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Cardiovascular autonomic and hemodynamic responses to vagus nerve stimulation in drug-resistant epilepsy
Seizure 45 (2017) 56–60
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Cardiovascular autonomic and hemodynamic responses to vagus nerve stimulation in drug-resistant epilepsy Iñigo Garamendia,* , Marian Aceraa , Marta Agundeza , Lara Galbarriatud , Ainhoa Marinasa , Iñigo Pomposod, Elena Vallea , Jose-Alberto Palmae, Juan C. Gomez-Estebanb,c,* a
Epilepsy Unit, Biocruces Research Institute, Barakado, Bizkaia, Spain Autonomic and Movement Disorders Unit, Biocruces Research Institute, Barakado, Bizkaia, Spain c Department of Neurosciences, University of Basque Country, Leioa, Spain d Department of Neurosurgery, Cruces University Hospital, Spain e Dysautonomia Center, Department of Neurology, New York University Medical Center, New York, NY, USA b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 14 September 2016 Received in revised form 20 November 2016 Accepted 22 November 2016 Available online xxx
Purpose: Vagus nerve stimulation (VNS) is used as an adjunctive therapy for treating patients with drugresistant epilepsy. The impact of VNS on cardiovascular autonomic function remains to be fully understood. We determined changes in cardiovascular sympathetic and parasympathetic, and hemodynamic function in association with VNS in patients with drug-resistant focal epilepsy. Method: Longitudinal (n = 15) evaluation of beat-to-beat blood pressure (BP) and heart rate variability (HRV), baroreflex sensibility, and hemodynamic function performed before VNS implantation, 6-months after implantation, and a mean of 12-months after implantation; and cross-sectional study (n = 14) of BP and HR variability and baroreflex sensitivity during VNS on and VNS off. Results: In the longitudinal study, no differences were observed between the baseline, the 6-month visit, and the final visit in markers of parasympathetic cardiovagal tone or baroreflex sensitivity. Systolic and diastolic BP upon 5-min of head-up tilt increased significantly after VNS implantation (Systolic BP: 16.69 5.65 mmHg at baseline, 2.86 16.54 mmHg at 6-month, 12.25 12.95 mmHg at final visit, p = 0.01; diastolic BP: 14.84 24.72 mmHg at baseline, 0.86 16.97 mmHg at 6-month, and 17 12.76 mmHg at final visit, p = 0.001). Conclusion: VNS does not seem to produce alterations in parasympathetic cardiovagal tone, regardless of the laterality of the stimulus. We observed a slight increase in sympathetic cardiovascular modulations. These changes had no significant hemodynamic implications. These findings contribute to the understanding of potential mechanisms of action of VNS. © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Vagus nerve stimulation Heart rate variability Blood pressure Autonomic nervous system
1. Introduction In 1997, the US Food and Drug Administration (FDA) approved vagus nerve stimulation (VNS) as adjunctive therapy for reducing the frequency of seizures in patients >12 years of age with partialonset seizures refractory to antiepileptic medications [1]. The mechanism of action of VNS remains largely unknown. The vagus nerve is comprised of 20% efferent (conveying signals from
* Corresponding authors at: Department of Neurology, Cruces University Hospital, Plaza de Cruces s/n, Barakaldo 48903, Spain. E-mail addresses: [email protected] (I. Garamendi), [email protected] (J.C. Gomez-Esteban).
the CNS to the organs) and 80% afferent (conveying sensory information from the viscera to the CNS) fibers. Presumed antiseizure mechanisms are mediated by modulation of vagal afferent pathways resulting in alterations of seizure-generating regions [2,3]. Conversely, modulations of vagal parasympathetic efferent pathways do not underlie anti-seizure effects [2]. Vagal efferent pathways innervating the heart induce inhibition of the pacemaker activity of the sinoatrial node resulting in decreased heart rate (HR), reduced atrioventricular conduction, and decreased excitability of the His-Purkinje system [4]. This fact has always raised concerns that VNS might affect the cardiac rhythm. However, the effects of VNS on cardiovascular autonomic tone of patients with refractory epilepsy remain to be fully understood.
http://dx.doi.org/10.1016/j.seizure.2016.11.018 1059-1311/© 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
I. Garamendi et al. / Seizure 45 (2017) 56–60
On the one hand, cardiac changes related to VNS in epilepsy have been reported to be rare (0.1%), and preliminary investigations on HR variability in patients with VNS revealed minor changes with no clinically relevant effects [5–7]; on the other hand, cases of VNS-induced bradyarrhythmia have been reported [8–13], and recent pilot studies showed higher vagal tone [14] and lower HR in patients with VNS [15]. In this work we tested the hypothesis that, because VNS acts on afferent ascending rather than efferent descending fibers, it exerts no significant effects on cardiovascular autonomic function. To this aim, we comprehensively studied cardiovascular autonomic reflexes and hemodynamics in a group of patients with drugresistant epilepsy being treated with VNS, and documented changes overtime. 2. Methods 2.1. Patient selection Consecutive patients with drug-resistant epilepsy [16] who were scheduled to undergo implantation of the VNS Therapy1 System (Implantable Pulse Generator model 103, lead model 304; Cyberonics, Inc., Houston, TX, USA) at the Comprehensive Epilepsy Center at Cruces University Hospital (Bilbao, Spain) over a twoyear period (2011–2013) were recruited [17]. Patients who agreed to participate in this study gave written informed consent prior to any study-specific procedures. The local Institutional Review Board approved the protocol and the study was conducted in accordance with the 2013 version of the Declaration of Helsinki. Implantation, postoperative care, and ramp-up and maintenance stimulation protocols were standard. Clinicians following standard clinical protocols adjusted the VNS settings without knowledge of cardiovascular autonomic testing results. As part of daily clinical practice, antiepileptic drug changes were allowed during the study period. Because antiepileptic drugs (AEDs) that modify sodium currents may modify the cardiac function, the following drugs were recorded: carbamazepine, oxcarbazepine, eslicarbazepine acetate, lamotrigine and lacosamide. 