Abstracts

Rationale: In recent decades, efforts have been made to uncover the underlying pathogenesis of drug-resistant-epilepsy. For Tuberous Sclerosis Complex (TSC), mutations in two genes (TSC1 and/or TSC2) are responsible for the constitutive activation of the mTOR pathway, leading to the development of lesions in several organ systems. For Focal Cortical Dysplasia IIB (FCD) only very recently, somatic mosaic mutations in multiple genes regulating the mTOR signalling have been identified. Both diseases show white matter deficiencies within epilepsy surgical tissue. However, little is known if seizures and their abnormal electrical activity are responsible for the severe white matter loss, or if the white matter pathology itself is part of the malformative process. Methods: We obtained epilepsy surgery specimens of 22 FCD IIB and 8 TSC patients and compared them to autopsy and biopsy cases. The entire lesional pathology was assessed using digital immunohistochemistry for mTOR (pS6), myelin (MBP, CNPase and MOBP), oligodendroglia (Olig2) and balloon/giant cell (vimentin) markers. Statistical analysis was performed with non-parametric tests using SPSS. Results: The white matter pathology was observed in 50% of FCD IIB and 88% of TSC cases and correlated with lowered amount of myelin producing cells (Olig2: Kendall-Tau-b R=0,366 p=0,002*). Lesional mTOR activation was significantly increased compared to control white matter (Kruskal-Wallis p=0,000*; pairwise comparison with Mann-Whitney-U: control ?" TSC p=0,011* and control ?" FCDIIB p=0,000*). mTOR was mainly expressed in balloon/giant cells and a subset of oligodendroglia. Furthermore, the deficiency within the myelin density highly correlated with raised mTOR activation (Kendall-Tau-b R=-0,345 p=0,003*). Conclusions: Increased mTOR activation might be linked to a decrease in oligodendroglia and myelination of FCD IIB and TSC white matter brain lesions suggesting a possible role for mTOR activation in drug-resistant-epilepsy progression. Funding: The project was supported by the European Union Seventh Framework Programme FP7/2007-2013 under the project EPISTOP (grant agreement n:602391), and the TSC research award 2015 form the German Tuberous Sclerosis Foundation.