Introdução: A hemimegalencefalia é uma rara malformação cerebral que envolve o crescimento anormalmente maior de um hemisfério cerebral. Clinicamente, observase macrocefalia, retardo mental, hemiparesia contralateral, hemianopsia e epilepsia intratável. A Esclerose tuberosa é uma doença genética rara, multissistêmica, caracterizada por tumores benignos e manifesta-se clinicamente com epilepsia e atraso cognitivo. A associação das duas patologias é rara, requer acompanhamento multidisciplinar e tratamentos medicamentoso e cirúrgico específicos. Objetivos: Identificar a presença de hemimegalencefalia em pacientes portadores de esclerose tuberosa com epilepsia atendidos no Centro de Cirurgia de Epilepsia (CIREP) do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. Realizar revisão de literatura sobre esclerose tuberosa e hemimegalencefalia, assim como a associação entre elas. Material e Métodos: Foi realizada revisão da literatura sobre esclerose tuberosa e hemimegalencefalia e também dos prontuários de pacientes que apresentam associação entre essas patologias. Resultados: Foram analisadas 1534 monitorizações por videoeletroencefalograma (VEEG) em crianças e adolescentes no CIREP. Dessas, 25 apresentavam hemimegalencefalia, e apenas duas com esclerose tuberosa associada. Foram, então, relatados os casos com descrição das etapas de avaliações pré-operatórias, cirurgia para o tratamento da epilepsia, e poslterior seguimento clínico, e também dos exames de imagem, neurofisiológicos e neuropatológicos. Conclusões: A associação entre hemimegalencefalia e esclerose tuberosa é uma manifestação rara, com apenas seis casos descritos na literatura. Contudo, tratandose de associação entre as doenças, a abordagem terapêutica e o seguimento dessas crianças com hemimegalencefalia se modifica, tanto na investigação quanto no acompanhamento clínico das manifestações sistêmicas da esclerose tuberosa. Os dois casos descritos apresentaram espasmos assimétricos, sendo iniciado tratamento com vigabatrina e posterior indicação cirúrgica. / Introduction: Hemimegalencephaly is a rare brain malformation that involves an abnormally larger growth of one cerebral hemisphere. Clinically, macrocephaly, mental retardation, contralateral hemiparesis, hemianopsia and intractable epilepsy are observed. Tuberous sclerosis is a rare, multisystemic genetic disease characterized by benign tumors and clinically manifested with epilepsy and cognitive delay. The association of these two pathologies is rare, requiring multidisciplinary care and specific drug and surgical treatment. Objectives: To identify the presence of hemimegalencephaly in patients with tuberous sclerosis with epilepsy attended at the Center for Epilepsy Surgery (CIREP, acronym in Portuguese) of the Clinics Hospital of Ribeirão Preto Medical School. To perform a literature review on tuberous sclerosis and hemimegalencephaly, as well as the association between them. Material and Methods: Review of the literature on tuberous sclerosis and hemimegalencephaly; review of patient records that show the association between these pathologies. Results: 1534 monitoring by VEEG in children and adolescents in CIREP were analyzed. Of these, 25 had hemimegalencephaly, and only two had associated tuberous sclerosis. The cases were reported with descriptions of the stages of preoperative evaluations, surgery for the treatment of epilepsy, with subsequent clinical care, as well as image, neurophysiological and neuropathological examinations. Conclusions: The association between hemimegalencephaly and tuberous sclerosis is a rare manifestation, with only six cases described in the literature. However, considering that it is an association between diseases, the therapeutic approach and the follow-up of these hemimegalencephalic children are specified, both in the investigation and in the clinical care of the systemic manifestations of tuberous sclerosis. Both described cases presented asymmetrical spasms, initiated treatment with vigabatrin with subsequent surgical indication and both presented renal alterations.