2.2. Study design This study had two parts. The first part was designed as a prospective longitudinal evaluation to assess autonomic and hemodynamic changes overtime in 15 patients with drug-resistant epilepsy undergoing VNS. Cardiovascular autonomic testing was performed on three occasions: 15–30 days before VNS implantation, 6-months after VNS implantation, and at the time when high stimulation parameters were achieved (in all cases 10–15 months from initial evaluation). The second part of this study was a cross-sectional assessment of 14 patients with drug-resistant epilepsy under active treatment with VNS in whom autonomic and hemodynamic testing was performed. Eight of these patients had been under VNS therapy for at least 2 years, and hence the device was operating at therapeutic parameters. We performed cardiovascular autonomic testing while the VNS was on (30 s) and, subsequently while the VNS was off, (5min) the same day. 2.3. Cardiovascular autonomic testing All individuals underwent a complete battery of autonomic and hemodynamic tests. Autonomic testing was carried out in the afternoon, and patients were instructed to avoid, in the previous 24 h, the intake of any medications, food or beverages that could potentially affect cardiovascular function. Exclusion criteria were a
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diagnosis of hypertension, diabetes mellitus, or cardiac or renal dysfunction. Testing was performed in a quiet environment with continuous non-invasive ECG tracing, beat-to-beat continuous blood pressure (BP, obtained with finger plethysmography), and impedance cardiography for all tests (Task Force1 Monitor, CNSystems Medizintechnik AG, Austria). Patients rested in a supine position for 10 min prior to testing. The 10-min ECG segment was used to calculate HR variability (HRV), which was analyzed in the frequency domain using the fast Fourier spectral transform. Accordingly, the beat stream of the Rto-R interval series was transformed to compute high-frequency (HF) power within the frequency band 0.150–0.400 Hz, and the low-frequency (LF) power within the frequency band 0.040– 0.150 Hz, reported in milliseconds squared. The LF/HF ratio was calculated as LF frequency divided by HF frequency and is unitless. HF HRV is an indicator of parasympathetic cardiovagal tone, whereas LF HRV and LF/HF ratio are indicators of autonomic tone and balance [18]. Similarly, the LF power of the diastolic BP variability (BPV) was also calculated. LF BPV oscillations are considered as a marker of sympathetic vasomotor activity. The HR response to paced breathing (6 cycles per minute), described as the average difference in maximum and minimum HR and the expiratory to inspiratory (E:I) ratio was evaluated and considered a measure of parasympathetic cardiovagal tone. A Valsalva maneuver was elicited by expiring against a 40-mmHg pressure for 15 s. The Valsalva ratio (a measure of parasympathetic cardiovagal function) was recorded. Only during the first part of the study, BP and HR were also measured noninvasively at 1-min intervals with an automated cuff sphygmomanometer over the brachial artery during a 60 head-up tilt for 5 min. HRV and BPV were also assessed during isometric muscle contraction (using a handgrip dynamometer). Baroreflex sensitivity (BRS) is a marker of the sensitivity of the autonomic reflexes to react upon BP changes by altering the length of the RR-interval. In normal conditions, if BP increases, the RRinterval is delayed (i.e., HR decreases). Conversely, if BP drops, the RR-interval shortens (i.e., HR increases). We determined the spontaneous baroreflex sensitivity (BRS) by means of the so called ‘sequence method’ [19]. According to this method, RR interval and beat-to-beat SBP data are scanned and sequences of three or more beats in which the BP and RR interval concomitantly increase (or decrease) higher than a threshold value are identified (for BP, the threshold is 1 mmHg per heart beat and for RR interval 4 ms per heart beat). The BRS is defined as the slope of the regression line between the data points in these sequences. At baseline, intermediate visit, and the final visit these values are calculated at rest after 10 min of registration. In the cross-sectional study (VNS ON and OFF) the duration of the registration periods is only 30 s. For this reason we repeated several times, until a reliable number of ramps was obtained which would allow the calculation of BRS. 2.4. Hemodynamic testing In addition, in the second part of the study, we used impedance cardiography to study specific hemodynamic parameters [20]: stroke index (SI) defined as the volume of blood the left ventricle ejects in one beat, divided by the body surface area, measured in milliliters per square meter (ml/m2); cardiac index (CI) defined as the cardiac output divided by the body surface area, measured in liters per minute per square meter (L/min/m2); left ventricular stroke work index (LVWI), a measure of left ventricular contractility, measured in mmHg l/(min m2); and acceleration index (ACI), defined as the maximum rate of change of blood velocity related to
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2.86 16.54 mmHg at 6-month, 12.25 12.95 mmHg at final visit, p = 0.01; diastolic BP: 14.84 24.72 mmHg at baseline, 0.86 16.97 mmHg at 6-month, and 17 12.76 mmHg at final visit, p = 0.001) (Fig. 1). BRS was not different between visits (Table 2). Similar results were observed in the patient with the VNS implanted in the right vagus nerve. In isometric contraction maneuver (isometric hand grip) no significant alterations were detected when comparing the final and intermediate visits with baseline
changes in aortic blood acceleration, measured in square seconds (s2). 2.5. Statistical analysis Data was tested for normality with the Kolmogorov–Smirnov test. Due to small sample size and the normality test were not homogeneous, it was decided to use nonparametric test. Differences in autonomic and hemodynamic parameters were analyzed with the Friedman test in the first part of the study (baseline vs. 6month vs. final) and with Wilcoxon test in the second part of the study (VNS on vs. VNS off) using SPSS for Windows (Version 12; SPSS, Chicago IL, USA). Data are reported as means standard deviation. p < 0.05 was considered statistically significant.
3.2. Second part Parasympathetic cardiovagal markers (E:I ratio, Valsalva ratio) were not different between on and off situations. BRS was not different between the on and off situations. Hemodynamic parameters (SI, ACI, or LVSWI) were not different during the on and off situations (Table 3).
