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January 02, 2018; 90 (1) Article

Precision therapy for epilepsy due to KCNT1 mutations

A randomized trial of oral quinidine

Saul A. Mullen, Patrick W. Carney, Annie Roten, Michael Ching, Paul A. Lightfoot, Leonid Churilov, Umesh Nair, Melody Li, Samuel F. Berkovic, Steven Petrou, Ingrid E. Scheffer
First published December 1, 2017, DOI: https://doi.org/10.1212/WNL.0000000000004769
Saul A. Mullen
From The Florey Institute of Neuroscience and Mental Health (S.A.M., P.W.C., L.C., U.N., M.L., S.P.), Epilepsy Research Centre, Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Paediatrics, Royal Children's Hospital (I.E.S.), University of Melbourne; Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Pharmacy (M.C.), Austin Health; and Department of Medicine (P.W.C.), Monash University and Eastern Health, Melbourne, Australia.
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Patrick W. Carney
From The Florey Institute of Neuroscience and Mental Health (S.A.M., P.W.C., L.C., U.N., M.L., S.P.), Epilepsy Research Centre, Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Paediatrics, Royal Children's Hospital (I.E.S.), University of Melbourne; Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Pharmacy (M.C.), Austin Health; and Department of Medicine (P.W.C.), Monash University and Eastern Health, Melbourne, Australia.
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Annie Roten
From The Florey Institute of Neuroscience and Mental Health (S.A.M., P.W.C., L.C., U.N., M.L., S.P.), Epilepsy Research Centre, Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Paediatrics, Royal Children's Hospital (I.E.S.), University of Melbourne; Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Pharmacy (M.C.), Austin Health; and Department of Medicine (P.W.C.), Monash University and Eastern Health, Melbourne, Australia.
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Michael Ching
From The Florey Institute of Neuroscience and Mental Health (S.A.M., P.W.C., L.C., U.N., M.L., S.P.), Epilepsy Research Centre, Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Paediatrics, Royal Children's Hospital (I.E.S.), University of Melbourne; Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Pharmacy (M.C.), Austin Health; and Department of Medicine (P.W.C.), Monash University and Eastern Health, Melbourne, Australia.
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Paul A. Lightfoot
From The Florey Institute of Neuroscience and Mental Health (S.A.M., P.W.C., L.C., U.N., M.L., S.P.), Epilepsy Research Centre, Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Paediatrics, Royal Children's Hospital (I.E.S.), University of Melbourne; Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Pharmacy (M.C.), Austin Health; and Department of Medicine (P.W.C.), Monash University and Eastern Health, Melbourne, Australia.
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Leonid Churilov
From The Florey Institute of Neuroscience and Mental Health (S.A.M., P.W.C., L.C., U.N., M.L., S.P.), Epilepsy Research Centre, Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Paediatrics, Royal Children's Hospital (I.E.S.), University of Melbourne; Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Pharmacy (M.C.), Austin Health; and Department of Medicine (P.W.C.), Monash University and Eastern Health, Melbourne, Australia.
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Umesh Nair
From The Florey Institute of Neuroscience and Mental Health (S.A.M., P.W.C., L.C., U.N., M.L., S.P.), Epilepsy Research Centre, Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Paediatrics, Royal Children's Hospital (I.E.S.), University of Melbourne; Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Pharmacy (M.C.), Austin Health; and Department of Medicine (P.W.C.), Monash University and Eastern Health, Melbourne, Australia.
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Melody Li
From The Florey Institute of Neuroscience and Mental Health (S.A.M., P.W.C., L.C., U.N., M.L., S.P.), Epilepsy Research Centre, Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Paediatrics, Royal Children's Hospital (I.E.S.), University of Melbourne; Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Pharmacy (M.C.), Austin Health; and Department of Medicine (P.W.C.), Monash University and Eastern Health, Melbourne, Australia.
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Samuel F. Berkovic
From The Florey Institute of Neuroscience and Mental Health (S.A.M., P.W.C., L.C., U.N., M.L., S.P.), Epilepsy Research Centre, Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Paediatrics, Royal Children's Hospital (I.E.S.), University of Melbourne; Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Pharmacy (M.C.), Austin Health; and Department of Medicine (P.W.C.), Monash University and Eastern Health, Melbourne, Australia.
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Steven Petrou
From The Florey Institute of Neuroscience and Mental Health (S.A.M., P.W.C., L.C., U.N., M.L., S.P.), Epilepsy Research Centre, Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Paediatrics, Royal Children's Hospital (I.E.S.), University of Melbourne; Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Pharmacy (M.C.), Austin Health; and Department of Medicine (P.W.C.), Monash University and Eastern Health, Melbourne, Australia.
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Ingrid E. Scheffer
From The Florey Institute of Neuroscience and Mental Health (S.A.M., P.W.C., L.C., U.N., M.L., S.P.), Epilepsy Research Centre, Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Paediatrics, Royal Children's Hospital (I.E.S.), University of Melbourne; Department of Medicine (S.A.M., A.R., P.A.L., S.F.B., I.E.S.), and Department of Pharmacy (M.C.), Austin Health; and Department of Medicine (P.W.C.), Monash University and Eastern Health, Melbourne, Australia.
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Full PDF
Citation
Precision therapy for epilepsy due to KCNT1 mutations
A randomized trial of oral quinidine
Saul A. Mullen, Patrick W. Carney, Annie Roten, Michael Ching, Paul A. Lightfoot, Leonid Churilov, Umesh Nair, Melody Li, Samuel F. Berkovic, Steven Petrou, Ingrid E. Scheffer
Neurology Jan 2018, 90 (1) e67-e72; DOI: 10.1212/WNL.0000000000004769

