Risk of Sudden Unexpected Death in Patients With Epilepsy, Cardiac Autonomic Dysfunction

Abnormal cardiac autonomic response to sympathetic stimulation by hyperventilation may influence mortality in patients with epilepsy.

Abnormal cardiac autonomic response to sympathetic stimulation by hyperventilation is associated with an increased risk for sudden unexpected death in epilepsy (SUDEP), according to study results published in Neurology.

While functional alterations of the autonomic nervous system may play a key role in the pathophysiology of SUDEP, previous studies have provided mixed data on the association between heart rate variability and the risk for SUDEP. The objective of the current study was to determine the effect of hyperventilation on heart rate variability (HRV) in patients with SUDEP and matched controls.

This retrospective, observational case-control study included all cases of SUDEP from 5 French university medical centers between January 1, 2010 and March 31, 2019. Heart rate and HRV parameters were assessed at rest, during and after hyperventilation performed during the last electroencephalogram recording before SUDEP. Study researchers matched controls with patients for epilepsy type, drug resistance, sex, age at electroencephalogram recording, age at onset of epilepsy, and duration of epilepsy.

They calculated several HRV indices for a 64 second time window: the standard deviation of normal-to-normal RR intervals, the root mean square of successive RR-interval differences (RMSSD), and low and high frequency power. Study researchers then averaged each HRV parameter for 56 consecutive time windows.

The study sample included 20 of 35 recorded SUDEP cases (men, 10; median age at onset of epilepsy, 12.5 years), including 3 definite SUDEP and 17 probable SUDEP cases.

At rest, there were no differences in HRV parameters between the SUDEP group and controls, except for high frequency power that was significantly higher in the SUDEP group (P =.033).

During the hyperventilation, heart rate increased and the RMSSD decreased before returning to the baseline values by around 2 and +4 minutes after the end of the hyperventilation, respectively, among patients in the control group. However, in the SUDEP group there were no significant changes in the heart rate and RMSSD during or after hyperventilation.

Differences in heart rate between the successive times before and after the hyperventilation enabled discrimination between SUDEP patients and controls; the greatest discriminating factor between the groups was recorded for the change in heart rate between the end of hyperventilation and 4 minutes later with a sensitivity of 85% and a specificity of 75%.

The study had several limitations, including the small sample size, exclusion of patients who were not able to perform hyperventilation, and retrospective design.

“Most of patients with subsequent SUDEP have an abnormal cardiac autonomic response to sympathetic stimulation through hyperventilation. An index reflecting the change in heart rate upon hyperventilation (dHRh) might be predictive of the risk of SUDEP and could be used to select patients at risk of SUDEP for inclusion in trials assessing protective measures,” concluded the study researchers.


Szurhaj W, Leclancher A, Nica A, et al. Cardiac autonomic dysfunction and risk of sudden unexpected death in epilepsy. Neurology. Published online April 9, 2021. doi:10.1212/WNL.0000000000011998