Effects of chronic epilepsy on heart rate variability
A case-control study*☆●
Yueloong Hsin1, 2, Cheryl C H Yang3, Terry B J Kuo3, Tomor Harnod1, 4

1School of Medicine, Tzu Chi University, Hualien  970, Taiwan
2Department of Neurology, Buddhist Tzu Chi General Hospital, Hualien  970, Taiwan
3Institute of Brain Science, National Yang Ming University, Taipei  112, Taiwan
4Department of Neurosurgery, Buddhist Tzu Chi General Hospital, Hualien  970, Taiwan

Yueloong Hsin☆, M.D., School of Medicine, Tzu Chi University, Hualien  970, Taiwan; Department of Neurology, Buddhist Tzu Chi General Hospital, Hualien 970, Taiwan

Corresponding author: Tomor Harnod, M.D., Ph.D., School of Medicine, Tzu Chi University, Hualien  970, Taiwan; Department of Neurosurgery, Buddhist Tzu Chi General Hospital, Hualien  970, Taiwan
nsha@tzuchi.com.tw

Supported by: a Grant from the Buddhist Tzu Chi General Hospital, Hualien, Taiwan*

Abstract
BACKGROUND: Dysfunctional autonomic cardiac regulation is thought to be associated with high mortality in epileptic patients.
OBJECTIVE: To explore changes in sympathetic and parasympathetic activities in epileptic patients with repetitive generalized tonic-clonic seizures by observing interictal heart rate.
DESIGN, TIME AND SETTING: A case-control study was performed at the Buddhist Tzu Chi Gen-eral Hospital from July 2006 to May 2009.
PARTICIPANTS: A total of 30 patients, comprising 15 males and 15 females, who presented with chronic epilepsy and repetitive generalized tonic-clonic seizures according to International League Against Epilepsy guidelines (ILAE, 1989), were selected. In addition, 30 matched, healthy volunteers were selected as controls.
METHODS: Lead I electrocardiogram was performed in the epilepsy and control groups for 5 min-utes during a daytime interictal period. Frequency-domain analysis of heart rate variability was performed using fast Fourier transformation.
MAIN OUTCOME MEASURES: Heart rate interval, high frequency (HF; 0.15–0.45 Hz) power, low frequency (LF; 0.04–0.15 Hz) power, and LF/(HF + LF) expressed in normalized units (LF%).
RESULTS: Compared with the control group, the epilepsy group exhibited a significantly lower mean heart rate interval and HF power, but a significantly greater LF% (P < 0.01). There was no significant difference in LF power between the groups (P = 0.17).
CONCLUSION: Patients with chronic epilepsy exhibited faster heart rates during interictal periods, which could contribute to higher sympathetic and lower parasympathetic activities.
Key Words: autonomic; epilepsy; heart rate; parasympathetic; sympathetic

INTRODUCTION
  
Impaired autonomic regulation of the heart has been reported in epileptic humans and animal epileptic models[1-5]. Autonomic dys-function has been associated with long-term mortality in epileptic patients, in particular with sudden unexpected death in epileptic patients (SUDEP)[3, 5-6]. The rate of SUDEP is approximately 1% per patient- year[6], and the risk factors involve generalized tonic-clonic seizure (GTC), early-onset or chronic epilepsy, multiple antiepileptic drugs, and refractory  epilepsy[5, 7-9]. The majority of studies that have addressed autonomic cardiac dysregulation in epilepsy have been confined to temporal lobe epilepsy and sympathetic dysregulation[10-11]. Autonomic function in patients with repetitive GTC has been explored over the past few years, but the mechanisms of sympathetic and para-sympathetic cardiac regulation in these pa-tients remains unclear[9, 12-13].
Frequency-domain analysis of heart rate variability (HRV) is a sophisticated and noninvasive method to explore neural regu-lation of heart rate[1, 14-15]. HRV includes a high-frequency (HF; 0.15–0.45 Hz) and low-frequency (LF; 0.04–0.15 Hz) power component. The LF component is regulated by sympathetic and parasympathetic inner-vation. The HF component is a result of respiratory sinus arrhythmia and is consid-ered to reflect vagal (parasympathetic) car-diac regulation. The LF/(HF+LF) fraction is expressed as a normalized unit (LF%) and is considered to mirror sympathetic regula-tion[16]. Standard procedures and interpreta-tions of HRV analyses were first reported in 1996[16], and modified procedures have been used in human subjects[17].
This study applied frequency-domain analy-sis of HRV to evaluate sympathetic and parasympathetic regulation of heart rate in epileptic patients with repetitive GTC.