3. Results All patients had a history of simple partial, complex partial, and secondarily generalized focal seizures. Patients’ characteristics are shown in Table 1. All patients except one had the VNS implanted in the left vagus nerve. Stimulation parameters were adjusted according to standard practice to treatment settings as defined by patient tolerability and clinical response (Table 2). No substantial changes in drug schedule were made. Most patients (85.7%) were on active treatment with sodium channel blocking AEDs. No seizures occurred during the procedures and therefore all recordings were interictal. ECG tracings were normal in all patients and no patient had a history of cardiac disease. The median seizure reduction was 40%, and the responder rate, defined as percentage of patients with a reduction of seizure frequency of at least 50%, was 42.9% and 45.5% at the intermediate and final visits respectively. No patient achieved freedom.
4. Discussion The main finding of this study is that VNS in patients with refractory epilepsy does not exert clinically significant changes in cardiovascular autonomic or hemodynamic control. We observed no modification in inotropic and chronotropic heart function 6month or 12-month after implantation of the device, or when comparing the VNS on and off conditions. There has been a slight increase in sympathetic response after implantation of the device in different maneuvers (increased of BP in IIb and IV phases in the Valsalva maneuver, increased systolic blood pressure within the first five minutes of tilt test). However, while the patients are at rest, there has been a decrease in blood pressure at six months and at the end of study, which correlates with decreased LFdPA, although this finding had no clinically significant implications. Overall, our results support our hypothesis that VNS exert no major autonomic cardiovascular or hemodynamic effects. Bradycardia has been reported during lead tests performed during implantation of the device, but in few cases during regular treatment [8,11,21,22]. Because most of these cases were intraoperative, a plausible mechanism is that bradycardia was due to vagal nerve traction or injury. Other potential mechanisms are stimulation of cervical cardiac branches of the vagus nerve either
3.1. First part No differences were observed between the baseline, the 6month visit, and the final visit in terms of E:I ratio, Valsalva ratio, or HRV HF, all markers of parasympathetic cardiovagal tone. Within the markers of sympathetic tone, only the change of systolic and diastolic BP upon 5-min of head-up tilt increased significantly after VNS implantation (Systolic BP: 16.69 5.65 mmHg at baseline,
Table 1 Patients’ characteristics. Variable
First part (Longitudinal study)
Second part (Cross-sectional study)
No. of subjects Age, mean (SD)
15 38.9 (7.8) years
14 32.4 (8.1) years
Sex, n (%) Men Women Caucasian, n (%)
13 (86.6%) 2 (13.3%) 15 (100%)
10 (71.4%) 4 (28.5%) 14 (100%)
Duration of epilepsy, n (%) >20 years <20 years
9 (60%) 6 (40%)
8 (57.1%) 6 (42.8%)
Etiology, n (%) Cryptogenic Trauma Malformations of cortical development Others
5 4 3 3
8 2 1 3
Frequency of seizures, n (%) >25 per year 10–25 per year 0–9 per year
10 (66.6%) 4 (26.6%) 1 (6.6%)
(33.3%) (26.6%) (20%) (20%)
(57.1%) (14.3%) (7.1%) (21.4%)
11 (78.6%) 2 (14.3%) 1 (7.1%)
I. Garamendi et al. / Seizure 45 (2017) 56–60
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Table 2 Longitudinal assessment of cardiovascular autonomic parameters in patients undergoing vagus nerve stimulation. Variable
Baseline (before VNS)
6-month after VNS
Final visit (10–15 months after VNS)
P-value
N/A
1.25 (1.00–1.50) 25 (25–30) 250 (250–500) 10
2 (1.75–2.5) 25 (20–30) 250 (250–500) 29 (16–38)
ns
Median seizure reduction, % (range)
N/A
40 (0–90)
40 (0–83)
ns
Responder rate (%)
N/A
42.9
45.5
ns
Median concomitant AEDs (range) Na+ channel blockers (%)
4 (2–4) 12 (85.7)
4 (3–4) 12 (85.7)
4 (3–4) 11 (84.6)
ns
AED dose change (%) AED change (%) AEDs increase (%)
N/A
2 (14.3) 2 (14.3) 1 (7.1)
3 (23.1) 4 (30.8) 1 (7.7)
ns
E:I ratio Valsalva ratio Increase in Valsalva BP Phase II, mmHg Increase in Valsalva BP Phase IV, mmHg Resting supine SBP, mmHg Resting supine DBP, mmHg Resting supine HR, bpm DSBP after 3-min head-up tilt, mmHg DDBP after 3-min head-up tilt, mmHg DHR after 3-min head-up tilt, bpm DSBP after 5-min head-up tilt, mmHg DDBP after 5-min head-up tilt, mmHg DHR after 5-min head-up tilt (bpm) LF HRV, ms2 HF HRV, ms2 LF/HF ratio LF DBP, mmHg2 BRS, ms/mmHg DTAD Isometric muscle contraction after 3 min DHR isometric muscle contraction after 3 min
1.30 (0.15) 1.25 (0.17) 8.13 (12.71) 19.00 (11.91) 141.31 (20.4) 99.38 (16.30) 77.85 (11.0) 2.31 (18.30) 3.69 (14.32) 2.69 (8.25) 16.69 (35.65) 14.84 (24.72) 0.84 (0.67) 1843.07 (1470.08) 441.07 (445.11) 5.53 (5.40) 31.17 (109.22) 20.37 (11.42) 6,42 (13.25) 6.00 (13.25)
1.29 (0.16) 1.38 (0.33) 2.83 (9.50) 26.75 (9.89) 135.07 (18.06) 95.07 (17,41) 72.14 (7.98) 9.71 (19.56) 9.57 (19.57) 6.78 (6.96) 2.86 (16.54) 0.86 (16.97) 8.35 (6.19) 3564.85 (3945.81) 656.39 (175.43) 10.60 (9.80) 16.02 (38.92) 19.66 (14.1) 11.00 (18.95) 1.50 (6.07)
1.33 (0.10) 1.36 (0.28) 0.41 (5.83) 27.66 (21.99) 122.83 (15.22) 76.67 (8.89) 69.33 (6.09) 3.08 (42.33) 12.42 (30.89) 7.81 (13.28) 12.25 (12.95) 17.00 (12.76) 10.25 (7.24) 4816.00 (6784.64) 619.93 (171.93) 8.12 (12.08) 7.38 (18.47) 19.18 (14.79) 1.01 (13.71) 3. 50 (6.73)
ns ns 0.09 ns 0.05 <0.001 0.08 ns ns ns 0.01 <0.001 0.004 ns ns ns ns ns ns ns
VNS parameters, median (range) Amplitude (mA) Frequency (Hz) Pulse width (ms) Duty cycle (%)
by collateral current spread or directly by inadvertent placement of the electrodes on one of these branches; improper plugging of the electrodes into the pulse generator, resulting in erratic varying intensity of stimulation; or reverse polarity [8]. To avoid these
Fig. 1. Boxplot representing monitoring the tilt table test at baseline, at six months and the period of maximum effectiveness of stimulators. It is observed as in the two postoperative visits there is a different behavior of blood pressure at 3 min and 5 min of tilt.
