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Cardiovascular modulation during vagus nerve stimulation therapy in patients with refractory epilepsy
Epilepsy Research (2010) 92, 145—152
journal homepage: www.elsevier.com/locate/epilepsyres
Cardiovascular modulation during vagus nerve stimulation therapy in patients with refractory epilepsy Christian Cadeddu ∗, Martino Deidda, Giuseppe Mercuro, Antonella Tuveri, Antonella Muroni, Silvio Nocco, Monica Puligheddu, Alberto Maleci, Francesco Marrosu Dept. of Cardiovascular and Neurological Sciences, University of Cagliari, Sardinia, Italy Received 5 May 2010; received in revised form 12 July 2010; accepted 22 August 2010 Available online 21 September 2010
KEYWORDS Refractory epilepsy; Vagus nerve stimulation; Tissue Doppler imaging; Heart rate variability
Summary To evaluate the effects of permanent vagal stimulation on cardiovascular system, 10 patients, affected by drug-resistant epilepsy with no primitive cardiovascular pathologies, were assessed prior to VNS surgery. A complete echocardiographic study [conventional and tissue Doppler imaging (TDI)], 24-h blood pressure (BP) monitoring and HRV evaluation were performed. The above mentioned parameters were investigated without any substantial changes to drug treatment during a check-up subsequent to VNS activation [mean: 7.7 months]. The results obtained show that while the anthropometrical data and both conventional and TDI echocardiography were unvaried compared to baseline, BP showed a significant increase of both systodiastolic values. Moreover, a close scrutiny of the most affected period of the BP increase (zenith between 16:31 and 17:30 pm) (systolic BP 114.7 mmHg vs 95.3 mmHg, P < 0.0001; diastolic BP 70.9 mmHg vs 56.9 mmHg, P < 0.001) showed a significant increase of the high frequencies components (HF) (28.4 ± 2.7 vs 36 ± 5.3, P < 0.05) and a significant reduction in low frequency/HF ratio (2.3 ± 0.3 vs 1.7 ± 0.3, P < 0.0001). The present study confirms the intrinsic cardiovascular safety and reliability of VNS procedures on both BP and HF and LF profiles and suggests that a primitive VNS-mediated central impingement on vagal efferents, independently by the antiepileptic mechanism, correlated to an moderate increase of parasympathetic activity, which in turn might play a protective role in seizure-triggered alterations of cardiovascular dynamic. © 2010 Elsevier B.V. All rights reserved.
∗ Corresponding author at: Department of Cardiovascular and Neurological Sciences, University Hospital of Cagliari, Azienda Ospedaliero Universitaria, SS Sestu KM 0,700, 09042 Monserrato (Cagliari), Italy. Tel.: +39 070 675 4951; fax: +39 070 675 4991. E-mail address: [email protected] (C. Cadeddu).
0920-1211/$ — see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2010.08.012
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Introduction The long-term application of vagus nerve stimulation (VNS) with intermittent electrical current is a well established low profile surgical solution in the treatment of refractory epilepsy in adults (Salinsky et al., 1996; Handforth and Ackermann, 1988; Labar et al., 1998; Binnie, 2000; Morris and Mueller, 1999), children (Hornig et al., 1997; Patwardhan et al., 2000) and the elderly (Sirven et al., 2000). Although the mechanism implicated in the therapeutic action of VNS is still partially unknown, several studies have suggested that VNS efficacy may be the result of complex interactions, mainly modulated by the principal afferent of the vagus nerve, the nucleus tractus solitarius (NTS) (Ben-Menachem, 2002, for a review). Moreover, it has been demonstrated that NTS, extensively connected to brainstem noradrenergic, serotonergic and cholinergic pathways, may activate different brain areas, some of which possibly uncorrelated with seizure modulations. In particular, several studies suggest a potential role for VNS in the parasympathetic regulation of cardiovascular responses, such as instantaneous heart rate (IHR), HR variability (HRV), blood pressure (BP) and R—R intervals (RRI) (Ronkainen et al., 2006; Stemper et al., 2008). These studies suggest that autonomic parameters of cardiac functions may undergo several subtle modifications following VNS, although none appear to produce substantial negative effects on cardiovascular modulation. However, though the evidence provided confirms the safety profile of VNS, its role in eliciting peripheral and/or central actions on autonomic control of the cardiovascular system remains unclear. In addition, the studies reported describe results obtained using different data collection methods, with marked differences in means of comparing the period of VNS device implantation/activation, modalities used to establish parameters measured, and temporal frames during which current phases were delivered (battery on/off) and cardiac functions were measured (Kamath et al., 1992; Galli et al., 2003; Ronkainen et al., 2006; Stemper et al., 2008). The above considerations underline the need to focus more pragmatic aspects of VNS effects on cardiovascular functions considering, once a steady state of VNS duty has been achieved, that these parameters may be taken at best in representing the putative effects reported on the most sensitive functions, namely on BP and HRV. Accordingly, the present study aimed to address this specific issue by monitoring BP and HRV over a 24-h period during VNS use in a selected group of drug-resistant patients affected by partial epilepsy. Examinations were performed prior to surgery and after a period of 7—9 months of stable stimulation, thus once the device had reached the desired therapeutic stimulation rate (±1.50 mA).
