M.Sc. (Med.), Faculty of Health Sciences, University of the Witwatersrand, 2011 / Epilepsy, a chronic, often treatable condition, is one of the most common neurological conditions globally, with the prevalence of epilepsy significantly higher in developing regions of the world. In 2008, a household survey was undertaken within the Agincourt Health and Demographic Surveillance System (AHDSS) in rural, northeastern South Africa to identify the prevalence of and risk factors for active convulsive epilepsy. A single question was administered as part of the annual census to each household head. This single question sought to identify people with convulsions, while a random sample of 4,500 individuals was drawn from the Agincourt HDSS population as a way to validate the Stage One screening tool. During initial piloting of the Stage One screening question, the question was found to be adequately sensitive and significant (98.3% and 93.1%, respectively). A more specific questionnaire was administered in Stage Two, while a clinical exam and history was performed in Stage Three to conclusively diagnose epilepsy. The adjusted prevalence of active convulsive epilepsy in the three-stage study was 3.26 per 1,000, while the adjusted prevalence in the population sample was 7.72 per 1,000 individuals highlighting a significant difference due to possible methodological or cultural issues. Furthermore, a heterogeneous, random distribution of active convulsive epilepsy was found across the site, with the identification of possible familial clustering in a number of households. By utilizing univariate and multivariate analysis, this study found sex and a family history of seizures to be significant risk factors for developing epilepsy in rural South Africa. Abnormal deliveries and problems after delivery were found to be significant in the bivariate analysis, but not the multivariate analysis. These findings highlight the need for additional research exploring epilepsy in rural South Africa.

Proefschrift--Utrecht. / Bibliography: p. 187-207.

Cat scratch's disease caused by Bartonella henselae, is known to be a self-limited benign process in immunocompetent children. The association with neurologic manifestations is very uncommon especially in patient with no immunologic defects and in cases without specific treatment. A 7 years old male patient, without any immunocompromised defect, presented an atypic presentation of the cat scratch disease. The patient came to the hospital in two opportunities in a status epilepticus, in both cases the diagnosis was encephalitis by Bartonella henselae and the evolution with treatment was monitored with PCR (polymerase chain reaction) in cerebrospinal fluid and blood, as well as IFI (IgM, IgG) serology (indirect immunofluorescence). The patient had a favorable clinical and laboratory evolution for 6 months showing no recurrence of the disease. / This work has been partially supported by the Programa Nacional de Innovacion para la Competitividad y Productividad ´ (Innovate Per ´ u), under the contract 116-PNICP-PIAP-2015.

Rasmussen’s encephalitis is a rare neurological disease first described in 1958 that is characterized by medico-refractory seizures, focal unilateral cerebral inflammation, and deficits such as hemiparesis. While we still do not have a full understanding of this disease, proposed theories behind its etiology include auto-immune manifestations, immune attack by T cells, and malfunctional alterations in genetic expression. It is classically considered a rare childhood malady with a median age of onset of six years, and cases in adolescents and adults are even rarer, representing up to 10% of all cases to date. In this report, we would like to share a rare case of Rasmussen's encephalitis that occurred in an adolescent. Our 17-year-old male patient presented with signs and symptoms beginning at age 14 and was initially diagnosed with cerebral palsy only to later present with additional symptoms and characteristic EEG and MRI findings that ultimately led to a diagnosis of Rasmussen’s encephalitis. Thus, with this case report, our intent is twofold: to shed light on an atypical presentation of an already rare disease, even rarer in adolescents and adults, and to underscore the importance of keeping a broad differential when it comes to evaluating a patient with seizures.

A non-convulsive status epilepticus (ncSE) is a potentially fatal complication for patients in neurointensive care. In patients with aneurysmal subarachnoid hemorrhage (SAH), ncSE remains scarcely investigated. In this study, we aim to investigate the frequency and influence of nonconvulsive status epilepticus on outcome in patients with SAH. We retrospectively analyzed data of consecutive patients with aneurysmal subarachnoid hemorrhage and evaluated clinical, radiological, demographical and electroencephalogram (EEG) data. Outcome was assessed according to the modified Rankin Scale (mRS) at 6 months and stratified into favorable (mRS 0-2) vs. unfavorable (mRS 3-6). We identified 171 patients with SAH, who received EEG between 01/2012 and 12/2020. ncSE was diagnosed in 19 patients (3.7%), only one of whom achieved favorable outcome. The multivariate regression analysis revealed four independent predictors of unfavorable outcome: presence of ncSE (p = 0.003; OR 24.1; 95 CI% 2.9–195.3), poor-grade SAH (p < 0.001; OR 14.0; 95 CI% 8.5–23.1), age (p < 0.001; OR 2.8; 95 CI% 1.6–4.6) and the presence of DIND (p < 0.003; OR 1.9; 95 CI% 1.2–3.1) as independent predictors for unfavorable outcome. According to our study, development of ncSE in patients suffering SAH might correlate with poor prognosis. Even when medical treatment is successful and no EEG abnormalities are detected, the long-term outcome remains poor.