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Abstract

Objective To evaluate quinidine as a precision therapy for severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1.

Methods A single-center, inpatient, order-randomized, blinded, placebo-controlled, crossover trial of oral quinidine included 6 patients with severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) due to KCNT1 mutation. Order was block randomized and blinded. Four-day treatment blocks were used with a 2-day washout between. Dose started at 900 mg over 3 divided doses then, in subsequent participants, was reduced to 600 mg, then 300 mg. Primary outcome was seizure frequency measured on continuous video-EEG in those completing the trial.

Results Prolonged QT interval occurred in the first 2 patients at doses of 900 and 600 mg quinidine per day, respectively, despite serum quinidine levels well below the therapeutic range (0.61 and 0.51 μg/mL, reference range 1.3–5.0 μg/mL). Four patients completed treatment with 300 mg/d without adverse events. Patients completing the trial had very frequent seizures (mean 14 per day, SD 7, median 13, interquartile range 10–18). Seizures per day were nonsignificantly increased by quinidine (median 2, 95% confidence interval −1.5 to +5, p = 0.15) and no patient had a 50% seizure reduction.

Conclusion Quinidine did not show efficacy in adults and teenagers with ADNFLE. Dose-limiting cardiac side effects were observed even in the presence of low measured serum quinidine levels. Although small, this trial suggests use of quinidine in ADNFLE is likely to be ineffective coupled with considerable cardiac risks.

Clinical trials registration Australian Therapeutic Goods Administration Clinical Trial Registry (trial number 2015/0151).

Classification of evidence This study provides Class II evidence that for persons with severe epilepsy due to gain of function mutations in the potassium channel gene KCNT1, quinidine does not significantly reduce seizure frequency.

Glossary

ADNFLE=
autosomal dominant nocturnal frontal lobe epilepsy;
CI=
confidence interval;
EIMFS=
epilepsy of infancy with migrating focal seizures

Footnotes

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

  • See page 16

  • Received May 21, 2017.
  • Accepted in final form September 15, 2017.
  • Copyright © 2017 American Academy of Neurology
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