Verbal memory deficits are among the most prominent cognitive sequelae in individuals with left temporal lobe epilepsy (LTLE). However, relationships between verbal memory function and white matter integrity (WMI) in the left temporal lobe remain unclear. Current study aims included determining fractional anisotropy (FA) and mean diffusivity (MD) differences as an index of WMI between participants with left temporal lobe epilepsy (LTLE), participants with right TLE (RTLE), and controls, establishing group differences based on verbal memory function between TLE groups, and describing relationships between WMI and verbal memory function within TLE groups. Probabilistic tractography defined the left fornix (FRX), left uncinate fasciculus (UF), left parahippocampal cingulum (PHC), and a control region, the left corticospinal tract (CST), in 26 LTLE, 29 RTLE, and 20 control participants. The LTLE group demonstrated significantly lower fractional anisotropy (FA) along the PHC compared with controls. LTLE and RTLE groups did not differ significantly on measures of verbal memory until analyses were restricted to participants with left-lateralized language functioning. PHC FA was negatively correlated with semantic memory function in LTLE, but positively associated with episodic memory functioning in RTLE. Overall, findings highlight the PHC as vulnerable in LTLE, and differentially related to verbal memory functioning based on TLE group. Both findings are likely secondary to left-lateralized white matter disruption in LTLE. The current study also highlighted the importance of identifying homogenous groups to more clearly identify brain-behavior relationships. Current findings further define left-lateralized white matter alternations and related verbal memory deficits in TLE. Implications for these findings are presented in context with previous TLE literature, and future directions for further study are discussed.

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The Wechsler Memory Scale (WMS) is the most extensively used battery for memory assessment of adults. The third edition of the WMS (WMS-111) represents a substantial revision of previous versions. Accordingly, issues of validity of the revised instrument need to be addressed. The purpose of these studies was to contribute to the validation of the scale in the assessment of patients with temporal lobe epilepsy WE). An important role of the neuropsychological evaluation in TLE is to aid in the localization and lateralization of dysfunction. This is based on the premise that the temporal lobes are specialized for the acquisition of material-specific information, with dysfunction in the left and right mesial temporal regions being associated with verbal and nonverbal memory impairment, respectively. Since the WMS is utilized by the vast majority of epilepsy centres, evaluation of its meaning and utility in this population is essential. In Study 1, the utility of the WMS-I11 in detecting lateralized impairment was examined in a sample of patients with left (n = 55) or right (n = 47) TLE. Methods of analysis included evaluation of group means on the various indexes and subtest scores, the use of ROC curves, and an examination of Auditory-Visual Index discrepancy scores. The Auditory- Visual Delayed Index difference score appeared most sensitive to side of temporal dysfunction, although patient classification rates were not within an acceptable range to have clinical utility. The ability to predict laterality based on statistically significant index score differences was particularly weak for those with left temporal dysfunction. The use of unusually large discrepancies led to improved prediction; however, the rarity of such scores limits their usefulness. ill In Study 2, five competing models specifying the factor structure underlying the WMS- 111 primarysubtest scores were evaluated in a large sample of patients with TLE (N = 254). Models specifying separate immediate and delayed constructs resulted in inadmissible parameter estimates and model specification error. There were negligible goodness-of-fit differences between a 3-factor model of working memory, auditory memory, and visual memory, and a nested- more parsimonious- 2-factor model of working memory and general memory. The results suggested that specifying a separate visual memory factor provided little advantage for this sample- an unexpected finding in a population with lateralized dysfunction, for which one might have predicted separate auditory and visual memory dimensions. These findings add to a growing literature which suggests that the WMS-I11 has little utility in detecting lateralized dysfunction in TLE. This has important implications for the preoperative assessment of epilepsy patients.