Entre 2 et 5% des enfants de 6 mois à 5 ans présentent au moins un épisode de Crise d’Épilepsie en contexte Fébrile (CEF). Bien que généralement bénignes, ces crises sont associées à un risque d’urgences neurologiques graves et curables dont l’élimination requiert la réalisation d’examens complémentaires douloureux et/ou irradiants. Actuellement, ce risque est évalué en fonction de trois facteurs : l’âge de l’enfant, le caractère simple ou complexe de la crise, et l’examen clinique.Cette thèse avait pour objectif de tester l’hypothèse que parmi les enfants consultant pour une CEF, seuls ceux avec un examen clinique anormal présentent un risque d’urgence neurologique grave et urgent. Pour ce faire, nous avons créé un outil informatique permettant une recherche exhaustive de cas parmi un million de dossiers médicaux informatisés dans sept services d’urgences pédiatriques entre 2007 et 2011. Nous avons alors identifié : les visites d’enfants présentant une CEF. Nous avons ensuite évalué le risque d’urgence neurologique grave et curable associé à ces visites, notamment lorsque l’examen clinique au décours était normal. Nous n’avons retrouvé aucune urgence neurologique grave et curable parmi les enfants consultant pour une CEF avec un examen clinique normal au décours, quels que soient l’âge et les caractéristiques de la crise. Ce travail de thèse associé aux données de la littérature confirme notre hypothèse et souligne la nécessité de recommandations quant à la prise en charge de ces enfants. Enfin, cette thèse constitue l’occasion de mener une réflexion méthodologique quant à l’utilisation de dossiers médicaux informatisés pour la recherche clinique. / Febrile seizures (FS) affect 2% to 5% of children aged 6 months to 5 years of age. Although FS are usually benign, they are associated with serious treatable neurological emergencies. Nowadays, three factors are used to evaluate this risk: the age of the child, whether the FS is simple or complex and the features of the clinical exam. The performance of a lumbar puncture and an emergent neuroimaging are required in order to rule out these emergencies. However, a lumbar puncture is painful and neuroimaging is irradiant. The objective of this thesis was to investigate the hypothesis that among children experiencing a FS, only those with an abnormal clinical exam are at risk of serious, treatable neurological emergencies. We first created an informatics tool in order to exhaustively search for cases among more than one million electronic medical records from seven pediatric emergency departments (PED) between 2007 and 2011. Then, we identified visits of children with a FS. Finally, we evaluated the proportion of serious, treatable neurological emergencies associated with these visits, and more specifically with visits of children with a normal clinical exam.We found no serious treatable neurological emergencies among children visiting the ED for a FS with a normal clinical exam, whatever the age and the features of the seizure were. The studies described in this thesis associated with the available data in the literature support our hypothesis and highlight the need of guidelines regarding the management of these children. Finally, this thesis gives us the opportunity to discuss some considerations on the use of electronic medical records for clinical research.

The content of the thesis is the surrealistic object and its reflection among the czech theorists. The first part of the thesis describes the problematic of surrealistic object and subject-objective relations in surrealism. Breton's philosophical approach is introduced, as well as his concept of object's crisis. The first part also outlines the meaning of found object, concept of convulsive beauty and Dali's paranoic-critical method as a source of surrealistic imagery. The second part of the thesis is focused on the reflection of surrealistic object presentation and on relations between arts and reality according to the concepts of Jan Mukařovský. The third part of the thesis is dedicated to conceptualization of aesthetics of Bohuslav Brouk in the light of surrealism. In this part the scope of Brouk's understanding of subject-objective relations is briefly described, as well his interpretation of surrealistic object.The last part of the thesis outlines the Teige's conception of surrealistic work in the terms of the sources of surrealistic imagination.