The prevalence of autism spectrum disorders [ASD] in epilepsy is approximately 20%-32%, with previous research reporting high rates of under-diagnosis of ASD in epilepsy. Current psychological assessments were adapted to provide epilepsy-specific measures of behaviour, which increased validity by addressing specific methodological problems highlighted by several researchers. The initial experiments provided a comprehensive investigation of autistic traits and characteristics in a heterogeneous group of adults with epilepsy without any ASD diagnosis to quantify the extent to which autistic characteristics are related to seizure activity. Adults with epilepsy showed higher autistic traits and impaired social responsiveness while systemizing and empathising abilities remained intact. Further, autistic traits and impaired social responsiveness increased again during seizure activity. Social responsiveness positively correlated with anti-epileptic drug [AED] control. Adults with epilepsy and seizure remission demonstrated significant improvements in restricted, repetitive behaviours compared to adults with current epileptic seizures. Together, these results demonstrate a relationship between seizure activity and autistic characteristics, and are consistent with previous suggestions that AEDs may mask autistic characteristics. The impaired social skills and communication are consistent with research suggesting that the pathogenesis of epilepsy may disrupt social functioning. However, whether this can be directly attributed to social cognitive deficits remains uncertain. The main research addresses this uncertainty by conducting three experiments to assess the Somatic Marker Hypothesis and the mechanisms which underpin it. The rationale is to establish whether this is a valid explanatory model for disrupted neurobiological factors implicated in social cognitive processing. This hypothesis is appropriate for investigating adults with epilepsy, some who may have developed typical social abilities in early life before epilepsy onset. Results from the IOWA Gambling Task demonstrated that adults with epilepsy had impaired decision making abilities compromising somatic marker formation, crucial for social cognition. However, this deficit occurred in the absence of other socio-emotional and memory impairments. In conclusion, adults with epilepsy have a higher rate of autistic characteristics, and their social difficulties may be associated with compromised somatic marker formation. Future research needs to determine the heritability of these autistic traits and characteristics.

The electroencephalogram (EEG) is a commonly used tool for studying the emergent electrical rhythms of the brain. It has wide utility in psychology, as well as bringing a useful diagnostic aid for neurological conditions such as epilepsy. It is of growing importance to better understand the emergence of these electrical rhythms and, in the case of diagnosis of neurological conditions, to find mechanistic differences between healthy individuals and those with a disease. Mathematical models are an important tool that offer the potential to reveal these otherwise hidden mechanisms. In particular Neural Mass Models (NMMs), which describe the macroscopic activity of large populations of neurons, are increasingly used to uncover large-scale mechanisms of brain rhythms in both health and disease. The dynamics of these models is dependent upon the choice of parameters, and therefore it is crucial to be able to understand how dynamics change when parameters are varied. Despite they are considered low-dimensional in comparison to micro-scale neural network models, with regards to understanding the relationship between parameters and dynamics NMMs are still prohibitively high dimensional for classical approaches such as numerical continuation. We need alternative methods to characterise the dynamics of NMMs in high dimensional parameter spaces. The primary aim of this thesis is to develop a method to explore and analyse the high dimensional parameter space of these mathematical models. We develop an approach based on statistics and machine learning methods called decision tree mapping (DTM). This method is used to analyse the parameter space of a mathematical model by studying all the parameters simultaneously. With this approach, the parameter space can efficiently be mapped in high dimension. We have used measures linked with this method to determine which parameters play a key role in the output of the model. This approach recursively splits the parameter space into smaller subspaces with an increasing homogeneity of dynamics. The concepts of decision tree learning, random forest, measures of importance, statistical tests and visual tools are introduced to explore and analyse the parameter space. We introduce formally the theoretical background and the methods with examples. The DTM approach is used in three distinct studies to: • Identify the role of parameters on the dynamic model. For example, which parameters have a role in the emergence of seizure dynamics? • Constrain the parameter space, such that regions of the parameter space which give implausible dynamic are removed. • Compare the parameter sets to fit different groups. How does the thalamocortical connectivity of people with and without epilepsy differ? We demonstrate that classical studies have not taken into account the complexity of the parameter space. DTM can easily be extended to other fields using mathematical models. We advocate the use of this method in the future to constrain high dimensional parameter spaces in order to enable more efficient, person-specific model calibration.