potential complications, we performed the first post-surgery assessments 6-months after implantation. We found an increase in systolic and diastolic BP after 5-min of head-up tilt. These results indicate a mild increase in sympathetic tone. Previous studies showed an increase in systolic and diastolic BP after VNS implantation as measured by 24-h ambulatory BP monitoring [23]. Increases in cardiac sympathetic tone have been also described in children treated with VNS [24] Classically, VNS surgery is performed on the left side because of early concerns that right VNS may cause greater reductions in HR than left-sided VNS [25]. However, there is no clear evidence for this. In fact, one of our patients with right VNS at high stimulation parameters had similar results to those of our patients with left VNS [26]. Interestingly, VNS has been shown to exert antiarrhythmic effects, improve cardiac function, and reduce mortality in patients with heart failure [27]. In this indication, though, stimulation parameters, dipole orientation, and generator management are different from that in drug-resistant epilepsy. It has been postulated that VNS may induce increases in sympathetic output that could contribute to its mechanism of action [25]. This is based on the finding that VNS-induced antiepileptic effects are associated with elevated hippocampal noradrenaline levels [28]. Also, the locus coeruleus, the principal noradrenergic nucleus of the brain, mediates some of the seizureattenuating effects of VNS [29]. Some antiepileptic drugs, especially those that block sodium or potassium channels may modify the cardiac function. In our series no substantial changes in AED schedule were performed and most patients were on active
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Table 3 Cross-sectional evaluation of cardiovascular autonomic and hemodynamic parameters during on and off situations. Variable
VNS off
VNS on
P-value
E:I ratio BRS, ms/mmHg Stroke index, ml/m2 Cardiac index, L/min/m2 Left ventricular stroke work index, mmHg l/(min m2) Acceleration index, 100/s2
1.42 11.83 48.76 3.38 4.01 81.42
1.39 11.14 47.87 3.39 4.00 78.71
0.64 0.57 0.50 0.94 0.97 0.35
treatment with sodium channel blockers before and after the implantation of the VNS. Nearly half of patients were responders, and this result is concordant with our historical series of patients that underwent VNS implantation [17]. The relatively limited size of the study at one center is a limitation; another limitation of the study is skewed gender distribution (male predominance): the power spectral density of HRV in females is characterized by significantly greater HFHRV and less LFHRV [30]. However, our results are robust and provide no significant hemodynamic changes in association with VNS at stimulation settings routinely used for seizure control. Also, we included only epilepsy patients with no additional risk factors, such as hypertension, diabetes mellitus, cardiac or renal dysfunction. Further studies are warranted to determine if the small increases in sympathetic tone seen during VNS in our subjects are more pronounced or are associated with negative outcomes in patients with concurrent diseases. 5. Conclusion Our findings support the hypothesis that, in the absence of surgical injury of the vagus, VNS does not seem to produce alterations in parasympathetic cardiovagal tone, regardless of the laterality of the stimulus. We observed a slight increase in sympathetic cardiovascular modulations, perhaps through afferent stimulation of brainstem areas and subsequent activation of sympathetic pathways, although this had no significant hemodynamic effects. Conflict of interest statement None of the authors has any conflict of interest to disclose. References [1] Morris 3rd GL, Gloss D, Buchhalter J, Mack KJ, Nickels K, Harden C. Evidencebased guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2013;81:1453–9. [2] Henry TR. Therapeutic mechanisms of vagus nerve stimulation. Neurology 2002;59:S3–14. [3] Schachter SC, Saper CB. Vagus nerve stimulation. Epilepsia 1998;39:677–86. [4] Palma JA, Benarroch EE. Neural control of the heart: recent concepts and clinical correlations. Neurology 2014;83:261–71. [5] Galli R, Limbruno U, Pizzanelli C, Giorgi FS, Lutzemberger L, Strata G, et al. Analysis of RR variability in drug-resistant epilepsy patients chronically treated with vagus nerve stimulation. Auton Neurosci 2003;107:52–9. [6] Stemper B, Devinsky O, Haendl T, Welsch G, Hilz MJ. Effects of vagus nerve stimulation on cardiovascular regulation in patients with epilepsy. Acta Neurol Scand 2008;117:231–6. [7] Ben-Menachem E. Vagus nerve stimulation, side effects, and long-term safety. J Clin Neurophysiol 2001;18:415–8. [8] Asconape JJ, Moore DD, Zipes DP, Hartman LM, Duffell Jr. WH. Bradycardia and asystole with the use of vagus nerve stimulation for the treatment of epilepsy: a rare complication of intraoperative device testing. Epilepsia 1999;40:1452–4.
