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September 06, 2016; 87 (10) Article

Sirolimus for epilepsy in children with tuberous sclerosis complex

A randomized controlled trial

Iris E. Overwater, André B. Rietman, Karen Bindels-de Heus, Caspar W.N. Looman, Dimitris Rizopoulos, Tafadzwa M. Sibindi, Perumpillichira J. Cherian, Floor E. Jansen, Henriëtte A. Moll, Ype Elgersma, Marie-Claire Y. de Wit
First published August 10, 2016, DOI: https://doi.org/10.1212/WNL.0000000000003077
Iris E. Overwater
From the Departments of Neurology (I.E.O., A.B.R., M.-C.Y.d.W.), Pediatrics (K.B.-d.H., H.A.M.), Public Health (C.W.N.L.), Biostatistics (D.R.), Neurophysiology (T.M.S., P.J.C.), and Neuroscience (Y.E.), ENCORE Expertise Centre for Neurodevelopmental Disorders (I.E.O., A.B.R., K.B.-d.H., H.A.M., Y.E., M.-C.Y.d.W.), Erasmus University Medical Centre, Rotterdam; and the Department of Pediatric Neurology (F.E.J.), Brain Center Rudolf Magnus, University Medical Centre Utrecht, the Netherlands.
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André B. Rietman
From the Departments of Neurology (I.E.O., A.B.R., M.-C.Y.d.W.), Pediatrics (K.B.-d.H., H.A.M.), Public Health (C.W.N.L.), Biostatistics (D.R.), Neurophysiology (T.M.S., P.J.C.), and Neuroscience (Y.E.), ENCORE Expertise Centre for Neurodevelopmental Disorders (I.E.O., A.B.R., K.B.-d.H., H.A.M., Y.E., M.-C.Y.d.W.), Erasmus University Medical Centre, Rotterdam; and the Department of Pediatric Neurology (F.E.J.), Brain Center Rudolf Magnus, University Medical Centre Utrecht, the Netherlands.
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Karen Bindels-de Heus
From the Departments of Neurology (I.E.O., A.B.R., M.-C.Y.d.W.), Pediatrics (K.B.-d.H., H.A.M.), Public Health (C.W.N.L.), Biostatistics (D.R.), Neurophysiology (T.M.S., P.J.C.), and Neuroscience (Y.E.), ENCORE Expertise Centre for Neurodevelopmental Disorders (I.E.O., A.B.R., K.B.-d.H., H.A.M., Y.E., M.-C.Y.d.W.), Erasmus University Medical Centre, Rotterdam; and the Department of Pediatric Neurology (F.E.J.), Brain Center Rudolf Magnus, University Medical Centre Utrecht, the Netherlands.
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Caspar W.N. Looman
From the Departments of Neurology (I.E.O., A.B.R., M.-C.Y.d.W.), Pediatrics (K.B.-d.H., H.A.M.), Public Health (C.W.N.L.), Biostatistics (D.R.), Neurophysiology (T.M.S., P.J.C.), and Neuroscience (Y.E.), ENCORE Expertise Centre for Neurodevelopmental Disorders (I.E.O., A.B.R., K.B.-d.H., H.A.M., Y.E., M.-C.Y.d.W.), Erasmus University Medical Centre, Rotterdam; and the Department of Pediatric Neurology (F.E.J.), Brain Center Rudolf Magnus, University Medical Centre Utrecht, the Netherlands.
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Dimitris Rizopoulos
From the Departments of Neurology (I.E.O., A.B.R., M.-C.Y.d.W.), Pediatrics (K.B.-d.H., H.A.M.), Public Health (C.W.N.L.), Biostatistics (D.R.), Neurophysiology (T.M.S., P.J.C.), and Neuroscience (Y.E.), ENCORE Expertise Centre for Neurodevelopmental Disorders (I.E.O., A.B.R., K.B.-d.H., H.A.M., Y.E., M.-C.Y.d.W.), Erasmus University Medical Centre, Rotterdam; and the Department of Pediatric Neurology (F.E.J.), Brain Center Rudolf Magnus, University Medical Centre Utrecht, the Netherlands.
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Tafadzwa M. Sibindi
From the Departments of Neurology (I.E.O., A.B.R., M.-C.Y.d.W.), Pediatrics (K.B.-d.H., H.A.M.), Public Health (C.W.N.L.), Biostatistics (D.R.), Neurophysiology (T.M.S., P.J.C.), and Neuroscience (Y.E.), ENCORE Expertise Centre for Neurodevelopmental Disorders (I.E.O., A.B.R., K.B.-d.H., H.A.M., Y.E., M.-C.Y.d.W.), Erasmus University Medical Centre, Rotterdam; and the Department of Pediatric Neurology (F.E.J.), Brain Center Rudolf Magnus, University Medical Centre Utrecht, the Netherlands.
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Perumpillichira J. Cherian