O lobo temporal mesial (LTM) é essencial para tarefas de memória e possui muitas conexões com diferentes áreas do cérebro. Pacientes com epilepsia do LTM, refratários ao tratamento medicamentoso, são candidatos à cirurgia para remoção do foco das crises. Portanto, antes da cirurgia, é essencial avaliar eventuais riscos de declínio das funções de memória, por meio de uma série de testes clínicos. Recentemente, abriu-se a possibilidade de estudar certos aspectos do funcionamento cerebral, de modo não invasivo, utilizando Imagens funcionais por Ressonância Magnética (fMRI). O objetivo deste trabalho foi desenvolver métodos que possibilitem a aplicação de protocolos de memória em estudos de fMRI, com vistas a pacientes com epilepsia. Para a manutenção da atenção durante os estudos de fMRI foi confeccionado um dispositivo infravermelho para registrar as respostas obtidas. Além disso, foi desenvolvido um programa (VOI Analyser) para a otimização das análises dos exames de fMRI. Tanto o dispositivo infravermelho como o programa foram amplamente utilizados em vários projetos de pesquisa permitindo o estudo de tarefas complexas. Neste estudo, a tarefa visava identificar as redes funcionais que participam do processo de codificação e recuperação de memória episódica utilizando tarefas visuais de identificação de cenas complexas. Foram estudados nesse estudo 12 voluntários assintomáticos e 7 pacientes com epilepsia do LTM. O estudo de grupo evidenciou o envolvimento de estruturas do LTM. A tarefa demonstrou ter um nível de dificuldade alta, em especial para pacientes, baseando-se na avaliação do tempo de resposta e nível de acertos. Além do estudo dos grupos, foi realizada uma análise por região de interesse (ROI), com ênfase no complexo amídala-hipocampo. Em seguida, o foco do estudo foi voltado para a assimetria hemisférica funcional, por meio do cálculo do índice de lateralização (IL). Além de rever os resultados obtidos pelo IL convencional, resultados preliminares levaram à proposta de um segundo índice corrigido, considerando a quantidade de voxels e a assimetria das ROI. A utilização do índice corrigido tornou a análise mais estável por diminuir a dependência do limiar estatístico considerado. A seguir, foi realizada uma subdivisão do hipocampo em porção anterior, central e posterior a qual indicou uma maior participação da região posterior na tarefa de codificação e da anterior na tarefa de recuperação, tanto entre os voluntários como em pacientes. / Medial temporal lobe (MTL) is essential for memory tasks and has many connections with different areas of the brain. Patients with MTL epilepsy refractory to medical treatment are candidates for surgery to remove the epileptiform tissue. Therefore, before surgery, it is essential to assess the risk of memory function decrease caused by the procedure, through a series of clinical trials. Recently, there is the possibility of studying certain aspects of brain functioning by using a non-invasive technique: functional Magnetic Resonance Imaging (fMRI). The aim of this work was to implement memory protocols in fMRI studies of epilepsy patients. For attention maintenance during the fMRI study an infrared device was built, in order to record the response times. In addition, a software was developed (VOI Analyser) to optimize the analysis of the fMRI examinations. Both have been widely used in several research projects enabling the study of complex tasks. In this study, the task was intended to identify the functional networks involved in the process of encoding and retrieving of episodic memory using a visual task involving complex scenes. 19 subjects were studied: 12 controls and 7 patients with refractory epilepsy. Group study showed the involvement of structures in MTL. The task has demonstrated a high level of difficulty, especially for patients, based on the analysis of response times and correct hits. In addition to the study of groups, an individual analysis was performed by region of interest (ROI), with emphasis on amigdala-hippocampus complex. Then, functional hemispheric asymmetry was studied, by means of the lateralization index (LI). In addition to the computation of conventional LI, an alternative LI was proposed, which considers voxels occupancy and ROI asymmetry. The use of such modified index tuned the analysis more stable by decreasing the dependence on considered statistical threshold. Moreover, LI was also computed on 3 portions of the hippocampus: anterior, middle and posterior. The results indicated a greater involvement of the posterior portion on the encoding task and anterior one in the recovery task, both for volunteers and patients.