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Cardiovascular autonomic and hemodynamic responses to vagus nerve stimulation in drug-resistant epilepsy Iñigo Garamendia,* , Marian Aceraa , Marta Agundeza , Lara Galbarriatud , Ainhoa Marinasa , Iñigo Pomposod, Elena Vallea , Jose-Alberto Palmae, Juan C. Gomez-Estebanb,c,* a
Epilepsy Unit, Biocruces Research Institute, Barakado, Bizkaia, Spain Autonomic and Movement Disorders Unit, Biocruces Research Institute, Barakado, Bizkaia, Spain c Department of Neurosciences, University of Basque Country, Leioa, Spain d Department of Neurosurgery, Cruces University Hospital, Spain e Dysautonomia Center, Department of Neurology, New York University Medical Center, New York, NY, USA b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 14 September 2016 Received in revised form 20 November 2016 Accepted 22 November 2016 Available online xxx
Purpose: Vagus nerve stimulation (VNS) is used as an adjunctive therapy for treating patients with drugresistant epilepsy. The impact of VNS on cardiovascular autonomic function remains to be fully understood. We determined changes in cardiovascular sympathetic and parasympathetic, and hemodynamic function in association with VNS in patients with drug-resistant focal epilepsy. Method: Longitudinal (n = 15) evaluation of beat-to-beat blood pressure (BP) and heart rate variability (HRV), baroreflex sensibility, and hemodynamic function performed before VNS implantation, 6-months after implantation, and a mean of 12-months after implantation; and cross-sectional study (n = 14) of BP and HR variability and baroreflex sensitivity during VNS on and VNS off. Results: In the longitudinal study, no differences were observed between the baseline, the 6-month visit, and the final visit in markers of parasympathetic cardiovagal tone or baroreflex sensitivity. Systolic and diastolic BP upon 5-min of head-up tilt increased significantly after VNS implantation (Systolic BP: 16.69 5.65 mmHg at baseline, 2.86 16.54 mmHg at 6-month, 12.25 12.95 mmHg at final visit, p = 0.01; diastolic BP: 14.84 24.72 mmHg at baseline, 0.86 16.97 mmHg at 6-month, and 17 12.76 mmHg at final visit, p = 0.001). Conclusion: VNS does not seem to produce alterations in parasympathetic cardiovagal tone, regardless of the laterality of the stimulus. We observed a slight increase in sympathetic cardiovascular modulations. These changes had no significant hemodynamic implications. These findings contribute to the understanding of potential mechanisms of action of VNS. © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Vagus nerve stimulation Heart rate variability Blood pressure Autonomic nervous system
1. Introduction In 1997, the US Food and Drug Administration (FDA) approved vagus nerve stimulation (VNS) as adjunctive therapy for reducing the frequency of seizures in patients >12 years of age with partialonset seizures refractory to antiepileptic medications [1]. The mechanism of action of VNS remains largely unknown. The vagus nerve is comprised of 20% efferent (conveying signals from
* Corresponding authors at: Department of Neurology, Cruces University Hospital, Plaza de Cruces s/n, Barakaldo 48903, Spain. E-mail addresses: [email protected] (I. Garamendi), [email protected] (J.C. Gomez-Esteban).
the CNS to the organs) and 80% afferent (conveying sensory information from the viscera to the CNS) fibers. Presumed antiseizure mechanisms are mediated by modulation of vagal afferent pathways resulting in alterations of seizure-generating regions [2,3]. Conversely, modulations of vagal parasympathetic efferent pathways do not underlie anti-seizure effects [2]. Vagal efferent pathways innervating the heart induce inhibition of the pacemaker activity of the sinoatrial node resulting in decreased heart rate (HR), reduced atrioventricular conduction, and decreased excitability of the His-Purkinje system [4]. This fact has always raised concerns that VNS might affect the cardiac rhythm. However, the effects of VNS on cardiovascular autonomic tone of patients with refractory epilepsy remain to be fully understood.
http://dx.doi.org/10.1016/j.seizure.2016.11.018 1059-1311/© 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
I. Garamendi et al. / Seizure 45 (2017) 56–60
On the one hand, cardiac changes related to VNS in epilepsy have been reported to be rare (0.1%), and preliminary investigations on HR variability in patients with VNS revealed minor changes with no clinically relevant effects [5–7]; on the other hand, cases of VNS-induced bradyarrhythmia have been reported [8–13], and recent pilot studies showed higher vagal tone [14] and lower HR in patients with VNS [15]. In this work we tested the hypothesis that, because VNS acts on afferent ascending rather than efferent descending fibers, it exerts no significant effects on cardiovascular autonomic function. To this aim, we comprehensively studied cardiovascular autonomic reflexes and hemodynamics in a group of patients with drugresistant epilepsy being treated with VNS, and documented changes overtime. 2. Methods 2.1. Patient selection Consecutive patients with drug-resistant epilepsy [16] who were scheduled to undergo implantation of the VNS Therapy1 System (Implantable Pulse Generator model 103, lead model 304; Cyberonics, Inc., Houston, TX, USA) at the Comprehensive Epilepsy Center at Cruces University Hospital (Bilbao, Spain) over a twoyear period (2011–2013) were recruited [17]. Patients who agreed to participate in this study gave written informed consent prior to any study-specific procedures. The local Institutional Review Board approved the protocol and the study was conducted in accordance with the 2013 version of the Declaration of Helsinki. Implantation, postoperative care, and ramp-up and maintenance stimulation protocols were standard. Clinicians following standard clinical protocols adjusted the VNS settings without knowledge of cardiovascular autonomic testing results. As part of daily clinical practice, antiepileptic drug changes were allowed during the study period. Because antiepileptic drugs (AEDs) that modify sodium currents may modify the cardiac function, the following drugs were recorded: carbamazepine, oxcarbazepine, eslicarbazepine acetate, lamotrigine and lacosamide. 