Quantification may help stratify SUDEP risk

People who died due to sudden unexpected death in epilepsy (SUDEP) had changes in frequency-domain measures of heart rate variability compared with living epilepsy controls, a retrospective, nested case-control study found.

Compared with non-SUDEP epilepsy controls, epilepsy patients who died with SUDEP had lower normalized awake low-frequency power (LFP) in heart rate data in earlier video electroencephalographic monitoring (median 42.5 versus 55.5 normalized units, P=0.015), according to Orrin Devinsky, MD, of New York University Grossman School of Medicine in New York City, and co-authors.

This difference remained after adjusting for relevant covariates. Increased normalized LFP in wakefulness was associated with a longer latency to SUDEP (HR 0.97, 95% CI 0.95-0.995, P=0.017). Each 1% incremental reduction to normalized LFP corresponded to a 2.7% decrease in latency to SUDEP, they reported in Neurology.

In contrast, increased high-frequency power (HFP) in sleep was associated with longer survival (P=0.002).

“Although there were no differences across the cohorts in terms of time-domain analysis of heart rate variability, spectral analysis did reveal significant differences in those who had subsequently died of SUDEP,” Devinsky and colleagues wrote. “These cases had significantly reduced LFP during wakefulness, which is a validated biomarker for sudden death in cardiac populations.”

“Further, we found that LFP and HFP associated with individual SUDEP risk. While several risk factors and biomarkers were associated with increased SUDEP risk in [previously published] group analyses, no clinical risk factor or biomarker exists to stratify risk on an individual basis,” the researchers said. “Our results show that deranged heart rate variability is significantly more pronounced in SUDEP cases and may be a clinical biomarker of SUDEP risk that can be readily obtained from routine diagnostic testing.”

“Heart rate variability quantification may help stratify individual SUDEP risk,” Devinsky and co-authors noted. “This study provides Class III evidence that in patients with epilepsy, some measures of heart rate variability are associated with SUDEP.”

From a pool of epilepsy patients who had epilepsy video monitoring at nine participating epilepsy centers, researchers compared heart rate data for 31 patients who later died of SUDEP (13 definite, 18 probable) with 56 living epilepsy controls. All were admitted for monitoring between January 2003 and December 2014.

Frequency-and time-domain components were extracted from 5-minute sleep and awake interictal EKG samples typically obtained during the first 24 hours after admission. Follow-up was 5 or more years from video monitoring (median 10 years), with deaths meeting SUDEP criteria identified through health and other records.

The median age in both cohorts was 34, and about 54% were male. Diagnoses in the SUDEP versus control groups, respectively, were focal epilepsy (84% versus 82%), generalized epilepsy (13% versus 16%), or combined (1.8% versus 3.2%). Polytherapy (two or more seizure medications) occurred in 87% of the SUDEP group and 80% of controls, with sodium channel blockers used by 71% versus 73%, respectively.

SUDEP patient median age at death was 39 and median time from monitoring to death was 4 years. A history of >50 tonic clonic seizures was more frequent among those who had SUDEP than controls (22.6% versus 3.6% respectively, P=0.004).

No difference between SUDEP and non-SUDEP patients was seen in having surgical intervention for epilepsy. However, a greater proportion of patients from the control group achieved post-operative seizure freedom, compared to those with SUDEP. This could contribute to between-group differences in heart rate variability since seizure freedom may decrease the risk for SUDEP, Devinsky and colleagues pointed out.

SUDEP affects about one per 1,000 adults with epilepsy annually, noted Roland Thijs, MD, PhD, of Leiden University Medical Center in the Netherlands, and Josemir Sander, MD, PhD, of University College London in England, in an accompanying editorial. “The inclusion of SUDEP discussion when counseling people with epilepsy and their families is important, but we still fail to predict individualized SUDEP risk accurately,” they wrote.

“More importantly, while a step in the right direction, this study did not fully validate the notion that low heart rate variability has independent predictive value,” Thijs and Sander observed. “We, therefore, still struggle to understand whether heart rate variability complements routine risk assessment using clinical variables such as seizure control.”

“Apart from studies in epilepsy monitoring units, the increasing availability of attractive wearable sensors holds promise for large-scale longitudinal heart rate variability studies in epilepsy,” they added.

Heart rate variability has been documented in patients with temporal lobe and refractory epilepsy. Coupled with an association with sudden death in people with cardiac conditions, this has led to substantial interest in heart rate variability as a predictive factor in SUDEP.

Rarely, SUDEP occurs during video monitoring; a 2013 study of 16 such cases showed early postictal, centrally mediated, severe alteration of respiratory and cardiac function induced by generalized tonic clonic seizure.

A 2020 review of SUDEP described risk factors including seizure frequency, generalized tonic clonic seizures, drug resistance, and polytherapy. “Mechanistically, the pendulum swung from the seizure-induced cardiac arrhythmias and cardiac fibrosis to the postictal impairment of brainstem function leading to deficits in arousal, reflex responses to hypercapnia, and respiration,” the review authors wrote. “The pendulum has swung again, with brain–heart and brain–respiratory interactions rising in relevance.”

Limitations of the current study include data constraints that precluded analysis of heart rate at the same time or sleep stage for all participants.

“Following tonic clonic seizures, sympathetic overactivity manifests as tachycardia and elevated plasma catecholamines,” Devinsky and co-authors noted. “In SUDEP cases, reduced LFP despite sympathetic overactivity may reflect abnormal central autonomic modulation.”

  1. People who died due to sudden unexpected death in epilepsy (SUDEP) had changes in frequency-domain measures of heart rate variability compared with living epilepsy controls, a retrospective study found.

  2. Heart rate variability quantification may help stratify individual SUDEP risk, the authors suggested.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This study was supported by Finding A Cure for Epilepsy and Seizures (FACES), and the Australian National Health and Medical Research Council.

Devinsky has equity interests in Qstate Biosciences, Tevard Biosciences, Regel Therapeutics and Script Biosciences, Privateer Holdings, Tilray, Receptor Life Sciences, Empatica, Engage, Egg Rock/Papa & Barkley, Rettco, SilverSpike, and California Cannabis Enterprises. He is an investigator for PTC Therapeutics, Inc., Stoke Therapeutics, Marinus, Ovid, and GW Pharmaceuticals.

Sander reported personal fees from Eisai, UCB Pharma, Arvelle, and Zogenix Pharma, and grants from Eisai, UCB Pharma, National Epilepsy Funds (Netherlands), National Institute for Health Research and GW Pharma. Thijs reported no relevant disclosures.

Cat ID: 34

Topic ID: 82,34,730,34,192,925