Aims: The initial aim of this thesis was to understand the relationship between non-psychotropic medication and risk of suicidality. This was achieved by conducting a systematic review, which, among other conclusions, identified the need for improved estimation of risk of suicide and attempted suicide associated with antiepileptic drugs (AEDs). This stimulated this programme of research which sought to estimate the risk of suicide and other causes of unnatural death in people with epilepsy, the role of AEDs in fatal poisonings, the risk of self-harm in people with epilepsy and factors associated with self-harm amongst those people with epilepsy. Methods: Cohorts of individuals with prevalent epilepsy were identified separately in two population-based linked-primary care datasets: the Clinical Practice Research Datalink (CPRD) in England and the Secure Anonymised Information Linkage (SAIL) in Wales. Individuals were matched on age, gender and general practice to up to 20 people without epilepsy. The risks of cause-specific types of unnatural death (e.g. suicide, accident) were estimated using stratified Cox proportional hazards models, adjusted for level of deprivation. From each of the prevalent epilepsy cohorts, individuals with incident epilepsy, no history of self-harm and who were new users of the AEDs; carbamazepine, lamotrigine or valproate, were identified. The risk of first self-harm event associated with each AED compared to valproate was estimated using Inverse Probability of Treatment Weighting propensity score analysis. Estimates from each dataset were combined in a random effects meta-analysis. In the CPRD, the risk of self-harm in the incident epilepsy cohort versus a comparison cohort was estimated using a stratified Cox proportional hazards model. From this cohort, a nested case-control study was constructed. Individuals with a first self-harm event (cases) were matched to up to 20 people with no history of self-harm (controls). Conditional logistic regression was used to estimate the risk of self-harm associated with various factors including history of mental illness diagnoses, referrals and AED utilisation. Results: There were 44,678 and 14,051 people in the prevalent epilepsy cohorts and 891,429 and 279,365 in the comparison cohorts, in the CPRD and the SAIL respectively. Increased risks of suicide (HR 2.15, 95%CI 1.51-3.08) and accidental death (HR 2.97, 95%CI 2.54-3.48) were observed for people with epilepsy versus the comparison cohort, from the deprivation-adjusted meta-analysed estimates. Overall, AEDs were involved in 9.7% (95%CI 3.6%-19.9%) of the 62 poisoning deaths in people with epilepsy. There were 5,107 new users of carbamazepine, lamotrigine or valproate with incident epilepsy in the CPRD and 2,654 in the SAIL. No increased risk of self-harm was evident for carbamazepine (HR 1.53, 95%CI 0.89-2.64) or lamotrigine (HR 1.35, 95%CI 0.79-2.29), compared to valproate, from the meta-analysed estimates. In the CPRD, there were 11,690 individuals with incident epilepsy and 215,569 in the comparison cohort. The deprivation-adjusted hazard ratios for first self-harm event were 5.31 (95%CI 4.08-6.89) in the year following diagnosis and 3.31 (95%CI 2.85-3.84) in subsequent years. The nested-case control study derived from this incident epilepsy cohort included 273 cases of first self-harm and 3,790 controls. An increased risk of self-harm was associated with history of a mental illness diagnosis (OR 4.08, 95% CI 3.06-5.42) or referral to specialist psychiatric services (OR 3.41, 95% CI 2.63-4.43), compared to none; or being prescribed no AEDs (OR 1.47, 95% CI 1.01-2.12) or two AEDs (OR 1.84, 95% CI 1.33-2.55) in the 90 days prior to index date, compared to a single AED. Augmentation of AED treatment carried an elevated risk (OR 2.12, 95% CI 1.38-3.26) whereas there was no evidence to indicate that switching from one AED to another altered risk (OR 0.69, 95% CI 0.21-2.23). Conclusions: Compared to those without the condition, people with epilepsy are at an elevated risk of unnatural death, including suicide and accidental death, and nonfatal self-harm. The risk of self-harm is particularly elevated in the year following diagnosis of epilepsy but persists beyond this. Factors associated with increased risk of self-harm within the epilepsy population include prior mental illness and referral to psychiatric services. There was no evidence of difference in the risk of self-harm associated with carbamazepine or lamotrigine compared to valproate, but further replication of this result would be beneficial. However, treatment with multiple AEDs and augmentation of AED treatment increase the risk of self-harm within this population. These may be markers of uncontrolled epilepsy.