Materials and methods Patients were selected from a total of 1650 individuals attending the Centre for Diagnosis and Treatment of Epilepsy of the University Hospital, University of Cagliari, Italy. From group of 24 patients affected by drug-resistant partial epilepsy implanted with a VNS device over the last 5
C. Cadeddu et al. years we selected 10 subjects (4 females and 6 men, mean [±SD] age 29 ± 18 years) affected by non-lesional epilepsy, homogeneous for age, type of seizures, number of seizure episodes and treatment (Table 1). The right hemisphere was considered the most likely site of epileptic focus in 6 subjects, while the left side was primarily involved in 4 patients on the basis of accounts reported by patients themselves and/or by family members. Additionally, as all patients had been monitored in our outpatient department for several years (mean, 5.2 years), diagnosis was well documented by several ictal Video-EEG recorded prior to VNS implantation. The main selection criteria for inclusion in the study were: relative stability of clinical features related to interictal EEG activity, resistance to classical first- and second-line antiepileptic drugs (AEDs) assessed monthly for optimal range, normal findings of neurological and psychiatric evaluations, and lack of abnormalities in cerebral structure examination as revealed by a recent 1.5-T MRI scan. The possibility and priority of treatment by means of a VNS device were discussed with patients, family members, and the institutional ethical ad hoc committee. Informed consent was obtained from patients and their relatives once the nature of the procedure had been fully explained and approved by institutional reviewers. In order to assess the results obtained by VNS, seizure number was calculated as: [(number of seizures per trimester after VNS implant) − (number of seizures per trimester before implant)]/(number of seizures per trimester before implant) and the percentage of relative modification in seizure frequency was accordingly calculated (Labar et al., 1998). During the trial, the approved protocol included no changes in anticonvulsant treatments, unless serious side effects were manifested. All patients were assessed before VNS implant and after 7.7 ± 2.3 months of VNS in a hospital setting.
Clinical examination No subjects were characterized by specific risk factors for cardiovascular disease such as high total cholesterol, lowdensity-lipoprotein and triglycerides, diabetes, obesity or habitual smoking. All patients underwent a full baseline cardiovascular assessment, including physical examination, 12-lead electrocardiogram (ECG) and trans-thoracic echocardiography to exclude the presence of cardiovascular congenital or acquired diseases.
Instrumental data A 12-lead electrocardiogram, a conventional M-Mode and a two-dimensional echocardiography were performed. In addition, LV longitudinal function in the mid-basal segment of LV septum and lateral wall was studied by means of an ultrasonic method of regional deformation quantification: strain () and strain rate (SR) imaging. and SR are usually more detailed than TDI velocities alone in detecting early changes in systolic function because they tend to be less affected by translational motion. Moreover, it has been shown that SR is a reliable index of LV contractility (Li et al., 2003). Echocardiographic images were recorded using a commercially available system equipped with TDI and
Cardiovascular modulation during vagus nerve stimulation therapy
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Table 1
Study population (n = 10).
Patient
Age (years) Gender
Age at seizure onset (years)
AEDs
Estimated site Pre-VNS of focal IEDs seizure frequency (/trim)
Post-VNS seizure frequency (/trim)
VNS-induced change in seizure frequency (% after 1 year)
1 2 3 4 5 6 7 8 9 10
38 24 29 18 31 45 39 23 44 33
14 7 19 18 7 8 17 3 6 10
CBZ + PB CBZ + LMT CBZ + VA CBZ + LEV CBZ + LEV TPR + LEV CBZ + VA LMT + LEV CBZ + VA FELB + CBZ
Right T Left FT Left FT Right F Right FT Left F Right FT Right F Right FT Left TP
8 15 11 18 22 12 11 19 21 14
(−50%) (−40%) (−74%) (−75%) (−60%) (−83%) (−61%) (−80%) (+10%) (−65%)
F M M M M F M F M F
16 25 42 72 54 68 28 77 19 39
Pre-VNS seizure frequency is the mean of the value obtained in the trimester immediately before implantation of the VNS device and that obtained 1 year previously. Post-VNS seizure frequency is the mean of the value obtained in the last trimester after 1 year from VNS implantation. VNS-induced change in seizure frequency (%after 1 year) indicates the percentage of seizure decrease (negative number) or increase (positive number) after 1 year of vagus stimulation. CBZ, carbamazepine; LEV, levetiracetam; FELB, felbamate; VA, valproic acid; LMT, lamotrigine; TPR, topiramate. FT, fronto-temporal lobe; TP, temporal-parietal lobe; F, frontal lobe.
and SR imaging (Toshiba APLIO CV ultrasound system-SSA 770A/CV; Toshiba Corp., Tochigi, Japan). Left ventricular ejection fraction (LVEF) was obtained from apical 4- and 2chamber views according to Simpson’s rule. A pulsed wave Doppler (PWD) examination of the left ventricle inflow from the 4-chamber view was performed with sample volume placed between the mitral leaflet tips. Early (E) and late (A) diastolic peak velocities and E deceleration time (DecT) were measured and E/A ratio was subsequently derived. Longitudinal function was evaluated by means of pulsed TD at the mitral annulus, by placing the sample volume in the basal segment of the interventricular septum (IVS) from the apical 4-chamber view: peak velocities in systole (Sm), isovolumic relaxation time (IVRT), early (Em) and late diastole (Am) were measured. The same experienced echocardiographer, blind to the clinical status of subjects and their possible therapeutic regimens, carried out all examinations. All echocardiographic data were read by two experienced observers and an average value for each measurement was calculated.
BP 24-h monitoring (BPM) All patients underwent a 24-h BPM (BP Monitor SpaceLabs Medical, Inc., Redmond, WA); the protocol was performed following the latest international recommendations (Chobanian et al., 2003). In particular, subjects were free to move within the hospital premises, although reclining and napping were not allowed; identical standard varied meals were served during both experimental sessions. All patients were required to retire to bed at 10:00 PM and remain recumbent until 6:00 AM the next morning. The sampling interval was 15 min between 6:00 AM and 10:00 PM (daytime period) and 30 min between 10:00 PM and 6:00 AM (night-time period).
