Epilepsy is a disease known to occur with autonomous phenomenons. Earlier studies indicate decreased heart rate variability (HRV) during ictal and interictal periods among epilepsy patients. In this study, we aim to investigate cardiac rhythm abnormalities and HRV during interictal period between drug-naïve patients with idiopathic generalized epilepsy (IGE) and healthy control group.
Twenty-six patients with IGE and 26 healthy individuals included in the study. In order to eliminate any structural cardiac pathology, transthoracic echocardiography was performed in all subjects and time and frequency domain parameters of HRV were evaluated after 24-hour rhythm holter monitoring.
Between two groups, no significant difference was detected in terms of mean heart rate and maximum duration between the start of the Q waves and the end of the T waves (QT intervals). In the time domain analysis of HRV, no statically significant difference was detected for standard deviation of all R - R intervals and root-mean-square of successive differences between patient and control group (
Our results suggest that there is no major effect of the epilepsy on HRV in patients with IGE. It should be emphasized that, in this study, HRV was evaluated only in patients with IGE and that the results are not proper to be generalized for patients with partial seizures.
Sudden unexpected death in epilepsy (SUDEP) is one of the most important causes of death in patients with epilepsy. Although the exact mechanism of SUDEP is still controversial, autonomic dysfunction has been considered to play a significant role. The theories proposed on the mechanism of SUDEP have focused on autonomic instability and contain possible cardiac arrhythmias.
The HRV reflects the balance of sympathetic and parasympathetic activities on the heart. While parasympathetic stimulation slows the heart rate, on the contrary, heart rate is accelerated by sympathetic stimuli. Autonomic control of the heart is generally regulated by parasympathetic system at rest.
The drug-naïve patients with IGE applied to the Marmara University, Department of Neurology outpatient clinic were evaluated prospectively. Patients in the 15–45 age range and diagnosed with IGE according to the International League Against Epilepsy (ILAE) 1989 classification were included in the study. Patients with a history of any disease that can lead to the cardiac autonomic dysfunction and/or patients receiving any medication other than antiepileptics known to affect the blood pressure and/or heart rate were excluded from the study. Magnetic resonance imaging was performed in all patients to exclude any structural pathology and interictal activated electroencephalography (EEG) was performed to confirm the clinical diagnosis. Patients who were clinically diagnosed with IGE with normal imaging were subjected to further evaluation. Patients who had a seizure during the previous 24-hour period of recordings were excluded from the study. None of the patients had any cardiopulmonary disease, diabetes mellitus and/or a history of substance abuse. Healthy volunteers with normal physical and neurological examinations were chosen from amongst hospital staff as a control group.
Fourteen female and 12 male, a total of 26 patients meeting the inclusion criteria and 26 gender matched (14 female and 12 male) healthy volunteers were included in the study. The mean age of patient group was 26,15 ± 5,97 and that of control group was 28,69 ± 4,76. There was no age difference between groups (
For each patient, first seizure date, frequency of seizures and history of febrile convulsion were questioned. In all cases, routine physical and neurological examinations were performed, liver and renal function tests and serum electrolytes were obtained and no pathological result was detected. Transthoracic echocardiography (TTE) was performed in all patients and healthy volunteers with General Electric Vivid 7, USA echocardiography device. Diastolic and systolic diameters of the cardiac chambers were measured by 2D, M-mode, Doppler and tissue Doppler echocardiographic examination and left ventricular ejection fractions (EF) were measured by Simpson’s method. The study protocol was in accordance with the Helsinki Declaration on Human Rights and was approved by the local ethics committee.
The 24-hour rhythm holter monitorings of the patients and control subjects were performed by using miniature holter device, “DMS 9800, USA”. During the recordings, patients were asked to continue their routine daily activities and night sleeps, no special activity was required. Electrocardiographic raw data recorded in three channels were digitalised with 128-Hz sampling rate. Evaluation of electrocardiographic data and HRV were performed by a physician blinded to clinical informations of the patients via using the software “Cardioscan 12.0, DMS, USA”. Holter recordings were obtained at least 24 hours after seizure attacks and none of the patients had any seizure during the recordings.
