Les crises épileptiques sont des épisodes paroxysmiques d'activité cérébrale hypersynchrone. Ce travail de thèse s'attache à examiner les mécanismes de propagation des crises d'épilepsie sur une échelle temporelle lente et une grande échelle spatiale dans le cerveau humain et à les appliquer au contexte clinique. Chez les patients souffrant d'épilepsie partielle réfractaire, les crises débutent dans certaines régions localisées du cerveau, dénommées zone épileptogène, avant de recruter des régions distantes. Le succès de l'ablation chirurgicale de la zone epileptogène dépend principalement de sa délimitation adéquate, un problème souvent épineux en pratique clinique. À cela s'ajoute notre compréhension parcellaire des mécanismes à l'origine des crises et de leur propagation. Nous utilisons un modèle mathématique de masse neuronale reproduisant le décours temporel de l'activité moyenne critique et intercritique d'une région cérébrale, guidé de manière autonome par une variable permittive lente. Nous introduisons tout d'abord un couplage permittif lent entre ces masses neuronales, afin de révéler l'importance de la variété lente dans le recrutement des régions cérébrales dans la crise. Nous présentons ensuite un pipeline de traitement des données structurelles et de diffusion IRM pour reconstruire automatiquement le cerveau virtuel d'un patient. Nous utilisons ensuite une analyse de stabilité linéaire et la connectivité large-échelle pour prédire la zone de propagation. Nous appliquons notre méthode à un jeu de données de 15 patients épileptiques et démontrons l'importance du connectome pour prédire la direction de propagation des crises. / Epileptic seizures are paroxysmal hypersynchronizations of brain activity, spanning several temporal and spatial scales. In the present thesis, we investigate the mechanisms of epileptic seizure propagation on a slow temporal and large spatial scale in the human brain and apply them to a clinical context. For patients with partial refractory epilepsy, seizures arise from a localized region of the brain, the so-called epileptogenic zone, before recruiting distant regions. Success of the resective surgery of the epileptogenic zone depends on its correct delineation, which is often difficult in clinical practice. Furthermore, the mechanisms of seizure onset and recruitment are still largely unknown. We use a mathematical neural mass model to reproduce the time course of interictal and ictal mean activity of a brain region, in which the switching between these states is guided by an autonomous slow permittivity variable. We first introduce a slow permittivity coupling function between these neural masses, hypothesizing the importance of the slow manifold in the recruitment of brain regions into the seizure. Before exploring large-scale networks of such coupled systems, we present a processing pipeline for automatic reconstruction of a patient's virtual brain, including surface and connectivity (i.e., connectome), using structural and diffusion MRI, and tractography methods. Using linear stability analysis and large-scale connectivity, we predict the propagation zone. We apply our method to a dataset of 15 epileptic patients and establish the importance of the connectome in determining large-scale propagation of epileptic seizures.

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Apresentamos dados e argumentos que indicam que: a) as crises epilépticas apresentadas por Trinomys yonenagae em campo e em cativeiro são espontâneas e idiopáticas; e b) elas podem ser decorrentes de processos evolutivos. A epilepsia nesta espécie foi caracterizada em cativeiro a partir de um cadastro iniciado há 16 anos, formado por progenitores e descendentes de seis colônias de T. yonenagae, coletados na Caatinga de Ibiraba (BA), e adultos (129,90 ± 5,92g) e filhotes nascidos em cativeiro num total de 295 indivíduos. A prevalência e a incidência em indivíduos epilépticos (EE) foram estimadas e as crises epilépticas foram analisadas por meio das manifestações comportamentais, baseando-se na escala de Racine. Aspectos da procriação (n=11), a locomoção, a ansiedade (testes de arena, n= 35) e índices fisiológicos (balanço hídrico-alimentar, n=6), importantes ao fitness, foram mensurados. Somente duas colônias apresentaram EE representando 9% e 28% dos nascimentos. Do total de indivíduos (165 e 130) 9,8% são EE (n=29; 14 e 15), sendo que as representam 52% e os 48%. A prevalência é de 20 a 30% e a incidência variou de 2 a 10 casos/ano, nos últimos cinco anos. As crises são observadas somente em adultos (n=24) a menor latência é de 13m e a frequência é variável (1 a 24 em seis anos). A maioria iniciou-se por congelamento e 50% atingiram o estágio 5 da escala de Racine. Em todos os casais, de 5 a 50% dos filhotes são EE e ocorreu estro pós-parto, como esperado para a espécie. Os filhotes são saudáveis e tanto a média de filhotes por ninhada (1,9±0,3), como a média do número de ninhadas por casal (6,5±5,0) é igual à de casais não epilépticos (NE). O teste de arena indica que descendentes de EE (DE) e as EE são