HRV analysis ECG recordings were performed in all patients at the same time through BPM with a digital three-channel recorder (Del Mar-Aria recorder; Del Mar Medical, Irvine, CA). During the 24-h ECG recording all patients were free to carry out daily tasks to the extent allowed by hospital regimen. Patients kept a diary to record seizures occurring during the 24-h ECG recording. ECG data were downloaded for the analysis of HR Variability on Impresario Holter Analysis System (Del Mar Reynolds Medical INC, Irvine, CA). All RR interval time series were automatically edited first. Manual editing was not performed due to the notsignificant presence of artefacts and premature beats. For final analysis, 24-h HR-variability data were divided into segments of 3600 s, and only segments with >85% sinus beats were included in analysis. Quantitative time domain analysis was performed on normal—normal (NN or RR) interval, and the following data were computed: mean, SDNN (standard deviation of NN intervals), SDNN index (mean of the standard deviations of NN intervals), SDANN (standard deviation of the averaged NN intervals), SDSD (standard deviation of successive NN differences), RMSSD (square root of the mean squared difference of the consecutive NN intervals), pNN50 (proportion of NN intervals differing more than 50 ms to the total number of NN intervals), and TINN (the integral of the density distribution of the number of all NN intervals plotted in a histogram divided by the maximum of the density distribution). An autoregressive model was used to estimate the power-spectrum densities of HR variability (Kay and Marple, 1981). Power spectra were quantified by measuring the area in three frequency bands: 0.005—0.04 Hz (very low frequency, VLF), 0.04—0.15 Hz (low frequency, LF), and 0.15—0.4 Hz (high frequency, HF). Given that HF, VLF and LF bands fluctuation of RR interval mainly reflects cardiovagal modulation, sympathetic excitation (Pagani et al., 1997) and sympathovagal balance (Eckberg, 1997), a sub analysis
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Table 2 Trans-thoracic conventional echocardiographic and TDI parameters. Pre-VNS
Post-VNS
Conventional echocardiography LVEF 64 ± 3.4% EDV 83.9 ± 24.7 ESV 30.3 ± 9.5 DecT 0.214 ± 0.03 E/A 1.33 ± 0.2 TDI Em Em/Am E/Em IVRT Sm
9.29 1.38 8.44 75.9 6.97
Strain rate imaging Radial (%) 68.7 SR (s−1 ) 3.1 Longitudinal (%) 28.9 SR (s−1 ) 1.82
P-Value
60.9 86.5 34.1 0.238 1.41
± ± ± ± ±
3.9% 13.4 7.4 0.05 0.4
P = ns P = ns P = ns P = ns P = ns
9.53 1.45 8.32 83.7 7.12
± ± ± ± ±
1.9 0.41 1.52 31.9 0.79
P = ns P = ns P = ns P = ns P = ns
± 32.3 ± 1.01
63.5 ± 20.6 2.88 ± 1.15
P = ns P = ns
± 14.7 ± 0.3
25.1 ± 10.7 1.88 ± 0.33
P = ns P = ns
± ± ± ± ±
1.7 0.32 1.67 16.7 0.95
Abbreviations: LVEF: left ventricular ejection fraction; EDV: end diastolic volume; ESV end systolic volume; DecT: deceleration time; E/A: early and late diastolic peak velocity ratio; Em: TD early diastolic peak velocity; Em/Am: TD early and late diastolic peak velocity ratio; IVRT: isovolumic relaxation time; Sm: TD systolic peak velocity; : strain; SR: strain rate.
were varied following long-term VNS treatment (Table 2). The latter findings underline how long-term vagal stimulation produces no significant changes in left ventricular and pressure load functions. On the contrary, a significant increase was observed for BP on averaging 24-h systolic (100 ± 21 vs 105.1 ± 22.2, P < 0.0001) and diastolic BP (61.7 ± 13.9 vs 64.5 ± 14.3, P < 0.0005; Figs. 1 and 2). The significant increase in systolic BP was evident both in the daytime (103.4 ± 24.7 vs 109 ± 26, P < 0.0001) and night-time (92.5 ± 32.5 vs 96.6 ± 33.9, P < 0.005). Similarly, the increase in diastolic BP was evident both during the day (65 ± 15.9 vs 67.9 ± 16.4, P < 0.01) and at night (54.3 ± 19.1 vs 56.9 ± 19.9, P < 0.005). This increase reached a peak between h.16.31 and h.17.30 when systolic BP recorded 114.7 mmHg post-VNS versus 95.3 baseline, while diastolic BP under VNS was 70.9 mmHg versus 56.9 baseline (Figs. 1 and 2). At HRV time domain analysis following VNS, a significant increase in SDSD, RMSSD and pNN50 was observed at night (Table 3). Analysis of the HRV power spectrum revealed a non-significant decreasing trend in LF/HF ratio both during the day and at night in all patients despite the variety of data collected (Table 3). Moreover, a close scrutiny of the most affected BP period revealed, at the zenith of BP, a significant rise in HF and a reduction in LF components at peak BP recordings, resulting in a significant reduction in their ratio (LF/HF) (Table 3). On the other hand, at peak BP no significant variations were observed for any powerspectrum components.
Discussion of the power-spectrum densities of HR variability was performed for all 24-h recordings and at the zenith and nadir of BP variation (zenith 16:31—17:30; nadir 6:31—7:30).