The HRV was evaluated by both time domain and frequency domain analysis. Mean heart rate, standard deviation of all R–R intervals (SDNN) and root-mean-square of successive differences (RMSSD) were measured in the time domain analysis of HRV. The misclassified drop beats deviating more than three standard deviations (SD) from the mean normal RR-interval of each epoch were detected and epochs with more than 4% of non-normal RR-intervals were excluded from further analysis. At least 50% analyzable data of 24-hour recording was seeked to be analyzed. For frequency domain parameters, spectral analysis was performed by using fast-Fourier transform method. The power in the heart rate spectrum between 0.003 and 0.40 Hz was defined as total power (TP). The power in the heart rate spectrum was divided into four different frequency bands including TP, very low frequency power (VLF), low frequency power (LF) and high frequency power (HF). From these parameters, LF/HF ratio was calculated.
Data recording and statistical analysis were performed by using SPSS for Mac, version 20, (SPSS Inc., Chicago, IL, USA). All continuous variables were expressed as mean ± SD. The normal distribution of the data was determined by Kolmogorov-Smirnov test. Student’s
The mean age of the patients was 26.15 ± 5.97 years, and the median time from their first seizure to enrolment in the study was 93 months. There was no history of febrile convulsion in any of the patients. While 17 patients have not received any medical assistance in the past, the other 9 patients did not use recommended antiepileptic treatments since they were diagnosed with epilepsy. All patients had been seizure free at least 24 hours before the recordings and none of the patients reported any seizure during the recording. There was no significant difference between patients and controls in terms of demographic data including age and sex. The following parameters were evaluated by TTE; left ventricular ejection fraction (EF), left ventricular mass (LVM), left ventricular end-diastolic capacity (LVDC), left ventricular end-systolic capacity (LVSC) and E/A ratio; left ventricular diastolic function marker. All of these parameters were within normal limits in patients and controls and there was no significant difference between two groups. The demographic data, clinical charasteristics and TTE findings of the subjects are summarized in
In terms of mean, minimum and maximum heart rates and maximum duration of QT intervals, no significant difference was detected between two groups. In the time domain analysis of HRV, no statically significant difference was detected for SDNN and RMSSD parameters between patient and control groups (
In this study, we aimed to investigate the presence of interictal cardiac rhythm abnormalities and extent of HRV in drug-naïve patients with IGE. The heart rhythm of all patients during interictal period was sinus rhythm and in terms of mean heart rate, there was no difference in patients when compared to control group. In studies investigating cardiac rhythm abnormalities in patients with epilepsy, although the majority of detected abnormalities are in ictal and postictal period, it has been reported that these abnormalities can also be detected in interictal period.
Strzelczyk et al. reported an increase in T wave variability during GTCSs and Lanz et al. reported ictal asystole in patients with epilepsy.
In our study, we could not demonstrate any statistically significant difference in any of the analysed parameters between two groups. In the frequency domain analysis of HRV, an increase in HF values shows more dominant parasympathetic effect, on the other hand, higher LF values indicate the dominance of sympathetic effect. But, studies in recent years have shown that parasympathetic activity may also affect the value of LF.
In 2005, Evrengül et al. reported statically significant decrease in HF values, an increase in LF values and increase in LF/HF ratio in 42 young military recuits with newly diagnosed GTCSs compared to healthy controls.
In a recent study carried out by Mativo et al.,
The HRV measures in our drug-naïve patients with IGE were not different in any respect from the results obtained from healthy controls but the trends in our study suggests lower TP and VLF in the frequency domain parameters of HRV. In their recent meta-analysis, Lofuto et al. confirmed the hypothesis of sympathovagal imbalance in epilepsy patients by showing lower HF, SDNN, and RMSSD values in patients with epilepsy when compared to controls and there was a trend for higher LF in patients receiving pharmacotherapy.
