Deeper Sleep, Slower Heart Rate Tied to Sudden Death in Epilepsy

Deeper sleep and slower heart rate following seizures may work synergistically to increase the risk for sudden unexpected death in epilepsy (SUDEP), new research suggests.

Investigators analyzed data on 100 seizures in 42 patients with epilepsy. They assessed the depth of the patients' sleep during the 5 minutes prior to the seizure and found that greater sleep depth was predictive of bradycardia following the episode. This finding suggests that the lower heart rate may increase the risk for SUDEP, which is more common during sleep than when patients are awake.

"The results from this study suggest that seizures during sleep are more likely to lead to slower heart rate, an effect that is likely secondary to the natural slowing of the heart rate during sleep and an increase in parasympathetic tone," lead author Andrew Schomer, MD, assistant professor of neurology, University of Virginia, Charlottesville, Virginia, told Medscape Medical News.

"We know there is an increased risk [for SUDEP] during sleep and if seizures are poorly controlled, and our study highlights the need for better understanding of the pathophysiologic mechanisms of SUDEP so that we might be able to better identify patients who are at an increased risk and try to prevent this tragic outcome," he added.

The study was published in the May issue of Epilepsia.

Unwitnessed Seizures

"The interactions between cardiac regulation and sleep may have clinical import, in that the majority of sudden unexpected deaths in epilepsy occur during sleep," the authors write.

"These events are typically unwitnessed, and many of the patients have had a history of nocturnal seizures," they add.

"SUDEP is a devastating outcome for some patients with epilepsy, and although a lot is known about some risk factors associated with this phenomenon — frequency of seizures, generalized tonic-clonic seizures [GTCSs], and an increased frequency during sleep — the pathophysiologic mechanism is still not fully understood," Schomer said.

During rapid eye movement (REM) sleep, parasympathetic tone decreases.

Bradycardia occurs postictally in roughly 3% to 4% of patients with seizures. The vagal response that decreases heart rate "likely potentiates the central parasympathetic disruption seen in the postictal state," the authors write. This might increase the risk for death following seizures that occur during sleep.

To investigate the effect of sleep seizures, the researchers monitored the brain and heart activity during sleep of 42 patients (mean age, 45 ± 14.6 years). The average duration of epilepsy diagnosis was 20.5 ± 16.9 years. Most patients were being treated with two or more antiepileptic drugs (AEDs).

The researchers recorded heart rate in the postictal period (10 minutes following the seizure). The lowest recorded value for each seizure — ie, the postictal nadir of heart rate (PINHR) — was determined by the slowest 10 beats within that window.

Sleep depth was the main independent variable. It was defined as the "weight sum of the preictal 3 minutes or 10 epochs" (with each epoch consisting of 30 seconds). The phases of sleep were accorded a score ― wake was scored at 0, and the remaining phases (N1, N2, and N3) were scored at 1, 2, and 3, respectively. Thus, scores could range from 0 (in which all epochs were wake) to 30 (in which all epochs were N3 sleep).

Because only a few epochs preceded seizures consisting of REM sleep, REM was excluded from sleep depth calculation. It was used as a secondary independent variable in a separate analysis.

Potential covariates included preictal heart rate, age, sex, number of AEDs taken over the patient's history, and seizure type.

Surrogate Marker?

Of the 101 recorded seizures, 35% were preceded by ≥1 epochs of sleep. The average sleep depth during the 5 minutes preceding the seizures was 4 ± 7.2.

"No patients had clinically significant cardiac changes," the authors report However, they note that one patient had an atrioventricular block in the postictal period.

"A greater depth of sleep was associated with lower postictal heart rates (Pearson correlation coefficient, -.229)," the authors state.

The mean recorded PINHR for all seizures was 71.1 ± 12.4, with a range from 43 to 118 BPM. Lower PINHR was associated with preictal heart rate, age, and seizures (other than GTCSs).

When these variables were included with sleep depth in a multivariate regression, the statistical model improved, in that a 1-point increase in sleep depth decreased minimal heart rate by -.254 (95% CI, -.375 to -.133).

Preictal heart rate and age remained significant in the multivariate analysis.

Only three seizures contained REM during the 5 minutes preceding the seizure, but the PINHR of those seizures was "markedly lower" in comparison with seizures not preceded by REM episodes. The authors note that because of the small sample, these differences could not be considered significant.

Sex, time of day of the seizure, and number of AEDs had no significant impact on PINHR.

"Although most seizures caused an increase in heart rate, around one third had a decline in heart rate," said Schomer.

The findings "support the overall hypothesis that postictal cardiac decelerations likely potentiate the normal physiologic effect of sleep," the authors write.

They suggest that bradycardia may be a "surrogate marker for those at increased risk of more severe cardiac deterioration after seizures" and that the findings "support the hypothesis that sleep state provides an autonomic environment that favors postictal cardiac dysregulation."

The authors acknowledge that more research "in a larger sample will allow an analysis of a greater variety of physiological measurements."

No Direct Evidence

Commenting on the study for Medscape Medical News, David Vossler, MD, medical director of the Neuroscience Institute, University of Washington, Renton, Washington, said the study "confirms what one might logically expect, namely, that slower heart rate after seizures correlates with deeper pre-seizure sleep stage."

The authors "suggested bradycardia may be a surrogate marker for an increase in more severe cardiac deterioration after a seizure, but of their 42 patients, only one was found with postictal atrioventricular block," noted Vossler, who is the vice chair of the Council on Clinical Activities at the American Epilepsy Society and was not involved in the study.

"Therefore, this study does not provide direct evidence that certain preictal sleep stages place patients with epilepsy at greater risk of postictal cardiac dysrhythmias or SUDEP," said Vossler.

The study was funded by the National Institute of Neurological Disorders and Stroke. The authors and vossler have disclosed no relevant financial relationships.

Epilepsia. 2021May;62:e65-e69. Abstract

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