2.2. Study design This study had two parts. The first part was designed as a prospective longitudinal evaluation to assess autonomic and hemodynamic changes overtime in 15 patients with drug-resistant epilepsy undergoing VNS. Cardiovascular autonomic testing was performed on three occasions: 15–30 days before VNS implantation, 6-months after VNS implantation, and at the time when high stimulation parameters were achieved (in all cases 10–15 months from initial evaluation). The second part of this study was a cross-sectional assessment of 14 patients with drug-resistant epilepsy under active treatment with VNS in whom autonomic and hemodynamic testing was performed. Eight of these patients had been under VNS therapy for at least 2 years, and hence the device was operating at therapeutic parameters. We performed cardiovascular autonomic testing while the VNS was on (30 s) and, subsequently while the VNS was off, (5min) the same day. 2.3. Cardiovascular autonomic testing All individuals underwent a complete battery of autonomic and hemodynamic tests. Autonomic testing was carried out in the afternoon, and patients were instructed to avoid, in the previous 24 h, the intake of any medications, food or beverages that could potentially affect cardiovascular function. Exclusion criteria were a
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diagnosis of hypertension, diabetes mellitus, or cardiac or renal dysfunction. Testing was performed in a quiet environment with continuous non-invasive ECG tracing, beat-to-beat continuous blood pressure (BP, obtained with finger plethysmography), and impedance cardiography for all tests (Task Force1 Monitor, CNSystems Medizintechnik AG, Austria). Patients rested in a supine position for 10 min prior to testing. The 10-min ECG segment was used to calculate HR variability (HRV), which was analyzed in the frequency domain using the fast Fourier spectral transform. Accordingly, the beat stream of the Rto-R interval series was transformed to compute high-frequency (HF) power within the frequency band 0.150–0.400 Hz, and the low-frequency (LF) power within the frequency band 0.040– 0.150 Hz, reported in milliseconds squared. The LF/HF ratio was calculated as LF frequency divided by HF frequency and is unitless. HF HRV is an indicator of parasympathetic cardiovagal tone, whereas LF HRV and LF/HF ratio are indicators of autonomic tone and balance [18]. Similarly, the LF power of the diastolic BP variability (BPV) was also calculated. LF BPV oscillations are considered as a marker of sympathetic vasomotor activity. The HR response to paced breathing (6 cycles per minute), described as the average difference in maximum and minimum HR and the expiratory to inspiratory (E:I) ratio was evaluated and considered a measure of parasympathetic cardiovagal tone. A Valsalva maneuver was elicited by expiring against a 40-mmHg pressure for 15 s. The Valsalva ratio (a measure of parasympathetic cardiovagal function) was recorded. Only during the first part of the study, BP and HR were also measured noninvasively at 1-min intervals with an automated cuff sphygmomanometer over the brachial artery during a 60 head-up tilt for 5 min. HRV and BPV were also assessed during isometric muscle contraction (using a handgrip dynamometer). Baroreflex sensitivity (BRS) is a marker of the sensitivity of the autonomic reflexes to react upon BP changes by altering the length of the RR-interval. In normal conditions, if BP increases, the RRinterval is delayed (i.e., HR decreases). Conversely, if BP drops, the RR-interval shortens (i.e., HR increases). We determined the spontaneous baroreflex sensitivity (BRS) by means of the so called ‘sequence method’ [19]. According to this method, RR interval and beat-to-beat SBP data are scanned and sequences of three or more beats in which the BP and RR interval concomitantly increase (or decrease) higher than a threshold value are identified (for BP, the threshold is 1 mmHg per heart beat and for RR interval 4 ms per heart beat). The BRS is defined as the slope of the regression line between the data points in these sequences. At baseline, intermediate visit, and the final visit these values are calculated at rest after 10 min of registration. In the cross-sectional study (VNS ON and OFF) the duration of the registration periods is only 30 s. For this reason we repeated several times, until a reliable number of ramps was obtained which would allow the calculation of BRS. 2.4. Hemodynamic testing In addition, in the second part of the study, we used impedance cardiography to study specific hemodynamic parameters [20]: stroke index (SI) defined as the volume of blood the left ventricle ejects in one beat, divided by the body surface area, measured in milliliters per square meter (ml/m2); cardiac index (CI) defined as the cardiac output divided by the body surface area, measured in liters per minute per square meter (L/min/m2); left ventricular stroke work index (LVWI), a measure of left ventricular contractility, measured in mmHg l/(min m2); and acceleration index (ACI), defined as the maximum rate of change of blood velocity related to
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2.86 16.54 mmHg at 6-month, 12.25 12.95 mmHg at final visit, p = 0.01; diastolic BP: 14.84 24.72 mmHg at baseline, 0.86 16.97 mmHg at 6-month, and 17 12.76 mmHg at final visit, p = 0.001) (Fig. 1). BRS was not different between visits (Table 2). Similar results were observed in the patient with the VNS implanted in the right vagus nerve. In isometric contraction maneuver (isometric hand grip) no significant alterations were detected when comparing the final and intermediate visits with baseline
changes in aortic blood acceleration, measured in square seconds (s2). 2.5. Statistical analysis Data was tested for normality with the Kolmogorov–Smirnov test. Due to small sample size and the normality test were not homogeneous, it was decided to use nonparametric test. Differences in autonomic and hemodynamic parameters were analyzed with the Friedman test in the first part of the study (baseline vs. 6month vs. final) and with Wilcoxon test in the second part of the study (VNS on vs. VNS off) using SPSS for Windows (Version 12; SPSS, Chicago IL, USA). Data are reported as means standard deviation. p < 0.05 was considered statistically significant.
3.2. Second part Parasympathetic cardiovagal markers (E:I ratio, Valsalva ratio) were not different between on and off situations. BRS was not different between the on and off situations. Hemodynamic parameters (SI, ACI, or LVSWI) were not different during the on and off situations (Table 3).
