Перинатальный артериальный ишемический инсульт - это цереброваскулярное заболевание, возникающее между 20-й неделей беременности и 28-м послеродовым днем, вызывающее двигательный и немоторный дефицит, причем церебральный паралич является частым исходом. Молодой мозг реагирует, реорганизуя свои поврежденные сети в ипсилезионное и/или контральезионное полушария, причем последнее больше связано с двигательными нарушениями. Префронтальная кора считается одной из наиболее уязвимых областей с когнитивным дефицитом, возникающим с задержкой, из-за ее длительного развития, достигающего своего пика синаптогенеза после первого послеродового года, в то время как другие области, такие как первичная кора, обычно проходят свою основную фазу синаптогенеза в течение первого послеродового семестра. Таким образом, раннее обнаружение низкого синаптогенеза может быть ранним признаком настоящего или предстоящего дефицита и привести к раннему вмешательству. Бета-диапазон недавно был предложен в качестве возможного биомаркера синаптогенеза, причем активность ГАМК связана с нейропластичностью и синаптогенезом. Основной целью настоящего исследования является установление роли абсолютной бета-1 мощности в синаптогенезе и исследование уязвимости префронтальной коры головного мозга. Были набраны сорок типичных детей и 10 детей с перинатальным артериальным ишемическим инсультом в их подкорковой средней мозговой артерии и были созданы 3 возрастные подгруппы: 5-месячная, 10-месячная и 24-месячная подгруппы. Запись ЭЭГ и тест Бейли-III использовались для измерения их фоновой активности и уровня развития. Хотя статистический анализ с помощью непараметрических инструментов (U-тест Манна-Уитни, тест Крускалла Уоллиса) не показал решающих результатов, потенциальная связь бета-диапазона с синаптогенезом может быть обнаружена при наблюдении низкой мощности бета-1 в моторных и когнитивных областях мозга и низкой моторной и когнитивной производительности, а также при обнаружении заднего или переднего созревания. Кроме того, ранняя уязвимость префронтальной коры может быть обнаружена в снижении двусторонней бета-1 мощности у 24-месячных детей с перинатальным инсультом, по сравнению с типичными детьми и более ранними односторонними различиями, наряду с некоторыми когнитивными дефицитами, которые начинают проявляться в той же группе. / Perinatal Arterial Ischemic Stroke is a cerebrovascular disease occurring between the 20th gestational week and the 28th postnatal day, causing motor and non-motor deficits with cerebral palsy being a frequent outcome. The young brain reacts by reorganizing its injured networks to ipsilesional and/or contralesional hemisphere with the latter relating more to motor impairment. The Prefrontal Cortex is considered one of the most vulnerable areas with cognitive deficits emerging with a delay, due to its lengthy development reaching its synaptogenesis peak after the first postnatal year, while other areas, such as the Primary Cortices undergo generally their major synaptogenesis phase during the first postnatal semester. So early detection of low synaptogenesis could be an early mark of present or upcoming deficits and lead to an early intervention. Beta band has been recently suggested as a possible biomarker of synaptogenesis with GABA’s activity being connected with neuroplasticity and synaptogenesis. The main goal of the current study is to establish the role of of the absolute beta-1 power to synaptogenesis and the investigate the vulnerability of the Prefrontal Cortex. Fourty typical children and 10 children with Perinatal Arterial Ischemic Stroke in their subcortical Middle Cerebral Artery were recruited and were created 3 age subgroups; 5month, 10month and 24month subgroup. EEG recording and Bayley-III test were used to measure their background activity and developmental level. Although the statistical analysis via non-parametric tools (Mann-Whitney U-test, Kruskall Wallis test) didn’t show decisive results, a potential connection of beta-band with synaptogenesis could be detected when observing low beta-1 power in motor and cognitive brain areas and low motor and cognitive performance and also by detecting a posterior to anterior maturation. Moreover the early vulnerability of Prefrontal Cortex may be found in the decreased bilateral beta-1 power in the 24month children with perinatal stroke, when compared with the typical children and the earlier unilateral differences, along with some cognitive deficits which begin to emerge in the same group.

No description available.

No description available.