Statistical analysis Categorical data are presented as percentages, and quantitative data as mean ± SD. Differences between pre-implant and follow up were assessed by means of Student’s 2-tailed t-test for paired data, after having verified the data normal distribution. Wilcoxon’s signed-rank test was used if data were not normally distributed. Categorical data comparison was performed by a Chi-Square analysis. P-Values were considered significant when P ≤ 0.05.
Results The clinical profiles of all patients are summarized in Table 1. All subjects but one displayed a modest to good improvement in seizure rating. At conventional and TDI echocardiography, no significant changes were found in common echocardiographic parameters of systolic function such as the ejection fraction, S wave peak at TDI analysis, and some less common but more sensitive parameters including and SR (Table 2). Neither common parameters of left ventricular diastolic function nor less common parameters such as IVRT, E/Em ratio (ratio between E wave peak measured with pulsed wave Doppler of the trans-mitralic flow and E wave peak measured with TDI)
The findings obtained in the present study confirm the cardiovascular safety profile and reliability of VNS as adjunctive antiepileptic therapy, while providing further evidence that several aspects of autonomic cardiocirculatory dynamics are intrinsically modulated by this treatment. Indeed, monitoring of cardiovascular functions both prior and subsequent to VNS implant revealed a significant increase in both systolic and diastolic BP values distributed at uneven intervals during the circadian cycle following VNS implant. In particular, increased BP values were recorded throughout the entire wake period (zenith between h.16:31 and 17:30) while, compared to pre-implant values, nadir increase of the same parameters was observed at night. The results obtained were independent by those correlated to the VNS antiseizure activity (Table 1), given that they had been replicated in all subjects, included the patients without substantial statistical variations in seizure regimen. Moreover, the variation of cardiovascular parameters cannot be attributed to modifications in AEDs, as already considered in other studies (Ansakorpi et al., 2000; Isojarvi et al., 1998), given that the therapeutic regimen was kept stable after VNS implant. Although the variations detected in BP are well below possible age-related risk parameters, the present study suggests that VNS modulation in cardiovascular functions may be viewed in a different perspective to a merely theoretical functional neutrality, thus ruling out the ‘‘null hypothesis’’ of VNS-induced cardio-dynamic effects. Accordingly, the increase in BP may be construed as one of the mani-
Cardiovascular modulation during vagus nerve stimulation therapy
Figure 1
Systolic blood pressure at baseline (Pre) and after VNS device implant (Post).
Figure 2
Diastolic blood pressure at baseline (Pre) and after VNS device implant (Post).
fold VNS effects mediated by a central modulation [in both its systolic and diastolic components (Figs. 1 and 2)] uncorrelated to antiepileptic effects. The characteristics of BP spectra and in particular the circadian peak values sug-
Table 3
149
gest that cardiac responses reflect the complex interplay of somato-autonomic, visceral, and sensory afferences which accomplish their integration and modulation at central level (Cechetto, 1987; Jänig, 1996).
HRV analysis. Pre-VNS
Time domain parameters (12 h night-time) SDNN 100.66 SDNN index (ms) 31.18 SDANN (ms) 94.00 rMSSD (ms) 23.96 SDSD (ms) 16.36 pNN50 (%) 1.90 TINN (ms) 318.76 Power-spectrum parameters (24 h) LF HF LF/HF
± ± ± ± ± ± ±
Post-VNS 48.84 14.16 46.38 10.69 7.35 0.39 160.87
49.2 ± 7.1 35.8 ± 6.8 2.1 ± 0.8
Power-spectrum parameters at the blood pressure zenith LF 51.8 ± 4.6 HF 29.7 ± 3.6 LF/HF 2.3 ± 0.3
93.98 32.72 88.86 26.62 18.07 2.93 421.9
± ± ± ± ± ± ±
44.40 14.07 46.06 12.01 8.14 0.8 189.00
P ns ns ns P < 0.05 P < 0.01 P < 0.05 ns
50.8 ± 7.9 36.3 ± 7.2 1.9 ± 0.7
ns ns ns
47.6 ± 4.2 37.3 ± 4.5 1.7 ± 0.3
P < 0.05 P < 0.0001 P < 0.0005
Abbreviations: SDNN: standard deviation of all normal sinus RR intervals over 24 h; SDNN index: mean of the standard deviations of all normal sinus RR intervals for all 5-min segments; SDANN: standard deviation of the averaged normal sinus RR intervals for all segments; rMSSD: root-mean-square of successive normal sinus RR interval difference; SDSD: standard deviation of successive normal sinus RR interval difference; pNN50: proportion of NN intervals differing more than 50 ms to the total number of NN intervals; TINN: triangular index, the integral of the density distribution of the number of all NN intervals plotted in a histogram divided by the maximum of the density distribution; LF, low frequency; HF, high frequency; LF/HF: low frequency and high frequency ratio.