3. Results All patients had a history of simple partial, complex partial, and secondarily generalized focal seizures. Patients’ characteristics are shown in Table 1. All patients except one had the VNS implanted in the left vagus nerve. Stimulation parameters were adjusted according to standard practice to treatment settings as defined by patient tolerability and clinical response (Table 2). No substantial changes in drug schedule were made. Most patients (85.7%) were on active treatment with sodium channel blocking AEDs. No seizures occurred during the procedures and therefore all recordings were interictal. ECG tracings were normal in all patients and no patient had a history of cardiac disease. The median seizure reduction was 40%, and the responder rate, defined as percentage of patients with a reduction of seizure frequency of at least 50%, was 42.9% and 45.5% at the intermediate and final visits respectively. No patient achieved freedom.
4. Discussion The main finding of this study is that VNS in patients with refractory epilepsy does not exert clinically significant changes in cardiovascular autonomic or hemodynamic control. We observed no modification in inotropic and chronotropic heart function 6month or 12-month after implantation of the device, or when comparing the VNS on and off conditions. There has been a slight increase in sympathetic response after implantation of the device in different maneuvers (increased of BP in IIb and IV phases in the Valsalva maneuver, increased systolic blood pressure within the first five minutes of tilt test). However, while the patients are at rest, there has been a decrease in blood pressure at six months and at the end of study, which correlates with decreased LFdPA, although this finding had no clinically significant implications. Overall, our results support our hypothesis that VNS exert no major autonomic cardiovascular or hemodynamic effects. Bradycardia has been reported during lead tests performed during implantation of the device, but in few cases during regular treatment [8,11,21,22]. Because most of these cases were intraoperative, a plausible mechanism is that bradycardia was due to vagal nerve traction or injury. Other potential mechanisms are stimulation of cervical cardiac branches of the vagus nerve either
3.1. First part No differences were observed between the baseline, the 6month visit, and the final visit in terms of E:I ratio, Valsalva ratio, or HRV HF, all markers of parasympathetic cardiovagal tone. Within the markers of sympathetic tone, only the change of systolic and diastolic BP upon 5-min of head-up tilt increased significantly after VNS implantation (Systolic BP: 16.69 5.65 mmHg at baseline,
Table 1 Patients’ characteristics. Variable
First part (Longitudinal study)
Second part (Cross-sectional study)
No. of subjects Age, mean (SD)
15 38.9 (7.8) years
14 32.4 (8.1) years
Sex, n (%) Men Women Caucasian, n (%)
13 (86.6%) 2 (13.3%) 15 (100%)
10 (71.4%) 4 (28.5%) 14 (100%)
Duration of epilepsy, n (%) >20 years <20 years
9 (60%) 6 (40%)
8 (57.1%) 6 (42.8%)
Etiology, n (%) Cryptogenic Trauma Malformations of cortical development Others
5 4 3 3
8 2 1 3
Frequency of seizures, n (%) >25 per year 10–25 per year 0–9 per year
10 (66.6%) 4 (26.6%) 1 (6.6%)
(33.3%) (26.6%) (20%) (20%)
(57.1%) (14.3%) (7.1%) (21.4%)
11 (78.6%) 2 (14.3%) 1 (7.1%)
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Table 2 Longitudinal assessment of cardiovascular autonomic parameters in patients undergoing vagus nerve stimulation. Variable
Baseline (before VNS)
6-month after VNS
Final visit (10–15 months after VNS)
P-value
N/A
1.25 (1.00–1.50) 25 (25–30) 250 (250–500) 10
2 (1.75–2.5) 25 (20–30) 250 (250–500) 29 (16–38)
ns
Median seizure reduction, % (range)
N/A
40 (0–90)
40 (0–83)
ns
Responder rate (%)
N/A
42.9
45.5
ns
Median concomitant AEDs (range) Na+ channel blockers (%)
4 (2–4) 12 (85.7)
4 (3–4) 12 (85.7)
4 (3–4) 11 (84.6)
ns
AED dose change (%) AED change (%) AEDs increase (%)
N/A
2 (14.3) 2 (14.3) 1 (7.1)
3 (23.1) 4 (30.8) 1 (7.7)
ns
E:I ratio Valsalva ratio Increase in Valsalva BP Phase II, mmHg Increase in Valsalva BP Phase IV, mmHg Resting supine SBP, mmHg Resting supine DBP, mmHg Resting supine HR, bpm DSBP after 3-min head-up tilt, mmHg DDBP after 3-min head-up tilt, mmHg DHR after 3-min head-up tilt, bpm DSBP after 5-min head-up tilt, mmHg DDBP after 5-min head-up tilt, mmHg DHR after 5-min head-up tilt (bpm) LF HRV, ms2 HF HRV, ms2 LF/HF ratio LF DBP, mmHg2 BRS, ms/mmHg DTAD Isometric muscle contraction after 3 min DHR isometric muscle contraction after 3 min
1.30 (0.15) 1.25 (0.17) 8.13 (12.71) 19.00 (11.91) 141.31 (20.4) 99.38 (16.30) 77.85 (11.0) 2.31 (18.30) 3.69 (14.32) 2.69 (8.25) 16.69 (35.65) 14.84 (24.72) 0.84 (0.67) 1843.07 (1470.08) 441.07 (445.11) 5.53 (5.40) 31.17 (109.22) 20.37 (11.42) 6,42 (13.25) 6.00 (13.25)
1.29 (0.16) 1.38 (0.33) 2.83 (9.50) 26.75 (9.89) 135.07 (18.06) 95.07 (17,41) 72.14 (7.98) 9.71 (19.56) 9.57 (19.57) 6.78 (6.96) 2.86 (16.54) 0.86 (16.97) 8.35 (6.19) 3564.85 (3945.81) 656.39 (175.43) 10.60 (9.80) 16.02 (38.92) 19.66 (14.1) 11.00 (18.95) 1.50 (6.07)
1.33 (0.10) 1.36 (0.28) 0.41 (5.83) 27.66 (21.99) 122.83 (15.22) 76.67 (8.89) 69.33 (6.09) 3.08 (42.33) 12.42 (30.89) 7.81 (13.28) 12.25 (12.95) 17.00 (12.76) 10.25 (7.24) 4816.00 (6784.64) 619.93 (171.93) 8.12 (12.08) 7.38 (18.47) 19.18 (14.79) 1.01 (13.71) 3. 50 (6.73)
ns ns 0.09 ns 0.05 <0.001 0.08 ns ns ns 0.01 <0.001 0.004 ns ns ns ns ns ns ns
VNS parameters, median (range) Amplitude (mA) Frequency (Hz) Pulse width (ms) Duty cycle (%)
by collateral current spread or directly by inadvertent placement of the electrodes on one of these branches; improper plugging of the electrodes into the pulse generator, resulting in erratic varying intensity of stimulation; or reverse polarity [8]. To avoid these
Fig. 1. Boxplot representing monitoring the tilt table test at baseline, at six months and the period of maximum effectiveness of stimulators. It is observed as in the two postoperative visits there is a different behavior of blood pressure at 3 min and 5 min of tilt.