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Seizures are a symptom of epilepsy, characterized by spontaneous firing due to an imbalance of excitatory and inhibitory features. While mammalian seizure models receive the most attention, the simplicity and tractability of invertebrate model systems, specifically C. elegans and D. melanogaster, have many advantages in understanding the molecular and cellular mechanisms of seizure behavior. This research explores C. elegans and D. melanogaster as electroconvulsive seizure models to investigate methods to both modulate and better understand seizure susceptibility. A common underlying feature of seizures in mammals, worms, and flies involves regulating excitation and inhibition. The C. elegans locomotor circuit is regulated via well characterized GABAergic and cholingeric motoneurons that innervate two rows of dorsal and ventral body wall muscles. In this research, we developed an electroconvulsive seizure assay which utilizes the locomotor circuit as a behavioral read out of neuronal function. When inhibition is decreased in the circuit, for example by decreasing GABAergic input, we find a general increase in the time to recovery from a seizure. After establishing the contribution of excitation and inhibition to seizure recovery, we explored a ubiquitin ligase, associated with comorbidity of an X-linked Intellectual Disorder and epilepsy in humans, and established that the worm homolog, eel-1, contributes to seizure susceptibility similarly to the human gene. Next, we investigated a cGMP-dependent protein kinase (PKG) that functions in the nervous system of both worms and flies and determined that increasing PKG activity, decreases the time to recovery from an electroconvulsive seizure. These experiments suggest a potential novel role for a major protein, PKG, in seizure susceptibility and that the C. elegans and D. melanogaster electroconvulsive seizure assays can be used to investigate possible genes involved in seizure susceptibility and future therapeutic to treat epilepsy. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

Introdução: pacientes com epilepsia em tratamento com politerapia podem manifestar sinais de efeitos adversos e/ou ineficácia terapêutica decorrentes das possíveis interações entre as diferentes drogas antiepilépticas (DAEs) que compõem o esquema terapêutico. Para contornar esta situação, as DAEs desenvolvidas atualmente apresentam perfil farmacocinético com menor potencial para interações farmacológicas. O levetiracetam é uma nova DAE aprovada para utilização como terapia adjuntiva no tratamento de crises focais em adultos. Seu metabolismo, por não depender de forma significativa do sistema oxidativo microssomal hepático, proporciona associações positivas com outras DAEs. Entretanto, observações clínicas de que a associação entre levetiracetam e DAEs indutoras enzimáticas (carbamazepina, fenitoína, fenobarbital e primidona) implicaria em menor disposição plasmática do levetiracetam têm sido confirmadas por alguns estudos e consideradas irrelevantes por outros. Objetivo: caracterizar e comparar o perfil farmacocinético do levetiracetam entre pacientes adultos com epilepsia em tratamento regular com DAEs indutoras enzimáticas e pacientes que estejam ou em tratamento com DAEs que não alteram a atividade das enzimas de metabolismo ou sem tratamento farmacológico. Casuística e Métodos: trinta pacientes foram selecionados, tendo sido alocados quinze em cada grupo, de acordo com o perfil das DAEs em uso regular (grupo indutor enzimático e grupo controle). A todos foi administrada dose única oral de levetiracetam 1000 mg. Ao longo de 24 horas foram coletadas sete amostras de sangue para determinação da concentração plasmática do levetiracetam e três amostras de urina para quantificação do levetiracetam eliminado inalterado e de seu principal metabólito inativo, o ucb L057. As amostras foram encaminhadas à Universidade de Pavia, Itália, e analisadas por cromatografia líquida de alta eficiência (HPLC). Resultados: foram calculados os seguintes parâmetros farmacocinéticos: concentração plasmática máxima de levetiracetam e o tempo decorrido até seu alcance; meia-vida de eliminação; constante de velocidade de eliminação; área sob a curva de concentração plasmática versus tempo; clearance oral aparente e clearance renal do levetiracetam; volume aparente de distribuição e quantidades excretadas na urina como fármaco inalterado e como ucb L057. Comparações entre os grupos foram feitas a partir dos testes t de Student ou Mann-Whitney, conforme apropriado. O grupo em tratamento com DAEs indutoras enzimáticas apresentou clearance oral aparente do levetiracetam significativamente maior e meia-vida de eliminação significativamente menor do que o grupo controle (p < 0,05). As quantidades tanto de levetiracetam quanto de ucb L057 eliminadas na urina não divergiram significativamente entre os dois grupos (p > 0,05). Discussão e