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Analysis of heart rate variability-related indexes in the interictal period in patients with focal epilepsy
Accepted Manuscript Analysis of heart rate variability-related indexes in the interictal period in patients with focal epilepsy
Yun-Li Yu, Na-Na Li, Meng-Ting Shi, Hong-Juan Lu PII: DOI: Reference:
S0024-3205(18)30480-6 doi:10.1016/j.lfs.2018.08.033 LFS 15880
To appear in:
Life Sciences
Received date: Revised date: Accepted date:
13 April 2018 9 August 2018 13 August 2018
Please cite this article as: Yun-Li Yu, Na-Na Li, Meng-Ting Shi, Hong-Juan Lu , Analysis of heart rate variability-related indexes in the interictal period in patients with focal epilepsy. Lfs (2018), doi:10.1016/j.lfs.2018.08.033
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Analysis of heart rate variability-related indexes in the interictal period in patients with focal epilepsy
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Running title: Analysis of HRV of Patients with FE
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Yun-Li Yu*, Na-Na Li, Meng-Ting Shi, Hong-Juan Lu
Department of Neurology, The Affiliated Hospital of Guizhou Medical University,
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Guiyang 550004, China.
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*Corresponding author
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Yun-Li Yu
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Department of Neurology,
Affiliated Hospital of Guizhou Medical University,
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No. 28, Gui Yi Street, Yunyan District, Guiyang 550004, China. Tel: +86 851 86855119 Fax: +86 851 86855119 E-mail: [email protected]
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Abstract Aims: Changes in cardiac autonomic nervous function have been evaluated by studying the related indexes of heart rate variability (HRV) in patients with focal epilepsy (FE) in the interictal period. Main methods: A total of 30 FE patients who were treated in our
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department from July 2015 to May 2017, were included into this study. These patients
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were divided into three pairs of groups: less frequent seizure group and more frequent seizure group; medication group and non-medication group; <10 years disease group and
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≥10 years disease group. In addition, 16 normal healthy subjects were enrolled as the
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control group. The time domain and frequency domain indexes of HRV indexes between subgroups and the control group were retrospectively analyzed. Key findings: The
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low-frequency/high-frequency ratio (LF/HF) in the interictal period was higher in the more frequent seizure group than in the control group and less frequent seizure group
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(P<0.05). Furthermore, differences in interictal LF/HF and very low frequency (VLF)
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between the medication group and non-medication group and control group were statistically significant (P<0.05). Significance: In interictal period FE patients who
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present with an imbalance in autonomic nervous function, LF/HF can serve as an indicator to evaluate the interictal cardiac sympathetic activity of FE patients.
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Furthermore, the dynamic observation of changes in the HRV-related indexes of FE patients can prevent the choice of antiepileptic drugs that affect heart function, which is of guiding significance for evaluating autonomic nervous function.
Keywords: focal epilepsy; interictal period; autonomic nerve; heart rate variability; LF/HF
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1. Introduction The mortality of epileptic patients is 2-3 times of that in the normal population [1]. Sudden unexpected death in epilepsy (SUDEP) accounts for 17% of the total mortality of epilepsy [2]. Especially for young patients with epilepsy, the incidence of SUDEP is 27 times of the sudden death in the general population [3]. The mechanism of SUDEP
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remains unknown. Postictal electroencephalography (EEG) suppression, fatal respiratory
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dysfunction, malignant cardiac dysfunction and central autonomic nervous system
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dysfunction may be correlated to SUDEP [4-6]. Most studies have suggested that tonic-clonic seizures are closely associated to SUDEP. Therefore, many studies on
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SUDEP mechanism related to tonic-clonic seizures have been carried out. However, it remains unclear whether focal epilepsy (FE) patients also have a risk of SUDEP. Some
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scholars found that [7] SUDEP was not associated with seizures. This suggests that the mechanism of SUDEP is complicated. Therefore, it is necessary to study the functional
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changes of the autonomic nerve in the interictal period in FE patients, in order to provide
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a basis for the study of the mechanism of SUDEP. Heart rate variability (HRV) can sensitively and intuitively reflect the early
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abnormal changes of the cardiovascular autonomic nerve [8, 9]. The investigators hope that the present study can provide guidance in the clinical selection of appropriate
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antiepileptic drug regimens, help find seizure-related HRV changes in time, remind the risk of related sudden death, and induce doctors and patients to pay attention to SUDEP.
2. Materials and Methods 2.1 Subjects This study was conducted in accordance with the declaration of Helsinki, and approved by the local Ethics Committee. On the basis of the informed consent provided
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by the patients, the investigators collected sporadic FE patients in Guizhou, 30 patients diagnosed with FE from July 2015 to May 2017 in the Department of Neurology, the Affiliated Hospital of Guizhou Medical University, were included into the present study. All FE patients were diagnosed based on the diagnostic criteria developed by the International League Against Epilepsy (ILAE) in 2017 [10], and the history of the disease
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in the seizure period was inquired in detail by deputy chief physicians or more senior
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experts at the Neurology Department of the Affiliated Hospital of Guizhou Medical
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University. In addition, these FE patients were confirmed to meet the diagnostic criteria by video electroencephalogram examination and imaging. Patients with the following
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conditions were excluded: (1) patients who did not meet the FE diagnosis; (2) patients with a heart disease; (3) patients with diseases that have an obvious impact on the
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autonomic nervous function of the heart, such as abnormal metabolism of the thyroid, diabetes, Parkinson's disease, multiple system atrophy, severe psychosis or intellectual
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impairment, and liver failure; (4) patients who used drugs that can affect autonomic
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nervous function other than antiepileptic drugs. Healthy volunteers with normal physical and neurological examinations were chosen from the physical examination center of our
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hospital as a control group. 2.2 Research methods
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2.2.1 24-hour ambulatory electrocardiogram All the participants completed the 24-hour ambulatory electrocardiogram examination (Nihon Kohden RAC-3012), Electrocardiographic raw data recorded in three channels were digitalised with 1024-Hz sampling rate. Before this examination, all patients took a rest in the supine position for 30 minutes. The monitoring was conducted in the video EEG examination room and the range of activity was limited. The subjects of the study were prohibited from drinking coffee, tea, alcohol and other beverages that
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affect the index of heart rate variation 12 hours before and the same day of the monitoring. They were also prohibited from smoking and strenuous exercise to maintain emotional stability. However, considering respiration has impact on HRV, we always ask objects not to breathe heavily during the test periods. Normal physiological activities were carried out, and set the sleeping time for 6-8 hours. In order to determine whether
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patients had a seizure during ECG monitoring, the family members were required to
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accompany during the monitoring. Dynamic electroencephalogram examination was
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performed simultaneously. If the patient had an attack during the monitoring period, his data would be excluded. Holter recordings were obtained at least 24 hours after seizure
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attacks and none of the patients had any seizure during the recordings. HRV data were analyzed to study the alteration trend of the function of the autonomic nervous system of
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FE patients by analyzing the changes in interictal HRV. The calculation of the HRV parameters based on 24-hour of ECG data. After the examination, the ECG signals were
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imported in the computer and automatically analyzed, which assisted with manual
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correction and editing. The dynamic electrocardiogram machine can automatically identify the RR interval less than 350ms or greater than 1500ms, and delete these
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unqualified data. In order to eliminate abnormal ECG caused by ventricular premature beats, missed beats, ectopic beats or body movements, manual deletion of artifact is
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required to avoid impact on analysis results. The above data analysis was performed by ECG professionals. Changes in related electrocardiogram indexes were automatically calculated. 2.2.2 HRV indexes Analysis of heart rate variability in the time and frequency domains were done according to the standards of the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology [11].