potential complications, we performed the first post-surgery assessments 6-months after implantation. We found an increase in systolic and diastolic BP after 5-min of head-up tilt. These results indicate a mild increase in sympathetic tone. Previous studies showed an increase in systolic and diastolic BP after VNS implantation as measured by 24-h ambulatory BP monitoring [23]. Increases in cardiac sympathetic tone have been also described in children treated with VNS [24] Classically, VNS surgery is performed on the left side because of early concerns that right VNS may cause greater reductions in HR than left-sided VNS [25]. However, there is no clear evidence for this. In fact, one of our patients with right VNS at high stimulation parameters had similar results to those of our patients with left VNS [26]. Interestingly, VNS has been shown to exert antiarrhythmic effects, improve cardiac function, and reduce mortality in patients with heart failure [27]. In this indication, though, stimulation parameters, dipole orientation, and generator management are different from that in drug-resistant epilepsy. It has been postulated that VNS may induce increases in sympathetic output that could contribute to its mechanism of action [25]. This is based on the finding that VNS-induced antiepileptic effects are associated with elevated hippocampal noradrenaline levels [28]. Also, the locus coeruleus, the principal noradrenergic nucleus of the brain, mediates some of the seizureattenuating effects of VNS [29]. Some antiepileptic drugs, especially those that block sodium or potassium channels may modify the cardiac function. In our series no substantial changes in AED schedule were performed and most patients were on active
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Table 3 Cross-sectional evaluation of cardiovascular autonomic and hemodynamic parameters during on and off situations. Variable
VNS off
VNS on
P-value
E:I ratio BRS, ms/mmHg Stroke index, ml/m2 Cardiac index, L/min/m2 Left ventricular stroke work index, mmHg l/(min m2) Acceleration index, 100/s2
1.42 11.83 48.76 3.38 4.01 81.42
1.39 11.14 47.87 3.39 4.00 78.71
0.64 0.57 0.50 0.94 0.97 0.35
treatment with sodium channel blockers before and after the implantation of the VNS. Nearly half of patients were responders, and this result is concordant with our historical series of patients that underwent VNS implantation [17]. The relatively limited size of the study at one center is a limitation; another limitation of the study is skewed gender distribution (male predominance): the power spectral density of HRV in females is characterized by significantly greater HFHRV and less LFHRV [30]. However, our results are robust and provide no significant hemodynamic changes in association with VNS at stimulation settings routinely used for seizure control. Also, we included only epilepsy patients with no additional risk factors, such as hypertension, diabetes mellitus, cardiac or renal dysfunction. Further studies are warranted to determine if the small increases in sympathetic tone seen during VNS in our subjects are more pronounced or are associated with negative outcomes in patients with concurrent diseases. 5. Conclusion Our findings support the hypothesis that, in the absence of surgical injury of the vagus, VNS does not seem to produce alterations in parasympathetic cardiovagal tone, regardless of the laterality of the stimulus. We observed a slight increase in sympathetic cardiovascular modulations, perhaps through afferent stimulation of brainstem areas and subsequent activation of sympathetic pathways, although this had no significant hemodynamic effects. Conflict of interest statement None of the authors has any conflict of interest to disclose. References [1] Morris 3rd GL, Gloss D, Buchhalter J, Mack KJ, Nickels K, Harden C. Evidencebased guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2013;81:1453–9. [2] Henry TR. Therapeutic mechanisms of vagus nerve stimulation. Neurology 2002;59:S3–14. [3] Schachter SC, Saper CB. Vagus nerve stimulation. Epilepsia 1998;39:677–86. [4] Palma JA, Benarroch EE. Neural control of the heart: recent concepts and clinical correlations. Neurology 2014;83:261–71. [5] Galli R, Limbruno U, Pizzanelli C, Giorgi FS, Lutzemberger L, Strata G, et al. Analysis of RR variability in drug-resistant epilepsy patients chronically treated with vagus nerve stimulation. Auton Neurosci 2003;107:52–9. [6] Stemper B, Devinsky O, Haendl T, Welsch G, Hilz MJ. Effects of vagus nerve stimulation on cardiovascular regulation in patients with epilepsy. Acta Neurol Scand 2008;117:231–6. [7] Ben-Menachem E. Vagus nerve stimulation, side effects, and long-term safety. J Clin Neurophysiol 2001;18:415–8. [8] Asconape JJ, Moore DD, Zipes DP, Hartman LM, Duffell Jr. WH. Bradycardia and asystole with the use of vagus nerve stimulation for the treatment of epilepsy: a rare complication of intraoperative device testing. Epilepsia 1999;40:1452–4.
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