Conclusões: estudos têm evidenciado o potencial das DAEs indutoras enzimáticas tanto para estimular a atividade de enzimas hidrolíticas, como as responsáveis pela conversão do levetiracetam a ucb L057, quanto para inibir e/ou competir pelos sítios de ligação dos transportadores presentes nos túbulos renais responsáveis pela secreção ativa do ucb L057. Embora o presente estudo não tenha objetivado identificar e caracterizar as vias de metabolismo e eliminação do levetiracetam, os dados encontrados evidenciam a diferença na disposição plasmática deste fármaco quando associado às DAEs indutoras enzimáticas. Considerando que o levetiracetam é majoritariamente prescrito em associações, as quais geralmente envolvem ao menos uma DAE indutora enzimática, o sucesso da terapêutica dos pacientes em que o levetiracetam for adicionado ao esquema medicamentoso prévio ou em que as DAEs indutoras enzimáticas tenham suas posologias modificadas pode ser prejudicado caso não haja o reconhecimento da possibilidade de ocorrência da alteração de perfil farmacocinético evidenciada. / Introduction: patients with epilepsy treated with two or more antiepileptic drugs (AEDs) associated (politherapy) can show signs of adverse effects and/or therapeutic inefficacy due to possible interactions among the different combined AEDs. As an attempt to handle this problem, the AEDs developed nowadays are showing pharmacokinetic characteristics that decrease their potential to get involved in pharmacological interactions. Levetiracetam is a new AED approved as add-on therapy for the treatment of focal seizures in adults. Its metabolism does not rely significantly on the hepatic microssomal oxidative system, what has been considered a positive aspect in favor of its use in association with other AEDs. However, clinical observations of decreased levetiracetam plasma disposition when it is associated with enzyme inducing AEDs (carbamazepine, phenytoin, phenobarbital and/or primidone) has been confirmed by some studies and considered irrelevant by others. Purpose: to describe and compare the pharmacokinetic profile of levetiracetam among adult patients with epilepsy in treatment with enzyme-inducers AEDs and patients in treatment with AEDs without any impact on enzymes activity or with no pharmacological treatment. Patients and Methods: a single oral dose of levetiracetam 1000 mg was administered for the thirty selected patients (fifteen per group). Over 24 hours, seven blood samples were collected to have their levetiracetam concentrations quantified, and three urine samples were collected to have their levetiracetam and ucb L057 (the main levetiracetam inactive metabolite) amounts quantified. The samples were sent to University of Pavia, Italy, to be analyzed by high performance liquid chromatography (HPLC). Results: the following pharmacokinetics parameters were calculated: the maximum plasma levetiracetam concentration and the time it occurred, elimination half-life, elimination rate constant, area under the curve, levetiracetam apparent oral clearance and renal clearance, volume of distribution and amount excreted in urine as unchanged drug and as ucb L057. Comparisons between the two groups were performed by Student t-test or Mann-Whitney test, as appropriate. The group of patients treated with enzyme-inducers AEDs showed the levetiracetam apparent oral clearance significantly higher and elimination half-life significantly lower than those from control group (p < 0,05). The amount excreted in urine as unchanged drug and as ucb L057 were not significantly different between the two groups (p > 0,05). Discussion: some studies highlight the capacity of enzyme inducing AEDs both to increase the activity of hydrolysis enzymes, such as those responsible for converting levetiracetam to ucb L057, and to inhibit and/or to compete for the binding sites on the transporters responsible for active tubular secretion of ucb L057. Although the present study did not aim to identify and describe the metabolic and elimination pathways of levetiracetam, the data found clearly show the difference in levetiracetam disposition when it is associated with enzyme inducing AEDs. Considering that levetiracetam is mainly prescribed in association with other drugs, and in most of these associations at least one drug is an enzyme inducer, neglecting this evident change in levetiracetam pharmacokinetic in cases such as those which levetiracetam is added to a previous regimen, or those which enzyme-inducers have their prescription changed, can negatively affect the success of the treatment and consequently the patients quality of life.