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(1)Commonly used indicators in time domain analysis, time domain analysis uses various statistical methods to quantitatively describe the changing characteristics of each cardiac cycle. In the time domain analysis of HRV, the variation of heart rate is usually represented by the change of RR interval. Such as the triangular index, standard deviation of average 5-minute intrinsic R-R intervals (SDANN), the standard deviation of normal
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NN intervals (SDNN) index, root mean square of successive differences (RMSSD),
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NN50 and the Edinburgh index (PNN50), were collected.
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(2) Frequency domain analysis is also known as spectrum analysis of the heart rate, where special computing methods, such as Fourier transformation and autoregressive
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model analysis, are used to decompose the time-varying heart rate fluctuation curve into the sum of sinusoidal curves of different frequencies and amplitudes. Hence, the
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spectrum of HRV is obtained. The human HRV power spectrum is often divided into four domains: high frequency zone (HF: 0.15-0.40 Hz), low frequency zone (LF: 0.04-0.15
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Hz), very low frequency zone (VLF: 0.0033-0.04 Hz), and ultra low frequency zone
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(ULF: <0.0033 Hz). The LH/FH ratio reflects the balance of the sympathetic and parasympathetic nerve.
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FE patients were grouped according to frequency of seizures, drug use and the course of disease, and a comparison among groups was conducted.
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2.3 Statistical analysis
Statistical analysis was conducted using statistical software SPSS 22.0. In the experimental results mentioned above, the measurement data were expressed as mean ± standard deviation, and analyzed using one-way analysis of variance. The pairwise comparison among groups was conducted using the least significant difference (LSD) test. Count data were compared using X2-test. P<0.05 was considered statistically significant.
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3. Results 3.1 Demographic and clinical data Among these patients, 17 patients were male and 13 patients were female. The age of these patients ranged within 18-64 years old, and the course of disease ranged from 6 months to 30 years. The control group comprised of 16 subjects, in which 9 subjects were
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male and 7 subjects were female. The age of these subjects ranged within 22-63 years old.
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There was no difference between groups regarding gender, age (p>0.05). Table 1 shows
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the demographic characteristics of the cohort. Demographic and clinical data of FE
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patients are summarized in Table 2.
3.2 Comparison of different frequencies of seizures among the control group and FE
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groups
According to different seizure frequencies, FE patients were divided into two groups:
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less frequent seizure group (≤3 times/year, n=14), and more frequent seizure group (>3
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times/year, n=16). The comparison of HRV indexes among the less frequent seizure group, more frequent seizure group and control group are presented in Table 3.
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Table 3 demonstrates that, except for LF/HF, the differences in the other HRV indexes among groups were not statistically significant (P>0.05). Table 4 demonstrates
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that the further pairwise comparison of LF/HF ratios revealed that the LF/HF ratio was significantly higher in the more frequent seizure group than in the control group, and the difference was statistically significant (P<0.01). Furthermore, the interictal LF/HF ratio was significantly higher in the more frequent seizure group than in the less frequent seizure group, and the difference was statistically significant (P=0.038).
3.2 Comparison of different medication situations between the control group and FE
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groups According to whether FE patients were treated with antiepileptic drugs, they were divided into two groups: medication group (n=14) and non-medication group (n=15). One patient was excluded due to unclear medication history. The HRV indexes were compared among the medication group, non-medication group and control group (Table
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3).
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Table 5 demonstrates that the differences in VLF (P=0.014) and LF/HF (P=0.021)
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were statistically significant. The pairwise comparison of VLF and LF/HF was conducted among the three groups. Table 6 demonstrates that the LF/HF ratio was higher in the
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medication group than in the control group, and the difference was statistically significant. Table 7 demonstrates that VLF was lower in the medication group than in the
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non-mediation group and control group, and the difference was statistically significant. 3.3 Comparison of the different courses of the disease between the control group
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and FE groups
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According to the length of the course of disease, FE patients were divided into two groups: <10 years group (n=16) and ≥10 years group (n=13). One patient who had a
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course of disease of ≥30 years, but experienced only one seizure, was excluded. The HRV indexes were compared among the <10 years group, ≥10 years group and control
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group (Table 8).
As shown in Tables 8, the differences in HRV indexes among the <10 years group, ≥10 years group and control group were not statistically significant (P>0.05).
4. Discussion In FE patients, interictal epileptiform discharges affect the functional area of the autonomic nervous system in the cortex and subcortical space, or even induce arrhythmia
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[12-14]. As an indicator for sensitive and noninvasive examinations, HRV is a reliable indicator for the assessment of cardiac autonomic nerve activity. In the HRV examination, the difference between continuous R-R reflects the degree of changes in heart rhythm, the changes in sympathetic and parasympathetic nervous tension, and the balance between these two. In the present study, the effects of seizure frequencies, the different courses of
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the disease, and the different medication conditions on HRV were investigated.
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In the present study, the comparison of HRV indexes between the less frequent
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seizure group, more frequent seizure group and control group revealed that the interictal LF/HF ratio was significantly higher in the more frequent seizure group than in the less
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frequent seizure group and control group, suggesting that the function of the autonomic nerve is gradually disturbed as the frequency of seizure increases, the sympathetic
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activity is enhanced, and the balance between the sympathetic and parasympathetic nerves is broken. The present study further verifies that epileptic seizures induce the
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excessive activation of neurons, and cause permanent damage to neurons. Frequent
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seizures lead to the accumulation of neuronal cell damage in the brain and the continuous aggravation of nervous dysfunction. This is consistent with the conclusion in previous
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studies that sudden epileptic death is more likely to occur in patients with poor control of epileptic seizures, particularly in patients with generalized tonic-clonic seizures (GTCS).
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GTCS is a high risk factor for sudden epileptic death. The incidence of sudden epileptic death in patients with more than three GTCS a year is up to 15.46% [15, 16], which is significantly higher compared with that in the normal population. This further suggests that epileptic seizure control can be used to predict the future trend of quality of life. The results of the comparison of HRV indexes among the medication group, non-medication group and control group suggest that VLF decreased and the LF/HF ratio significantly increased in the medication group, and the differences were statistically
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significant. These further suggest that the parasympathetic nerve activity was suppressed, the sympathetic activity was enhanced, and dominant position was taken. A previous study revealed that the incidence of SUDEP in untreated epileptic patients was seven times of that in patients who had achieved effective results by taking antiepileptic drugs [17]. However, the present study revealed that the cardiac autonomic nervous dysfunction
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was more obvious in the medication group than in the non medication group. It was
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considered that the reason was due to the fact that all epileptic patients were FE patients
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in the present study. According to ILAE guidelines for the treatment of epilepsy [18], most of the antiepileptic drugs used by patients were targeted to FE, such as ion channel
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blocker carbamazepine, oxcarbazepine, phenytoin sodium and lamotrigine. The result is consistent with the conclusion of some foreign studies that carbamazepine and
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lamotrigine [19, 20] could lead to an increased incidence of SUDEP. The reason was that in the medication group (n=14, including eight patients with frequent seizures), the
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curative effect of antiepileptic drugs was poor and the seizures were frequent. SUDEP is
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more likely to occur in chronic epileptic patients. The difference in HRV indexes between the non-medication group and control group was not statistically significant, and
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the reason may be due to the short course of disease in the non-medication group (n=15, 10 patients had a course of disease of <10 years). For patients taking antiepileptic drugs,
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follow-ups for HRV should be carried out, and the function of the autonomic nerve should be assessed. This would help guide doctors to avoid choosing antiepileptic drugs that may affect heart function. In the present study, statistically significant differences in HRV indices among groups with different courses of disease and the control group were not found, but the results revealed that FE patients with a course of disease of ≥10 years had a higher LF/HF ratio, compared with patients with a course of disease of <10 years. This suggests that
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with the prolongation of the course of disease of FE patients, sympathetic activity was enhanced, which is in line with the high incidence of sudden epileptic death in patients with chronic epilepsy. With the prolongation of the course of disease, the LF/HF index, which reflects the balance between sympathetic and parasympathetic activity, is significantly elevated. This reveals a rising trend on the excitability of the sympathetic
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nerve. In a study that involved patients who encountered sudden epileptic death, HRV
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was monitored at nine months, five months and month before death, and the results
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revealed that as time passed, RMMSD, an index of HRV that reflects parasympathetic nerve activity, gradually decreased. Furthermore, the decline was more pronounced at
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five months before death, compared with that at one month before death. That is, the activity of the sympathetic nerve is gradually strengthened with time before sudden
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epileptic death. Therefore, it can be deduced that sympathetic nervous tension in the autonomic nervous system increases with time, with the gradual decline or large decline
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in HRV indexes. This represents the parasympathetic nervous tension, and can reflect the
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possibility of sudden epileptic death [17]. No statistical difference in these indexes was found in the present study, and the reason may be due to the small sample size.
