TY - JOUR
T1 - Association of short-term heart rate variability and sudden unexpected death in epilepsy
AU - Sivathamboo, Shobi
AU - Friedman, Daniel
AU - Laze, Juliana
AU - Nightscales, Russell
AU - Chen, Zhibin
AU - Kuhlmann, Levin
AU - Devore, Sasha
AU - Macefield, Vaughan
AU - Kwan, Patrick
AU - D’Souza, Wendyl
AU - Berkovic, Samuel F.
AU - Perucca, Piero
AU - O'Brien, Terence John
AU - Devinsky, Orrin
AU - on behalf of MS-BioS study group
N1 - Funding Information:
S. Sivathamboo is supported by a Bridging Postdoctoral Fellowship from Monash University (BPF20-3253672466) and the Victorian Medical Research Acceleration Fund and reports salary support from Kaoskey and Optalert for clinical trial–related activities; Dr. Sivathamboo receives no personal income for these activities. D. Friedman receives salary support for consulting and clinical trial related activities performed on behalf of The Epilepsy Study Consortium, a nonprofit organization; Dr. Friedman receives no personal income for these activities. NYU receives a fixed amount from the Epilepsy Study Consortium towards Dr. Friedman's salary. Within the past 2 years, The Epilepsy Study Consortium received payments for research services performed by Dr. Friedman from Axcella, Biogen, Cerevel, Crossject, Engage Pharmaceuticals, Eisai, Lundbeck, Pfizer, SK Life Science, Xenon, and Zynerba. He has also served as a paid consultant for Eisai and Neurelis Pharmaceuticals; has received travel support from Medtronics, Eisai, and the Epilepsy Foundation; has received research support from the Centers for Disease Control and Prevention, National Institute of Neurological Disorders and Stroke, Epilepsy Foundation, Empatica, Epitel, UCB, Inc., and Neuropace unrelated to this study; serves on the scientific advisory board for Receptor Life Sciences; holds equity interests in Neuroview Technology and Receptor Life Sciences; and received royalty income from Oxford University Press. J. Laze and R. Nightscales report no disclosures relevant to the manuscript. Z. Chen is supported by an Early Career Fellowship from the National Health and Medical Research Council (GNT1156444). L. Kuhlmann is supported by a Project Grant from the National Health and Medical Research Council (GNT1160815). S. Devore reports no disclosures relevant to the manuscript. V.G. Macefield is supported by a Baker Fellowship. P. Kwan is supported by a Medical Research Future Fund from the National Health and Medical Research Council of Australia (APP1136427) and the Victorian Medical Research Acceleration Fund; reports grants and personal fees from Eisai, UCB Pharma, and LivaNova; reports grants from Zynerba, Biscayne, and GW Pharmaceuticals; and has received travel, speaker honoraria, or consultancy fees from Sun Pharmaceuticals, Supernus Pharmaceuticals, Novartis, and Eisai. W. D'Souza receives salary support from The University of Melbourne; has received travel, investigator-initiated, scientific advisory board, and speaker honoraria from UCB Pharma Australia & Global; has received investigator-initiated, scientific advisory board, and travel and speaker honoraria from Eisai Australia & Global; has received advisory board honoraria from Liva Nova; has received educational grants from Novartis Pharmaceuticals, Pfizer Pharmaceuticals, and Sanofi-Synthelabo; has received educational, travel, and fellowship grants from GSK Neurology Australia and honoraria from SciGen Pharmaceuticals; and has shareholdings in the device company EpiMinder and health software company KeyLead. S.F. Berkovic is supported by a Program Grant from the National Health and Medical Research Council of Australia (APP1091593); reports grants from Eisai, UCB Pharma, and SciGen; and has a patent for SCN1A licensed to various diagnostic companies with no financial return, a patent for PRRT2 gene licensed to Athena Diagnostics, and a patent for Diagnostic and Therapeutic Methods for Epilepsy and Mental Retardation Limited to Females (EFMR) licensed to Athena Diagnostics. P. Perucca is supported by an Early Career Fellowship from the National Health and Medical Research Council (APP1163708), the Epilepsy Foundation, the Royal Australasian College of Physicians, The University of Melbourne, Monash University, and the Weary Dunlop Medical Research Foundation; has received speaker honoraria or consultancy fees to his institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus, and UCB Pharma; and is an Associate Editor for Epilepsia Open. T.J. O'Brien is supported by a Program Grant (APP1091593) and Investigator Grant (APP1176426) from the National Health and Medical Research Council of Australia and the Victorian Medical Research Acceleration Fund and reports grants and personal fees from Eisai, UCB Pharma, Praxis, Biogen, ES Therapeutics, and Zynerba. O. Devinsky is supported by Finding a Cure for Epilepsy and Seizures, the National Institute of Neurological Disorders and Stroke, National Institute of Mental Health, Multidisciplinary University Research Initiatives, Centers for Disease Control and Prevention, and National Science Foundation. O. Devinsky has equity interests in Qstate Biosciences, Tevard Biosciences, Regel Therapeutics, Script Biosciences, Privateer Holdings, Tilray, Receptor Life Sciences, Empatica, Engage, Egg Rock/Papa & Barkley, Rettco, SilverSpike, and California Cannabis Enterprises and is an investigator for PTC Therapeutics, Inc., Stoke Therapeutics, Marinus, Ovid, and GW Pharmaceuticals. Go to Neurology.org/N for full disclosures.
