Pathogenesis and epileptogenicity in tuberous sclerosis and focal cortical dysplasia

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Two types of epileptogenic foci, cortical tubers of tuberous sclerosis (TS) and lesions of focal cortical dysplasia (FCD), show similar histopathologic findings. Using cerebral tissue materials obtained by surgery or necropsy, we compared the immunopathologic features of TS and FCD. First, the expression of protein products of the genes responsible for TS, hamartin and tuberin, was studied immunohistochemically. In the cortical tubers of TS, immunoreactivities for these proteins were weak in normal sized neurons and glial cells, and moderate in abnormal giant cells. In the FCD lesions, immunoreactivities of normal sized cells were comparable to control tissues, and many abnormal giant cells were strongly positive for tuberin. Next, the expression of proteins regulating neuronal migration, doublecortin and fukutin, was studied. Some abnormal giant cells showed an overdue expression of these fetal proteins, the number of which was larger in TS than in FCD. However, the expression levels were highly variable among patients, lesions and cells, excluding clear distinction between TS and FCD based on immunohistochemical findings alone.Many of the TS-associated tumors in the kidneys and heart result from loss of heterozygosity (LOH) involving either the TSC1 or TSC2 gene. By contrast, previous studies have failed to detect LOH in most cortical tubers. Using a cortical tuber of the Eker rat, an animal model of TS, we examined the Tsc2 gene status of individual cytomegalic neurons, by microdissection and nested PCR. The results indicated the absence of LOH in the cytomegalic neurons, demonstrating that the pathogenesis of corticaltubers is different from that of TS-associated tumors.