Abstracts

Rationale: Tuberous Sclerosis Complex (TSC) is a neurogenetic disorder causing multiorgan dysplastic growths. Neurological complications include seizures, cognitive impairment, and hydrocephalus. Magnetic resonance imaging (MRI) has revealed dysmyelination, subependymal nodules, and giant cell astrocytomas, which lead to ventriculomegaly.   Everolimus, which acts through the mTOR pathway, has been shown to diminish size of TSC-related lesions. Children with TSC offered everolimus are undergoing active CNS myelination and it is important to determine the impact of everolimus on white matter integrity, the extent of which is currently unknown.  Methods: This retrospective observational cohort study analyzed clinically-acquired MRI studies, including diffusion tensor imaging (DTI).  Fractional anisotropy (FA) and mean diffusivity (MD) of the genu of the corpus callosum (GCC) and splenium of the corpus callosum (SCC) in children with TSC started on everolimus and TSC patients not treated with everolimus were compared to those obtained from age- and sex- matched healthy controls over time. Linear mixed effects models were employed to evaluate change in FA and MD over 12 months on serial images.    Results: 24 serial scans of 12 subjects with TSC (6 treated with everolimus[BBL1] ) and 36 serial scans of 18 healthy controls were included. In younger patients (months[BBL2] ), everolimus exposure trended towards improvement in both FA and MD in the SCC, (FA: .19, p = 0.06; MD: -0.19, p = 0.09). Younger patients tended to show more improvement in FA and MD in response to treatment than did those who were older; this effect was significant for MD in the genu of the corpus callosum (-0.31; p = 0.023) and nearly so in the splenium of the corpus callosum (-0.40, p = 0.055) Conclusions: Everolimus exposure, particularly at a younger age, leads to improved white matter integrity in TSC. Prospective study is required to confirm these findings.  Funding: The Children's Hospital of Philadelphia