Tse Kai Kong. / Thesis submitted in: August 1998. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves 116-122). / Abstract also in Chinese. / ABSTRACT --- p.ii / 摘要 --- p.v / ACKNOWLEDGEMENTS --- p.viii / CONTENTS --- p.ix / LIST OF FIGURES --- p.xiii / LIST OF TABLES --- p.xvii / ABBREVIATIONS --- p.xix / Chapter CHAPTER ONE --- Introduction --- p.1 / Chapter 1 --- Introduction --- p.2 / Chapter 1.1 --- Definition and Prevalence of Epilepsy --- p.2 / Chapter 1.2 --- Neurophysiology and Pathophysiology of Epilepsy --- p.3 / Chapter 1.3 --- Drugs Currently Used in the Treatment of Epilepsy --- p.5 / Chapter 1.4 --- Triazolines Aminoalkylpyridines as a New Class of Potential Antiepileptic Drugs --- p.9 / Chapter 1.5 --- Chemical Synthesis of Aminoalkylpyridines --- p.14 / Chapter 1.6 --- Metabolism of Aminoalkylpyridines --- p.15 / Chapter 1.7 --- Anticonvulsant Activities of Aminoalkylpyridines --- p.16 / Chapter 1.8 --- Aim and Scope of the Present Study --- p.18 / Chapter CHAPTER TWO --- Experimental --- p.19 / Chapter 2.1 --- MATERIALS --- p.20 / Chapter 2.2 --- PREFORMULATION STUDIES ON AMINOALKYLPYRIDINES --- p.22 / Chapter 2.2.1 --- Determination of Partition Coefficient --- p.22 / Chapter 2.2.2 --- Determination of Aqueous Solubilities --- p.22 / Chapter 2.2.3 --- Determination of Thermal Properties --- p.23 / Chapter 2.3 --- DEVELOPMENT OF A HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC ASSAY FORp-C1 AMINOALKYLPYRIDINES --- p.24 / Chapter 2.3.1 --- HPLC Apparatus and Conditions --- p.24 / Chapter 2.3.2 --- Animal Treatments and Biological Fluid Collection --- p.24 / Chapter 2.3.3 --- Solid Phase Extraction --- p.25 / Chapter 2.3.4 --- Construction of Calibration Curves for p-Cl AAP in Rat Blood --- p.25 / Chapter 2.3.5 --- Construction of Calibration Curves for p-Cl AAP in Rat Urine --- p.26 / Chapter 2.3.6 --- Accuracy and Precision in the Quantitation of p-C1 AAP in Biological Fluids --- p.26 / Chapter 2.4 --- PRELIMINARY PHARMACOKINETICS OF p-C1 AAP FOLLOWING INTRAVENOUS ADMINISTRATION --- p.27 / Chapter 2.4.1 --- Cannulae Preparation --- p.27 / Chapter 2.4.2 --- Dosage --- p.27 / Chapter 2.4.3 --- Animal Surgery and Sample Collection --- p.28 / Chapter 2.4.4 --- Pharmacokinetic Calculations --- p.29 / Chapter 2.5 --- URINARY METABOLIC STUDIES OF p-C1 AAP --- p.30 / Chapter 2.5.1 --- Animal Treatment and Urine Collection --- p.30 / Chapter 2.5.2 --- Deconjugation Assay --- p.30 / Chapter 2.5.3 --- Non-deconjugated Urine Sample Treatment --- p.31 / Chapter 2.5.4 --- Separation of Metabolites by HPLC --- p.31 / Chapter 2.5.5 --- Identification of Metabolites by LC/MS --- p.31 / Chapter 2.5.6 --- Quantitative Analysis --- p.32 / Chapter 2.5.7 --- Preparation of the authentic β-amino alcohol --- p.34 / Chapter 2.6 --- STATISTICAL ANALYSIS --- p.34 / Chapter CHAPTER THREE --- Results and Discussion --- p.35 / Chapter 3.1 --- PREFORMULATION STUDIES ON AMINOALKYLPYRIDINES --- p.36 / Chapter 3.1.1 --- PARTITION COEFFICIENT (K°W) --- p.36 / Chapter 3.1.2 --- AQUEOUS SOLUBILITY --- p.37 / Chapter 3.1.3 --- THERMAL ANALYSIS --- p.41 / Chapter 3.2 --- DEVELOPMENT OF A HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC ASSAY FOR p-C1 AMINOALKYLPYRIDINES --- p.49 / Chapter 3.2.1 --- SOLID PHASE EXTRACTION --- p.49 / Chapter 3.2.2 --- CONSTRUCTION OF CALIBRATION CURVES FOR p-C1 AAP IN THE RAT BLOOD --- p.49 / Chapter 3.2.3 --- CONSTRUCTION OF CALIBRATION CURVES FOR p-C1 AAP IN THE RAT URINE --- p.52 / Chapter 3.2.4 --- ACCURACY AND PRECISION IN THE QUANTITATION OF p-Cl IN THE BIOLOGICAL FLUIDS --- p.54 / Chapter 3.3 --- PRELIMINARY PHARMACOKINETICS OF p-C1 AAP FOLLOWING INTRAVENOUS ADMINISTRATION --- p.57 / Chapter 3.4 --- URINARY METABOLIC STUDIES OF p-C1AAP --- p.61 / Chapter 3.4.1 --- QUALITATIVE STUDIES : IDENTIFICATION OF METABOLITES --- p.61 / Chapter 3.4.2 --- QUANTITATIVE STUDIES --- p.94 / Chapter CHAPTER FOUR --- Conclusion --- p.111 / REFERENCES --- p.115 / APPENDIX Published Papers --- p.121

The thesis titled Educational Specifics of Children with Epilepsy aims to find out what are the specifics of education of children with epilepsy. The theoretical part of the thesis defines the characteristics of epilepsy, contains information about epilepsy and epileptic seizure, it deals with etiology of epilepsy, classification of epileptic and non epileptic seizures. It deals with the provocative factors of epileptic seizure and informs about the possibilities of treating this disease. The diploma thesis further outlines the current topic of today, and this is the education of children with epilepsy in the family and especially at school. In the thesis one can read about the issues of family education and healthy siblings of a child with disabilities, as well as some prejudices that an individual with epilepsy can encounter today. The work highlights the educational specifics of the education of children with epilepsy and does not forget to mention the legislative framework and the possibilities of education. It explains the support measures and the concept of inclusion. In the practical part, it contains the questions and the objectives that have been answered by qualitative research. Four case studies of epilepsy children aged between 5 and 16 years, a semi-structured interview with the family...