La thrombolyse intraveineuse (TIV) est le seul traitement médical autorisé à la phase aiguë de l’infarctus cérébral (IC). Malgré ce traitement, un patient sur deux présente un mauvais pronostic fonctionnel à 3 mois (score mRS>2), ce qui s’explique le plus souvent par l’absence de recanalisation précoce ou la survenue d’une hémorragie intracrânienne symptomatique (sICH). Nos objectifs étaient, d’une part, de déterminer s’il est possible d’estimer le pronostic fonctionnel (mRS) 3 mois après TIV à partir de variables cliniques et IRM disponibles à l’admission, et, d’autre part, d’étudier les relations entre l’évolution au cours des premières 24 heures et le mRS à 3 mois. Nous avons collecté les données cliniques et d’IRM de l’ensemble des patients traités par TIV pour un IC≤4h30 entre 2003 et 2015 à l’hôpital Sainte-Anne. (1) Nous avons proposé le score MRI-DRAGON, un outil simple basé sur 7 variables cliniques et IRM disponibles à l’admission, qui permet une prédiction satisfaisante du mRS>2. 3 mois après un IC traité par TIV (c=0,83 [0,78-0,88]). (2) Nous avons ensuite réalisé une validation externe de ce score sur la cohorte du CHRU de Lille, confirmant qu’il présente une discrimination et une calibration satisfaisantes, malgré une surestimation du risque de mRS>2 en cas de score MRI-DRAGON élevé. (3) Afin d’essayer d’améliorer la prédiction, nous avons étudié les relations entre microsaignements (CMBs) sur l’IRM initiale et pronostic fonctionnel, et montré que le nombre de CMBs n’était pas un prédicteur indépendant du mRS à 3 mois, après ajustement sur les facteurs de confusion (âge, HTA). Nous avons par ailleurs étudié les relations entre l’évolution clinique très précoce après TIV et mRS à 3 mois, à partir de deux situations: (4) Premièrement, l’absence d’amélioration neurologique 1 heure après le début de la TIV en cas d’occlusion artérielle proximale, présente chez 77% des patients et fortement associée au mRS à 3 mois, mais qui n’améliorait pas la prédiction par rapport au score MRI-DRAGON. (5) Deuxièmement, l’aggravation neurologique survenant dans les 24 heures après le début de la TIV (END), dont l’incidence au sein de notre revue systématique était de 14%. (6) Au sein de notre cohorte, la valeur prédictive positive de l’END pour le mRS>2 à 3 mois était de 90%. L’END de cause indéterminée représentait 70% des END, et était associé à l’absence d’antiplaquettaire avant l’admission, la présence d’une occlusion artérielle proximale, d’un important mismatch diffusion-perfusion, et l’absence de recanalisation. Nous avons proposé un score simple permettant de prédire dès l’admission le pronostic fonctionnel à 3 mois d’un patient traité par TIV pour IC aigu. Il pourrait être utilisé pour guider la décision thérapeutique en identifiant les patients ayant une forte probabilité de mRS ≤2 après TIV seule. Par ailleurs, notre travail suggère que la prise en compte des CMBs avant TIV ne permet pas d’améliorer la prédiction pronostique, et que l’association entre CMBs et mRS n’est pas indépendante. Nous participons actuellement à une méta-analyse internationale sur données individuelles visant à déterminer si un sous-groupe de patients avec CMBs présente un risque de sICH si important qu’il pourrait annuler le bénéfice attendu de la TIV. Bien que l’absence d’amélioration neurologique à 1 heure soit fortement associée au mRS>2 à 3 mois, elle ne semble pas être un outil suffisamment robuste pour guider la décision d’une thrombectomie complémentaire à la TIV (bridging therapy), et ne doit donc pas retarder le geste endovasculaire. Enfin, nos résultats suggèrent que la majorité des END sont favorisés par la persistance d’une hypoperfusion cérébrale, et qu’une part d’entre eux pourrait être prochainement évitée, depuis la démonstration fin 2014, de la nette supériorité du bridging therapy par rapport à la TIV seule concernant la recanalisation artérielle. (...) / Intravenous thrombolysis (IVT) is the only licensed drug for acute ischemic stroke (AIS). However, about half of the treated patients do not achieve functional independence at 3 months (mRS>2), mostly due to lack of early recanalization or symptomatic intracranial hemorrhage (sICH). Firstly, we aimed to determine if 3-month outcome (mRS) after IVT can be reliably predicted based on clinical and MRI variables available at admission. Secondly, we assessed the relationships between the clinical course within 24 hours after IVT and 3-month mRS. We collected clinical