From the Departments of Neurology (I.E.O., A.B.R., M.-C.Y.d.W.), Pediatrics (K.B.-d.H., H.A.M.), Public Health (C.W.N.L.), Biostatistics (D.R.), Neurophysiology (T.M.S., P.J.C.), and Neuroscience (Y.E.), ENCORE Expertise Centre for Neurodevelopmental Disorders (I.E.O., A.B.R., K.B.-d.H., H.A.M., Y.E., M.-C.Y.d.W.), Erasmus University Medical Centre, Rotterdam; and the Department of Pediatric Neurology (F.E.J.), Brain Center Rudolf Magnus, University Medical Centre Utrecht, the Netherlands.
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Floor E. Jansen
From the Departments of Neurology (I.E.O., A.B.R., M.-C.Y.d.W.), Pediatrics (K.B.-d.H., H.A.M.), Public Health (C.W.N.L.), Biostatistics (D.R.), Neurophysiology (T.M.S., P.J.C.), and Neuroscience (Y.E.), ENCORE Expertise Centre for Neurodevelopmental Disorders (I.E.O., A.B.R., K.B.-d.H., H.A.M., Y.E., M.-C.Y.d.W.), Erasmus University Medical Centre, Rotterdam; and the Department of Pediatric Neurology (F.E.J.), Brain Center Rudolf Magnus, University Medical Centre Utrecht, the Netherlands.
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Henriëtte A. Moll
From the Departments of Neurology (I.E.O., A.B.R., M.-C.Y.d.W.), Pediatrics (K.B.-d.H., H.A.M.), Public Health (C.W.N.L.), Biostatistics (D.R.), Neurophysiology (T.M.S., P.J.C.), and Neuroscience (Y.E.), ENCORE Expertise Centre for Neurodevelopmental Disorders (I.E.O., A.B.R., K.B.-d.H., H.A.M., Y.E., M.-C.Y.d.W.), Erasmus University Medical Centre, Rotterdam; and the Department of Pediatric Neurology (F.E.J.), Brain Center Rudolf Magnus, University Medical Centre Utrecht, the Netherlands.
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Ype Elgersma
From the Departments of Neurology (I.E.O., A.B.R., M.-C.Y.d.W.), Pediatrics (K.B.-d.H., H.A.M.), Public Health (C.W.N.L.), Biostatistics (D.R.), Neurophysiology (T.M.S., P.J.C.), and Neuroscience (Y.E.), ENCORE Expertise Centre for Neurodevelopmental Disorders (I.E.O., A.B.R., K.B.-d.H., H.A.M., Y.E., M.-C.Y.d.W.), Erasmus University Medical Centre, Rotterdam; and the Department of Pediatric Neurology (F.E.J.), Brain Center Rudolf Magnus, University Medical Centre Utrecht, the Netherlands.
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Marie-Claire Y. de Wit
From the Departments of Neurology (I.E.O., A.B.R., M.-C.Y.d.W.), Pediatrics (K.B.-d.H., H.A.M.), Public Health (C.W.N.L.), Biostatistics (D.R.), Neurophysiology (T.M.S., P.J.C.), and Neuroscience (Y.E.), ENCORE Expertise Centre for Neurodevelopmental Disorders (I.E.O., A.B.R., K.B.-d.H., H.A.M., Y.E., M.-C.Y.d.W.), Erasmus University Medical Centre, Rotterdam; and the Department of Pediatric Neurology (F.E.J.), Brain Center Rudolf Magnus, University Medical Centre Utrecht, the Netherlands.
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Citation
Sirolimus for epilepsy in children with tuberous sclerosis complex
A randomized controlled trial
Iris E. Overwater, André B. Rietman, Karen Bindels-de Heus, Caspar W.N. Looman, Dimitris Rizopoulos, Tafadzwa M. Sibindi, Perumpillichira J. Cherian, Floor E. Jansen, Henriëtte A. Moll, Ype Elgersma, Marie-Claire Y. de Wit
Neurology Sep 2016, 87 (10) 1011-1018; DOI: 10.1212/WNL.0000000000003077

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Abstract

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.

GLOSSARY

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

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Editorial, page 974

  • Supplemental data at Neurology.org

  • Received December 15, 2015.
  • Accepted in final form April 20, 2016.
  • © 2016 American Academy of Neurology
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Disputes & Debates: Rapid online correspondence

  • Author Response: Sirolimus treatment is effective in children with TSC and epilepsy
    • Marie-Claire Y. de Wit, Pediatric Neurologist, Erasmus MC-ENCORE expertise centerm.c.y.dewit@erasmusmc.nl
    • I.E. Overwater, Rotterdam, The Netherlands
    Submitted October 13, 2016
  • Sirolimus treatment is effective in children with TSC and epilepsy
    • Li-Ping Zou, Director, Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, China; Department of Pediatrics,Zouliping21@hotmail.com
    • Yu-Tian Liu, Beijing, China
    Submitted October 05, 2016
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