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Most of the previous studies on FE have focused on temporal lobe epilepsy or intractable epilepsy, which revealed that the sympathetic activity of epileptic patients
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significantly increased during the peri-ictal period, especially in male epileptic patients with epileptic focus on the right side. The reason is that the limbic system of the central insula of the autonomic nerve is closely connected to the temporal lobe, and the close connection between the temporal lobe and insular lobe facilitates the propagation of a neural discharge, which affects the autonomic nerve. In different studies, changes in the autonomic nerve in the interictal period varied. In the present study, FE patients, including patients with temporal lobe epilepsy, were analyzed. Among these patients, 20
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patients had temporal lobe epilepsy and 10 patients had non-temporal lobe epilepsy. The present study revealed that in the interictal period, FE patients presented with autonomic nervous system dysfunction, suggesting that epileptic seizures outside the limbic system also affect the autonomic nervous function center through the neural network, which leads to the disturbance of autonomic nervous balance.
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HRV examination is an easy, noninvasive and sensitive examination for the
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assessment of cardiac autonomic nervous function in epileptic patients in the interictal
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period. It has potential value in clinical applications. Therefore, the long-term dynamic HRV monitoring and comparison of HRV time domain and frequency domain indicators,
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especially LF/HF, is important and instructive for FE patients. All epileptic patients included in the present study met the FE diagnostic criteria.
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However, the 24-hour ambulatory electrocardiogram examination for the patients were all carried out in the interictal period, the sample size was relatively small, and the
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primary epileptic focus, the side of the focus, gender, age, epilepsy control after
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medication and drug types were not further classified and compared. Therefore, the differences in several frequency domain indicators were not statistically significant. In
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the future, it remains necessary to further expand the sample size and improve the continuous HRV examination of FE patients during the interictal and perictal periods.
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Furthermore, changes in HRV indexes and changes in sympathetic and parasympathetic nerve activity in FE patients should be further understood.
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Acknowlegdgements None.
Funding: This work was supported by Guizhou Science and Technology Plan Project “The Role and Mechanism of Nectin-1 in Chronic Epilepsy with Lithium-Pilocarpine
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Epilepsy”[grant number LH [2016] 7238].
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Conflict of Interest statement
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The authors declare that there are no conflicts of interest.
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Table 1 Demographic characteristics of FE patients and control subjects Demographic
Age
2
p
36.37±3.56
2.826
0.113
7/9
0.103
FE group
Control group
(n=30)
(n=16)
(mean±SD, 42.71±1.97
13/17
0.947
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Genders (F/M)
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years)
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Note: FE, focal epilepsy; F, femal; M, male.
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Table 2 Demographic and clinical data of FE patients
s
Age
Epilepsy
(year)
duration
Seizure type
Epilepsy
PT
Patient Gender
M
41
12.5
Focal aware seizure
RFLE
O
2
M
20
1
Focal impaired awareness seizure
RTLE
N
3
F
29
3
Focal impaired awareness seizure
LTLE
L
4
M
53
31
Focal to bilateral tonic–clonic seizure
LTLE
V
5
F
32
12
Focal to bilateral tonic–clonic seizure
LFLE
O
6
M
22
2
Focal impaired awareness seizure
LTLE
N
7
M
52
14
Focal impaired awareness seizure
RTLE
N
8
M
27
13
Focal to bilateral tonic–clonic seizure
RTLE
V
9
F
51
3
Focal impaired awareness seizure
LTLE
N
10
F
47
14
Focal aware seizure
LFLE
O
11
M
64
1
Focal to bilateral tonic–clonic seizure
RTLE
N
12
M
43
21
Focal aware seizure
ROLE
N
13
M
26
1.5
Focal aware seizure
LTLE
N
14
M
29
14
Focal to bilateral tonic–clonic seizure
RTLE
O
15
F
57
16
Focal to bilateral tonic–clonic seizure
LFLE
C
16
F
28
11
Focal impaired awareness seizure
LTLE
N
17
M
19
0.5
Focal impaired awareness seizure
LTLE
N
18
F
55
9
Focal impaired awareness seizure
RTLE
O
MA
D
PT E
CE
SC
1
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type
AC
RI
(year)
A
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37
10
Focal to bilateral tonic–clonic seizure
RTLE
N
20
M
64
24
Focal to bilateral tonic–clonic seizure
LFLE
P
21
F
63
1
Focal impaired awareness seizure
LTLE
N
22
F
61
17
Focal aware seizure
RFLE
C
23
F
23
3
Focal impaired awareness seizure
RTLE
N
24
M
23
1.5
Focal to bilateral tonic–clonic seizure
RTLE
N
25
F
18
4
Focal impaired awareness seizure
ROLE
L
26
M
18
2
Focal to bilateral tonic–clonic seizure
LFLE
N
27
F
29
10.5
Focal aware seizure
LFLE
O
28
M
45
17
Focal to bilateral tonic–clonic seizure
LTLE
V
29
F
47
13
Focal to bilateral tonic–clonic seizure
LTLE
N
30
M
23
5
Focal impaired awareness seizure
RTLE
n
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D
MA
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PT
19
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19
Note: F, femal; M, male; R, right; L, left; TLE, temporal lobe epilepsy; FLE, frontal lobe
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epilepsy; OLE, occipital lobe epilepsy; OXC, Oxcarbazepine; LTG, Lamotrigine; VPA, Sodium valproate; LEV, Levetiracetam; PTH, phenytoin sodium; Non use, No
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antiepileptic drugs were used 1 month before examine.