menos ansiosas que as NE. Não há diferença entre os grupos dos índices fisiológicos estimados. A diferença no número de EE nas colônias, a alta prevalência e % de filhotes EE, e a diferença de comportamento das fêmeas DE indicam a base genética desta epilepsia. Neste contexto, consideramos que em Trinomys yonenagae, a epilepsia límbica não compromete o fitness, o que abre possibilidades de ser decorrente de processos evolutivos envolvendo o escalonamento de respostas de anti-predação / We present data and discuss the possibility that: a) the seizures presented by Trinomys yonenagae in the wild and in captivity are spontaneous and idiopathic, and b) they may be due to evolutionary processes. Epilepsy was characterized in this species in captivity from a survey started 16 years ago, made up of parents and descendants from six colonies of T. yonenagae collected in the Caatinga of Ibiraba (BA), and adults (129.90 ± 5.92 g) and pups born in captivity in a total of 295 individuals. The prevalence and incidence in individuals with epilepsy (EE) were estimated and seizures were analyzed by behavioral manifestations, based on Racine´s scale. Locomotion and anxiety indexes (open-field test, n = 35), as well as aspects of breeding (n = 11) and physiological indicators (balance food and water, n = 6), important to fitness were measured. Only two colonies showed EE, representing 9% and 28% of births. Approximately 10% of total individuals (165 and 130 ) are EE (n = 29, 14 and 15 ), and the represent 52 and 48%. In the last five years prevalence is 20-30%, and incidence ranged from 2 to 10 cases/ year. Seizures are only observed in adults (n = 24), the lowest latency is 13 months and the frequency is variable (1 to 24 in six years). The first stage is freezing and 50% reached stage 5 of Racine´s scale. In all couples, 5-50% of puppies are EE and occurred postpartum estrus, as expected for the species. The puppies are healthy and both the average offspring per litter (1.9 ± 0.3), as well as the average number of litters per couple (6.5 ± 5.0) is equal to values presented by non-epileptic couples (NE). The open-field test indicates that descendants of EE (DE) and EE are less anxious than NE. There is no difference between EE and NE regarding food and water intake. The difference in the number of EE in the colonies, the high percentage of EE pups, and the difference in the behavior of DE indicate the genetic basis of this epilepsy. In this context, we consider that in Trinomys yonenagae the limbic epilepsy seems to not compromise the fitness, which opens possibilities to be the result of evolutionary processes involving the escalation of antipredator responses

Assessing complex brain activity as a function of the type of epilepsy and in the context of the 3D source of seizure onset remains a critical and challenging endeavor. In this dissertation, we tried to extract the attributes of the epileptic brain by looking at the modular interactions from scalp electroencephalography (EEG). A classification algorithm is proposed for the connectivity-based separation of interictal epileptic EEG from normal. Connectivity patterns of interictal epileptic discharges were investigated in different types of epilepsy, and the relation between patterns and the epileptogenic zone are also explored in focal epilepsy. A nonlinear recurrence-based method is applied to scalp EEG recordings to obtain connectivity maps using phase synchronization attributes. The pairwise connectivity measure is obtained from time domain data without any conversion to the frequency domain. The phase coupling value, which indicates the broadband interdependence of input data, is utilized for the graph theory interpretation of local and global assessment of connectivity activities. The method is applied to the population of pediatric individuals to delineate the epileptic cases from normal controls. A probabilistic approach proved a significant difference between the two groups by successfully separating the individuals with an accuracy of 92.8%. The investigation of connectivity patterns of the interictal epileptic discharges (IED), which were originated from focal and generalized seizures, was resulted in a significant difference ( ) in connectivity matrices. It was observed that the functional connectivity maps of focal IED showed local activities while generalized cases showed global activated areas. The investigation of connectivity maps that resulted from temporal lobe epilepsy individuals has shown the temporal and frontal areas as the most affected regions. In general, functional connectivity measures are considered higher order attributes that helped the delineation of epileptic individuals in the classification process. The functional connectivity patterns of interictal activities can hence serve as indicators of the seizure type and also specify the irritated regions in focal epilepsy. These findings can indeed enhance the diagnosis process in context to the type of epilepsy and effects of relative location of the 3D source of seizure onset on other brain areas.