SUBJECTS AND METHODS

Design
A case control study.
Time and setting
The experiment was performed at the Buddhist Tzu Chi General Hospital from July 2006 to May 2009.
Participants
Epilepsy group
Between July 2006 and May 2009, 15 males and 15 females, who presented with chronic epilepsy and re-petitive GTC, were enrolled in the present study from the Epilepsy Center of the Buddhist Tzu Chi General Hospital, Hualien, Taiwan. The patients were inter-viewed and seizure types were classified according to the International League Against Epilepsy Guidelines (ILAE, 1989)[18]. Brain magnetic resonance imaging (MRI) was used to detect possible structural lesions, and 24-hour electroencephalography (EEG) was used to detect epileptogenic zones and seizure types.
None of the patients presented with a history of arrhyth-mia, hypertension, cardiovascular disease, diabetes mellitus, or other systemic disease. Patients with promi-nent mental retardation, uncooperative emotion to the study, or with drug treatment that could affect autonomic function (such as carbamazepine[19]), were excluded from the study.
Clinical features of epileptic patients are listed in Table 1.
 

Control group
A total of 15 male and 15 female volunteers were in-cluded in the control group, who were anthropometric matched to the epilepsy group. There was no history of physical or psychological disease in the controls.
This study was approved by the Ethical Committee of the Tzu Chi University and Hospital. The subjects were not related, and written informed consent was ob-tained.
Methods
Clinical examination
Brain MRI and 24-hour EEG were used to detect possible structural lesions and epileptogenic zones at admission. A daytime electrocardiogram (ECG) was interictally performed on awake participants. ECG was recorded over a 5-minute period, while the subject lay quietly at a 45° angle with the head up and breathing normally. Lead I ECG signals were retrieved using a self-developed, analog-to-digital converter, with a sampling rate of 512 Hz. The digitized ECG signals were analyzed on-line and were simultaneously stored on a hard disk for off-line analysis[1, 17]. ECG was performed in the controls using the same pro-cedures.
Processing of ECG signals
Signal acquisition, storage, and processing were per-formed using an IBM-compatible personal computer. Each QRS complex was identified using a computer algorithm, and each ventricular premature complex or noise was rejected according to likelihood using a standard QRS template. Stationary R-R values were re-sampled and interpolated at a rate of 7.11 Hz to pro-vide continuity in a time-domain[1, 17].
Frequency-domain analysis of HRV
Frequency-domain analysis was performed using a nonparametric method of fast Fourier transformation (FFT). The direct current component was deleted and a Hamming window was used to attenuate the leakage effect. For each time segment (288 seconds; 2 048 data points), the power spectrum density was estimated on the basis of FFT. The resulting power spectrum was corrected for attenuation resulting from sampling and the Hamming window[1, 17]. The power spectrum was subse-quently quantified into standard frequency-domain measurements, as defined by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology[1, 16], including R-R intervals (the intervals between two neighboring R waves, RR), HF (0.15–0.45 Hz) power, LF (0.04–0.15 Hz) power, and LF%. The HF and LF power data were loga-rithmically transformed to correct for skews in the distri-bution[1, 17].
Main outcome measures
Heart rate interval, HF power, LF power, and LF%.
Statistical analysis
Statistical analyses were performed using SPSS ver-sion 15.0 (SPSS, Chicago, IL, USA). Continuous, normally distributed data were presented as Mean ± SD, and nonparametric data were presented as the median (range). The significance of differences be-tween groups was examined using Student’s t-test for independent continuous variables. If the data were far from normal distribution, the Mann-Whitney U test was applied. All statistical assessments were two-sided, and P < 0.05 was considered statistically significant.

RESULTS

Quantitative analysis of participants
All 30 epileptic patients and 30 healthy volunteers were included in the final analysis.
Basic data from epilepsy and control groups
Basic data from all 60 participants is listed in Table 2.

There was no significant difference in gender, age, body mass, height, and body mass index between epilepsy and control groups.
HRV and spectrum
HRV spectrum analysis shows that the epileptic patients had less variable heart rate and lower spectral power between 0.04 Hz and 0.45 Hz (Figure 1).