150 Furthermore, as the HF-component of HRV is related to the parasympathetic system while LF band relates to the sympathetic system, the hypothesis whereby VNS and its main afferent NTS may be involved in optimizing the homeostatic balance of sympatho-vagal responses between concurrent autonomic components (Lambertz et al., 1993; Seagard et al., 2001; Boscan et al., 2002) is of particular interest. However, in view of the different protocols applied to the studies performed to assess the effects of VNS stimulation on autonomic function, it is hardly surprisingly that considerably controversial results have been obtained. For instance, some studies have reported a reduction in HF power during the night and no change of sympatho-vagal circadian values (Galli et al., 2003), while another study showed a slight increase in the baroreflex and HF power spectrum during vagal stimulation (Stemper et al., 2008). The latter result is in line with the data obtained in the present study, which shows a slight increase in HF power and LF/HF ratio over a 24-h recording, though the suggestion that responders may reflect a favourable VNS effect on HRV, while non-responders fail to show modulation of cardiac autonomic control, has been recently considered (Ronkainen et al., 2006). Though the mechanism by which VNS-induced BP variations remains to be clarified, the findings of this study suggest that the HRV-related BP increase could be mediated by the baroreflex, a relationship which implies a central modulation (Balan et al., 2004). Moreover, it has been shown that the cardiac sympathetic afferent reflex is inhibited by NTS barosensitive neurons and excited by NTS chemosensitive neurons, suggesting that NTS plays an important role in processing the interactions between these cardiovascular reflexes that contribute towards modulating HRV (Wang et al., 2006). In addition, other experimental studies have proposed that BP regulation, which would appear to be increasingly correlated to physiological circadian fluctuations, may be modulated by NTS pathways impinging on noradrenergic pathways (Silva de Oliveira et al., 2007; Machado, 2001). Accordingly, it has been shown that stimulation of NTS excites putative vasopressin-secreting cells of the supraoptic nucleus via a catecholaminergic projection to the hypothalamus due to activation of a relay projection through A1 noradrenergic cell group of the caudal ventrolateral medulla. Another possible BP regulation by VNS-modulated central mechanisms might be represented by impingement upon the locus coeruleus by NTS (Aston-Jones et al., 1991). It has furthermore been demonstrated that LC not only plays a crucial role in the complex antiepileptic mechanism of VNS (Krahl et al., 1998; Gale, 1992) but also, through its projections, increases norepinephrine content in prefrontal cortex and limbic areas (Follesa et al., 2007), both related to BP regulation (Lovallo, 2005). The role of VNS-driven noradrenergic modulation through NTS either via a complex relay projection through the A1 cell group (Day, 1989) or via locus coeruleus projections (Randich et al., 1990), is largely in line with the findings of the present study. Indeed, the circadian profile of both systolic and diastolic BP suggests that VNS might induce a simple increase in a physiological trend in the hours between 16:00 and 18:00. Indeed, the fact that during the rest of the day it has been recorded only a slight BP increase negligibly persist-
C. Cadeddu et al. ing during the night, is in accordance with the observation that noradrenergic cells exert their lowest activity at night and increase their firing rate during daylight hours (Park, 2002). The report of severe HRV alterations and autonomic (sympathetic—parasympathetic) imbalances in intractable epileptic subjects compared to responders is of considerable interest in focusing the reduced parasympathetic drive to heart function (Mukherjee et al., 2009). Other studies have suggested an enhanced sympathetic tone or relative increase in sympathetic activity (via a decrease of parasympathetic tone) in chronic epileptic patients (Hennessy et al., 2001). The latter observations would appear to suggest an increased risk of sudden unexpected death in epileptic subjects (SUDEP) (Diehl et al., 1997; Hilz et al., 2002; Harnod et al., 2009). Although the subjects at high risk of SUDEP may present a complex clinical profile, as the causes range from a direct effect of seizures on critical neurovegetative areas to apneusic brainstem-modulated reflexes, nonetheless the cardiac autonomic vegetative regulation, whether or not induced by seizure, is likely to play a relevant role in SUDEP pathophysiology (Isojarvi et al., 1998; Tennis et al., 1995). In addition, while the SUDEP risk factor represented by interictal HRV changes, has yet under scrutiny (Surges et al., 2009), it is worthy of mention how in our patients VNS induced a significant reduction of night-time RMMSD and pNN50, a factor potentially supporting the hypothesis of a VNS role in contrasting SUDEP risk (Annegers et al., 2000). The present results, though obtained in a small size of selected patients, add further data to the ongoing debate on the autonomic modulation of VNS as a complex phenomenon and welcome the setting up of more multicentric studies in order to investigate VNS aspects not strictly pertaining to antiseizure activity.
Conflict of interest statement None of the authors has any conflict of interest to disclose.
Acknowledgment Authors warmly thank Veronica Tola for her support in the writing of the text.
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journal homepage: www.elsevier.com/locate/epilepsyres
Cardiovascular modulation during vagus nerve stimulation therapy in patients with refractory epilepsy Christian Cadeddu ∗, Martino Deidda, Giuseppe Mercuro, Antonella Tuveri, Antonella Muroni, Silvio Nocco, Monica Puligheddu, Alberto Maleci, Francesco Marrosu Dept. of Cardiovascular and Neurological Sciences, University of Cagliari, Sardinia, Italy Received 5 May 2010; received in revised form 12 July 2010; accepted 22 August 2010 Available online 21 September 2010
KEYWORDS Refractory epilepsy; Vagus nerve stimulation; Tissue Doppler imaging; Heart rate variability
Summary To evaluate the effects of permanent vagal stimulation on cardiovascular system, 10 patients, affected by drug-resistant epilepsy with no primitive cardiovascular pathologies, were assessed prior to VNS surgery. A complete echocardiographic study [conventional and tissue Doppler imaging (TDI)], 24-h blood pressure (BP) monitoring and HRV evaluation were performed. The above mentioned parameters were investigated without any substantial changes to drug treatment during a check-up subsequent to VNS activation [mean: 7.7 months]. The results obtained show that while the anthropometrical data and both conventional and TDI echocardiography were unvaried compared to baseline, BP showed a significant increase of both systodiastolic values. Moreover, a close scrutiny of the most affected period of the BP increase (zenith between 16:31 and 17:30 pm) (systolic BP 114.7 mmHg vs 95.3 mmHg, P < 0.0001; diastolic BP 70.9 mmHg vs 56.9 mmHg, P < 0.001) showed a significant increase of the high frequencies components (HF) (28.4 ± 2.7 vs 36 ± 5.3, P < 0.05) and a significant reduction in low frequency/HF ratio (2.3 ± 0.3 vs 1.7 ± 0.3, P < 0.0001). The present study confirms the intrinsic cardiovascular safety and reliability of VNS procedures on both BP and HF and LF profiles and suggests that a primitive VNS-mediated central impingement on vagal efferents, independently by the antiepileptic mechanism, correlated to an moderate increase of parasympathetic activity, which in turn might play a protective role in seizure-triggered alterations of cardiovascular dynamic. © 2010 Elsevier B.V. All rights reserved.