and MRI data of all patients treated by IVT ≤4.5 hrs for AIS between 2003 and 2015 in Sainte-Anne hospital, Paris. (1) We derived the MRI-DRAGON score, a simple tool consisting of 7 clinical and MRI variables available at admission, which can reliably predict 3-month mRS>2 (c-statistic=0.83 [0.78-0.88]). (2) We then performed an external validation of this score in the Lille cohort, showing good discrimination and calibration of the model, despite an overestimation of the risk of mRS>2 in patients with a high MRI-DRAGON score. (3) Trying to find additional predictors of long-term outcome, we showed that the cerebral microbleed (CMB) burden at baseline was not an independent predictor of 3-month mRS after adjusting for confounding factors (age and hypertension).Furthermore, we assessed the relationships between early clinical course after IVT and 3-month mRS, based on two common clinical events: (4) Firstly, the lack of very early neurological improvement (VENI) 1 hour after IVT, which was observed in 77% patients and strongly associated with 3-month mRS, but did not improve the predictive ability of the model when incorporated into the MRI-DRAGON score. (5) Secondly, early neurological deterioration (END) within 24 hours after IVT, occuring in 14% patients in our systematic review and meta-analysis. (6) In our cohort, the positive predictive value of END for 3-month mRS>2 prediction was 90%. END of undetermined cause (ENDunexplained) accounted for 70% of ENDs, and was associated with no prior use of antiplatelets, proximal artery occlusion, DWI-PWI mismatch volume and lack of recanalization. We proposed a simple score to predict 3-month mRS soon after admission in patients treated by IVT for AIS. It may be used to help therapeutic decisions, by identifying patients likely to achieve 3-month mRS ≤2 after IVT alone. We have also shown that CMB burden before IVT is not an independent predictor or 3-month outcome. We participate in an ongoing international individual patient data meta-analysis to determine whether there is a subgroup of patients with CMBs, which seems to have an independent risk of poor 3-month outcome so important that it might outweigh the expected benefit of IVT. Although lack of VENI 1 hour after IVT is strongly associated with 3-month mRS>2, it doesn’t seem to be specific enough to guide decision-making regarding additional thrombectomy (bridging therapy), and should therefore not delay an endovascular procedure. Finally, our results suggest that a persistent cerebral hypoperfusion contributes to most ENDs. Therefore, many ENDs might be avoided in a near future, given the recent proof of the clear superiority of bridging therapy over IVT alone regarding recanalization. This revolution in acute stroke management leads the way to important clinical research perspectives, such as developing a tool to accurately predict 3-month mRS after bridging therapy. Important research efforts will be needed to develop a personalized treatment algorithm, helping to determine which therapeutic option (bridging therapy, IVT alone, thrombectomy alone, or no recanalization therapy) would be the best for each patient.

This thesis deals with a part of the treatment process in patients with acute ischemic stroke. Specifically, it examines the time interval from patient entry to a healthcare facility to initiation of treatment with intravenous thrombolysis - so called Door-to- Needle Time. The theoretical part describes the stroke and its division according to etiology. Furthermore, there are summarized clinical studies that have taken place in the world since the 1960s to the present, the development of care for patients with stroke in Czech Republic, recommended procedures of professional organizations in Czech Republic and the identification and management of treatment of stroke patients. In conclusion, the theoretical part summarizes the studies focused on the reduction of the Door-to-Needle Time, which took place in the world and in the Czech Republic. The aim of the practical part is to evaluate work procedures and conditions of health teams of individual stroke centers and to identify causes of Door-to-Needle Time median differences. The chosen method of research is a quantitative questionnaire survey in the form of an online Google Forms questionnaire sent to the leading members of these teams. Based on the research results, factors affecting reduction of Door-to-Needle Time median consists in to deepen and...

