |
| Shandra, Oleksii; Moshé, Solomon L; Galanopoulou, Aristea S (2017) Inflammation in Epileptic Encephalopathies. Adv Protein Chem Struct Biol 108:59-84 |
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