Longitudinal Effects of Everolimus on White Matter Diffusion in Tuberous Sclerosis Complex

Pediatr Neurol. 2019 Jan:90:24-30. doi: 10.1016/j.pediatrneurol.2018.10.005. Epub 2018 Oct 18.


Objective: We studied the longitudinal effects of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), on callosal white matter diffusion tensor imaging (DTI) in patients with tuberous sclerosis complex (TSC).

Methods: Serial imaging data spanning nine years were used from the open label, Phase I/II trial (NCT00411619) and open-ended extension phase of everolimus for the treatment of subependymal giant cell astrocytoma associated with TSC. From 28 patients treated with everolimus and 25 untreated control patients, 481 MRI scans were available. Rigorous quality control resulted in omission of all scans with diffusion weighted imaging data in less than 15 directions or more than eight artifacted volumes, and all postsurgical scans. We applied a linear mixed-effects model to the remaining 125 scans (17 treated, 24 controls) for longitudinal analysis of each DTI metric of manually drawn callosal regions of interest.

Results: On a population level, mTOR inhibition was associated with a decrease in mean diffusivity. In addition, in treated patients only, a decrease of radial diffusivity was observed; in untreated patients only, an increase of axial diffusivity was seen. In patients below age 10, effect-sizes were consistently greater, and longer treatment was associated with greater rate of diffusion change. There was no correlation between DTI metrics and reduction of subependymal giant cell astrocytoma volume, or everolimus serum levels.

Conclusions: Effects from mTOR overactivity on white matter microstructural integrity in TSC were modified through pharmacologic inhibition of mTOR. These changes sustained over time, were greater with longer treatment and in younger patients during a time of rapid white matter maturation.

Keywords: Children; Diffusion tensor imaging; Mechanistic target of rapamycin; Tuberous sclerosis complex; mTOR.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Astrocytoma / diagnostic imaging
  • Astrocytoma / drug therapy*
  • Brain Neoplasms / diagnostic imaging
  • Brain Neoplasms / drug therapy*
  • Child
  • Child, Preschool
  • Diffusion Tensor Imaging
  • Everolimus / pharmacology*
  • Everolimus / therapeutic use
  • Female
  • Humans
  • Longitudinal Studies
  • Male
  • Neuroimaging
  • Treatment Outcome
  • Tuberous Sclerosis / diagnostic imaging
  • Tuberous Sclerosis / drug therapy*
  • White Matter / diagnostic imaging
  • White Matter / drug effects*
  • Young Adult


  • Antineoplastic Agents
  • Everolimus

Associated data

  • ClinicalTrials.gov/NCT00411619