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Table 3 The comparison of HRV indices among the more frequent seizure group, less frequent seizure group and control group
Less frequent
Control group
seizure group
seizure group
(n=16)
(n=16)
(n=14)
122.19±28.03
124.00±48.76
SDNN index
58.38±20.11
60.64±29.15
RMSSD (ms)
33.81±18.48
37.07±22.77
PNN50 (%)
13.81±14.93
Triangular
27.88±9.03
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SDANN (ms)
F
p
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More frequent
187.50±224.80
1.165
0.322
0.102
0.904
38.31±18.34
0.219
0.805
28.14±54.57
15.19±13.68
0.876
0.424
24.64±10.46
30.81±8.32
1.659
0.202
0.226
0.799
62.00±19.25
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(ms)
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HRV indices
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index TP (ms2)
2238.00±1521.32 2330.48±1179.7 4
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2042.19±995.42
592.23±760.68
390.33±400.50
1.419
0.289
614.87±432.31
598.97±432.58
514.18±351.22
0.145
0.866
LF/HF (nu)
2.89±1.40
1.90±1.04
1.81±0.68
4.801
0.013*
VLF (ms2)
1144.17±402.45
1046.36±472.70
1202.96±489.71
2.225
0.120
HF (ms2)
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LF (ms2)
283.52±267.71
Note: HRV, heart rate variability; SDANN, standard deviation of average 5-minute intrinsic R-R intervals; SDNN, the standard deviation of normal NN intervals; RMSSD, root mean square of successive differences; PNN50, percent of the number whose difference between adjacent NN interval are more than 50 ms; TP, total power; HF,
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high-frequency power; LF, low-frequency power; LF/HF, low-frequency/high-frequency ratio; VLF, very low frequency power; *Comparison of the three groups, the differences
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PT E
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NU
SC
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PT
were statistically significant, p＜0.05.
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Table 4 Results of the comparison of LF/HF (nu) among the three groups LF/HF (nu)
comparison among groups
P
More frequent seizure group Vs Less frequent 0.038* seizure group
Less frequent seizure group Vs Control group
0.01*
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More frequent seizure group Vs Control group
0.794
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differences were statistically significant, p＜0.05.
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Note: LF/HF, low-frequency/high-frequency ratio; *Comparison of the two groups, the
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Table 5 The comparison of different medication situations among the control group and FE groups
Non-medication
Control group
group (n=14)
group (n=15)
(n=16)
F
p
108.93±28.88
134.20±43.878
187.50±224.80
1.290
0.280
SDNN index
50.00±22.71
67.87±24.05
62.00±19.25
2.465
0.097
RMSSD (ms)
29.07±20.11
40.80±20.11
38.31±18.34
1.448
0.247
PNN50 (%)
10.50±15.25
17.13±13.90
15.19±13.68
0.824
0.446
Triangular
23.21±8.24
29.33±10.59
30.81±8.32
2.851
0.069
2610.53±1299.6
2330.48±1179.7
2.708
0.078
8
4
609.93±726.00
390.33±400.50
2.052
0.141
482.16±432.67
727.29±411.20
514.18±351.22
1.523
0.230
2.97±1.27
2.18±1.41
1.81±0.68
3.872
0.02*
900.70±453.22
1273.66±334.28
1202.96±489.71
4.760
0.01*
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(ms)
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SDANN (ms)
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PT
Medication
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HRV indices
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index TP (ms2)
8 HF (ms2)
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1614.57±1052.1
LF (ms2)
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LF/HF (nu)
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231.97±270.23
VLF (ms2)
Note: FE, focal epilepsy; HRV, heart rate variability; SDANN, standard deviation of average 5-minute intrinsic R-R intervals; SDNN, the standard deviation of normal NN intervals; RMSSD, root mean square of successive differences; PNN50, percent of the number whose difference between adjacent NN interval are more than 50 ms; TP, total
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power;
HF,
high-frequency
power;
LF,
low-frequency
power;
LF/HF,
low-frequency/high-frequency ratio; VLF, very low frequency power; *Comparison of
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PT E
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NU
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PT
the three groups, the differences were statistically significant, p＜0.05.
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Table 6 Results of the comparison of LF/HF (nu) among the three groups comparison among groups
P
Medication group Vs Non-medication group
0.125
Medication group Vs Control group
0.04*
Non-medication group Vs Control group
0.364
PT
LF/HF (nu)
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Note: LF/HF, low-frequency/high-frequency ratio; *Comparison of the two groups, the
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PT E
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differences were statistically significant, p＜0.05.
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Table 7 Results of the comparison of VLF (ms2) among the three groups comparison among groups
P
Medication group Vs Non-medication group
0.017*
Medication group Vs Control group
0.012*
Non-medication group Vs Control group
0.451
PT
VLF (ms2)
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Note: VLF, very low frequency power; *Comparison of the two groups, the differences
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were statistically significant, p＜0.05.
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Table 8 The comparison of the different courses of the disease among the control group and FE groups
≥10 years group
Control group
(n=16)
(n=13)
(n=16)
F
p
132.69±45.34
114.08±25.67
187.50±224.80
1.149
0.327
SDNN index
64.00±26.83
55.77±20.82
62.00±19.25
0.502
0.609
RMSSD (ms)
38.69±20.04
33.00±20.66
0.364
0.697
PNN50 (%)
16.56±13.74
26.92±57.41
15.19±13.68
0.531
0.651
Triangular
28.13±10.72
25.00±8.26
30.8±8.32
0.253
0.253
TP (ms2)
2351.13±1420.28
2330.48±1179.74
0.439
0.593
HF (ms2)
552.53±718.41
296.63±289.72
390.33±400.50
0.929
0.403
LF (ms2)
669.85±430.83
603.10±445.88
541.18±351.22
0.384
0.683
LF/HF (nu)
2.17±1.10
2.89±1.47
1.81±0.68
3.507
0.064
VLF (ms2)
1131.05±456.99
1101.99±401.70
1217.85±484.60
1.807
0.177
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SDANN (ms)
RI
PT
＜10 years group
D
HRV indices
(ms)
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NU
38.31±18.34
index
AC
CE
PT E
1962.69±1010.57
Note: FE, focal epilepsy; HRV, heart rate variability; SDANN, standard deviation of average 5-minute intrinsic R-R intervals; SDNN, the standard deviation of normal NN intervals; RMSSD, root mean square of successive differences; PNN50, percent of the number whose difference between adjacent NN interval are more than 50 ms; TP, total power;
HF,
high-frequency
power;
LF,
low-frequency
low-frequency/high-frequency ratio; VLF, very low frequency power.
power;
LF/HF,
Yun-Li Yu, Na-Na Li, Meng-Ting Shi, Hong-Juan Lu PII: DOI: Reference:
S0024-3205(18)30480-6 doi:10.1016/j.lfs.2018.08.033 LFS 15880
To appear in:
Life Sciences
Received date: Revised date: Accepted date:
13 April 2018 9 August 2018 13 August 2018
Please cite this article as: Yun-Li Yu, Na-Na Li, Meng-Ting Shi, Hong-Juan Lu , Analysis of heart rate variability-related indexes in the interictal period in patients with focal epilepsy. Lfs (2018), doi:10.1016/j.lfs.2018.08.033
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Analysis of heart rate variability-related indexes in the interictal period in patients with focal epilepsy
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Running title: Analysis of HRV of Patients with FE
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Yun-Li Yu*, Na-Na Li, Meng-Ting Shi, Hong-Juan Lu
Department of Neurology, The Affiliated Hospital of Guizhou Medical University,
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Guiyang 550004, China.