∗ Corresponding author at: Department of Cardiovascular and Neurological Sciences, University Hospital of Cagliari, Azienda Ospedaliero Universitaria, SS Sestu KM 0,700, 09042 Monserrato (Cagliari), Italy. Tel.: +39 070 675 4951; fax: +39 070 675 4991. E-mail address: [email protected] (C. Cadeddu).
0920-1211/$ — see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.eplepsyres.2010.08.012
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Introduction The long-term application of vagus nerve stimulation (VNS) with intermittent electrical current is a well established low profile surgical solution in the treatment of refractory epilepsy in adults (Salinsky et al., 1996; Handforth and Ackermann, 1988; Labar et al., 1998; Binnie, 2000; Morris and Mueller, 1999), children (Hornig et al., 1997; Patwardhan et al., 2000) and the elderly (Sirven et al., 2000). Although the mechanism implicated in the therapeutic action of VNS is still partially unknown, several studies have suggested that VNS efficacy may be the result of complex interactions, mainly modulated by the principal afferent of the vagus nerve, the nucleus tractus solitarius (NTS) (Ben-Menachem, 2002, for a review). Moreover, it has been demonstrated that NTS, extensively connected to brainstem noradrenergic, serotonergic and cholinergic pathways, may activate different brain areas, some of which possibly uncorrelated with seizure modulations. In particular, several studies suggest a potential role for VNS in the parasympathetic regulation of cardiovascular responses, such as instantaneous heart rate (IHR), HR variability (HRV), blood pressure (BP) and R—R intervals (RRI) (Ronkainen et al., 2006; Stemper et al., 2008). These studies suggest that autonomic parameters of cardiac functions may undergo several subtle modifications following VNS, although none appear to produce substantial negative effects on cardiovascular modulation. However, though the evidence provided confirms the safety profile of VNS, its role in eliciting peripheral and/or central actions on autonomic control of the cardiovascular system remains unclear. In addition, the studies reported describe results obtained using different data collection methods, with marked differences in means of comparing the period of VNS device implantation/activation, modalities used to establish parameters measured, and temporal frames during which current phases were delivered (battery on/off) and cardiac functions were measured (Kamath et al., 1992; Galli et al., 2003; Ronkainen et al., 2006; Stemper et al., 2008). The above considerations underline the need to focus more pragmatic aspects of VNS effects on cardiovascular functions considering, once a steady state of VNS duty has been achieved, that these parameters may be taken at best in representing the putative effects reported on the most sensitive functions, namely on BP and HRV. Accordingly, the present study aimed to address this specific issue by monitoring BP and HRV over a 24-h period during VNS use in a selected group of drug-resistant patients affected by partial epilepsy. Examinations were performed prior to surgery and after a period of 7—9 months of stable stimulation, thus once the device had reached the desired therapeutic stimulation rate (±1.50 mA).
Materials and methods Patients were selected from a total of 1650 individuals attending the Centre for Diagnosis and Treatment of Epilepsy of the University Hospital, University of Cagliari, Italy. From group of 24 patients affected by drug-resistant partial epilepsy implanted with a VNS device over the last 5
C. Cadeddu et al. years we selected 10 subjects (4 females and 6 men, mean [±SD] age 29 ± 18 years) affected by non-lesional epilepsy, homogeneous for age, type of seizures, number of seizure episodes and treatment (Table 1). The right hemisphere was considered the most likely site of epileptic focus in 6 subjects, while the left side was primarily involved in 4 patients on the basis of accounts reported by patients themselves and/or by family members. Additionally, as all patients had been monitored in our outpatient department for several years (mean, 5.2 years), diagnosis was well documented by several ictal Video-EEG recorded prior to VNS implantation. The main selection criteria for inclusion in the study were: relative stability of clinical features related to interictal EEG activity, resistance to classical first- and second-line antiepileptic drugs (AEDs) assessed monthly for optimal range, normal findings of neurological and psychiatric evaluations, and lack of abnormalities in cerebral structure examination as revealed by a recent 1.5-T MRI scan. The possibility and priority of treatment by means of a VNS device were discussed with patients, family members, and the institutional ethical ad hoc committee. Informed consent was obtained from patients and their relatives once the nature of the procedure had been fully explained and approved by institutional reviewers. In order to assess the results obtained by VNS, seizure number was calculated as: [(number of seizures per trimester after VNS implant) − (number of seizures per trimester before implant)]/(number of seizures per trimester before implant) and the percentage of relative modification in seizure frequency was accordingly calculated (Labar et al., 1998). During the trial, the approved protocol included no changes in anticonvulsant treatments, unless serious side effects were manifested. All patients were assessed before VNS implant and after 7.7 ± 2.3 months of VNS in a hospital setting.