Publisher Copyright:
Copyright © 2021 American Academy of Neurology
PY - 2021/12/14
Y1 - 2021/12/14
N2 - Background and Objectives We compared heart rate variability (HRV) in sudden unexpected death in epilepsy (SUDEP) cases and living epilepsy controls. Methods This international, multicenter, retrospective, nested case–control study examined patients admitted for video-EEG monitoring (VEM) between January 1, 2003, and December 31, 2014, and subsequently died of SUDEP. Time domain and frequency domain components were extracted from 5-minute interictal ECG recordings during sleep and wakefulness from SUDEP cases and controls. Results We identified 31 SUDEP cases and 56 controls. Normalized low-frequency power (LFP) during wakefulness was lower in SUDEP cases (median 42.5, interquartile range [IQR] 32.6–52.6) than epilepsy controls (55.5, IQR 40.7–68.9; p = 0.015, critical value = 0.025). In the multivariable model, normalized LFP was lower in SUDEP cases compared to controls (contrast −11.01, 95% confidence interval [CI] −20.29 to 1.73; p = 0.020, critical value = 0.025). There was a negative correlation between LFP and the latency to SUDEP, where each 1% incremental reduction in normalized LFP conferred a 2.7% decrease in the latency to SUDEP (95% CI 0.95–0.995; p = 0.017, critical value = 0.025). Increased survival duration from VEM to SUDEP was associated with higher normalized high-frequency power (HFP; p = 0.002, critical value = 0.025). The survival model with normalized LFP was associated with SUDEP (c statistic 0.66, 95% CI 0.55–0.77), which nonsignificantly increased with the addition of normalized HFP (c statistic 0.70, 95% CI 0.59–0.81; p = 0.209). Conclusions Reduced short-term LFP, which is a validated biomarker for sudden death, was associated with SUDEP. Increased HFP was associated with longer survival and may be cardioprotective in SUDEP. HRV quantification may help stratify individual SUDEP risk.
AB - Background and Objectives We compared heart rate variability (HRV) in sudden unexpected death in epilepsy (SUDEP) cases and living epilepsy controls. Methods This international, multicenter, retrospective, nested case–control study examined patients admitted for video-EEG monitoring (VEM) between January 1, 2003, and December 31, 2014, and subsequently died of SUDEP. Time domain and frequency domain components were extracted from 5-minute interictal ECG recordings during sleep and wakefulness from SUDEP cases and controls. Results We identified 31 SUDEP cases and 56 controls. Normalized low-frequency power (LFP) during wakefulness was lower in SUDEP cases (median 42.5, interquartile range [IQR] 32.6–52.6) than epilepsy controls (55.5, IQR 40.7–68.9; p = 0.015, critical value = 0.025). In the multivariable model, normalized LFP was lower in SUDEP cases compared to controls (contrast −11.01, 95% confidence interval [CI] −20.29 to 1.73; p = 0.020, critical value = 0.025). There was a negative correlation between LFP and the latency to SUDEP, where each 1% incremental reduction in normalized LFP conferred a 2.7% decrease in the latency to SUDEP (95% CI 0.95–0.995; p = 0.017, critical value = 0.025). Increased survival duration from VEM to SUDEP was associated with higher normalized high-frequency power (HFP; p = 0.002, critical value = 0.025). The survival model with normalized LFP was associated with SUDEP (c statistic 0.66, 95% CI 0.55–0.77), which nonsignificantly increased with the addition of normalized HFP (c statistic 0.70, 95% CI 0.59–0.81; p = 0.209). Conclusions Reduced short-term LFP, which is a validated biomarker for sudden death, was associated with SUDEP. Increased HFP was associated with longer survival and may be cardioprotective in SUDEP. HRV quantification may help stratify individual SUDEP risk.
UR - http://www.scopus.com/inward/record.url?scp=85119682702&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000012946
DO - 10.1212/WNL.0000000000012946
M3 - Article
C2 - 34649884
AN - SCOPUS:85119682702
SN - 0028-3878
VL - 97
SP - E2357-E2367
JO - Neurology
JF - Neurology
IS - 24
ER -