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*Corresponding author
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Yun-Li Yu
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Department of Neurology,
Affiliated Hospital of Guizhou Medical University,
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No. 28, Gui Yi Street, Yunyan District, Guiyang 550004, China. Tel: +86 851 86855119 Fax: +86 851 86855119 E-mail: [email protected]
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Abstract Aims: Changes in cardiac autonomic nervous function have been evaluated by studying the related indexes of heart rate variability (HRV) in patients with focal epilepsy (FE) in the interictal period. Main methods: A total of 30 FE patients who were treated in our
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department from July 2015 to May 2017, were included into this study. These patients
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were divided into three pairs of groups: less frequent seizure group and more frequent seizure group; medication group and non-medication group; <10 years disease group and
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≥10 years disease group. In addition, 16 normal healthy subjects were enrolled as the
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control group. The time domain and frequency domain indexes of HRV indexes between subgroups and the control group were retrospectively analyzed. Key findings: The
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low-frequency/high-frequency ratio (LF/HF) in the interictal period was higher in the more frequent seizure group than in the control group and less frequent seizure group
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(P<0.05). Furthermore, differences in interictal LF/HF and very low frequency (VLF)
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between the medication group and non-medication group and control group were statistically significant (P<0.05). Significance: In interictal period FE patients who
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present with an imbalance in autonomic nervous function, LF/HF can serve as an indicator to evaluate the interictal cardiac sympathetic activity of FE patients.
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Furthermore, the dynamic observation of changes in the HRV-related indexes of FE patients can prevent the choice of antiepileptic drugs that affect heart function, which is of guiding significance for evaluating autonomic nervous function.
Keywords: focal epilepsy; interictal period; autonomic nerve; heart rate variability; LF/HF
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1. Introduction The mortality of epileptic patients is 2-3 times of that in the normal population [1]. Sudden unexpected death in epilepsy (SUDEP) accounts for 17% of the total mortality of epilepsy [2]. Especially for young patients with epilepsy, the incidence of SUDEP is 27 times of the sudden death in the general population [3]. The mechanism of SUDEP
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remains unknown. Postictal electroencephalography (EEG) suppression, fatal respiratory
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dysfunction, malignant cardiac dysfunction and central autonomic nervous system
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dysfunction may be correlated to SUDEP [4-6]. Most studies have suggested that tonic-clonic seizures are closely associated to SUDEP. Therefore, many studies on
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SUDEP mechanism related to tonic-clonic seizures have been carried out. However, it remains unclear whether focal epilepsy (FE) patients also have a risk of SUDEP. Some
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scholars found that [7] SUDEP was not associated with seizures. This suggests that the mechanism of SUDEP is complicated. Therefore, it is necessary to study the functional
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changes of the autonomic nerve in the interictal period in FE patients, in order to provide
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a basis for the study of the mechanism of SUDEP. Heart rate variability (HRV) can sensitively and intuitively reflect the early
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abnormal changes of the cardiovascular autonomic nerve [8, 9]. The investigators hope that the present study can provide guidance in the clinical selection of appropriate
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antiepileptic drug regimens, help find seizure-related HRV changes in time, remind the risk of related sudden death, and induce doctors and patients to pay attention to SUDEP.
2. Materials and Methods 2.1 Subjects This study was conducted in accordance with the declaration of Helsinki, and approved by the local Ethics Committee. On the basis of the informed consent provided
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by the patients, the investigators collected sporadic FE patients in Guizhou, 30 patients diagnosed with FE from July 2015 to May 2017 in the Department of Neurology, the Affiliated Hospital of Guizhou Medical University, were included into the present study. All FE patients were diagnosed based on the diagnostic criteria developed by the International League Against Epilepsy (ILAE) in 2017 [10], and the history of the disease
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in the seizure period was inquired in detail by deputy chief physicians or more senior
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experts at the Neurology Department of the Affiliated Hospital of Guizhou Medical
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University. In addition, these FE patients were confirmed to meet the diagnostic criteria by video electroencephalogram examination and imaging. Patients with the following
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conditions were excluded: (1) patients who did not meet the FE diagnosis; (2) patients with a heart disease; (3) patients with diseases that have an obvious impact on the
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autonomic nervous function of the heart, such as abnormal metabolism of the thyroid, diabetes, Parkinson's disease, multiple system atrophy, severe psychosis or intellectual
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impairment, and liver failure; (4) patients who used drugs that can affect autonomic
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nervous function other than antiepileptic drugs. Healthy volunteers with normal physical and neurological examinations were chosen from the physical examination center of our
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hospital as a control group. 2.2 Research methods
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2.2.1 24-hour ambulatory electrocardiogram All the participants completed the 24-hour ambulatory electrocardiogram examination (Nihon Kohden RAC-3012), Electrocardiographic raw data recorded in three channels were digitalised with 1024-Hz sampling rate. Before this examination, all patients took a rest in the supine position for 30 minutes. The monitoring was conducted in the video EEG examination room and the range of activity was limited. The subjects of the study were prohibited from drinking coffee, tea, alcohol and other beverages that
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affect the index of heart rate variation 12 hours before and the same day of the monitoring. They were also prohibited from smoking and strenuous exercise to maintain emotional stability. However, considering respiration has impact on HRV, we always ask objects not to breathe heavily during the test periods. Normal physiological activities were carried out, and set the sleeping time for 6-8 hours. In order to determine whether
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patients had a seizure during ECG monitoring, the family members were required to
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accompany during the monitoring. Dynamic electroencephalogram examination was
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performed simultaneously. If the patient had an attack during the monitoring period, his data would be excluded. Holter recordings were obtained at least 24 hours after seizure
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attacks and none of the patients had any seizure during the recordings. HRV data were analyzed to study the alteration trend of the function of the autonomic nervous system of
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FE patients by analyzing the changes in interictal HRV. The calculation of the HRV parameters based on 24-hour of ECG data. After the examination, the ECG signals were
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imported in the computer and automatically analyzed, which assisted with manual
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correction and editing. The dynamic electrocardiogram machine can automatically identify the RR interval less than 350ms or greater than 1500ms, and delete these
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unqualified data. In order to eliminate abnormal ECG caused by ventricular premature beats, missed beats, ectopic beats or body movements, manual deletion of artifact is
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required to avoid impact on analysis results. The above data analysis was performed by ECG professionals. Changes in related electrocardiogram indexes were automatically calculated. 2.2.2 HRV indexes Analysis of heart rate variability in the time and frequency domains were done according to the standards of the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology [11].
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(1)Commonly used indicators in time domain analysis, time domain analysis uses various statistical methods to quantitatively describe the changing characteristics of each cardiac cycle. In the time domain analysis of HRV, the variation of heart rate is usually represented by the change of RR interval. Such as the triangular index, standard deviation of average 5-minute intrinsic R-R intervals (SDANN), the standard deviation of normal
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NN intervals (SDNN) index, root mean square of successive differences (RMSSD),
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NN50 and the Edinburgh index (PNN50), were collected.
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(2) Frequency domain analysis is also known as spectrum analysis of the heart rate, where special computing methods, such as Fourier transformation and autoregressive
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model analysis, are used to decompose the time-varying heart rate fluctuation curve into the sum of sinusoidal curves of different frequencies and amplitudes. Hence, the
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spectrum of HRV is obtained. The human HRV power spectrum is often divided into four domains: high frequency zone (HF: 0.15-0.40 Hz), low frequency zone (LF: 0.04-0.15
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Hz), very low frequency zone (VLF: 0.0033-0.04 Hz), and ultra low frequency zone
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(ULF: <0.0033 Hz). The LH/FH ratio reflects the balance of the sympathetic and parasympathetic nerve.
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FE patients were grouped according to frequency of seizures, drug use and the course of disease, and a comparison among groups was conducted.
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2.3 Statistical analysis
Statistical analysis was conducted using statistical software SPSS 22.0. In the experimental results mentioned above, the measurement data were expressed as mean ± standard deviation, and analyzed using one-way analysis of variance. The pairwise comparison among groups was conducted using the least significant difference (LSD) test. Count data were compared using X2-test. P<0.05 was considered statistically significant.