Clinical examination No subjects were characterized by specific risk factors for cardiovascular disease such as high total cholesterol, lowdensity-lipoprotein and triglycerides, diabetes, obesity or habitual smoking. All patients underwent a full baseline cardiovascular assessment, including physical examination, 12-lead electrocardiogram (ECG) and trans-thoracic echocardiography to exclude the presence of cardiovascular congenital or acquired diseases.
Instrumental data A 12-lead electrocardiogram, a conventional M-Mode and a two-dimensional echocardiography were performed. In addition, LV longitudinal function in the mid-basal segment of LV septum and lateral wall was studied by means of an ultrasonic method of regional deformation quantification: strain () and strain rate (SR) imaging. and SR are usually more detailed than TDI velocities alone in detecting early changes in systolic function because they tend to be less affected by translational motion. Moreover, it has been shown that SR is a reliable index of LV contractility (Li et al., 2003). Echocardiographic images were recorded using a commercially available system equipped with TDI and
Cardiovascular modulation during vagus nerve stimulation therapy
147
Table 1
Study population (n = 10).
Patient
Age (years) Gender
Age at seizure onset (years)
AEDs
Estimated site Pre-VNS of focal IEDs seizure frequency (/trim)
Post-VNS seizure frequency (/trim)
VNS-induced change in seizure frequency (% after 1 year)
1 2 3 4 5 6 7 8 9 10
38 24 29 18 31 45 39 23 44 33
14 7 19 18 7 8 17 3 6 10
CBZ + PB CBZ + LMT CBZ + VA CBZ + LEV CBZ + LEV TPR + LEV CBZ + VA LMT + LEV CBZ + VA FELB + CBZ
Right T Left FT Left FT Right F Right FT Left F Right FT Right F Right FT Left TP
8 15 11 18 22 12 11 19 21 14
(−50%) (−40%) (−74%) (−75%) (−60%) (−83%) (−61%) (−80%) (+10%) (−65%)
F M M M M F M F M F
16 25 42 72 54 68 28 77 19 39
Pre-VNS seizure frequency is the mean of the value obtained in the trimester immediately before implantation of the VNS device and that obtained 1 year previously. Post-VNS seizure frequency is the mean of the value obtained in the last trimester after 1 year from VNS implantation. VNS-induced change in seizure frequency (%after 1 year) indicates the percentage of seizure decrease (negative number) or increase (positive number) after 1 year of vagus stimulation. CBZ, carbamazepine; LEV, levetiracetam; FELB, felbamate; VA, valproic acid; LMT, lamotrigine; TPR, topiramate. FT, fronto-temporal lobe; TP, temporal-parietal lobe; F, frontal lobe.
and SR imaging (Toshiba APLIO CV ultrasound system-SSA 770A/CV; Toshiba Corp., Tochigi, Japan). Left ventricular ejection fraction (LVEF) was obtained from apical 4- and 2chamber views according to Simpson’s rule. A pulsed wave Doppler (PWD) examination of the left ventricle inflow from the 4-chamber view was performed with sample volume placed between the mitral leaflet tips. Early (E) and late (A) diastolic peak velocities and E deceleration time (DecT) were measured and E/A ratio was subsequently derived. Longitudinal function was evaluated by means of pulsed TD at the mitral annulus, by placing the sample volume in the basal segment of the interventricular septum (IVS) from the apical 4-chamber view: peak velocities in systole (Sm), isovolumic relaxation time (IVRT), early (Em) and late diastole (Am) were measured. The same experienced echocardiographer, blind to the clinical status of subjects and their possible therapeutic regimens, carried out all examinations. All echocardiographic data were read by two experienced observers and an average value for each measurement was calculated.
BP 24-h monitoring (BPM) All patients underwent a 24-h BPM (BP Monitor SpaceLabs Medical, Inc., Redmond, WA); the protocol was performed following the latest international recommendations (Chobanian et al., 2003). In particular, subjects were free to move within the hospital premises, although reclining and napping were not allowed; identical standard varied meals were served during both experimental sessions. All patients were required to retire to bed at 10:00 PM and remain recumbent until 6:00 AM the next morning. The sampling interval was 15 min between 6:00 AM and 10:00 PM (daytime period) and 30 min between 10:00 PM and 6:00 AM (night-time period).
HRV analysis ECG recordings were performed in all patients at the same time through BPM with a digital three-channel recorder (Del Mar-Aria recorder; Del Mar Medical, Irvine, CA). During the 24-h ECG recording all patients were free to carry out daily tasks to the extent allowed by hospital regimen. Patients kept a diary to record seizures occurring during the 24-h ECG recording. ECG data were downloaded for the analysis of HR Variability on Impresario Holter Analysis System (Del Mar Reynolds Medical INC, Irvine, CA). All RR interval time series were automatically edited first. Manual editing was not performed due to the notsignificant presence of artefacts and premature beats. For final analysis, 24-h HR-variability data were divided into segments of 3600 s, and only segments with >85% sinus beats were included in analysis. Quantitative time domain analysis was performed on normal—normal (NN or RR) interval, and the following data were computed: mean, SDNN (standard deviation of NN intervals), SDNN index (mean of the standard deviations of NN intervals), SDANN (standard deviation of the averaged NN intervals), SDSD (standard deviation of successive NN differences), RMSSD (square root of the mean squared difference of the consecutive NN intervals), pNN50 (proportion of NN intervals differing more than 50 ms to the total number of NN intervals), and TINN (the integral of the density distribution of the number of all NN intervals plotted in a histogram divided by the maximum of the density distribution). An autoregressive model was used to estimate the power-spectrum densities of HR variability (Kay and Marple, 1981). Power spectra were quantified by measuring the area in three frequency bands: 0.005—0.04 Hz (very low frequency, VLF), 0.04—0.15 Hz (low frequency, LF), and 0.15—0.4 Hz (high frequency, HF). Given that HF, VLF and LF bands fluctuation of RR interval mainly reflects cardiovagal modulation, sympathetic excitation (Pagani et al., 1997) and sympathovagal balance (Eckberg, 1997), a sub analysis
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C. Cadeddu et al.
