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April 26, 2022; 98 (17) Research Article

Sudden Death and Cardiac Arrythmia With Lamotrigine

A Rapid Systematic Review

View ORCID ProfileJohanna W. Bunschoten, View ORCID ProfileNafisa Husein, View ORCID ProfileOrrin Devinsky, View ORCID ProfileJacqueline A. French, View ORCID ProfileJosemir W. Sander, View ORCID ProfileRoland D. Thijs, View ORCID ProfileMark R. Keezer
First published March 8, 2022, DOI: https://doi.org/10.1212/WNL.0000000000200164
Johanna W. Bunschoten
From the Stichting Epilepsie Instellingen Nederland (SEIN) (J.W.B., J.W.S., R.D.T., M.R.K.), Heemstede; Department of Neurology (J.W.B., R.D.T.), Leiden University Medical Centre, the Netherlands; School of Public Health (N.H., M.R.K.) and Department of Neurosciences (M.R.K.), Université de Montréal, Canada; Department of Neurology (O.D., J.A.F.), New York University Grossman School of Medicine and NYU Langone Health, New York; UCL Queen Square Institute of Neurology (J.W.S., R.D.T.), London; and Chalfont Centre for Epilepsy (J.W.S., R.D.T.), Chalfont St Peter, UK.
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Nafisa Husein
From the Stichting Epilepsie Instellingen Nederland (SEIN) (J.W.B., J.W.S., R.D.T., M.R.K.), Heemstede; Department of Neurology (J.W.B., R.D.T.), Leiden University Medical Centre, the Netherlands; School of Public Health (N.H., M.R.K.) and Department of Neurosciences (M.R.K.), Université de Montréal, Canada; Department of Neurology (O.D., J.A.F.), New York University Grossman School of Medicine and NYU Langone Health, New York; UCL Queen Square Institute of Neurology (J.W.S., R.D.T.), London; and Chalfont Centre for Epilepsy (J.W.S., R.D.T.), Chalfont St Peter, UK.
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Orrin Devinsky
From the Stichting Epilepsie Instellingen Nederland (SEIN) (J.W.B., J.W.S., R.D.T., M.R.K.), Heemstede; Department of Neurology (J.W.B., R.D.T.), Leiden University Medical Centre, the Netherlands; School of Public Health (N.H., M.R.K.) and Department of Neurosciences (M.R.K.), Université de Montréal, Canada; Department of Neurology (O.D., J.A.F.), New York University Grossman School of Medicine and NYU Langone Health, New York; UCL Queen Square Institute of Neurology (J.W.S., R.D.T.), London; and Chalfont Centre for Epilepsy (J.W.S., R.D.T.), Chalfont St Peter, UK.
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Jacqueline A. French
From the Stichting Epilepsie Instellingen Nederland (SEIN) (J.W.B., J.W.S., R.D.T., M.R.K.), Heemstede; Department of Neurology (J.W.B., R.D.T.), Leiden University Medical Centre, the Netherlands; School of Public Health (N.H., M.R.K.) and Department of Neurosciences (M.R.K.), Université de Montréal, Canada; Department of Neurology (O.D., J.A.F.), New York University Grossman School of Medicine and NYU Langone Health, New York; UCL Queen Square Institute of Neurology (J.W.S., R.D.T.), London; and Chalfont Centre for Epilepsy (J.W.S., R.D.T.), Chalfont St Peter, UK.
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Josemir W. Sander
From the Stichting Epilepsie Instellingen Nederland (SEIN) (J.W.B., J.W.S., R.D.T., M.R.K.), Heemstede; Department of Neurology (J.W.B., R.D.T.), Leiden University Medical Centre, the Netherlands; School of Public Health (N.H., M.R.K.) and Department of Neurosciences (M.R.K.), Université de Montréal, Canada; Department of Neurology (O.D., J.A.F.), New York University Grossman School of Medicine and NYU Langone Health, New York; UCL Queen Square Institute of Neurology (J.W.S., R.D.T.), London; and Chalfont Centre for Epilepsy (J.W.S., R.D.T.), Chalfont St Peter, UK.
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Roland D. Thijs
From the Stichting Epilepsie Instellingen Nederland (SEIN) (J.W.B., J.W.S., R.D.T., M.R.K.), Heemstede; Department of Neurology (J.W.B., R.D.T.), Leiden University Medical Centre, the Netherlands; School of Public Health (N.H., M.R.K.) and Department of Neurosciences (M.R.K.), Université de Montréal, Canada; Department of Neurology (O.D., J.A.F.), New York University Grossman School of Medicine and NYU Langone Health, New York; UCL Queen Square Institute of Neurology (J.W.S., R.D.T.), London; and Chalfont Centre for Epilepsy (J.W.S., R.D.T.), Chalfont St Peter, UK.
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Mark R. Keezer
From the Stichting Epilepsie Instellingen Nederland (SEIN) (J.W.B., J.W.S., R.D.T., M.R.K.), Heemstede; Department of Neurology (J.W.B., R.D.T.), Leiden University Medical Centre, the Netherlands; School of Public Health (N.H., M.R.K.) and Department of Neurosciences (M.R.K.), Université de Montréal, Canada; Department of Neurology (O.D., J.A.F.), New York University Grossman School of Medicine and NYU Langone Health, New York; UCL Queen Square Institute of Neurology (J.W.S., R.D.T.), London; and Chalfont Centre for Epilepsy (J.W.S., R.D.T.), Chalfont St Peter, UK.
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  • ORCID record for Mark R. Keezer
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Sudden Death and Cardiac Arrythmia With Lamotrigine
A Rapid Systematic Review
Johanna W. Bunschoten, Nafisa Husein, Orrin Devinsky, Jacqueline A. French, Josemir W. Sander, Roland D. Thijs, Mark R. Keezer
Neurology Apr 2022, 98 (17) e1748-e1760; DOI: 10.1212/WNL.0000000000200164

