Abstracts

Rationale: Despite prominent improvement in seizures following surgical resection of epileptogenic cortical tuber(s) in patients with tuberous sclerosis complex (TSC), the exact location of seizure onset in TSC remains unclear. Several reports have stressed the possible involvement of MRI negative, “normal” perituberal tissue in the generation of recurrent seizures. Most TSC surgical resections include portions of perituberal tissue, and the exact histological margin between tuber and perituberal tissue is not always readily apparent. Methods: To determine the presence of abnormalities that may be related to neuronal hyperexcitability in perituberal tissue, we performed immunohistochemical analysis of MRI normal perituberal samples resected during surgery in TSC patients. All of these perituberal samples were part of the epileptogenic zone based on invasive EEG monitoring. Results: In every sample of perituberal tissue (6/6 cases), there were large cells with an immune phenotype of giant cells in tubers. These cells showed upregulation of vimentin, nestin, S100 beta, alphaB-crystallin, glutamine synthetase, and phosphorylated components of mTOR cascade(4EBP-1, p70S6k, S6). These perituberal giant cells showed minimal expression of GFAP or neuronal markers. Clusters of three to eight giant cells were found in deep layers of gray matter and in subcortical white matter. Perituberal giant cells were consistently surrounded by large, reactive-appearing astrocytes with a high level of GFAP, vimentin and S100 beta immunoreactivity. We term these cellular aggregates “microtubers.” Nearby microglia were not activated. Conclusions: Pathological "microtubers" were found in perituberal epileptogenic tissue in all examined cases of TSC epilepsy. We hypothesize that microtubers could be involved in two pathogenic processes: (1) initiation/propagation of seizure activity and (2) growth of tubers. Additionally, this suggests that optimal surgical management for seizures in TSC may involve resection of perituberal epileptogenic tissue in addition to cortical tubers. The possible presence of microtubers in non-epileptogenic cortical tissue requires further investigation.