As técnicas de processamento digital de imagens têm sido vastamente aplicadas às imagens médicas. Um dos benefícios ocasionado por estas ferramentas é o de prover medidas de parâmetros que são difíceis de estimar e suscetíveis a viés do médico. O presente trabalho teve por objetivo desenvolver um software semi-automático de segmentação das áreas isquêmicas, core e penumbra, no acidente vascular cerebral, utilizando técnicas de segmentação por limiarização e baseada em regiões. Os dois algoritmos de segmentação (estatística local e limiarização) foram aplicados aos mapas de perfusão, calculados em um software separado, o stroketool-ct (Wittsack, University of Duesseldorf, Alemanha). Este software dispõe de três métodos de cálculo dos mapas, a partir das imagens de tomografia computadorizada de perfusão, que diferem no modelo matemático utilizado. O software aqui desenvolvido funciona como um módulo do stroketool-ct, não tendo acesso ao código fonte, apenas às estruturas de dados. O algoritmo de estatística local funciona através da expansão de uma amostra selecionada pelo usuário, na região isquêmica de interesse. Os resultados obtidos pelo algoritmo de estatística local foram comparados, através de um algoritmo de quantificação, com o padrão ouro, que consistiu na segmentação manual das regiões isquêmicas realizada pelo médico especialista. Respeitando as limitações pertinentes à técnica aplicada, os resultados obtidos pelo software de segmentação se mostraram satisfatórios. O algoritmo de limiarização utiliza os limiares fisiológicos de perfusão sangüínea estabelecidos na literatura para distinguir as áreas isquêmicas. A confiabilidade da segmentação reside no método específico de cálculo dos mapas de perfusão adotado. Além disso, os algoritmos fizeram o display dos resultados da segmentação em menos de 5 minutos em um computador pessoal, um tempo de espera razoável para o especialista que pode utilizar o resultado da segmentação do algoritmo para a tomada de decisão sobre a aplicação de terapia trombolítica / The techniques of digital image processing have been widely applied to medical imaging. One of the benefits brought about by these tools is to provide measurements of parameters that are difficult to estimate and likely to bias the physician. This study aimed to develop semi-automatic software of segmentation of the ischemic areas, core and penumbra in stroke, using techniques of thresholding and segmentation based on regions. The two segmentation algorithms (thresholding and local statistics) were applied to the perfusion maps that are calculated in a separate software, the stroketool-ct (Wittsack, University of Duesseldorf, Germany). This package provides three methods of calculation of maps, from images of perfusion computer tomography, which differ in the mathematical model used. The software developed here serves as a module stroketool-ct, not having access to source code, only the data structures. The statistical algorithm expands from a sample selected by the user, in the ischemic region of interest. The results obtained by the local statistical algorithm were compared by an algorithm of quantification with the gold standard, which is the manual segmentation of ischemic regions performed by the specialist. In spite of the limitations inherent to the technique applied, the results obtained by the local statistic algorithm were satisfactory. The thresholding algorithm uses the physiological perfusion thresholds established in the literature to distinguish the ischemic areas. The reliability of the segmentation obtained by thresholding algorithm resides on the specific method for the calculation of the perfusion maps that were adopted. Moreover, the algorithms provided the display of the segmentation results in less than 5 minutes in a standard computer, a reasonable waiting time for the specialist who can use the feedback to make the decision of whether applying the thrombolytic therapy

