Decreased heart rate and enhanced sinus arrhythmia during interictal sleep demonstrate autonomic imbalance in generalized epilepsy

Abstract

We hypothesized that epilepsy affects the activity of the autonomic nervous system even in the absence of seizures, which should manifest as differences in heart rate variability (HRV) and cardiac cycle. To test this hypothesis, we investigated ECG traces of 91 children and adolescents with generalized epilepsy and 25 neurologically normal controls during 30 min of stage 2 sleep with interictal or normal EEG. Mean heart rate (HR) and high-frequency HRV corresponding to respiratory sinus arrhythmia (RSA) were quantified and compared. Blood pressure (BP) measurements from physical exams of all subjects were also collected and analyzed. RSA was on average significantly stronger in patients with epilepsy, whereas their mean HR was significantly lower after adjusting for age, body mass index, and sex, consistent with increased parasympathetic tone in these patients. In contrast, diastolic (and systolic) BP at rest was not significantly different, indicating that the sympathetic tone is similar. Remarkably, five additional subjects, initially diagnosed as neurologically normal but with enhanced RSA and lower HR, eventually developed epilepsy, suggesting that increased parasympathetic tone precedes the onset of epilepsy in children. ECG waveforms in epilepsy also displayed significantly longer TP intervals (ventricular diastole) relative to the RR interval. The relative TP interval correlated positively with RSA and negatively with HR, suggesting that these parameters are linked through a common mechanism, which we discuss. Altogether, our results provide evidence for imbalanced autonomic function in generalized epilepsy, which may be a key contributing factor to sudden unexpected death in epilepsy.

Keywords: SUDEP; cardiac cycle; children; heart rate variability; parasympathetic tone.

Fig. 1.

Heart rate variability (HRV) in representative control (left) and epilepsy (right) subjects. A and B: raw ECG traces over periods of 30 s; decreased HR is readily apparent in the subject with epilepsy. C and D: instantaneous HR over the same 30-s periods as in A and B; lower baseline and increased variability are visible in the patient with epilepsy. E and F: power spectral densities of HR over a 30-min period, filtered above 0.1 Hz; high-frequency modulation of HR, corresponding to respiratory sinus arrhythmia (RSA), is enhanced in epilepsy.

Fig. 2.

Analysis of HRV across control (circles) and epilepsy (diamonds) subjects. A: RSA tends to be increased in patients with epilepsy. B: frequency of RSA (a measure of the respiratory frequency) is not different in epilepsy compared with the control group. C: mean HR tends to be lower in epilepsy. D: after adjusting for age, body mass index (BMI), and sex, HR is still significantly lower in epilepsy. E: RSA and HR are negatively correlated, consistent with their being mediated by parasympathetic activity. F: frequency of RSA and HR are positively correlated, as expected. r, correlation coefficient. **P < 0.01 (highly significant); n.s., not significant.

Fig. 3.

Sensitivity (SE) and specificity (SP) of HRV parameters and comparison of blood pressures (BPs). A–C: receiver-operating characteristic curves for power of RSA, mean HR, and the RSA/HR ratio, respectively. Solid diagonal lines mark the optimal thresholds for classification, and their numerical values are shown. D: comparison of SE, SP, and accuracy for RSA, HR, and the RSA/HR ratio. E and F: systolic and diastolic BPs at rest are similar in both control (circles) and epilepsy (diamonds) groups. n.s., not significant.

Fig. 4.

ECG waveform analyses. A: comparison of mean-subtracted, cycle-triggered, average ECG traces centered at R wave and plotted over 2 beat-to-beat periods (RR interval). B and C: the QT interval relative to the RR interval appears to be shortened in epilepsy (diamonds) compared with controls (circles); however, after adjusting for age, BMI, and sex, there is no significant difference in QT interval between groups. D: in contrast, the relative PR interval (atrial systole) is significantly shorter and does not depend on age, BMI, or sex. E and F: this relative shortening occurs at the expense of a longer relative ventricular diastole (TP/RR). G and H: the adjusted relative ventricular diastole correlates positively with the RSA power and negatively with the adjusted HR. I: the RS relative amplitude is not significantly different between groups. **P < 0.01 (highly significant); n.s., not significant.