Introdução: A epilepsia é uma doença de grande relevância médica e social, trazendo grande impacto aos pacientes e a sociedade como um todo. A Epilepsia do Lobo Temporal Mesial (ELTM) é a epilepsia refratária mais prevalente, tendo em sua causalidade o impacto do desequilíbrio entre circuitos neuronais excitatórios e inibitórios, necessitando da remoção cirúrgica das estruturas alteradas e da interrupção das suas vias para melhor controle das crises e qualidade de vida dos pacientes. Objetivo: Buscando ampliar o esclarecimento do papel da amígdala junto as modificações intrínsecas nos receptores de neurotransmissores e em suas subunidades nos mecanismos de ictogênese e epileptogênese, possibilitando o aprimoramento das técnicas cirúrgicas atualmente empregadas, além de novas modalidades terapêuticas, o presente estudo analisou as expressões gênicas das subunidades de receptores excitatórios, NMDA (NR2C e NR3A, genes GRIN2C e GRIN3A), Cainato (GluK1 e GluK2, genes GRIK1 e GRIK2), e subunidade de receptor inibitório GABAA (?4 e ?5, genes GABRA4 e GABRA5) e subtipos de receptor de neuropeptídio Y (Y2 e Y5, com genes NPY2R e NPY5R), em núcleos basolaterais de amígdalas humanas de pacientes com ELTM. Material e Métodos: Foram utilizados fragmentos de amígdala de 20 pacientes que fizeram amigdalohipocampectomia junto ao Serviço de Neurocirurgia do HC-FMRP-USP, sendo 10 pacientes com controle efetivo pós-operatório (Engel 1) e 10 pacientes com controle inadequado das crises(Engel 3 e 4), 10 amígdalas obtidas de autópsias (controle), utilizando a qPCR. Resultados: Foram evidenciadas diferenças da expressão nas subunidades NR2C (p=0,006) e ?4 do GABAAr (p=0,008), subtipo de NPYr Y2(p=0.013), com tendência junto a subunidade NR3A(p=0,077). Não evidenciando significância estatísticas nas análises das subunidades GluK1(p=0,147), GluK2(p=0,182) e?5 do GABAAr (p=0,272), para o subtipo NPYr Y1(p=0,242). Conclusão: As análises sugerem diferenças na expressão de receptores de neurotransmissores em pacientes com epilepsia em relação ao controle contendo as subunidadeNR2C e ?4 do GABAAr, com tendências a subunidade NR3A, indicando modificações neuronais amigdalianas possivelmente envolvidas com a zona epileptogênica, possibilitando aprimoramentos terapêuticos junto ao tratamento dasepilepsias refratárias. Também podemos inferir que os mecanismos neuronais envolvendo as subunidades?4 doGABAAr e GRIN2C, e do subtipo Y2 do NPYr na epileptogênese e ictogênese da ELTM podem ser semelhantes entre amígdala e hipocampo, enquanto os envolvendo as subunidades GLUK1 e GLUK2 parecem ser diferenciados; o gene GABRA5 pode ser utilizado como gene de controle endógeno em estudos com amigdala e hipocampo na ELTM. / Introduction: Epilepsy is a disease whith highly medical and social relevance, bringing impact on patients and society as a whole. Mesial Temporal Lobe Epilepsy (MTLE) is the most prevalent refractory epilepsy, in its causality the impact of the imbalance between excitatory neuronal circuits and inhibitory, needing a surgical removal of the altered structures and the interruption of their way to better seizure control and quality of life pacientes. Goal: Searching to increase understanding the role of the amygdala with intrinsic changes in neurotransmitter receptors and their subunits in ictogenesis mechanisms and epileptogenesis, enabling the improvement of surgical techniques currently used, as well as new therapeutic modalities, this study analyzed gene expression on the subunits of excitatory receptors, NMDA (NR2 and NR3A, GRIN2C and GRIN3A genes) and kainate (GluK1 and GluK2, GRIK1 and GRIK2 genes), and inhibitory receptor subunit GABA (?4 and ?5, genes GABRA4 and GABRA5 ), neuropeptide Y receptor subtypes (Y2 and Y5, and NPY5R with NPY2R gene) in the basolateral nucleus of human amygdala of patients with MTLE. Material and Methods: Amygdala fragments were used in 20 patients who made amigdalohipocampectomia with the Service neurosurgery HC-FMRP-USP, 10 patients with postoperative effective control (Engel 1) and 10 patients with inadequate control of seizures (Engel 3:04), and 10 amygdalas obtained from autopsies (control) using qPCR. Results: Were differences evidenced expression in NR2C subunits (p = 0.006) e?4 the GABAAr (p = 0.008), and subtype NPYr Y2 (p = 0.013), along with a tendency of NR3A subunits (p = 0.077). Showing no statistical significance in the analysis of GluK1 subunits (p = 0.147), GluK2 (p = 0.182) e?5 the GABAAr (p = 0.272), and the NPYr Y1 subtype (p = 0.242). Conclusion: The analyzes suggest differences in expression of neurotransmitter receptors in epilepsy patients on control containing the NR2C subunits and ?4 of GABAAr with NR3A subunits trends indicating amygdala neuronal modifications possibly involved in the epileptogenic zone, enabling therapeutic improvements with the refractory epilepsy treatment. As well can infer that the neural mechanisms involving the subunits ?4 GABAAr, GRIN2C and Y2 NPYr subtype in epileptogenesis and ictogenesis of TLE can be similar between the amygdala and hippocampus, while involving GLUK1 and GLUK2 subunits appear to be different; the GABRA5 gene can be used as endogenous control gene in studies of hippocampus and amygdala in TLE.

Em mulheres com epilepsia, sabe-se que a síndrome epiléptica, a freqüência de crises e as drogas antiepilépticas podem ter influência na função sexual, comportamento sexual e na capacidade reprodutora. Muitos fatores têm sido relacionados a estas alterações, tais como: duração e gravidade da epilepsia, tipo de droga antiepiléptica e localização da lesão epileptogênica. Baseado no conhecimento adquirido com as mulheres assume-se que as adolescentes sofram influência semelhante. Este estudo teve como objetivo avaliar aspectos relacionados à função e ao comportamento sexual, à educação sexual e à função gonadal em adolescentes do sexo feminino com epilepsia. Para isso, foram estudadas prospectivamente 35 pacientes do sexo feminino, com epilepsia parcial e generalizada, com idades entre 10 a 20 anos, com epilepsia ativa, sendo o diagnóstico da síndrome epiléptica realizado segundo os critérios da Liga Internacional Contra a Epilepsia (1989). Os critérios de exclusão foram: ausência de menarca; uso de contraceptivo hormonal ou dispositivo intra-uterino, no momento da avaliação ou nos últimos três meses; antecedente de cirurgia ginecológica ou distúrbio endocrinológico; presença de doença crônica associada, ou deficiência mental moderada a grave que impossibilitassem o seguimento do protocolo a ser instituído. As informações sobre a função sexual, comportamento sexual e a educação sexual das adolescentes com epilepsia foram avaliadas através de um questionário padrão. O protocolo de estudo da função gonadal incluiu a análise dos seguintes critérios: ciclo menstrual regular, presença de dismenorréia, dosagem dos níveis hormonais (FSH, LH, estradiol, progesterona, prolactina, testosterona, T3, T4 livre, TSH), ultra-sonografia pélvica, gestação em curso ou recente. A função gonadal foi considerada normal se pelo menos um ou mais parâmetros acima foi adequado. Não foi observada diferença entre a idade da primeira relação sexual (p=0,54), atividade sexual (p=0,23), libido (p=1,00) e orgasmo (p=0,23) entre as adolescentes com epilepsia, em relação ao grupo controle. Todas as adolescentes sexualmente ativas relataram o uso de métodos contraceptivos, porém apenas 20,1% com orientação de algum profissional de saúde. A idade da menarca nos dois grupos foi similar. No entanto, o uso de valproato próximo à menarca e crises freqüentes foram fatores antecipadores da menarca. As adolescentes com epilepsia apresentaram uma freqüência de ciclos menstruais irregulares superior à do grupo controle. A irregularidade menstrual relacionou-se com a presença de crises tônico-clônicas generalizadas (p=0,02), sem relação com a síndrome epiléptica. Houve uma tendência a irregularidades menstruais em adolescentes que apresentavam duração da doença mais prolongada (p=0,06), independente