Le syndrome de West (SW), communément appelé spasmes infantiles (SI), est un trouble épileptique généralement caractérisé par la triade de spasmes infantiles, un modèle d'électroencéphalogramme (EEG) pathognomonique appelé hypsarythmie, et la régression du développement. Alors que des études précédentes ont été en mesure d'obtenir une réponse relativement adéquate par rapport au contrôle des spasmes et la résolution d’hypsarythmie, elles n’ont pas réussi à fournir des options thérapeutiques décisives à l’égard des séquelles neurodéveloppementales souvent associées aux SI. Notre étude, sur laquelle est basée cette thèse, est la première à utiliser un traitement complémentaire aux médicaments antiépileptiques conventionnels, avec l'intention d'améliorer les résultats neurodéveloppementaux de cette population. Les patients recrutés dans notre essai clinique randomisé (ECR) original ont suivi un protocole de traitement standardisé composé de vigabatrin (VGB) comme traitement de première intention pendant deux semaines, suivi de l'hormone corticotrope (ACTH) chez les non-répondeurs pour une période de deux autres semaines, et le topiramate dans les cas réfractaires. En plus, les patients ont été randomisés pour recevoir soit le traitement expérimental, flunarizine, soit un placebo, pendant six mois. Notre ECR multicentrique consistait à recruter et évaluer 68 patients, la plupart suivis à 8 différentes visites sur une période de cinq ans afin de précisément évaluer leurs progrès neurodéveloppementaux. Notre essai clinique a généré trois études principales qui forment le coeur de cette thèse. Dans une première étude, les données cliniques et cognitives des deux premières années d’évaluation ont été analysées. Les résultats cliniques à court terme indiquent un taux élevé de cessation de spasmes et de l’hypsarythmie. De plus, cette étude rapporte les premiers résultats cognitifs mesurés par le Bayley Scales of Infant Development (BSID) et le Vineland Adaptive Behavior Scale (VABS). Notre deuxième étude a essentiellement fourni des données cognitives à plus long terme, 5 ans après le début de son initiation. Les réponses cognitives ont été mesurées par le BSID, le VABS, et aussi par le Stanford-Binet Intelligence Scale (SB5) chez les patients ayant un fonctionnement cognitif plus élevé. Une amélioration significative et progressive des fonctions cognitives a été observée, indépendamment de la thérapie adjuvante. Des facteurs de risque cognitifs à long terme ont également été révélés dans cette étude. Notre dernière étude a essayé d’élucider la relation entre les SI et les troubles du spectre autistique (TSA). Un test de dépistage avec le Checklist for Autism in Toddlers (CHAT) a été effectué à 24 mois, et un diagnostic a été obtenu par moyen du Autism Diagnostic Observation Schedule (ADOS) à 30 et 60 mois. L’ADOS a évalué 44 patients, dont 10 ont été diagnostiqués avec TSA. Une description des facteurs de risque associés aux TSA ont été présentés dans cet article. Enfin, basé sur nos résultats et les informations à ce sujet dans la littérature, nous avons tenté d'élucider les caractéristiques physiopathologiques de la maladie. Une description des mécanismes biologiques sous-jacents impliqués dans le syndrome de West et des traitements cibles associés ont été présentés. Bien que le traitement complémentaire, le flunarizine ne se soit pas avéré être avantageux pour notre cohorte, notre protocole de traitement a tout de même été en mesure de démontrer des résultats cliniques et cognitifs supérieurs dans le sous-groupe de patients avec SI dont l’étiologie est inconnue. Ces résultats, ainsi que l’identification de nouveaux facteurs de risque neurodéveloppementaux potentiels, pourraient être utilisés cliniquement afin d’améliorer le diagnostic et le suivi médical des patients atteints du syndrome de West. / West syndrome (WS), commonly referred to as infantile spasms (IS), is an epileptic disorder usually characterized by the triad of infantile spasms, a pathognomonic electroencephalogram (EEG) pattern called hypsarrhythmia, and developmental regression. While previous treatment studies were able to achieve relatively adequate spasm control and hypsarrhythmia resolution in this population of patients, they have failed to provide conclusive and definite therapeutic options aimed at improving the poor cognitive outcome often associated to IS. Our study, on which this thesis is based, was the first to