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3. Results 3.1 Demographic and clinical data Among these patients, 17 patients were male and 13 patients were female. The age of these patients ranged within 18-64 years old, and the course of disease ranged from 6 months to 30 years. The control group comprised of 16 subjects, in which 9 subjects were
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male and 7 subjects were female. The age of these subjects ranged within 22-63 years old.
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There was no difference between groups regarding gender, age (p>0.05). Table 1 shows
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the demographic characteristics of the cohort. Demographic and clinical data of FE
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patients are summarized in Table 2.
3.2 Comparison of different frequencies of seizures among the control group and FE
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groups
According to different seizure frequencies, FE patients were divided into two groups:
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less frequent seizure group (≤3 times/year, n=14), and more frequent seizure group (>3
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times/year, n=16). The comparison of HRV indexes among the less frequent seizure group, more frequent seizure group and control group are presented in Table 3.
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Table 3 demonstrates that, except for LF/HF, the differences in the other HRV indexes among groups were not statistically significant (P>0.05). Table 4 demonstrates
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that the further pairwise comparison of LF/HF ratios revealed that the LF/HF ratio was significantly higher in the more frequent seizure group than in the control group, and the difference was statistically significant (P<0.01). Furthermore, the interictal LF/HF ratio was significantly higher in the more frequent seizure group than in the less frequent seizure group, and the difference was statistically significant (P=0.038).
3.2 Comparison of different medication situations between the control group and FE
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groups According to whether FE patients were treated with antiepileptic drugs, they were divided into two groups: medication group (n=14) and non-medication group (n=15). One patient was excluded due to unclear medication history. The HRV indexes were compared among the medication group, non-medication group and control group (Table
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3).
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Table 5 demonstrates that the differences in VLF (P=0.014) and LF/HF (P=0.021)
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were statistically significant. The pairwise comparison of VLF and LF/HF was conducted among the three groups. Table 6 demonstrates that the LF/HF ratio was higher in the
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medication group than in the control group, and the difference was statistically significant. Table 7 demonstrates that VLF was lower in the medication group than in the
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non-mediation group and control group, and the difference was statistically significant. 3.3 Comparison of the different courses of the disease between the control group
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and FE groups
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According to the length of the course of disease, FE patients were divided into two groups: <10 years group (n=16) and ≥10 years group (n=13). One patient who had a
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course of disease of ≥30 years, but experienced only one seizure, was excluded. The HRV indexes were compared among the <10 years group, ≥10 years group and control
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group (Table 8).
As shown in Tables 8, the differences in HRV indexes among the <10 years group, ≥10 years group and control group were not statistically significant (P>0.05).
4. Discussion In FE patients, interictal epileptiform discharges affect the functional area of the autonomic nervous system in the cortex and subcortical space, or even induce arrhythmia
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[12-14]. As an indicator for sensitive and noninvasive examinations, HRV is a reliable indicator for the assessment of cardiac autonomic nerve activity. In the HRV examination, the difference between continuous R-R reflects the degree of changes in heart rhythm, the changes in sympathetic and parasympathetic nervous tension, and the balance between these two. In the present study, the effects of seizure frequencies, the different courses of
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the disease, and the different medication conditions on HRV were investigated.
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In the present study, the comparison of HRV indexes between the less frequent
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seizure group, more frequent seizure group and control group revealed that the interictal LF/HF ratio was significantly higher in the more frequent seizure group than in the less
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frequent seizure group and control group, suggesting that the function of the autonomic nerve is gradually disturbed as the frequency of seizure increases, the sympathetic
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activity is enhanced, and the balance between the sympathetic and parasympathetic nerves is broken. The present study further verifies that epileptic seizures induce the
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excessive activation of neurons, and cause permanent damage to neurons. Frequent
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seizures lead to the accumulation of neuronal cell damage in the brain and the continuous aggravation of nervous dysfunction. This is consistent with the conclusion in previous
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studies that sudden epileptic death is more likely to occur in patients with poor control of epileptic seizures, particularly in patients with generalized tonic-clonic seizures (GTCS).
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GTCS is a high risk factor for sudden epileptic death. The incidence of sudden epileptic death in patients with more than three GTCS a year is up to 15.46% [15, 16], which is significantly higher compared with that in the normal population. This further suggests that epileptic seizure control can be used to predict the future trend of quality of life. The results of the comparison of HRV indexes among the medication group, non-medication group and control group suggest that VLF decreased and the LF/HF ratio significantly increased in the medication group, and the differences were statistically
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significant. These further suggest that the parasympathetic nerve activity was suppressed, the sympathetic activity was enhanced, and dominant position was taken. A previous study revealed that the incidence of SUDEP in untreated epileptic patients was seven times of that in patients who had achieved effective results by taking antiepileptic drugs [17]. However, the present study revealed that the cardiac autonomic nervous dysfunction
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was more obvious in the medication group than in the non medication group. It was
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considered that the reason was due to the fact that all epileptic patients were FE patients
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in the present study. According to ILAE guidelines for the treatment of epilepsy [18], most of the antiepileptic drugs used by patients were targeted to FE, such as ion channel
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blocker carbamazepine, oxcarbazepine, phenytoin sodium and lamotrigine. The result is consistent with the conclusion of some foreign studies that carbamazepine and
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lamotrigine [19, 20] could lead to an increased incidence of SUDEP. The reason was that in the medication group (n=14, including eight patients with frequent seizures), the
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curative effect of antiepileptic drugs was poor and the seizures were frequent. SUDEP is
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more likely to occur in chronic epileptic patients. The difference in HRV indexes between the non-medication group and control group was not statistically significant, and
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the reason may be due to the short course of disease in the non-medication group (n=15, 10 patients had a course of disease of <10 years). For patients taking antiepileptic drugs,
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follow-ups for HRV should be carried out, and the function of the autonomic nerve should be assessed. This would help guide doctors to avoid choosing antiepileptic drugs that may affect heart function. In the present study, statistically significant differences in HRV indices among groups with different courses of disease and the control group were not found, but the results revealed that FE patients with a course of disease of ≥10 years had a higher LF/HF ratio, compared with patients with a course of disease of <10 years. This suggests that
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with the prolongation of the course of disease of FE patients, sympathetic activity was enhanced, which is in line with the high incidence of sudden epileptic death in patients with chronic epilepsy. With the prolongation of the course of disease, the LF/HF index, which reflects the balance between sympathetic and parasympathetic activity, is significantly elevated. This reveals a rising trend on the excitability of the sympathetic
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nerve. In a study that involved patients who encountered sudden epileptic death, HRV
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was monitored at nine months, five months and month before death, and the results
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revealed that as time passed, RMMSD, an index of HRV that reflects parasympathetic nerve activity, gradually decreased. Furthermore, the decline was more pronounced at
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five months before death, compared with that at one month before death. That is, the activity of the sympathetic nerve is gradually strengthened with time before sudden
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epileptic death. Therefore, it can be deduced that sympathetic nervous tension in the autonomic nervous system increases with time, with the gradual decline or large decline
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in HRV indexes. This represents the parasympathetic nervous tension, and can reflect the
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possibility of sudden epileptic death [17]. No statistical difference in these indexes was found in the present study, and the reason may be due to the small sample size.