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Abstract

Background and Objectives A recent Food and Drug Administration warning concerning an arrhythmogenic potential of lamotrigine created concern in the neurologic community. This warning was based on in vitro studies, but no clinically relevant risk was considered. This rapid systematic review aims to elucidate the risk of lamotrigine on sudden death or ECG abnormalities.

Methods We conducted a systematic search of Ovid Medline and Ovid Embase, including randomized controlled trials and observational studies and studies of people with or without epilepsy, with the outcome measures sudden unexpected death in epilepsy (SUDEP) or sudden cardiac death as well as the development or worsening of ECG abnormalities. We evaluated the sudden death definitions used in all included studies, as some could have used unclear or overlapping definitions. We used the American Academy of Neurology risk of bias tool to evaluate the class of evidence and the GRADE approach to evaluate our confidence in the evidence.

Results We included 26 studies with 24,962 participants, of whom 2,326 used lamotrigine. Twelve studies showed no significant risk of SUDEP for lamotrigine users. One study reporting on sudden cardiac death and 3 studies with unclear sudden death definitions did not report an elevated risk of death in lamotrigine users compared to controls. In 10 studies reporting on ECG measures, there was no statistically significant increased risk among lamotrigine users except in 2 studies. These 2 studies reported either “slight increases” in PR interval or an increased PQ interval that the primary study authors believed to be related to structural cardiac differences rather than an effect of lamotrigine. One study was rated Class II; all others were Class III or IV. We had very low confidence in the evidence following the GRADE assessment. None of the studies examined the risk of lamotrigine in people with preexisting cardiac conditions.

Discussion There is insufficient evidence to support or refute that lamotrigine is associated with sudden death or ECG changes in people with or without epilepsy as compared to antiseizure medication or placebo, due to the high risk of bias in most studies and low precision and inconsistency in the reported results.

Glossary

AAN=
American Academy of Neurology;
ASM=
antiseizure medication;
FDA=
Food and Drug Administration;
GRADE=
Grading of Recommendations Assessment, Development and Evaluation;
HRV=
heart rate variability;
SUDEP=
sudden unexpected death in epilepsy

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.

  • ↵* These authors contributed equally to this work.

  • Editorial, page 697

  • CME Course: NPub.org/cmelist

  • Podcast: NPub.org/Podcast9817

  • Received August 6, 2021.
  • Accepted in final form January 21, 2022.
  • © 2022 American Academy of Neurology
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