In a study designed to determine SUDEP risk factors, De Giorgio et al. performed correlation analysis between HRV parameters and SUDEP-7 inventory scores and RMSSD values were determined positively correlated with the risk of SUDEP.
In conclusion, in our study we sought to investigate the presence of interictal cardiac rhythm abnormalities, extent of HRV and related factors in drug-naïve patients with IGE and we could not demonstrate any significant difference in any of the analyzed HRV parameters between our patients and healthy volunteers despite the non-significant trend towards lower values in TP and VLF among patients. Therefore, our results suggest that there is no remarkable effect of the epilepsy as such on HRV in patients with IGE. It should be emphasized that in this study, HRV was evaluated only in patients with IGE and that the results are not proper to be generalized for patients with partial seizures and other types of generalized seizures. Because of the limited number of included patients, further studies are needed to assess the effects of idiopathic generalized epilepsy on HRV in drug-naïve patients with IGE.
Demographic data, clinical charasteristics and TTE findings of the subjects
Patients | Controls | ||
---|---|---|---|
Female/male | 14/12 | 14/12 | NA |
Age (years) | 26.15 ± 5.97 | 28.69 ± 4.76 | 0.09 |
Age at onset (years) | 18.26 ± 8.91 | NA | NA |
Duration of illness (years) | 7.88 ± 8.64 | NA | NA |
Seizure frequency (per year) | 1.50 ± 0.92 | NA | NA |
Interictal EEG findings | |||
Generalized spike and waves | N: 19 | NA | NA |
Normal | N: 7 | NA | NA |
EF (%) | 68.45 ± 5.70 | 68.22 ± 5.22 | 0.89 |
LVM (gram) | 127.22 ± 17.13 | 141.31 ± 33.39 | 0.06 |
LVDC (mm) | 43.92 ± 4.12 | 45.95 ± 4.02 | 0.09 |
LVSC (mm) | 26.65 ± 3.45 | 27.81 ± 4.01 | 0.28 |
E/A ratio | 1.50 ± 0.36 | 1.45 ± 0.36 | 0.65 |
Values are presented as mean ± standard deviation unless otherwise indicated.
TTE, transthoracic echocardiography; NA, not applicable; EEG, electroencephalography; EF, ejection fraction; LVM, left ventricular mass; LVDC, left ventricular end-diastolic capacity; LVSC, left ventricular end-systolic capacity; E/A, left ventricular diastolic function marker; mm, millimeter; N, number of patients.
Time domain analysis of heart rate variability in patients with epilepsy and controls
Patients | Controls | ||
---|---|---|---|
Mean heart rate (beats/min) | 78.23 ± 7.80 | 74.50 ± 6.94 | 0.075 |
SDNN (ms) | 150.38 ± 26.39 | 165.76 ± 33.21 | 0.070 |
RMSSD (ms) | 38.19 ± 10.31 | 42.96 ± 10.42 | 0.104 |
Values are presented as mean ± standard deviation unless otherwise indicated.
SDNN, standard deviation of R-R intervals; RMSSD, root mean square successive difference of intervals.
Frequency domain analysis of heart rate variability in patients with epilepsy and controls
Patients | Controls | ||
---|---|---|---|
TP (ms2) | 4,028.0 ± 1,259.2 | 4,801.2 ± 1,604.0 | 0.059 |
HF (ms2) | 410.5 ± 283.4 | 497.1 ± 266.2 | 0.261 |
LF (ms2) | 985.1 ± 327.4 | 1,090.7 ± 277.8 | 0.216 |
VLF (ms2) | 2,605.4 ± 853.5 | 3,217.0 ± 1,301.7 | 0.051 |
LF/HF | 3.06 ± 1.56 | 2.65 ± 1.09 | 0.277 |
Values are presented as mean ± standard deviation unless otherwise indicated.
TP, total power; HF, high frequency absolute power; LF, low frequency absolute power; VLF, very low frequency absolute power; LF/HF, low frequency to high frequency ratio.