use an add-on treatment to conventional antiepileptic drugs, with the intent to improve long-term cognitive outcome in this population. Patients recruited in our original randomized clinical trial (RCT) followed a standardized treatment protocol consisting of vigabatrin (VGB) as first-line treatment for two weeks, followed by adrenocorticotropic hormone (ACTH) in non-responders for another two-week period, and topiramate in refractory cases. In addition, patients were randomized to either receive placebo or flunarizine adjunct therapy for six months. Our multi-centric RCT recruited and evaluated 68 patients, most of which were followed at 8 different time points over a five-year period, to precisely evaluate their neurodevelopmental progress. Our clinical trial generated three main studies which comprise the core of this thesis. In a first study, clinical and cognitive data from the first two years were analyzed. Spasm arrest and hypsarrhythmia resolution were the short-term clinical endpoint measures, while the Vineland Adaptive Behavior Scale (VABS) and Bayley Scales of Infant Development (BSID) were used as cognitive outcome measures at 2 years. This first study most importantly reports on the superior short-term clinical response rate achieved in our study population. Preliminary cognitive results were also presented in this work. Our second study essentially presented long-term cognitive data 5 years after the start of the study. Cognitive outcome measures were similar to those used at two years with the addition of the Stanford-Binet Intelligence Scale, Fifth Edition (SB5) for higher functioning patients. Most IS patients, particularly those with no known etiology, displayed a significant and progressive improvement of cognitive functions, irrespective of adjunctive therapy. Risk factors of long term poor cognitive outcome were also revealed in this study. Our last study tried to understand the relationship between IS and autism spectrum disorders (ASD). Autism was initially screened by means of the Checklist for Autism in Toddlers (CHAT) at 24 months, and formally assessed at the 30-and 60-month follow-up visits using the Autism Diagnostic Observation Schedule (ADOS). ADOS was performed in 44 patients, 10 of which were diagnosed with ASD. A description of risk factors associated with an ASD outcome in the IS population were presented in this article. Finally, based on our study results and in conjunction with literature information on the topic, we attempted to elucidate the pathophysiological characteristics of the disorder. A conceivable description of the underlying biological mechanisms implicated in West syndrome and associated target treatments were presented. Although our complementary treatment, flunarizine, did not prove to be beneficial in our cohort, our treatment protocol was nonetheless able to demonstrate superior clinical and cognitive outcomes in patients with unknown etiologies. These findings, as well as the identification of new potential neurodevelopmental risk factors, could be used clinically to improve the diagnosis and medical follow-up of patients with West syndrome.

The thesis "The social view of the impact of epilepsy on adults" is focusing on the specification of psychosomatic factors that are influencing the life of an adult with epilepsy. The thesis is divided into three parts. In the theoretical part, the disease epilepsy, diagnostic, therapy and treatment are defined, a fit of epilepsy is classified, and moreover, the first aid during the epileptic fit is described. Another part of the thesis is dedicated to description of some areas of life of the adult with epilepsy, which are bringing certain limitations to everyday life. This includes the family life and also problematic of professional life and possible job restrictions. These areas are described with regards to influences of lifestyle, medication, sleeping habits and leisure time activities on the life of a person with epilepsy. The thesis also focus on the problematic of social stigmatization, social isolation and on the list of possible psychological changes and cognitive problems of people with epilepsy, that occurs as a result of this diagnosis. The practical part of the thesis is dedicated to processing of results from conducted survey. The main research task of the survey was to discover, which parts of the life of an adult with epilepsy are affected the most. The results are sorted,...

