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Is anti-seizure medication the culprit of SUDEP?

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Abstract

Background

Heart rate variability (HRV) reduction is a potential biomarker for sudden cardiac death. This study aimed to study the effects of anti-seizure medications (ASMs), adjusted with reported factors associated with sudden unexpected death in epilepsy (SUDEP) on HRV parameters.

Methods

We recruited patients who were admitted in our epilepsy monitoring unit between January 2013 and December 2021. Two 5-min electrocardiogram epochs during wakefulness and sleep were selected in each patient. HRV analysis with Python® software was performed. The imputed datasets were used for linear regression analysis to assess association between each ASM item and all HRV parameters. The effects of ASM on HRV parameters were subsequently adjusted with the significant clinical characteristics and the concomitant use of other ASMs, respectively.

Results

Carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), and clonazepam (CZP) were statistically significantly associated with changes of sleep HRV parameters. Only CBZ showed negative effects with reduction in HRV, evidenced as lower standard deviation of RR interval (SDNN), even when adjusted with concomitant use of other ASMs (p = 0.045) and had a trend of significance when adjusted with significant clinical characteristics of concurrent taking of beta-blocker drug (p = 0.052). LEV and CZP showed opposite effects with increased HRV even when adjusted with significant clinical characteristics and the concomitant use of other ASMs.

Conclusions

CBZ showed negative effects on HRV. We proposed that CBZ should be cautiously used in patients with known risks for SUDEP. In addition, HRV assessment should be performed prior to commencing CBZ and re-performed in follow-up in cases of prolonged use.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We wish to thank Veera Saidoung for helping with HRV analysis and EEG database management.

Author information

Author notes

  1. Chusak Limotai is equally contributing author.

Authors and Affiliations

  1. Division of Neurology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Danist Leosuthamas & Chusak Limotai

  2. Chulalongkorn Comprehensive Epilepsy Center of Excellence (CCEC), King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand

    Chusak Limotai

  3. Division of Neurology, King Chulalongkorn Memorial Hospital, 1873 Seventh Floor Bhumisiri Building, Rama IV Road, Pathumwan, Bangkok, 10330, Thailand

    Chusak Limotai

  4. Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    Nattawut Unwanatham & Sasivimol Rattanasiri

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  1. Danist Leosuthamas
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  4. Sasivimol Rattanasiri
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Contributions

Danist Leosuthamas: Carried out data acquisition, drafted the manuscript, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Chusak Limotai: Designed the study, carried out data acquisition and data analysis, drafted the manuscript, critically revised the manuscript, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Nattawut Unwanatham: Carried out data analysis, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Sasivimol Rattanasiri: Carried out data analysis, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy.

Corresponding author

Correspondence to Chusak Limotai.

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Conflict of interest

All authors declare no conflict of interest.

Ethical approval

The study was approved by the Institutional Review Board of Faculty of Medicine, Chulalongkorn University. 

Informed consent

Informed consent was waived because of the retrospective nature of the study and the analysis used anonymous clinical data.

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Highlights

• Reductions in HRV were found in epilepsy subgroups at high risk for SUDEP, i.e., chronic TLE and Dravet’s syndrome.

• Controversy still surrounds whether or not ASMs are related to SUDEP.

• In our study population, i.e., drug-resistant focal epilepsy mainly TLE, negative effect of CBZ, and reduction in HRV was demonstrated.

• CBZ should be cautiously used in patients with known risks for SUDEP.

• HRV assessment should be performed prior to commencing CBZ and re-performed in follow-up in cases of prolonged use.

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Leosuthamas, D., Limotai, C., Unwanatham, N. et al. Is anti-seizure medication the culprit of SUDEP?. Neurol Sci 44, 3659–3668 (2023). https://doi.org/10.1007/s10072-023-06871-0

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  • DOI: https://doi.org/10.1007/s10072-023-06871-0

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