TY - JOUR
T1 - Everolimus alters white matter diffusion in tuberous sclerosis complex
AU - Tillema, Jan Mendelt
AU - Leach, James L.
AU - Krueger, Darcy A.
AU - Franz, David Neal
N1 - Funding Information:
Dr. Tillema has received funding for travel from Novartis. Dr. Leach has received research support from the NIH. Dr. Krueger has served on scientific advisory boards for Novartis and Lundbeck, Inc.; serves on the speakers' bureaus for and has received speaker honoraria and funding for travel from Novartis; and receives research support from Novartis and Lundbeck, Inc. Dr. Franz has received grant funding and support for travel from Novartis Pharmaceuticals; has received consulting fees from Novartis Pharmaceuticals and from UCB Pharma; has served on a scientific advisory board and as a consultant for Novartis; serves on the speakers' bureaus for and has received funding for travel and speaker honoraria from Novartis and UCB; has received research support to his institution from Novartis; and has served as an expert witness in medico-legal cases.
PY - 2012/2/21
Y1 - 2012/2/21
N2 - Objective: Diffusion tensor imaging (DTI) analysis was performed on patients with tuberous sclerosis complex (TSC) to investigate potential changes in normal-appearing white matter after treatment with everolimus, a mammalian target of rapamycin (mTOR) inhibitor. Methods: Recently, a phase I/II trial of everolimus demonstrated significant reductions in sub-ependymal giant cell astrocytoma (SEGA) volume and decreased seizure frequency. Subgroup analysis was performed on DTI data available from this study. TSC patients with SEGA received everolimus, titrated to tolerability to achieve target trough concentrations of 5-15 ng/mL. DTI (1.5 T, 15 directions) was used to calculate fractional anisotropy (FA) and axial, radial, and mean diffusivity within regions of interest (ROIs). Baseline scans were compared to 12-18 months post-treatment and compared to a TSC age- and gender-matched nontreatment control cohort. Results: Of 28 enrolled patients, 20 had sufficient DTI data. Comparing baseline values with those acquired 12-18 months after treatment, a significant change in FA was observed in the corpus callosum, internal capsule, and geniculo-calcarine region (p < 0.05). Mean change in FA was 0.04 (p < 0.01), driven primarily by a significant decrease in radial diffusivity. Mean diffusivity of the combined ROIs decreased slightly (p < 0.05), axial diffusivity remained stable. The control group showed no change over time. Conclusion: Significant changes in FA and radial diffusivity were observed after treatment with everolimus in patients with TSC, suggesting that the genetic defect of TSC in the brain may be modified pharmacologically, even in normal-appearing white matter.
AB - Objective: Diffusion tensor imaging (DTI) analysis was performed on patients with tuberous sclerosis complex (TSC) to investigate potential changes in normal-appearing white matter after treatment with everolimus, a mammalian target of rapamycin (mTOR) inhibitor. Methods: Recently, a phase I/II trial of everolimus demonstrated significant reductions in sub-ependymal giant cell astrocytoma (SEGA) volume and decreased seizure frequency. Subgroup analysis was performed on DTI data available from this study. TSC patients with SEGA received everolimus, titrated to tolerability to achieve target trough concentrations of 5-15 ng/mL. DTI (1.5 T, 15 directions) was used to calculate fractional anisotropy (FA) and axial, radial, and mean diffusivity within regions of interest (ROIs). Baseline scans were compared to 12-18 months post-treatment and compared to a TSC age- and gender-matched nontreatment control cohort. Results: Of 28 enrolled patients, 20 had sufficient DTI data. Comparing baseline values with those acquired 12-18 months after treatment, a significant change in FA was observed in the corpus callosum, internal capsule, and geniculo-calcarine region (p < 0.05). Mean change in FA was 0.04 (p < 0.01), driven primarily by a significant decrease in radial diffusivity. Mean diffusivity of the combined ROIs decreased slightly (p < 0.05), axial diffusivity remained stable. The control group showed no change over time. Conclusion: Significant changes in FA and radial diffusivity were observed after treatment with everolimus in patients with TSC, suggesting that the genetic defect of TSC in the brain may be modified pharmacologically, even in normal-appearing white matter.
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U2 - 10.1212/WNL.0b013e318247ca8d
DO - 10.1212/WNL.0b013e318247ca8d
M3 - Article
C2 - 22262746
AN - SCOPUS:84858136146
SN - 0028-3878
VL - 78
SP - 526
EP - 531
JO - Neurology
JF - Neurology
IS - 8
ER -