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Most of the previous studies on FE have focused on temporal lobe epilepsy or intractable epilepsy, which revealed that the sympathetic activity of epileptic patients
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significantly increased during the peri-ictal period, especially in male epileptic patients with epileptic focus on the right side. The reason is that the limbic system of the central insula of the autonomic nerve is closely connected to the temporal lobe, and the close connection between the temporal lobe and insular lobe facilitates the propagation of a neural discharge, which affects the autonomic nerve. In different studies, changes in the autonomic nerve in the interictal period varied. In the present study, FE patients, including patients with temporal lobe epilepsy, were analyzed. Among these patients, 20
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patients had temporal lobe epilepsy and 10 patients had non-temporal lobe epilepsy. The present study revealed that in the interictal period, FE patients presented with autonomic nervous system dysfunction, suggesting that epileptic seizures outside the limbic system also affect the autonomic nervous function center through the neural network, which leads to the disturbance of autonomic nervous balance.
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HRV examination is an easy, noninvasive and sensitive examination for the
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assessment of cardiac autonomic nervous function in epileptic patients in the interictal
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period. It has potential value in clinical applications. Therefore, the long-term dynamic HRV monitoring and comparison of HRV time domain and frequency domain indicators,
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especially LF/HF, is important and instructive for FE patients. All epileptic patients included in the present study met the FE diagnostic criteria.
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However, the 24-hour ambulatory electrocardiogram examination for the patients were all carried out in the interictal period, the sample size was relatively small, and the
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primary epileptic focus, the side of the focus, gender, age, epilepsy control after
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medication and drug types were not further classified and compared. Therefore, the differences in several frequency domain indicators were not statistically significant. In
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the future, it remains necessary to further expand the sample size and improve the continuous HRV examination of FE patients during the interictal and perictal periods.
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Furthermore, changes in HRV indexes and changes in sympathetic and parasympathetic nerve activity in FE patients should be further understood.
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Acknowlegdgements None.
Funding: This work was supported by Guizhou Science and Technology Plan Project “The Role and Mechanism of Nectin-1 in Chronic Epilepsy with Lithium-Pilocarpine
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Epilepsy”[grant number LH [2016] 7238].
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Conflict of Interest statement
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The authors declare that there are no conflicts of interest.
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epilepsy: the role of the heart, Cleve Clin J Med. 74 Suppl 1 (2007) S121-S127.
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[3] Holst AG, Winkel BG, Risgaard B, Nielsen JB, Rasmussen PV, Haunsø S, Sabers A,
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Uldall P, Tfelt-Hansen J, Epilepsy and risk of death and sudden unexpected death in the young: a nationwide study, Epilepsia. 54 (2013) 1613-1620.
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[4] Duble SN, Thomas SV, Sudden unexpected death in epilepsy, Indian J Med Res. 145
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(2017) 738-745.
[5] Terra VC, Cysneiros R, Cavalheiro EA, Scorza FA, Sudden unexpected death in
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epilepsy: from the lab to the clinic setting, Epilepsy Behav. 26 (2013) 415-420.
PT E
[6] Allen LA, Harper RM, Kumar R, Guye M, Ogren JA, Lhatoo SD, Lemieux L, Scott CA, Vos SB, Rani S, Diehl B, Dysfunctional Brain Networking among Autonomic
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Regulatory Structures in Temporal Lobe Epilepsy Patients at High Risk of Sudden
AC
Unexpected Death in Epilepsy, Front Neurol. 8 (2017) 544. [7] Lhatoo SD, Nei M, Raghavan M, Sperling M, Zonjy B, Lacuey N, Devinsky O, Nonseizure SUDEP: Sudden unexpected death in epilepsy without preceding epileptic seizures, Epilepsia. 57 (2016) 1161-1168. [8] Maheshwari A, Norby FL, Soliman EZ, Adabag S, Whitsel EA, Alonso A, Chen LY, Low Heart Rate Variability in a 2-Minute Electrocardiogram Recording Is Associated with an Increased Risk of Sudden Cardiac Death in the General Population: The
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Atherosclerosis Risk in Communities Study, PLoS One. 11 (2016) e0161648. [9] Kataoka M, Ito C, Sasaki H, Yamane K, Kohno N, Low heart rate variability is a risk factor for sudden cardiac death in type 2 diabetes, Diabetes Res Clin Pract. 64 (2004) 51-58.
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[10] Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, Lagae L, Moshé
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SL, Peltola J, Roulet Perez E, Scheffer IE, Zuberi SM, Operational classification of
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seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology, Epilepsia. 58 (2017) 522-530.
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[11] Heart rate variability. Standards of measurement, physiological interpretation, and
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Epilepsia. 51 (2010) 725-37.
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[12] Sevcencu C, Struijk JJ, Autonomic alterations and cardiac changes in epilepsy,
[13] Park KJ, Sharma G, Kennedy JD, Seyal M, Potentially high-risk cardiac arrhythmias
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with focal to bilateral tonic-clonic seizures and generalized tonic-clonic seizures are
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CE
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Table 1 Demographic characteristics of FE patients and control subjects Demographic
Age
2
p
36.37±3.56
2.826
0.113
7/9
0.103
FE group
Control group
(n=30)
(n=16)
(mean±SD, 42.71±1.97
13/17
0.947
SC
RI
Genders (F/M)
PT
years)
AC
CE
PT E
D
MA
NU
Note: FE, focal epilepsy; F, femal; M, male.
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Table 2 Demographic and clinical data of FE patients
s
Age
Epilepsy
(year)
duration
Seizure type
Epilepsy
PT
Patient Gender
M
41
12.5
Focal aware seizure
RFLE
O
2
M
20
1
Focal impaired awareness seizure
RTLE
N
3
F
29
3
Focal impaired awareness seizure
LTLE
L
4
M
53
31
Focal to bilateral tonic–clonic seizure
LTLE
V
5
F
32
12
Focal to bilateral tonic–clonic seizure
LFLE
O
6
M
22
2
Focal impaired awareness seizure
LTLE
N
7
M
52
14
Focal impaired awareness seizure
RTLE
N
8
M
27
13
Focal to bilateral tonic–clonic seizure
RTLE
V
9
F
51
3
Focal impaired awareness seizure
LTLE
N
10
F
47
14
Focal aware seizure
LFLE
O
11
M
64
1
Focal to bilateral tonic–clonic seizure
RTLE
N
12
M
43
21
Focal aware seizure
ROLE
N
13
M
26
1.5
Focal aware seizure
LTLE
N
14
M
29
14
Focal to bilateral tonic–clonic seizure
RTLE
O
15
F
57
16
Focal to bilateral tonic–clonic seizure
LFLE
C
16
F
28
11
Focal impaired awareness seizure
LTLE
N
17
M
19
0.5
Focal impaired awareness seizure
LTLE
N
18
F
55
9
Focal impaired awareness seizure
RTLE
O
MA
D
PT E
CE
SC
1
NU
type
AC
RI
(year)
A
ACCEPTED MANUSCRIPT M
37
10
Focal to bilateral tonic–clonic seizure
RTLE
N
20
M
64
24
Focal to bilateral tonic–clonic seizure
LFLE
P
21
F
63
1
Focal impaired awareness seizure
LTLE
N
22
F
61
17
Focal aware seizure
RFLE
C
23
F
23
3
Focal impaired awareness seizure
RTLE
N
24
M
23
1.5
Focal to bilateral tonic–clonic seizure
RTLE
N
25
F
18
4
Focal impaired awareness seizure
ROLE
L
26
M
18
2
Focal to bilateral tonic–clonic seizure
LFLE
N
27
F
29
10.5
Focal aware seizure
LFLE
O
28
M
45
17
Focal to bilateral tonic–clonic seizure
LTLE
V
29
F
47
13
Focal to bilateral tonic–clonic seizure
LTLE
N
30
M
23
5
Focal impaired awareness seizure
RTLE
n
PT E
D
MA
NU
SC
PT
19
RI
19
Note: F, femal; M, male; R, right; L, left; TLE, temporal lobe epilepsy; FLE, frontal lobe
CE
epilepsy; OLE, occipital lobe epilepsy; OXC, Oxcarbazepine; LTG, Lamotrigine; VPA, Sodium valproate; LEV, Levetiracetam; PTH, phenytoin sodium; Non use, No
AC
antiepileptic drugs were used 1 month before examine.