Les épilepsies acquises se déclarent après un processus graduel appelé épileptogenèse. Bien que cliniquement silencieux, ce processus implique des modifications fonctionnelles observables notamment par électroencéphalographie. Cette thèse vise i) à identifier des marqueurs électrophysiologiques apparaissant au cours de l’épileptogenèse, et ii) à comprendre les modifications physiopathologiques sous-jacentes responsables de ces marqueurs et de leur évolution temporelle. Dans un premier temps, nous avons, dans un modèle d’épilepsie partielle chez la souris, monitoré des signaux électrophysiologiques intracérébraux pendant la mise en place de la maladie. Nous avons observé dans ces signaux expérimentaux, l’émergence d’événements transitoires pathologiques appelés pointes épileptiques. Nous avons développé des méthodes de traitement du signal pour détecter et caractériser automatiquement ces événements. Ainsi, nous avons pu mettre en évidence certains changements dans la forme des pointes épileptiques au cours de l’épileptogenèse ; en particulier l’apparition et l’augmentation d’une onde qui suit la pointe épileptique. Une hypothèse défendue dans ces travaux est que ces changements morphologiques peuvent constituer des marqueurs de l’épileptogenèse dans ce modèle animal. Dans un second temps, afin d’interpréter ces modifications électrophysiologiques en termes de processus neurophysiologiques sous-jacents, nous avons implémenté un modèle biomathématique, physiologiquement argumenté, capable de simuler des pointes épileptiques. Formellement, ce modèle est un système dynamique non linéaire qui reproduit les interactions synaptiques (excitatrices et inhibitrices) dans une population de neurones. Une analyse de sensibilité de ce modèle a permis de mettre en évidence le rôle critique de certains paramètres de connectivité dans la morphologie des pointes. Nos résultats montrent en effet, qu’une diminution de l’inhibition GABAergique entraîne un accroissement de l’onde dans les pointes épileptiques. À partir du modèle théorique, nous avons pu ainsi émettre des hypothèses sur les modifications opérant au cours du processus d’épileptogenèse. Ces hypothèses ont pu être en partie vérifiées expérimentalement en bloquant artificiellement l’inhibition GABAergique, dans le modèle in vivo chez la souris, et dans un modèle in vitro chez le rat. En conclusion, ce travail de thèse fournit, dans un modèle animal, un biomarqueur électrophysiologique de l’épileptogenèse et tente d’expliquer, grâce à une modélisation biomathématique, les processus neurophysiologiques sous-jacents qu’il reflète. / Acquired epilepsies occur after a process called epileptogenesis. Although clinically silent, this process involves some functional modifications which can be observed by electroencephalography. The objectives of this thesis are i) to identify electrophysiological markers occurring during epileptogenesis, and ii) to understand which underlying pathophysiological modifications are responsible for these markers and their evolution. Firstly, using an in vivo experimental mouse model of partial epilepsy, we have monitored intracranial electrophysiological signals during epileptogenesis. We observed the emergence of pathological transient events called epileptic spikes. We have developed signal processing methods in order to automatically detect and characterize these events. Hence, we observed and quantified morphological changes of epileptic spikes during epileptogenesis. In particular, we noticed the emergence and the increase of a wave which directly follows the spike component. In this work, we defend the hypothesis that these morphological modifications can constitute markers of the epileptogenesis process in this animal model of epilepsy. Secondly, in order to interpret these electrophysiological modifications in terms of underlying pathophysiological processes, we have implemented a computational model able to simulate epileptic spikes. This neural mass model is a neurophysiologically-plausible mesoscopic representation of synaptic interactions (excitation and inhibition) in the hippocampus. Based on a sensitivity analysis of model parameters, we were able to determine some connectivity parameters that play a key role in the morphology of simulated epileptic spikes. In particular, our results show that a diminution of GABAergic inhibition leads to an increase of the aforementioned wave. Thus, using this theoretical model, we defined some hypotheses about pathophysiological modifications occurring during the epileptogenesis process. One of these hypotheses has been confirmed in blocking GABAa receptors in the in vivo mouse model, as well as in an in vitro model (rat, organotypic slices). In summary, based on the shape features of epileptic spikes, we devised an electrophysiological biomarker of epileptogenesis observed in a mouse model but useful in Human studies as well. Moreover, a computational modeling approach has permitted to suggest which pathophysiological processes might underlie this biomarker.

After the dispensation of the White Paper 6 in schools, there were no detailed guidelines to accommodate the learners with invisible impairments like absence epilepsy, especially those who live in underprivileged communities. Affected learners are still struggling and not receiving proper instruction in ordinary schools because of the nature of absence epilepsy. It seems like it is unknown that they are suffering, because the symptoms are absent. These learners are performing poorly; they are having learning and behavioural problems. At home parents are ignorant of their plight, teachers are oblivious of their problems and at schools they are being discriminated against by other children. As a result, they repeat grades and some end up leaving school to join the unemployed. They have a low self-esteem and remain unsociable. This is because they suffer from absence epilepsy which is a medical problem. Absence epilepsy is unknown to both parents and teachers in these communities. Cultural beliefs and ignorance prevent parents from taking these children to clinics for identification, which results in them not being supported in schools. / Inclusive Education / M. Ed. (Inclusive Education)