Nach einer Läsion im Gehirn kommt es trotz der Bildung autoreaktiver T-Zellen zu keiner autoimmunen Neuropathologie. Foxp3+ regulatorische T-Zellen (Tregs) vermitteln möglicherweise Immuntoleranz nach zerebraler Läsion. Deswegen wurde in dieser Studie die Rolle der Tregs 7, 14 und 30 Tage nach einem transienten Verschluss der mittleren Hirnarterie (MCAO), einem Modell für ischämischen Schlaganfall, und nach entorhinaler Kortexläsion (ECL) in der Maus untersucht. Durchflusszytometrisch wurde in beiden Modellen 14 und 30 Tage nach Läsion eine Akkumulation der Tregs in der ipsilateralen Hemisphäre beobachtet. Mikroskopisch wurden an der Läsion Zellkontakte der Tregs mit antigenpräsentierenden Zellen beobachtet. Weitere Experimente wurden ausschließlich nach MCAO durchgeführt. Am Tag 14 und 30 war in der ipsilateralen Hemisphäre eine Akkumulation der Mikroglia zu beobachten. Makrophagen und dendritische Zellen wurden an den Tagen 7, 14 und 30 detektiert. Am Tag 7 und 14 waren ipsilateral im Gehirn ca. 60 % der Tregs positiv für den Proliferationsmarker Ki-67. In zwei Versuchsansätzen wurden naive CD45RBhigh/CD4+ Zellen aus lymphatischen Organen von Foxp3EGFP Mäusen, mit Wildtyp T-Zellrezeptor (TCR), oder 2D2.Foxp3EGFP Mäusen, mit TCR spezifisch gegen Myelin-Oligodendrozyten-Glykoprotein, isoliert. Die Zellen wurden einen Tag vor MCAO in RAG1-/- Mäuse, welche keine adulten T- und B-Zellen besitzen, transferiert. Am Tag 14 nach MCAO war in den RAG1-/- Mäusen keine de novo Induktion Foxp3EGFP+ Tregs zu beobachten. CD25+ Tregs wurden durch die Injektion eines Antikörpers gegen CD25 depletiert, um deren Wirkung nach MCAO zu untersuchen. Nach Depletion konnte bis zu 27 Tage nach MCAO keine Veränderung des Läsionsvolumen und des Gangverhaltens beobachtet werden. In dieser Studie wurde im Gehirn eine späte Präsenz und Proliferation Foxp3+ Tregs nach Läsion nachgewiesen. Mikroglia und periphere Immunzellen sind langfristig an Immunvorgängen im lädierten Gehirn beteiligt. / After brain lesion autoreactive T cells specific against brain antigens are expanded, but no delayed autoimmune neuropathology evolves. Immune suppressive CD4+/Foxp3+ regulatory T cells (Tregs) could have an important role in maintaining immune tolerance in the lesioned brain. Therefore, this study sought to analyse the role of Tregs in mice 7, 14 and 30 days after transient middle cerebral artery occlusion (MCAO), a model for ischemic stroke, and entorhinal cortex lesion (ECL). An accumulation of Tregs was detected in the brain by flow cytometry in both models at days 14 and 30 after lesion. Using immunohistochemistry Tregs were found in close cell-cell contact with antigen presenting cells at the lesion site. Further experiments were performed solely with MCAO. On days 14 and 30 after MCAO a strong accumulation of microglia occurred in the ipsilesional hemisphere. Macrophages and dendritic cells were found ipsilesionally on days 7, 14 and 30. On days 7 and 14 about 60% of Tregs were positive for the proliferation marker Ki-67 in the lesioned hemisphere. In two different setups naïve CD45RBhigh/CD4+ cells were isolated from lymphatic organs of Foxp3EGFP mice, carrying a wild type T cell receptor (TCR), or 2D2.Foxp3EGFP mice, carrying a TCR specific for myelin oligodendrocyte glycoprotein. One day before MCAO naïve CD45RBhigh/CD4+ cells depleted of Foxp3EGFP+ Tregs were transferred into RAG1-/- mice, which lack adult B and T cells. At day 14 after MCAO no de novo generation of Foxp3EGFP+ Tregs was observed. The effects of Tregs on stroke outcome were tested by depleting CD25+/Foxp3EGFP+ Tregs with an antibody against CD25. After depletion no effects on lesion volumes and gait parameters were detected up to 27 days following MCAO. The present study demonstrates for the first time a sustained presence and proliferation of Tregs in the lesioned brain. Local microglia and peripheral immune cells are involved in long-lasting immune processes following brain lesion.