Statistical results demonstrated that the epilepsy group exhibited a significantly lower mean heart rate interval and HF power, as well as a significantly higher LF%, compared with the control group (P < 0.01), but there were no differences in LF power (P = 0.17, Table 3).

DISCUSSION

The hypothalamus is an autonomic regulatory region of the brain[20]. Impaired hypothalamic function has been demonstrated during GTC seizures[21], and changes in hypothalamic function could alter heart rate regulation. Results from the present study confirmed that chronic epilepsy with repetitive GTC seizures affected interictal regulation of autonomic cardiac function. Heart rate and HRV in epileptic patients with repetitive GTC seizures has been shown to respond to a simultaneous increase in sympathetic, and decrease in parasympathetic activity. Increased sympathetic activity has been shown to be responsible for cardiac tachyarrhythmia and SUDEP[11]. However, recent studies have demonstrated that repeti-tive seizures resulted in either decreased parasympa-thetic or increased sympathetic indicators[2-3].
SUDEP has been described in TLE, as well as other forms of epilepsy[6-7, 9, 13]. Based on previous    stud-ies[1-3, 6-10, 19], indicators of HRV could be used to predict SUDEP risk and guide epilepsy treatment. It has been hypothesized that SUDEP is primarily due to increased sympathetic regulation[2, 6, 9-13]. Therefore, treatments that reduce sympathetic activity are favored to reduce the risk of sudden death[19]. One study reported that increased parasympathetic or vagal activity protected against SUDEP by suppressing atrial or ventricular fibrillation[22]. These results suggested that SUDEP risk was greater great in patients with chronic epilepsies, and that the increased risk was a result of higher sympathetic or lower parasympathetic regulation.
HRV varies widely, even in healthy populations[16], and this is most likely due to effects of circadian rhythms[4, 23], gender[17], age[17, 24-25], body mass index[26], and posture or activity[25]. In the present study, all interictal heart rates were recorded during the daytime to avoid major cir-cadian effects, and all participants were placed at a 45° angle in a head-up position and were asked to breathe quietly to avoid effects of posture or activity. In addition, differences between epilepsy and control groups with known anthropometric factors, such as gender, age, body mass, height, and body mass index, were excluded. Because there were no significant differences between groups with regard to circadian and anthropometric characteristics, the effect of chronic epilepsy on HRV was more accurate.
Phenytoin has been used as an anti-arrhythmic drug to modulate heart rates over longer periods of time. How-ever, currently used antiepileptic drugs, other than car-bamazepine, which has been reported to suppress autonomic cardiac activity[18], do not exhibit any known effects on HRV[5]. Autonomic cardiac dysfunction has been well documented in patients with hypertension, diabetes mellitus, cardiac arrhythmia, and cardiovascular disease[27], therefore these patients were excluded in the present study. Epilepsy could result from a variety of pathologies, including focal or generalized anomalies in brain structure, and these appear to exhibit possible ef-fects on HRV or epileptic seizures. Through the use of brain MRI, patients with presumed idiopathic or crypto-genic epilepsy were enrolled in the present study, and altered HRV was thought to relate to epilepsy itself, rather than to other confounding factors[14]. However, the sample size of the present study was relatively small. Patients were included who: (1) received a combination of antiepileptic drugs that most likely (although not known to) affected autonomic function, or (2) suffered seizure types other than GTC seizures. All these factors could affect the results.
Autonomic cardiac function can be monitored via re-peated 5-minute ECG, and heart rate can be measured using frequency-domain analysis of HRV, in a single subject. These recordings can be performed in a ward, clinic, hospice, or in a patient’s home to minimize the effects of stress on autonomic nervous system. The digi-tized data file in the 5-minute recording is relatively small and can be transmitted via the Internet. This technology is especially valuable in patients uncooperative or un-willing to undergo 24-hour ECG monitoring with HRV analysis (e.g., school children, young children, mentally handicapped adults and children, or patients with be-havioral problems)[1, 15]. Although the 24-hour recording was superior to the 5-minute recording, the 5-minute recording was highly assessable and obtained a positive result, which allowed for further testing (i.e., 24-hour ECG recording with analysis).
In conclusion, epileptic patients with repetitive GTC exhibited shorter, interictal heart rate intervals and faster heart rates, which are possibly due to higher sympathetic and lower parasympathetic regulation of autonomic cardiac activity.

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 (Edited by Wang LC, Shi J/Su LL/Song LP)