PRACA ORYGINALNA

ORIGINAL ARTICLE

THE PECULIARITIES OF THE HEART RATE VARIABILITY AND ELECTROENCEPHALOGRAM CHANGES IN PATIENTS WITH EPILEPSY AND CARDIOVASCULAR PATHOLOGY

CHARAKTERYSTYKA ZMIENNOŚCI RYTMU SERCA I ZMIAN W ELEKTROENCEFALOGRAMIE U PACJENTÓW Z PADACZKĄ I CHOROBĄ UKŁADU SERCOWO-NACZYNIOWEGO

Tetiana Litovchenko1, Valeriia Grymailo2, Oksana Tondiy1, Vartanush Florikian1, Olena Zavalna1, Anna Voitiuk1

1Department of Neurology and Child Neurology, Kharkiv Medical Academy of Post-Graduate Education, Kharkiv, Ukraine

2Kharkiv Railway Clinical Hospital №1 of Branch of «HC» JSC «Ukrzaliznytsia», Kharkiv, Ukraine

ABSTRACT

Introduction: Epidemiological studies have shown that the risk of myocardial infarction and stroke is significantly higher in patients with epilepsy compared with people not suffering from epilepsy.

The aim of the study was to study the parameters of HRV and EEG in patients with epilepsy to identify risk factors for cardiovascular pathology.

Materials and methods: We observed 50 patients with epilepsy without cardiovascular pathology (group 1) and 56 patients with epilepsy and cardiovascular pathology (group 2). All patients underwent clinical neurological examination, EEG, HRV and ECG assessment.

Results: There was a significant decrease in the HRV power in both groups of patients compared with general population data (p <0.02). Also in patients of the 2nd group, TP and the power of HRV in the LF, HF ranges were significantly decreased (p <0.001). Unstrained autonomic balance was detected in 40% in the 1st group and in 6% of patients in the 2nd group (p <0.001). Each patient had as higher LF/HF ratio as less time to next seizure left (rs = 0.72; p <0.05). There was no correlation of the heart rate (ECG) and the time to the next seizure (rs = 0.12; p <0.05). A correlation of the LF / HF ratio with β rhythm (EEG) was revealed for patients in both groups (for group 1: rs = 0.48; for group 2: rs = 0.52; p <0.02). When evaluating HRV in both groups, depending on the taken AEDs, it was found that the average values of TP, VLF, LF, HF, SDNN were significantly lower in patients receiving carbamazepine when compared with patients receiving other AEDs (p<0.001).

Conclusions: The factors of increased cardiovascular risk were: tense autonomic balance with a tendency to sympathicotonia, signs of a decrease in parasympathetic activity, a decrease in the TP, an increase in the representation of the EEG β-rhythm. The magnitude of the change in the frequency of the α rhythm in response to hyperventilation as well as the magnitude of the change in TP in orthostasis can serve as indicators of the adaptation reserve in patients with epilepsy. The development of an acute vascular event may increase the frequency of seizures and the presence of paroxysmal EEG phenomena. HRV is more informative to determine the oncoming of the seizure, than the routine ECG. Levetiracetam and lamotrigine have a more favorable effect on the autonomic balance of the heart than carbamazepine and valproic acid.

Key words: epilepsy, HRV, EEG, cardiac disorders

Wiad Lek 2019, 72, 2, 165-168

INTRODUCTION

Epidemiological studies have shown that the risk of myocardial infarction and stroke (both ischemic and hemorrhagic) in patients with epilepsy is higher than in people who are not suffering from epilepsy. Cleary et al. found that patients who develop epileptic seizures after 60 years have an increased risk of stroke [1,2,3].

Another study presents data on increasing the risk of stroke in young patients with epilepsy, which according to the authors is because of both long-term course of epilepsy (seizures since childhood) and long-term use of AEDs. It has been shown that carbamazepine, phenytoin, phenobarbital and valproic acid can adversely affect risk factors for cardiovascular and cerebrovascular diseases [4].

The reason for the increased risk of cardiovascular and cerebrovascular diseases in patients with epilepsy is considered to be dyslipidemia, an increase in the thickness of the intima media complex, an increase in the level of markers of systemic inflammation and oxidative stress, homocysteine and a high level of C-reactive protein in blood plasma, which increases the activity of the blood coagulation system and the risk of atherosclerosis. The above changes according to the authors correlate with the duration of administration and dose taken AEDs (carbamazepine, valproates, phenobarbital). However, carbamazepine and valproic acid remain the most commonly used AEDs in most countries due to their effectiveness and availability [2,4].

Several studies have been conducted on risk factors for vascular disease in patients with epilepsy. However, the effect of AEDs on patients with established cardiovascular diseases has not been studied, and no methods have been developed to detect diseases of the cardiovascular system at the preclinical stage in patients with epilepsy [5].

THE AIM

The aim of the work was to study changes in the parameters of HRV and EEG, as well as their correlation in patients with epilepsy and cardiovascular pathology in comparison with patients with epilepsy without cardiovascular pathology in order to identify cardiac risk factors in patients with epilepsy.

MATERIALS AND METHODS

One of the methods of early detection of imbalance in the cardiovascular system is to evaluate heart rate variability.

HRV parameters reflect the autonomic balance of the body and functional reserves of its management mechanisms. For the purpose of quantitative assessment of autonomic regulation of heart rhythm using the estimation of HRV indices [5,5].

Spectral analysis of HRV was used, which allowed to quantify the influence of various regulatory systems on the heart function in patients with epilepsy.

We observed the first group is the 50 patients suffering from epilepsy without cardiovascular pathology (CVP) at the age of 18-40 years and the second group is the 56 patients suffering from epilepsy and CVP at the age of 38-65 years. The number of patients of both sexes was comparable in each group. The disease’s duration was on average of 9.7 ± 0,58 years in the 1st group 15,3 ± 0,72 years in the 2st group. The duration of intake of AEDs has averaged 7.4 ± 0,95 years in the 1st group and 11,32 ± 0,86 years in the 2st group.

All patients underwent clinical and neurological examination, standard electrocardiographic examination (ECG), electroencephalographic examination (EEG), study of heart rate variability (HRV).

The obtained data were processed by methods of variation and correlation statistics using computer software. The probability of discrepancies was determined using Student’s criterion (t), and differences between the indicators, which have a distribution other than normal, were determined with the help of the Manna-Whitney test. The results were processed using Microsoft Excel 2010 (Microsoft Corporation) and Statistica 10.0 for Windows. Correlation analysis was performed by calculating the Spearman correlation coefficient (r). Differences were considered statistically significant at p ≤ 0.05.

RESULTS AND DISCUSSION

All patients received AEDs monotherapy in a stable medium-therapeutic dosage: valproates from 10 to 20 mg/kg/day, carbamazepine from 10 to 20 mg/kg/day, lamotrigine from 1.5 to 3.5 mg/kg/day, levetiracetam from 12 to 20 mg/kg/day.

Cardiac pathology in patients of the second group was represented by hypertension (HT) I, II, III stages are 29 (57%) patients, coronary heart disease (CHD): stable angina stress II A, II B functional classes are 6 (13%) patients, a combination of HT and CHD are 15 (30%) patients.

It is known that low HRV rates may indicate a disturbance of autonomic control of cardiac activity. It is shown that in patients with heart failure, as well as those who have had myocardial infarction, there is a persistent decrease in HRV. Signs of increased tone sympathetic autonomic nervous system observed in patients with hypertension [7]. In addition, there was an increased risk of fatal arrhythmias in patients with signs of increased sympathetic or decreased parasympathetic activity. It is assumed that autonomic cardiac dysfunction is important in the development of SUDEP [8].

The studies in patients with epilepsy showed signs of parasympathetic insufficiency and a tendency to increase sympathetic activity [9,10]. In the calculation and analysis of the relation LF/HF signs of sympathicotonia (LF/HF greater than or equal to 3) was observed in 2 patients of the 1st group and 3 patients of the 2nd group. The difference between the groups is unreliable (p>0.05), which forced to consider the power balance of the HRV spectrum in different ranges in more detail. It is known that the power ratio of the HRV spectrum in the range LF, HF, VLF reflects the autonomic balance of regulation of cardiac activity, which is considered to be unstrained if HF>VLF>LF (parasympathetic variant) or LF>HF>VLF (sympathicotonic variant) provided a sufficient value of TP (more than 2000 ms2). In persons under chronic stress, the autonomic balance in most cases looks like VLF>LF>HF or LF>VLF>HF, which reflects the activation of the sympathetic link of the VNS, the transition of the autonomic regulation to the suprasegmental level, i.e. excessive tension of adaptive mechanisms to ensure the activity of the body, its adaptation to changes in the conditions of functioning [11].

Intense autonomic balance was observed in 48% of patients of the 1st group and in 56% of patients of the 2nd group. The difference is again unreliable (p> 0.05). However, the unstrained balance was observed in 40% of patients of group 1 and only in 6% of patients of group 2 (p<0.001). In addition, the number of patients whose HRV power prevailed in the VLF range was significantly higher among patients of group 2 (70% in the second group, 42% in group 1, p<0.05). Patients of the first group, in which there was a predominance of the power spectrum of HRV in the VLF range, marked ECG changes (incomplete blockade feet beam Guisa, the reduction of repolarization, slowing intraventricular conduction and vnutriepreserdnaya, strengthening of potentials of the left ventricle) in contrast to patients, whose power spectrum was dominated in the range of LF and HF>HF.

There was a decrease in HRV output in patients with epilepsy [12,13]. When determining the HRV spectrum power, the examined patients showed a significant decrease in the total HRV power in both groups compared to the general population data (p<0.02). There were also significantly lower rates of TP in patients of the second group compared to the first (p<0.001). In addition, the significantly lower were indicators of the power spectrum of the HRV in the LF, HF range in the 2nd group (p<0.001). A similar trend was observed for VLF, but the differences are not statistically significant (p>0.05) (Table 1).

Changing the total power of HRV during the orthostatic test displays the adaptive capacity of the body to meet changing needs during the change of mode of operation. The greater the difference, the greater the” adaptive reserve “ of the organism [13]. The difference in TP at rest and in orthostasis was significantly higher on average in group 1 patients (p<0.001). In addition, it is known that the transition from a horizontal to a vertical position in the normal TP is reduced mainly due to a decrease in parasympathetic activity. The increase in TР in the orthostatic test may indicate an overstrain of compensatory mechanisms for ensuring activity [12]. The number of patients whose TP decreased in orthostasis compared to rest was significantly higher in group 1 patients (p<0.05). And back – the number of participants whose TP was growing in orthostasis is higher for the patients of the 2nd group (p<0.05).

It is considering that HRV changes could be a predictor of development of cardiovascular pathology and mortality from diseases of cardiovascular system [14], the obtained data demonstrate that patients with epilepsy have the increased risk of development of cardiovascular diseases owing to autonomic cardiac dysfunction. HRV can be applied to assessment of risk of development of cardiovascular pathology in patients with epilepsy.

It was noted that the closer the next seizure, the greater the ratio of LF/HF in patients of both groups (1-st groop rs=-0,37; р<0,05; 2-nd groop rs=-0,43; р<0,05), which did not correlate (1-st groop rs= 0.15; 2-nd groop rs= 0.17) with the change in the mean heart rate (according to ECG), possibly due to the short period of routine ECG recording (Fig.1). Thus, HRV is more informative for determining the seizure oncoming than a routine ECG.

When evaluated HRV in both groups, depending on the taken AEDs, it was found that the average values of TP, VLF, LF, HF, SDNN were significantly lower in patients receiving carbamazepine when compared with patients receiving other AEDs (p<0.001). It was also noted that the power in the HF range in group 1 patients was comparable in patients receiving carbamazepine and valproates, but this index was significantly higher in patients receiving lamotrigine and levetiracetam (p<0.02). A similar trend was observed in patients of the second group, but the differences were unreliable (p>0.05), probably due to a larger number of patients with intense autonomic balance among patients of the second group. Given that the decrease in parasympathetic activity is one of the predictors of cardiovascular disease, it can be assumed that levetiracetam and lamotrigine have a more favorable effect on the autonomic balance of the heart.

In addition, among the patients of the second group, there was a subgroup of patients with epilepsy who had experienced an acute vascular event (AVE), which, however, was not the cause of epilepsy (23 patients). These patients were compared with other patients of the 2nd group (33 patients) for the same period of time. The appearance of paroxysmal EEG phenomena was observed in 10 (44%) patients from those who had experienced AVE and in 3 (9%) patients without AVE (p <0.05). Generalization of paroxysmal activity in patients with focal paroxysmal activity and an increase in its amplitude was observed in 11 (48%) patients from those who had AVE and 5 (15%) patients without AVE (p <0.05). Also among the patients of this subgroup, an increase in the frequency of epileptic seizures after AVE was observed: the average frequency of seizures in the subgroup before AVE was 4.6 ± 0.33 per month; after AVE – 8.2 ± 0.87 per month (p <0.05).

We also studied the relationship of cardiovascular and nervous systems in the first and second groups according to HRV, ECG and EEG. It was found that the heart rate is inversely proportional to the total power of HRV (TR) (rs= – 0,65; p<0,02). This can be explained by the fact that the main contribution to heart rate variability is made by the parasympathetic component, and an increase in parasympathetic tone leads to a decrease in heart rate. It was also noted that TR is directly proportional to SDNN, probably due to the fact that SDNN is one of the main indicators of parasympathetic activity. Interestingly, the value of SDNN in turn correlated with the frequency of rhythm α in hyperventilation (rs= 0.58; p<0.001) and was significantly lower in patients of the second group (p<0.001). In addition, there was a correlation between the ratio of LF/HF and the representation of β EEG rhythm in patients of both groups (for group 1: rs= 0.48; for group 2: rs= 0.52; p<0.02).

The value of rhythm α frequency change in response to hyperventilation within 2 minutes was significantly less in patients of the second group (p<0.02). This can be explained by a decrease in the elasticity of the vascular wall, in particular arterioles, brain, their rigidity in patients of the second group. In addition, the value of rhythm α frequency change in response to hyperventilation correlated with the value of TP change in orthostasis compared to rest (rs= 0.43; p<0.02). Thus, both of these parameters can serve as indicators of adaptive reserve in patients with epilepsy (the value of the change in the frequency of rhythm α in response to hyperventilation, the value of TP changes in orthostasis compared to rest).

Despite the fact that the most used antiepileptic drugs such as carbamazepine and valproic acid have normotymic properties, in a large number of patients with epilepsy revealed a tense autonomic balance with a tendency to sympathicotony, which is not only a predictor of cardiac disorders, but can also contribute to the development of seizures and even be one of the factors of evaluation of the patient with epilepsy without seizures to continue antiepileptic therapy. Despite the fact that the number of patients with tense autonomic balance did not differ significantly in both groups, the unstrained balance was observed only in some patients of the second group (6%), unlike the first, which may indicate that cardiovascular disease also violates the autonomic regulation of cardiac activity.

Patients with epilepsy who have a tense autonomic balance with a tendency to sympathicotony may have an increased risk of developing cardiac pathology, although the effect of cardiovascular disease on the course of epilepsy remains a debatable issue. In such patients, it may be appropriate to use additional methods of correction of autonomic disorders, such as physical therapy, reducing stress – psychological support, the inclusion in therapy of drugs with vegetostabilizing properties.

CONCLUSIONS

1. The factors of increased cardiovascular risk were: tense autonomic balance with a tendency to sympathicotonia, signs of a decrease in parasympathetic activity, a decrease in the TP, an increase in the representation of the EEG β-rhythm. The magnitude of the change in the frequency of the α rhythm in response to hyperventilation as well as the magnitude of the change in TP in orthostasis can serve as indicators of the adaptation reserve in patients with epilepsy.

2. The development of an acute vascular event may increase the frequency of seizures and the presence of paroxysmal EEG phenomena

3. Levetiracetam and lamotrigine have a more favorable effect on the autonomic balance of the heart than carbamazepine and valproic acid.

4. HRV, namely the increase in the ratio of LH/HF is more informative to determine the oncoming seizure than the routine ECG.

references

1. Katherine S. Eggleston, Bryan D. Olin, Robert S. Fisher. Ictal tachycardia: The head–heart connection. Seizure – European Journal of Epilepsy Volume 23, Issue 7, Pages 496–505, August 2014

2. Fatar M, Akin I, Borggrefe M, Platten M, Alonso A. Interaction between heart and brain in sudden cardiac death. Herz. 2017 Apr;42(2):171-175. doi: 10.1007/s00059-017-4547-4.

3. Chang CS, Liao CH, Lin CC, Lane HY, Sung FC, Kao CH. Patients with epilepsy are at an increased risk of subsequent stroke: A population-based cohort study. Seizure. 2014 May; 23(5): 377-81. PMID: 24630806. DOI: 10.1016/j.seizure.2014.02.007

4. Park KJ, Sharma G, Kennedy JD, Seyal M. Potentially high-risk cardiac arrhythmias with focal to bilateral tonic-clonic seizures and generalized tonic-clonic seizures are associated with the duration of periictal hypoxemia. Epilepsia. 2017 Dec;58(12):2164-2171. doi: 10.1111/epi.13934. Epub 2017 Nov 3

5. Baysal-Kirac L, Serbest NG, Şahin E et al. Analysis of heart rate variability and risk factors for SUDEP in patients with drug-resistant epilepsy. Epilepsy Behav. 2017 Jun;71(Pt A):60-64. doi: 10.1016/j.yebeh.2017.04.018. Epub 2017 May 23.

6. Cygankiewicz I1, Zareba W. Heart rate variability. Handb Clin Neurol. 2013;117:379-93. doi: 10.1016/B978-0-444-53491-0.00031-6.

7. Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. The Lancet Neurology. 2013 Oct; 12(10): 966-77. PMID: 24012372. DOI: 10.1016/S1474-4422(13)70214-X

8. Myers KA, Bello-Espinosa LE, Symonds JD et all. Heart rate variability in epilepsy: A potential biomarker of sudden unexpected death in epilepsy risk. Epilepsia. 2018 Jul;59(7):1372-1380. doi: 10.1111/epi.14438. Epub 2018 Jun 6.

9. Mańka-Gaca I, Łabuz-Roszak B, Machowska-Majchrzak A, Kalarus Z, Średniawa B, Pierzchała K. Interictal heart rate in patients with epilepsy. Wiad Lek. 2016; 69(3 pt 2): 443-8. PMID: 28478403

10. Billeci L, Marino D, Insana L, Vatti G, Varanini M. Patient-specific seizure prediction based on heart rate variability and recurrence quantification analysis. PLoS One. 2018 Sep 25;13(9):e0204339. doi: 10.1371/journal.pone.0204339.

11. Behbahani S. A review of significant research on epileptic seizure detection and prediction using heart rate variability. Turk Kardiyol Dern Ars. 2018 Jul;46(5):414-421. doi: 10.5543/tkda.2018.64928.

12. Mańka-Gaca I, Łabuz-Roszak B, Machowska-Majchrzak A. Interictal heart rate in patients with epilepsy. Wiad Lek. 2016;69(3 pt 2):443-448.

13. Galli A, Lombardi F Heart rate variability regression and risk of sudden unexpected death in epilepsy. Med Hypotheses. 2017 Feb;99:49-52. doi: 10.1016/j.mehy.2016.11.016. Epub 2016 Nov 25

14. Moridani MK, Farhadi H. Heart rate variability as a biomarker for epilepsy seizure prediction. Bratisl Lek Listy. 2017;118(1):3-8. doi: 10.4149/BLL_2017_001.

Authors’ contributions:

According to the order of the Authorship.

Conflict of interest:

The Authors declare no conflict of interest.

CORRESPONDING AUTHOR

Valeriia Grymailo

5 Balakirev lane, 61103 Kharkiv, Ukraine

tel: +3 80637160022

e-mail: lelia.grim@gmail.com

Received: 15.09.2018

Accepted: 10.01.2019