La thrombolyse intraveineuse (TIV) est le seul traitement médical autorisé à la phase aiguë de l’infarctus cérébral (IC). Malgré ce traitement, un patient sur deux présente un mauvais pronostic fonctionnel à 3 mois (score mRS>2), ce qui s’explique le plus souvent par l’absence de recanalisation précoce ou la survenue d’une hémorragie intracrânienne symptomatique (sICH). Nos objectifs étaient, d’une part, de déterminer s’il est possible d’estimer le pronostic fonctionnel (mRS) 3 mois après TIV à partir de variables cliniques et IRM disponibles à l’admission, et, d’autre part, d’étudier les relations entre l’évolution au cours des premières 24 heures et le mRS à 3 mois. Nous avons collecté les données cliniques et d’IRM de l’ensemble des patients traités par TIV pour un IC≤4h30 entre 2003 et 2015 à l’hôpital Sainte-Anne. (1) Nous avons proposé le score MRI-DRAGON, un outil simple basé sur 7 variables cliniques et IRM disponibles à l’admission, qui permet une prédiction satisfaisante du mRS>2. 3 mois après un IC traité par TIV (c=0,83 [0,78-0,88]). (2) Nous avons ensuite réalisé une validation externe de ce score sur la cohorte du CHRU de Lille, confirmant qu’il présente une discrimination et une calibration satisfaisantes, malgré une surestimation du risque de mRS>2 en cas de score MRI-DRAGON élevé. (3) Afin d’essayer d’améliorer la prédiction, nous avons étudié les relations entre microsaignements (CMBs) sur l’IRM initiale et pronostic fonctionnel, et montré que le nombre de CMBs n’était pas un prédicteur indépendant du mRS à 3 mois, après ajustement sur les facteurs de confusion (âge, HTA). Nous avons par ailleurs étudié les relations entre l’évolution clinique très précoce après TIV et mRS à 3 mois, à partir de deux situations: (4) Premièrement, l’absence d’amélioration neurologique 1 heure après le début de la TIV en cas d’occlusion artérielle proximale, présente chez 77% des patients et fortement associée au mRS à 3 mois, mais qui n’améliorait pas la prédiction par rapport au score MRI-DRAGON. (5) Deuxièmement, l’aggravation neurologique survenant dans les 24 heures après le début de la TIV (END), dont l’incidence au sein de notre revue systématique était de 14%. (6) Au sein de notre cohorte, la valeur prédictive positive de l’END pour le mRS>2 à 3 mois était de 90%. L’END de cause indéterminée représentait 70% des END, et était associé à l’absence d’antiplaquettaire avant l’admission, la présence d’une occlusion artérielle proximale, d’un important mismatch diffusion-perfusion, et l’absence de recanalisation. Nous avons proposé un score simple permettant de prédire dès l’admission le pronostic fonctionnel à 3 mois d’un patient traité par TIV pour IC aigu. Il pourrait être utilisé pour guider la décision thérapeutique en identifiant les patients ayant une forte probabilité de mRS ≤2 après TIV seule. Par ailleurs, notre travail suggère que la prise en compte des CMBs avant TIV ne permet pas d’améliorer la prédiction pronostique, et que l’association entre CMBs et mRS n’est pas indépendante. Nous participons actuellement à une méta-analyse internationale sur données individuelles visant à déterminer si un sous-groupe de patients avec CMBs présente un risque de sICH si important qu’il pourrait annuler le bénéfice attendu de la TIV. Bien que l’absence d’amélioration neurologique à 1 heure soit fortement associée au mRS>2 à 3 mois, elle ne semble pas être un outil suffisamment robuste pour guider la décision d’une thrombectomie complémentaire à la TIV (bridging therapy), et ne doit donc pas retarder le geste endovasculaire. Enfin, nos résultats suggèrent que la majorité des END sont favorisés par la persistance d’une hypoperfusion cérébrale, et qu’une part d’entre eux pourrait être prochainement évitée, depuis la démonstration fin 2014, de la nette supériorité du bridging therapy par rapport à la TIV seule concernant la recanalisation artérielle. (...) / Intravenous thrombolysis (IVT) is the only licensed drug for acute ischemic stroke (AIS). However, about half of the treated patients do not achieve functional independence at 3 months (mRS>2), mostly due to lack of early recanalization or symptomatic intracranial hemorrhage (sICH). Firstly, we aimed to determine if 3-month outcome (mRS) after IVT can be reliably predicted based on clinical and MRI variables available at admission. Secondly, we assessed the relationships between the clinical course within 24 hours after IVT and 3-month mRS. We collected clinical and MRI data of all patients treated by IVT ≤4.5 hrs for AIS between 2003 and 2015 in Sainte-Anne hospital, Paris. (1) We derived the MRI-DRAGON score, a simple tool consisting of 7 clinical and MRI variables available at admission, which can reliably predict 3-month mRS>2 (c-statistic=0.83 [0.78-0.88]). (2) We then performed an external validation of this score in the Lille cohort, showing good discrimination and calibration of the model, despite an overestimation of the risk