Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial

Neurology. 2016 Sep 6;87(10):1011-8. doi: 10.1212/WNL.0000000000003077. Epub 2016 Aug 10.


Objective: To investigate whether mammalian target of rapamycin complex 1 (mTORC1) inhibitors could reduce seizure frequency in children with tuberous sclerosis complex (TSC).

Methods: Due to slow inclusion rate, target inclusion of 30 children was not reached. Twenty-three children with TSC and intractable epilepsy (age 1.8-10.9 years) were randomly assigned (1:1) to open-label, add-on sirolimus treatment immediately or after 6 months. Sirolimus was titrated to trough levels of 5-10 ng/mL. Primary endpoint was seizure frequency change during the sixth month of sirolimus treatment.

Results: Intention-to-treat analysis showed sirolimus treatment resulted in 41% seizure frequency decrease (95% confidence interval [CI] -69% to +14%; p = 0.11) compared to the standard-care period. Per protocol analysis of 14 children who reached sirolimus target trough levels in the sixth sirolimus month showed a seizure frequency decrease of 61% (95% CI -86% to +6%; p = 0.06). Cognitive development did not change. All children had adverse events. Five children discontinued sirolimus prematurely.

Conclusions: We describe a randomized controlled trial for a non-antiepileptic drug that directly targets a presumed causal mechanism of epileptogenesis in a genetic disorder. Although seizure frequency decreased, especially in children reaching target trough levels, we could not show a significant benefit. Larger trials or meta-analyses are needed to investigate if patients with TSC with seizures benefit from mTORC1 inhibition. This trial was registered at (NTR3178) and supported by the Dutch Epilepsy Foundation.

Classification of evidence: This study provides Class III evidence that sirolimus does not significantly reduce seizure frequency in children with TSC and intractable epilepsy. The study lacked the precision to exclude a benefit from sirolimus.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Anticonvulsants / adverse effects
  • Anticonvulsants / blood
  • Anticonvulsants / therapeutic use*
  • Child
  • Child, Preschool
  • Cross-Over Studies
  • Drug Resistant Epilepsy / blood
  • Drug Resistant Epilepsy / complications*
  • Drug Resistant Epilepsy / drug therapy*
  • Drug Resistant Epilepsy / genetics
  • Drug Therapy, Combination
  • Female
  • Follow-Up Studies
  • Humans
  • Infant
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes / antagonists & inhibitors
  • Neuropsychological Tests
  • Sirolimus / adverse effects
  • Sirolimus / blood
  • Sirolimus / therapeutic use*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Treatment Outcome
  • Tuberous Sclerosis / blood
  • Tuberous Sclerosis / complications*
  • Tuberous Sclerosis / drug therapy*
  • Tuberous Sclerosis / genetics


  • Anticonvulsants
  • Multiprotein Complexes
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • Sirolimus