Serotonin gilt als Hauptangriffsstelle gängiger Antidepressiva bei schweren Depressionen, wie bspw. selektive Serotonin-Wiederaufnahmehemmer (SSRI), und -Enhancer (SSRE). Es bleibt offen, ob SSRI / E ausschließlich über die Manipulation des Serotoninspiegels wirken, oder ob alternative Signalwege daran beteiligt sind. Ansatzpunkte hierfür sind beispielsweise die neurotrophen Signalwege (spez. Brain derived neurotophic factor, BDNF) oder die Hypothalamus-Hypophysen-Nebennieren- (HPA) – Signalwege des Stressachsensystems. Ebenfalls wurde in Nagetiermodellen beobachtet, dass mit der Dysregulation des zentralen Serotoninsystems bei schweren Depressionen, ein Rückgang der Neurogenese im Gyrus dentatus des Hippocampus einhergeht. Ziel dieser Arbeit war, das Zusammenspiel von Serotonin, BDNF, adulter Neurogenese und der Stressachse zu untersuchen. Zentrum der Studien ist ein Mausmodell, mit einer genetischen Depletion des zentralen Serotonin-synthetisierenden Enzyms Tryptophanhydroxylase 2 (sog. Tph2-/- Mäuse). Es wurden die physiologische Reaktionen auf die Behandlung mit gängigen Antidepressiva abhängig von der Abwesenheit von Serotonin untersucht, um mögliche alternative Signalwege aufzeigen zu können. Die bekannte Zunahme der Neurogenese nach SSRI/SSRE-Behandlung wurde in Wildtyptieren beobachtet, während die Therapie in Tph2-/- Mäusen keine direkte kausale Wirkung zeigte. Im Gegensatz dazu waren die BDNF-Spiegel in depressionsrelevanten Hirnregionen in Tph2-/- Mäusen nach SSRI, signifikant verringert. Auch zeigen die Studien eine neurobiologische Relevanz von Serotonin im ZNS, bei den antidepressiven Mechanismen einer Elektrokonvulsiven Krampftherapie. Ebenfalls deuten erhöhte Neurogeneseraten bei lebenslanger Abwesenheit von Serotonin im ZNS, Therapiemethoden-unabhängig, möglicherweise auf eine modulierte Stressreaktion hin. Untersuchungen der Parameter des HPA-Stressachsensystems, wiesen auf einen grundlegend veränderten Stresshormonspiegel in Tph2-/- Mäusen hin. / Serotonin, the "molecule of happiness" is an important target for antidepressants. The mainly prescribed drugs in major depression are selective serotonin re-uptake inhibitors (SSRI); but recently, SSR-enhancer (SSRE) have also attracted clinical attention. However, only a quarter of patients responds to treatment. It needs to be determined, whether SSRI/E act solely via manipulating serotonin levels or whether other pathways are involved, e.g. neurotrophic signaling (brain-derived neurotrophic factor, BDNF) or the hypothalamus-pituitary-adrenal (HPA)-axis. Furthermore, in major depression, dysregulation of central serotonin signaling is accompanied with a decline in hippocampal neurogenesis, as has been observed in rodent models. At the center of this thesis is a mouse model deficient in the central serotonin-synthesizing enzyme, tryptophan hydroxylase 2 (Tph2-/- mice). I have investigated physiological responses to antidepressant treatment in the absence of brain serotonin, and the possible role of alternative pathways. I observed the typical increase in neurogenesis upon SSRI treatment in WT mice, while it had no effect in Tph2-/- mice. In contrast, BDNF levels were significantly decreased in Tph2-/- mice after treatment with no effect in WT control mice. Furthermore, my results show a critical role of brain serotonin in the neurobiological effects of electroconvulsive seizure. Surprisingly, in animals lacking central serotonin, increased neurogenesis was observed independently of the treatment. The gathered data indicated an altered stress response; therefore, parameters of the HPA-axis have been studied, indicating a downregulated HPA system in Tph2-/-animals in baseline state, but showed no difference in treatment or feedback control. This thesis gives insight into the mechanisms of antidepressant action and reveals ideas for novel pathways involved in the process that could be used as targets in therapeutic approaches and further research in major depression.