Many children with epilepsy have severe and permanent adverse cognitive, behavioral and quality of life outcomes. However, the relative contributions of seizures, epileptic discharges in the EEG and etiology to those long term outcomes are not usually known. Current treatment strategies emphasize the role of antiepileptic drugs (AEDs) for termination of seizures with the hope that this will also minimize cognitive and behavioral impairments. Unfortunately clinical evidence for better outcomes following AED therapy is disappointing, and may even make cognition worse. If the major determinants of outcome are not seizure related phenomena but rather the underlying brain disorder, then therapeutic approaches which are broader than antiepileptic drug use (e.g.educational programs) may ultimately have major positive impacts on outcomes of childhood epilepsy. We now propose to test the hypothesis that the additional effect of seizures in the context of malformations of cortical development is minor. We further hypothesize that these adverse outcomes are related to abnormalities in brain structure and in the integration of single unit firing with oscillatory activities. Finally, these adverse outcomes will be worsened by AEDs and improved with cognitive training. In an animal model of cortical dysplasia we will investigate the additional impact of early life seizures, during development and in adulthood, on spatial cognition and prefrontal cortex function. We will also investigate the structural and electrophysiological mechanisms underlying those outcomes and evaluate the therapeutic potential of cognitive training.

Public Health Relevance

If our hypothesis that etiology is a major predictor of outcomes then the results of the proposed studies should lead to major conceptual changes in research directions and on the most appropriate therapeutic strategies for children with epilepsies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075249-02
Application #
8320291
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Fureman, Brandy E
Project Start
2011-09-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$345,625
Indirect Cost
$126,875
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Hernan, Amanda E; Alexander, Abigail; Lenck-Santini, Pierre-Pascal et al. (2014) Attention deficit associated with early life interictal spikes in a rat model is improved with ACTH. PLoS One 9:e89812
Hernan, Amanda E; Alexander, Abigail; Jenks, Kyle R et al. (2014) Focal epileptiform activity in the prefrontal cortex is associated with long-term attention and sociability deficits. Neurobiol Dis 63:25-34
Scott, Rod C (2014) Consequences of febrile seizures in childhood. Curr Opin Pediatr 26:662-7
Titiz, A S; Mahoney, J M; Testorf, M E et al. (2014) Cognitive impairment in temporal lobe epilepsy: role of online and offline processing of single cell information. Hippocampus 24:1129-45
Bender, Alex C; Natola, Heather; Ndong, Christian et al. (2013) Focal Scn1a knockdown induces cognitive impairment without seizures. Neurobiol Dis 54:297-307