Understanding memory deficits in patients with drug-resistant epilepsy: key factors and impact on quality of life

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Epilepsy is a neurological disorder characterized by a predisposition to experience seizures and the associated neurobiological, cognitive, psychosocial, and social consequences, and can be a potentially stressful condition. This disease is mainly treated with antiepileptic drugs (AEDs). However, 30% of patients have drug-resistant epilepsy and may be candidates for surgical procedures, with proven efficacy in seizure control. Both repeated exposure to seizures and different treatments used for its control can lead to relatively variable cognitive deficits, with memory impairment being a complaint referred by more than 70% of patients. These memory deficits may compromise patients' quality of life, the main therapeutic objective. Different factors, mostly directly related to seizures, have been proposed as possible modulators of memory performance in patients with drug-resistant epilepsy (i.e., location and lateralization of the seizure focus, seizure frequency and type, presence of hippocampal sclerosis, and characteristics of different treatments). However, other factors, mostly not directly related to seizures, have been understudied. These factors include those related to the neural substrate of memory such as the morphology of the hippocampus along its anterior-posterior axis, the functional activation during cognitive processing, and the age at temporal lobe surgery. Other relevant factors could be considered as indicators of the individual’s well-being such as cortisol levels and negative affectivity. For this, this thesis focuses on clarifying the factors involved in memory functioning in people with drug-resistant epilepsy and the impact of memory functioning on quality of life in this population. The first chapter contains a general introduction, beginning its first section with the definition of epilepsy and memory, and the description of the knowledge currently available about the intervening factors in memory in people with epilepsy, emphasizing the issues that remain unresolved. The second section of the chapter defines the concept of quality of life, presents a model of quality of life in people with epilepsy, and addresses available knowledge about the impact of memory functioning on quality of life in this population. Cortisol, the main stress hormone, is one of the factors included in the first chapter whose role on memory has been understudied in people with epilepsy. Considering that epilepsy can be a potential model of chronic stress in humans and that cortisol has been proposed as an indicator of the health status involved in memory functioning in other populations, the study of cortisol levels is particularly interesting. To analyze its impact on memory in patients with epilepsy, knowledge about the levels of this hormone in this population and how it interacts with other epilepsy-related factors is needed. To this end, the second chapter includes a systematic review of cortisol and seizures in people with epilepsy, describing existing data on cortisol levels in baseline conditions and in stressful situations such as seizures or experimental manipulations. The third chapter is focused on the main objectives and hypotheses of the doctoral thesis, which are then developed in the studies included in the following chapters. The fourth, fifth, sixth and seventh chapters include four empirical studies designed to investigate the involved factors in memory functioning in people with drug-resistant epilepsy such as the neural substrates underlying the cognitive processing of this population (studies 1 and 2), surgical intervention on this substrate (study 3) and other endocrine and psychological factors (study 4). Thus, the first study examines the influence of hippocampal morphology along its anterior-posterior axis and its relationship to memory encoding and performance in temporal lobe epilepsy. The second study aims to clarify the role of the asymmetry in the hemispheric activation during language processing in memory performance, considering possible mediating factors. The third study focuses on determining whether age at surgery is a reliable predictor of memory evolution in patients undergoing temporal lobe surgery from a multivariate perspective. The fourth study focuses on determining the impact of cortisol levels and negative affectivity on memory in this population, considering the role of other possible influencing factors. The eighth chapter presents the fifth empirical study of the doctoral thesis, focused on clarifying the role of memory functioning on quality of life in patients with drug-resistant epilepsy, considering the role of seizures related variables and other physical, social and psychological factors not directly related to seizures. Each study described in the chapters of the present thesis contains a brief introduction, methods, results, and discussion of the main findings. The ninth chapter includes a general discussion of the main results of the doctoral thesis, and its clinical implications and limitations, suggesting some future directions. The tenth chapter includes the main conclusions of the doctoral thesis. Finally, the eleventh and twelfth chapters include a comprehensive summary of the thesis in English and Spanish, respectively, in which the objectives and hypotheses, the studies carried out, and the main results and conclusions are presented.
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