Characterization of Tuberous Sclerosis´ (TSC) brain lesions

Tuberous sclerosis complex (TSC) is a genetic disease leading to distinct manifestation in kidney, heart, skin, lung and brain. However, the brain is affected in over 90% of the cases thus resulting in hard-to-control epilepsy and mental retardation. In some cases respective epilepsy surgery can be offered. However, the issues of TSC brain lesions, genetics and phenotype have not yet been addressed. We will define the specific histopathological features of cortical tubers resected during epilepsy surgery and collected at autopsy, with both histological and immunocytochemical analysis. When available, the neocortex (defined on imaging as perituberal, but considered part of the epileptogenic zone) will also be examined. We will generate a classification system, based on selected histopathological features that will allow the definition of tuber types (as in the classification system recently developed for Focal Cortical Dysplasia (FCD)). It is important to provide consistent objective criteria for the tuber variants that can be easily translated between laboratories, with the minimum number of special stains required, and that are reproducible between neuropathologists. The next objective is to relate the different defined subtypes to clinical and identify neuroimaging characteristics, as well as to the expression level and celluar distribution of potential biomarkers and molecular targets for antiepileptogenesis therapy. To determine whether the presence of specific tuber types correlates with TSC genotype, with seizure severity (including a history of infantile spasms), neuroimaging features and, with the surgical/neurodevelopmental outcome (surgical cases), both a retrospective analysis (of the patients who already underwent epilepsy surgery) and a prospective study will be performed.

Tuberous sclerosis complex (TSC) is a genetic disease leading to distinct manifestation in kidney, heart, skin, lung and brain. However, the brain is affected in over 90% of the cases thus resulting in hard-to-control epilepsy and mental retardation. In some cases respective epilepsy surgery can be offered. However, the issues of TSC brain lesions have not yet been addressed. Within this project, we were able to define the features of cortical tubers resected during epilepsy surgery. We were able to establish a three-tiered classification system to divide cortical tubers into the groups A-B-C. It was possible to relate these groups to specific features on presurgical imaging. Because of that it might be relevant in a near future to predict post-surgical outcome of these patients before the actual resection. Additionally, we looked at formation of cortical tubers compared to other malformations of cortical development, such as Focal Cortical Dysplasia. We were able to detect impaired maturation of the late stages of brain development also involving the white matter tracts. Furthermore, we explored the effects of inflammation in these lesions. In summary, we evaluated with this project several aspects of epilepsy and seizure development in the context of malformations of the brain in order to serve as potential biomarkers to support treatment management in these patients.