da freqüência de crises epilépticas. Observaram-se índices de gravidez superiores entre as adolescentes com epilepsia em comparação às controles (p<.0001). Não houve diferença na freqüência de aborto entre as adolescentes com epilepsia. Neste estudo, as adolescentes com epilepsia apresentaram comportamento e função sexual similares às adolescentes sem doenças crônicas. Embora a função gonadal destas pacientes estivesse preservada, os distúrbios menstruais foram significantes, sugerindo que estas adolescentes possam estar em um processo em evolução com ciclos anovulatórios e disfunção reprodutora na vida adulta. Portanto, os aspectos relacionados à função e comportamento sexual, contracepção e função gonadal, em adolescentes com epilepsia, requerem atenção especial por parte dos profissionais de saúde. / It is known that in women with epilepsy, the epileptic syndrome, seizure frequency and antiepileptic drugs may act on sexual function, sexual behavior and reproductive function. Several factors have been associated with these changes such as: duration and severity of the epilepsy, kind of antiepileptic drug and locality of the epileptogenic lesion. Based on knowledge acquired with studies in women, it is assumed that female adolescents suffer similar influences. This study aimed to evaluate several aspects related to sexual function, to sexual behavior, to sexual education and to gonadal function in female adolescents with epilepsy. We prospectively studied 35 females, with ages between 10 and 20 years, with active partial and generalized epilepsies and epileptic syndromes classified according to ILAE criteria (1989). Criteria of exclusion were: patients that had not yet had their menarche, those in use of hormonal contraceptives or intrauterine devices, either at the moment of the evaluation or in the last three months; patients with previous gynecological surgery or endocrine disorders; patients with associated chronic disease or moderate to severe mental deficiency that might hinder completion of the study protocol. Information on sexual function and education were obtained with a standard questionnaire. Our study protocol for gonadal function included analysis of the following criteria: regular menstrual cycles, dysmenorrhea, hormonal levels (FSH, LH, stradiol, progesterone, prolactin, testosterone, T3, free T4, TSH), pelvic ultrasound study, and recent or ongoing pregnancy. Gonadal function was considered normal when at least one of the above parameters was found to be adequate. No significant differences were observed between age at first sexual intercourse (p=0.54), sexual activity (p=0.23), libido (p=1,00) and orgasm (p=0.23) among patients with epilepsy, when compared to controls. Sexually active adolescents reported the use of contraceptives, although only 20.1% with orientation done by a health professional. Age of menarche was similar in both groups, but the use of valproate close to menarche and frequent seizures were factors that anticipated this event. Moreover, adolescents with epilepsy presented irregular menstrual cycles more frequently than controls. Menstrual irregularity was correlated to the presence of tonic-clonic generalized seizures (p=0.02), regardless the epilepsy type or syndrome, and with longer disease duration (p=0.06), despite of seizure frequency. Higher rates of pregnancy were observed in adolescents with epilepsy compared to controls (p<.0001). Abortion rates were similar in both groups. In this study, adolescents with epilepsy presented sexual function and behavior similar to their peers without chronic diseases. Although the gonadal function of these patients was spared, menstrual disorders were significant, suggesting that these adolescents may be in an ongoing process with anovulatory cycles and reproductive dysfunction in later adulthood. Therefore, aspects related to sexual behavior and function, contraception and gonadal function in adolescents with epilepsy require special attention by health professionals.