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Table 3 The comparison of HRV indices among the more frequent seizure group, less frequent seizure group and control group
Less frequent
Control group
seizure group
seizure group
(n=16)
(n=16)
(n=14)
122.19±28.03
124.00±48.76
SDNN index
58.38±20.11
60.64±29.15
RMSSD (ms)
33.81±18.48
37.07±22.77
PNN50 (%)
13.81±14.93
Triangular
27.88±9.03
RI
SDANN (ms)
F
p
PT
More frequent
187.50±224.80
1.165
0.322
0.102
0.904
38.31±18.34
0.219
0.805
28.14±54.57
15.19±13.68
0.876
0.424
24.64±10.46
30.81±8.32
1.659
0.202
0.226
0.799
62.00±19.25
D
MA
NU
(ms)
SC
HRV indices
PT E
index TP (ms2)
2238.00±1521.32 2330.48±1179.7 4
CE
2042.19±995.42
592.23±760.68
390.33±400.50
1.419
0.289
614.87±432.31
598.97±432.58
514.18±351.22
0.145
0.866
LF/HF (nu)
2.89±1.40
1.90±1.04
1.81±0.68
4.801
0.013*
VLF (ms2)
1144.17±402.45
1046.36±472.70
1202.96±489.71
2.225
0.120
HF (ms2)
AC
LF (ms2)
283.52±267.71
Note: HRV, heart rate variability; SDANN, standard deviation of average 5-minute intrinsic R-R intervals; SDNN, the standard deviation of normal NN intervals; RMSSD, root mean square of successive differences; PNN50, percent of the number whose difference between adjacent NN interval are more than 50 ms; TP, total power; HF,
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high-frequency power; LF, low-frequency power; LF/HF, low-frequency/high-frequency ratio; VLF, very low frequency power; *Comparison of the three groups, the differences
AC
CE
PT E
D
MA
NU
SC
RI
PT
were statistically significant, p＜0.05.
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Table 4 Results of the comparison of LF/HF (nu) among the three groups LF/HF (nu)
comparison among groups
P
More frequent seizure group Vs Less frequent 0.038* seizure group
Less frequent seizure group Vs Control group
0.01*
PT
More frequent seizure group Vs Control group
0.794
AC
CE
PT E
D
MA
SC
NU
differences were statistically significant, p＜0.05.
RI
Note: LF/HF, low-frequency/high-frequency ratio; *Comparison of the two groups, the
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Table 5 The comparison of different medication situations among the control group and FE groups
Non-medication
Control group
group (n=14)
group (n=15)
(n=16)
F
p
108.93±28.88
134.20±43.878
187.50±224.80
1.290
0.280
SDNN index
50.00±22.71
67.87±24.05
62.00±19.25
2.465
0.097
RMSSD (ms)
29.07±20.11
40.80±20.11
38.31±18.34
1.448
0.247
PNN50 (%)
10.50±15.25
17.13±13.90
15.19±13.68
0.824
0.446
Triangular
23.21±8.24
29.33±10.59
30.81±8.32
2.851
0.069
2610.53±1299.6
2330.48±1179.7
2.708
0.078
8
4
609.93±726.00
390.33±400.50
2.052
0.141
482.16±432.67
727.29±411.20
514.18±351.22
1.523
0.230
2.97±1.27
2.18±1.41
1.81±0.68
3.872
0.02*
900.70±453.22
1273.66±334.28
1202.96±489.71
4.760
0.01*
NU
(ms)
SC
SDANN (ms)
RI
PT
Medication
MA
HRV indices
D
index TP (ms2)
8 HF (ms2)
PT E
1614.57±1052.1
LF (ms2)
AC
LF/HF (nu)
CE
231.97±270.23
VLF (ms2)
Note: FE, focal epilepsy; HRV, heart rate variability; SDANN, standard deviation of average 5-minute intrinsic R-R intervals; SDNN, the standard deviation of normal NN intervals; RMSSD, root mean square of successive differences; PNN50, percent of the number whose difference between adjacent NN interval are more than 50 ms; TP, total
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power;
HF,
high-frequency
power;
LF,
low-frequency
power;
LF/HF,
low-frequency/high-frequency ratio; VLF, very low frequency power; *Comparison of
AC
CE
PT E
D
MA
NU
SC
RI
PT
the three groups, the differences were statistically significant, p＜0.05.
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Table 6 Results of the comparison of LF/HF (nu) among the three groups comparison among groups
P
Medication group Vs Non-medication group
0.125
Medication group Vs Control group
0.04*
Non-medication group Vs Control group
0.364
PT
LF/HF (nu)
RI
Note: LF/HF, low-frequency/high-frequency ratio; *Comparison of the two groups, the
AC
CE
PT E
D
MA
NU
SC
differences were statistically significant, p＜0.05.
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Table 7 Results of the comparison of VLF (ms2) among the three groups comparison among groups
P
Medication group Vs Non-medication group
0.017*
Medication group Vs Control group
0.012*
Non-medication group Vs Control group
0.451
PT
VLF (ms2)
RI
Note: VLF, very low frequency power; *Comparison of the two groups, the differences
AC
CE
PT E
D
MA
NU
SC
were statistically significant, p＜0.05.
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Table 8 The comparison of the different courses of the disease among the control group and FE groups
≥10 years group
Control group
(n=16)
(n=13)
(n=16)
F
p
132.69±45.34
114.08±25.67
187.50±224.80
1.149
0.327
SDNN index
64.00±26.83
55.77±20.82
62.00±19.25
0.502
0.609
RMSSD (ms)
38.69±20.04
33.00±20.66
0.364
0.697
PNN50 (%)
16.56±13.74
26.92±57.41
15.19±13.68
0.531
0.651
Triangular
28.13±10.72
25.00±8.26
30.8±8.32
0.253
0.253
TP (ms2)
2351.13±1420.28
2330.48±1179.74
0.439
0.593
HF (ms2)
552.53±718.41
296.63±289.72
390.33±400.50
0.929
0.403
LF (ms2)
669.85±430.83
603.10±445.88
541.18±351.22
0.384
0.683
LF/HF (nu)
2.17±1.10
2.89±1.47
1.81±0.68
3.507
0.064
VLF (ms2)
1131.05±456.99
1101.99±401.70
1217.85±484.60
1.807
0.177
SC
SDANN (ms)
RI
PT
＜10 years group
D
HRV indices
(ms)
MA
NU
38.31±18.34
index
AC
CE
PT E
1962.69±1010.57
Note: FE, focal epilepsy; HRV, heart rate variability; SDANN, standard deviation of average 5-minute intrinsic R-R intervals; SDNN, the standard deviation of normal NN intervals; RMSSD, root mean square of successive differences; PNN50, percent of the number whose difference between adjacent NN interval are more than 50 ms; TP, total power;
HF,
high-frequency
power;
LF,
low-frequency
low-frequency/high-frequency ratio; VLF, very low frequency power.
power;
LF/HF,