Tuberous Sclerosis Complex (TSC) is a genetic hamartoma syndrome frequently associated with severe intractable epilepsy. In some TSC patients epilepsy surgery is a promising treatment option provided that the epileptogenic zone can be precisely delineated. TSC brain lesions (cortical tubers) contain dysmorphic neurons, brightly eosinophilic giant cells and white matter alterations in various proportions. However, a histological classification system has not been established for tubers. Therefore, the aim of this study was to define distinct histological patterns within tubers based on semi-automated histological quantification and to find clinically significant correlations. In total, we studied 28 cortical tubers and seven samples of perituberal cortex from 28 TSC patients who had undergone epilepsy surgery. We assessed mammalian target of rapamycin complex 1 (mTORC1) activation, the numbers of giant cells, dysmorphic neurons, neurons, and oligodendrocytes, and calcification, gliosis, angiogenesis, inflammation, and myelin content. Three distinct histological profiles emerged based on the proportion of calcifications, dysmorphic neurons and giant cells designated types A, B, and C. In the latter two types we were able to subsequently associate them with specific features on presurgical MRI. Therefore, these histopathological patterns provide consistent criteria for improved definition of the clinico-pathological features of cortical tubers identified by MRI and provide a basis for further exploration of the functional and molecular features of cortical tubers in TSC.

Department of Clinical Genetics Erasmus MC Rotterdam The Netherlands

Department of Neurosurgery Medical University Vienna Vienna Austria

Department of Pathology Academic Medical Center Amsterdam The Netherlands

Department of Pathology and Molecular Medicine Charles University 2nd Medical School Motol University Hospital Prague Czech Republic

Department of Pathology University Medical Center Utrecht Utrecht The Netherlands

Department of Pediatric Neurology Brain Center Rudolf Magnus University Medical Center Utrecht Utrecht The Netherlands

Department of Pediatric Neurology Charles University 2nd Medical School Motol University Hospital Prague Czech Republic

Department of Pediatrics Medical University Vienna Vienna Austria

Department of Radiology Medical University Vienna Vienna Austria

Institute of Neurology Medical University Vienna Vienna Austria

Shriners Hospital Pediatric Research Center and Department of Neurology Temple University Philadelphia United States of America

Stichting voor Epilepsie in Nederland Hemstede The Netherlands

Swammerdam Institute for Life Sciences Center for Neuroscience University of Amsterdam Amsterdam The Netherlands

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