Understanding the factors shaping neuronal spiking is a central problem in neuroscience. Neurons may have complicated sensitivity and, often, are embedded in dynamic networks whose ongoing activity may influence their likelihood of spiking. One approach to characterizing neuronal spiking is the point process generalized linear model (GLM), which decomposes spike probability into explicit factors. This model represents a higher level of abstraction than biophysical models, such as Hodgkin-Huxley, but benefits from principled approaches for estimation and validation. Here we address how to infer factors affecting neuronal spiking in different types of neural systems. We first extend the point process GLM, most commonly used to analyze single neurons, to model population-level voltage discharges recorded during human seizures. Both GLMs and descriptive measures reveal rhythmic bursting and directional wave propagation. However, we show that GLM estimates account for covariance between these features in a way that pairwise measures do not. Failure to account for this covariance leads to confounded results. We interpret the GLM results to speculate the mechanisms of seizure and suggest new therapies. The second chapter highlights flexibility of the GLM. We use this single framework to analyze enhancement, a statistical phenomenon, in three distinct systems. Here we define the enhancement score, a simple measure of shared information between spike factors in a GLM. We demonstrate how to estimate the score, including confidence intervals, using simulated data. In real data, we find that enhancement occurs prominently during human seizure, while redundancy tends to occur in mouse auditory networks. We discuss implications for physiology, particularly during seizure. In the third part of this thesis, we apply point process modeling to spike trains recorded from single units in vitro under external stimulation. We re-parameterize models in a low-dimensional and physically interpretable way; namely, we represent their effects in principal component space. We show that this approach successfully separates the neurons observed in vitro into different classes consistent with their gene expression profiles. Taken together, this work contributes a statistical framework for analyzing neuronal spike trains and demonstrates how it can be applied to create new insights into clinical and experimental data sets.

Prior studies have demonstrated that a sizeable percentage of children presenting to the epilepsy monitoring unit for evaluation of paroxysmal events (seizures) are found to have non-epileptic seizures (NES) (Asano et al., 2005). The importance of identifying NES cannot be overstated since misdiagnosis often leads to treatment with antiepileptic drugs, which may have side effects that may negatively impact cognition (Chen, Chow, & Lee, 2001) and perhaps even cognitive development. While studies in adults with epilepsy or NES have demonstrated impaired executive functioning and social outcome compared to healthy peers, less work is present among pediatric populations (Cragar, Berry, Fakhoury, Cibula, & Schmitt, 2002; Rantanen, Eriksson, & Nieminen, 2012). Furthermore, research is void of information regarding social skills between these pediatric groups. The aims of this study were to examine group differences between social skills and executive functioning between pediatric epileptic and NES patients, determine if social skills predict diagnostic classification, and examine correlations between executive functioning and social skill measures. This study was conducted on the epilepsy monitoring units (EMU) at Phoenix Children's Hospital and Primary Children's Medical Center. The parent/caregiver of patients admitted to the EMU for video-EEG diagnosis of seizures was approached regarding study participation. A total of 43 children and parent/caregiver participated in this study. The NES group consisted of15 participants (67% female; M age at testing = 12.62, SD = 3.33), and the epilepsy (ES) group consisted of 28 participants (50% female, M age at testing = 11.79, SD = 3.12). Both the parents and children completed brief questionnaires measuring executive functioning and social skills. These measures included The Behavior Rating Inventory of Executive Functioning, The Behavioral Assessment System for Children, Second Edition, and the Social Skills Improvement System Rating Scales. Binomial logistic regression analysis showed social skills did not significantly predict diagnostic group. No group differences were found between children with epilepsy and NES on measures of executive functioning or social skills. Parents of both groups rated their children as having below average social skills, while children rated their social skills in the average range compared to healthy peers. Both children and parents of both groups rated their executive functioning within the average range. Executive functioning scores and social skill scores significantly correlated and regression analyses indicated that the Behavioral Regulation Index on the BRIEF significantly predicted Social Skills on the SSIS. Interpretationof results, limitations, and future directions are discussed.

One woman examines her experiences with epilepsy over the past twenty years.