of mRS>2 in patients with a high MRI-DRAGON score. (3) Trying to find additional predictors of long-term outcome, we showed that the cerebral microbleed (CMB) burden at baseline was not an independent predictor of 3-month mRS after adjusting for confounding factors (age and hypertension).Furthermore, we assessed the relationships between early clinical course after IVT and 3-month mRS, based on two common clinical events: (4) Firstly, the lack of very early neurological improvement (VENI) 1 hour after IVT, which was observed in 77% patients and strongly associated with 3-month mRS, but did not improve the predictive ability of the model when incorporated into the MRI-DRAGON score. (5) Secondly, early neurological deterioration (END) within 24 hours after IVT, occuring in 14% patients in our systematic review and meta-analysis. (6) In our cohort, the positive predictive value of END for 3-month mRS>2 prediction was 90%. END of undetermined cause (ENDunexplained) accounted for 70% of ENDs, and was associated with no prior use of antiplatelets, proximal artery occlusion, DWI-PWI mismatch volume and lack of recanalization. We proposed a simple score to predict 3-month mRS soon after admission in patients treated by IVT for AIS. It may be used to help therapeutic decisions, by identifying patients likely to achieve 3-month mRS ≤2 after IVT alone. We have also shown that CMB burden before IVT is not an independent predictor or 3-month outcome. We participate in an ongoing international individual patient data meta-analysis to determine whether there is a subgroup of patients with CMBs, which seems to have an independent risk of poor 3-month outcome so important that it might outweigh the expected benefit of IVT. Although lack of VENI 1 hour after IVT is strongly associated with 3-month mRS>2, it doesn’t seem to be specific enough to guide decision-making regarding additional thrombectomy (bridging therapy), and should therefore not delay an endovascular procedure. Finally, our results suggest that a persistent cerebral hypoperfusion contributes to most ENDs. Therefore, many ENDs might be avoided in a near future, given the recent proof of the clear superiority of bridging therapy over IVT alone regarding recanalization. This revolution in acute stroke management leads the way to important clinical research perspectives, such as developing a tool to accurately predict 3-month mRS after bridging therapy. Important research efforts will be needed to develop a personalized treatment algorithm, helping to determine which therapeutic option (bridging therapy, IVT alone, thrombectomy alone, or no recanalization therapy) would be the best for each patient.

In unseren Studien haben wir uns unter Verwendung von in vitro und in vivo Modellen des neuronalen Zelltodes mit verschiedenen neuroprotektiven Mechanismen beschäftigt. Uns interessierten Faktoren aus drei verschiedenen Komplexen, die an zellulärer Vitalität teilhaben. Im Mittelpunkt unserer Untersuchung stand ein antioxidatives Enzym und dessen Rolle bezüglich des neuronalen Zelltodes - die NAD(P)H-Quinonoxidoreduktase1. In den Sudien haben wir die Aktivität, Expression und die Lokalisation dieses Enzyms nach neuronalem Schaden untersucht. Wir konnten zeigen, dass die Quinonoxidoreduktase den neuronalen Schaden exazerbieren kann. Ein anderer Schwerpunkt unserer Arbeit bildete das Steroidhormon 17-beta-Estradiol und sein neuroprotektiver Einfluss auf neurodegenerative Prozesse. Wir deckten verschiedene Expressionen der beiden Estradiolrezeptoren alpha und beta in kortikalen, septalen und hippokampalen Nervenzellen auf und das daraus folgende unterschiedliche neuroprotektive Potenzial des Hormons. Im dritten Teil der Studien konnten wir den Einfluss des zytoskelettmodulierenden Proteins Gelsolin auf die Progression des neuronalen Zelltodes nach zellulärem Schaden charakterisieren. / In our studies we characterized different neuroprotective mechanism by in vitro and in vivo models of neuronal cell death. We were interested in factors of three different complexes wich play a role in cellulare vitality. In the centre of our studies there was an antioxidative enzyme and his role in the neuronal cell death-the NAD(P)H:quinone oxidoreductase1. We have investigated in the activity, expression and localisation of this enzyme after neuronal damage. We could show that this enzyme can exacerbate neuronal cell death. Another point of our work were the steroid hormon 17-beta-Estradiol and the neuroprotective character in neurodegeneration. We discovered different expression of the two estradiol- receptors alpha and beta in brain caused in different protective potential to cortical, septal and hippocampal structures by the hormon. The cytoskeletal structures modulate by the protein gelsolin was the third part of the studies. We could show that the modulation of the cytoskeleton were involved in the progression of neuronal cell death after cellulare damage.

