RT Journal Article
SR Electronic
T1 Sirolimus for epilepsy in children with tuberous sclerosis complex
JF Neurology
JO Neurology
FD Lippincott Williams & Wilkins
SP 1011
OP 1018
DO 10.1212/WNL.0000000000003077
VO 87
IS 10
A1 Overwater, Iris E.
A1 Rietman, André B.
A1 Bindels-de Heus, Karen
A1 Looman, Caspar W.N.
A1 Rizopoulos, Dimitris
A1 Sibindi, Tafadzwa M.
A1 Cherian, Perumpillichira J.
A1 Jansen, Floor E.
A1 Moll, Henriëtte A.
A1 Elgersma, Ype
A1 de Wit, Marie-Claire Y.
YR 2016
UL http://n.neurology.org/content/87/10/1011.abstract
AB 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 trialregister.nl (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.AED=antiepileptic drug; CI=confidence interval; DSMB=data safety monitoring board; IQR=interquartile range; mTORC1=mammalian target of rapamycin complex 1; TSC=tuberous sclerosis complex