title: Everolimus alters white matter diffusion in tuberous sclerosis complex.
abstract: 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 subependymal 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Jan-Mendelt
authors.initials: JM
authors.lastname: Tillema
authors.forename: James L
authors.initials: JL
authors.lastname: Leach
authors.forename: Darcy A
authors.initials: DA
authors.lastname: Krueger
authors.forename: David Neal
authors.initials: DN
authors.lastname: Franz
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003337:Corpus Callosum / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D056324:Diffusion Tensor Imaging; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014402:Tuberous Sclerosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus