Heart Rate Variability and Vagus Nerve Stimulation in Epilepsy Patients

Abstract Background Vagus nerve stimulation (VNS) exerts a cortical modulating effect through its diffuse projections, especially involving cerebral structures related to autonomic regulation. The influence of VNS on cardiovascular autonomic function in drug-resistant epilepsy patients is still debated. We aimed to evaluate the impact of VNS on cardiovascular autonomic function in drug-resistant epilepsy patients, after three months of neurostimulation, using the heart rate variability (HRV) analysis. Methodology Multiple Trigonometric Regressive Spectral analysis enables a precise assessment of the autonomic control on the heart rate. We evaluated time and frequency-domain HRV parameters in resting condition and during sympathetic and parasympathetic activation tests in five epilepsy patients who underwent VNS procedure. Results We found appropriate cardiac autonomic responses to sympathetic and parasympathetic activation tests, described by RMSSD, pNN50, HF and LF/HF dynamics after three months of VNS. ON period of the neurostimulation may generate a transient vagal activation reflected on heart rate and RMSSD values, as observed in one of our cases. Conclusion VNS therapy in epilepsy patients seems not to disrupt the cardiac autonomic function. HRV represents a useful tool in evaluating autonomic activity. More extensive studies are needed to further explore cardiac autonomic response after neurostimulation.


Introduction
Epilepsy affects approximately 65 million people worldwide [1]. Although therapy has substantially developed, about a third of patients remain resistant to drug treatment [1]. This leads to high mortality and morbidity [2,3]. Prevention measures and recognition of modifiable risk factors may reduce epilepsy mortality.
Patients with drug-resistant epilepsy, defined as seizure occurrence despite judicious association of two or more antiepileptic drugs over a minimum of 12 months period [4], may benefit from epilepsy surgery. Currently, this is performed in a small subset of drug-resistant patients. Vagus nerve stimulation (VNS) represents an adjuvant treatment for medically refractory partial-onset seizures in adults and adolescents [5]. VNS consists of chronic intermittent electrical stimulation of the vagus nerve, delivered by a programmable pulse generator [5]. VNS may represent an earlier stage option in treating pharmacoresistant epilepsy, with positive long-term effects [6,7], reducing the frequency of seizures and ameliorating the quality of the interictal period [7].
VNS exerts through its diffuse projection via the nucleus of the solitary tract, or the reticular system, a cortical modulating effect, especially involving cerebral structures related to autonomic regulation, such as thalamus, amygdala or prefrontal region [8]. The impact of VNS on cardiovascular autonomic function in drug-resistant epilepsy patients remains a controversial subject and in need of further studies [9].
Heart rate variability (HRV) represents a simple and non-invasive method to evaluate the sympathovagal balance, outlining the cardiac ability to adapt to hemodynamic and pathological conditions. Sympathetic hyperactivation and reduced cardiac vagal modulation associated with low HRV determines higher risk of cardiac arrhythmia and sudden death [10].
Rüdiger et al. proposed a novel algorithm to detect physiological oscillations of the heart rate (HR) based on RR intervals measurements -multiple trigonometric regressive spectral (MTRS) analysis [11]. HRV analysis in epilepsy provides essential information about the risk of sudden death by cardiac arrhythmias in these patients [12]. based on the trigonometric regressive analysis [13]. The HRV parameters are often analyzed by Fourier Transform. The mathematical approach using trigonometric regressions excluded the RR intervals equidistance issue, arising with the method of Fourier Transform [11]. noradrenergic outflows [15]. As a consequence, the physiological basis for LF/HF is difficult to discern [14]. The LF and HF values may also be calculated in normalized units (LFnu, HFnu), defining the relative values of each frequency spectrum reported to the total spectral power, from which the VLF component was excluded from the calculation.
The following time-domain parameters were considered: pNN50 (the proportion of pairs of successive RR intervals that differ by more than 50 ms to the total number of NN intervals) and RMSSD (the square root of the mean squared differences of successive NN intervals). These two parameters reflect the parasympathetic influence on the cardiac rhythm [10].
HRV is significantly correlated with an average HR, dependent on the influence of autonomic nervous system activity [10] and also mathematically determined (i.e., the inverse non-linear relationships between HR and RR interval) [16]. Therefore it is needed to distinguish if the clinical significance of HRV comes from the variability or from HR [17]. If the variability of a slow HR is compared with a fast HR (based on the fluctuations of RR intervals), greater HRV in patients with former than with the latter can be obtained [18]. To reduce this influence, we corrected the HRV for the average HR. The correction consisted of dividing or multiplying standard HRV indices by the power of two of their corresponding mean RR interval (mRR) [16].
This correction procedure does not remove any information about the signal's oscillations but only makes the oscillations relative to the signal's average value [18]. This allows the comparison of HRV among patients with different average HRs [19,20].
HRV is also influenced by the respiratory rate (RespRate). Therefore, alterations in these parameters may impose changes in HRV [16,21]. A decrease in respiratory frequency generally corresponds with a lengthening of the heart period [22,23]

Discussion
Patients with refractory epilepsy may present decreased HRV, raising the concern that altered autonomic function might contribute to sudden unexpected death in epilepsy (SUDEP) [25,26]. Long-term recordings in these patients indicated that severe bradycardia or asystole may occur [27,28], probably related to increased vagal tone associated with sleep.
Clinical significance and potential association with the sympathovagal alteration still needs to be clarified. Epileptic seizures involving temporal or insular lobe are susceptible to such complications [28,29], highlighting the importance of interictal cardiac evaluation in these patients. predominantly parasympathetic preganglionic axons [34]. Parasympathetic preganglionic projections arising bilaterally from nucleus amibiguus innervate multiple intrinsic cardiac ganglionic plexuses located within atrial and ventricular tissues, making direct contact with parasympathetic postganglionic neurons [35].
There is anatomic and functional evidence indicating that the vagosympathetic trunk also contains a small number of sympathetic efferent fibers [35,36], that modulate cardiac function via the intrinsic cardiac nervous system [37], contributing to the beat-to-beat regulation. Left cervical VNS is believed to minimize potential bradycardia or asystole, primarily mediated by the right vagus nerve [38]. While left cervical VNS is approved for refractory epilepsy and resistant depression, right cervical VNS was clinically tested for heart failure [38].
Seizure suppression by VNS in drug-resistant epilepsy patients may, therefore, depend on the release of noradrenaline, a neuromodulator that has anticonvulsant effects.
Another cortical structure involved in autonomic regulation is insula. Insular lesions are associated with mortality through autonomic dysfunction [29]. Electrical stimulation of the human insula produced cardiac chronotropic and blood pressure responses in epilepsy patients [49]. Transformation, is the assessment of shorter local data segments [11,13]. An adequate correction designed to remove the HR influence on HRV should always be performed, due to physiological but also mathematical reasons [17][18][19].
One of the limits of our report is the reduced number of patients while the other is using surface EEG study, because of the distant location of the insular cortex relative to scalp electrodes and the rapidly spreading activity.
Autonomic nervous system should be evaluated in epilepsy patients because of the risk of cardiac arrhythmias and SUDEP, particularly in the drug-resistant ones. We propose HRV analysis as a useful tool to assess sympathovagal balance and identify high-risk patients for cardiac arrhythmias. Moreover, HRV analysis could be a practical tool in identifying suitable patients for VNS therapy.

Disclosure of interest
The authors report no conflicts of interest.

Acknowledgments
The support of Dr. Heinz Rüdiger for providing the MTRS software and the constructive cooperation of the five patients in this study is gratefully acknowledged.  Legend: rs = Spearman's rank correlation coefficient, bpm= beats per minute.