As técnicas de processamento digital de imagens têm sido vastamente aplicadas às imagens médicas. Um dos benefícios ocasionado por estas ferramentas é o de prover medidas de parâmetros que são difíceis de estimar e suscetíveis a viés do médico. O presente trabalho teve por objetivo desenvolver um software semi-automático de segmentação das áreas isquêmicas, core e penumbra, no acidente vascular cerebral, utilizando técnicas de segmentação por limiarização e baseada em regiões. Os dois algoritmos de segmentação (estatística local e limiarização) foram aplicados aos mapas de perfusão, calculados em um software separado, o stroketool-ct (Wittsack, University of Duesseldorf, Alemanha). Este software dispõe de três métodos de cálculo dos mapas, a partir das imagens de tomografia computadorizada de perfusão, que diferem no modelo matemático utilizado. O software aqui desenvolvido funciona como um módulo do stroketool-ct, não tendo acesso ao código fonte, apenas às estruturas de dados. O algoritmo de estatística local funciona através da expansão de uma amostra selecionada pelo usuário, na região isquêmica de interesse. Os resultados obtidos pelo algoritmo de estatística local foram comparados, através de um algoritmo de quantificação, com o padrão ouro, que consistiu na segmentação manual das regiões isquêmicas realizada pelo médico especialista. Respeitando as limitações pertinentes à técnica aplicada, os resultados obtidos pelo software de segmentação se mostraram satisfatórios. O algoritmo de limiarização utiliza os limiares fisiológicos de perfusão sangüínea estabelecidos na literatura para distinguir as áreas isquêmicas. A confiabilidade da segmentação reside no método específico de cálculo dos mapas de perfusão adotado. Além disso, os algoritmos fizeram o display dos resultados da segmentação em menos de 5 minutos em um computador pessoal, um tempo de espera razoável para o especialista que pode utilizar o resultado da segmentação do algoritmo para a tomada de decisão sobre a aplicação de terapia trombolítica / The techniques of digital image processing have been widely applied to medical imaging. One of the benefits brought about by these tools is to provide measurements of parameters that are difficult to estimate and likely to bias the physician. This study aimed to develop semi-automatic software of segmentation of the ischemic areas, core and penumbra in stroke, using techniques of thresholding and segmentation based on regions. The two segmentation algorithms (thresholding and local statistics) were applied to the perfusion maps that are calculated in a separate software, the stroketool-ct (Wittsack, University of Duesseldorf, Germany). This package provides three methods of calculation of maps, from images of perfusion computer tomography, which differ in the mathematical model used. The software developed here serves as a module stroketool-ct, not having access to source code, only the data structures. The statistical algorithm expands from a sample selected by the user, in the ischemic region of interest. The results obtained by the local statistical algorithm were compared by an algorithm of quantification with the gold standard, which is the manual segmentation of ischemic regions performed by the specialist. In spite of the limitations inherent to the technique applied, the results obtained by the local statistic algorithm were satisfactory. The thresholding algorithm uses the physiological perfusion thresholds established in the literature to distinguish the ischemic areas. The reliability of the segmentation obtained by thresholding algorithm resides on the specific method for the calculation of the perfusion maps that were adopted. Moreover, the algorithms provided the display of the segmentation results in less than 5 minutes in a standard computer, a reasonable waiting time for the specialist who can use the feedback to make the decision of whether applying the thrombolytic therapy