Table 2 Trans-thoracic conventional echocardiographic and TDI parameters. Pre-VNS
Post-VNS
Conventional echocardiography LVEF 64 ± 3.4% EDV 83.9 ± 24.7 ESV 30.3 ± 9.5 DecT 0.214 ± 0.03 E/A 1.33 ± 0.2 TDI Em Em/Am E/Em IVRT Sm
9.29 1.38 8.44 75.9 6.97
Strain rate imaging Radial (%) 68.7 SR (s−1 ) 3.1 Longitudinal (%) 28.9 SR (s−1 ) 1.82
P-Value
60.9 86.5 34.1 0.238 1.41
± ± ± ± ±
3.9% 13.4 7.4 0.05 0.4
P = ns P = ns P = ns P = ns P = ns
9.53 1.45 8.32 83.7 7.12
± ± ± ± ±
1.9 0.41 1.52 31.9 0.79
P = ns P = ns P = ns P = ns P = ns
± 32.3 ± 1.01
63.5 ± 20.6 2.88 ± 1.15
P = ns P = ns
± 14.7 ± 0.3
25.1 ± 10.7 1.88 ± 0.33
P = ns P = ns
± ± ± ± ±
1.7 0.32 1.67 16.7 0.95
Abbreviations: LVEF: left ventricular ejection fraction; EDV: end diastolic volume; ESV end systolic volume; DecT: deceleration time; E/A: early and late diastolic peak velocity ratio; Em: TD early diastolic peak velocity; Em/Am: TD early and late diastolic peak velocity ratio; IVRT: isovolumic relaxation time; Sm: TD systolic peak velocity; : strain; SR: strain rate.
were varied following long-term VNS treatment (Table 2). The latter findings underline how long-term vagal stimulation produces no significant changes in left ventricular and pressure load functions. On the contrary, a significant increase was observed for BP on averaging 24-h systolic (100 ± 21 vs 105.1 ± 22.2, P < 0.0001) and diastolic BP (61.7 ± 13.9 vs 64.5 ± 14.3, P < 0.0005; Figs. 1 and 2). The significant increase in systolic BP was evident both in the daytime (103.4 ± 24.7 vs 109 ± 26, P < 0.0001) and night-time (92.5 ± 32.5 vs 96.6 ± 33.9, P < 0.005). Similarly, the increase in diastolic BP was evident both during the day (65 ± 15.9 vs 67.9 ± 16.4, P < 0.01) and at night (54.3 ± 19.1 vs 56.9 ± 19.9, P < 0.005). This increase reached a peak between h.16.31 and h.17.30 when systolic BP recorded 114.7 mmHg post-VNS versus 95.3 baseline, while diastolic BP under VNS was 70.9 mmHg versus 56.9 baseline (Figs. 1 and 2). At HRV time domain analysis following VNS, a significant increase in SDSD, RMSSD and pNN50 was observed at night (Table 3). Analysis of the HRV power spectrum revealed a non-significant decreasing trend in LF/HF ratio both during the day and at night in all patients despite the variety of data collected (Table 3). Moreover, a close scrutiny of the most affected BP period revealed, at the zenith of BP, a significant rise in HF and a reduction in LF components at peak BP recordings, resulting in a significant reduction in their ratio (LF/HF) (Table 3). On the other hand, at peak BP no significant variations were observed for any powerspectrum components.
Discussion of the power-spectrum densities of HR variability was performed for all 24-h recordings and at the zenith and nadir of BP variation (zenith 16:31—17:30; nadir 6:31—7:30).
Statistical analysis Categorical data are presented as percentages, and quantitative data as mean ± SD. Differences between pre-implant and follow up were assessed by means of Student’s 2-tailed t-test for paired data, after having verified the data normal distribution. Wilcoxon’s signed-rank test was used if data were not normally distributed. Categorical data comparison was performed by a Chi-Square analysis. P-Values were considered significant when P ≤ 0.05.
Results The clinical profiles of all patients are summarized in Table 1. All subjects but one displayed a modest to good improvement in seizure rating. At conventional and TDI echocardiography, no significant changes were found in common echocardiographic parameters of systolic function such as the ejection fraction, S wave peak at TDI analysis, and some less common but more sensitive parameters including and SR (Table 2). Neither common parameters of left ventricular diastolic function nor less common parameters such as IVRT, E/Em ratio (ratio between E wave peak measured with pulsed wave Doppler of the trans-mitralic flow and E wave peak measured with TDI)
The findings obtained in the present study confirm the cardiovascular safety profile and reliability of VNS as adjunctive antiepileptic therapy, while providing further evidence that several aspects of autonomic cardiocirculatory dynamics are intrinsically modulated by this treatment. Indeed, monitoring of cardiovascular functions both prior and subsequent to VNS implant revealed a significant increase in both systolic and diastolic BP values distributed at uneven intervals during the circadian cycle following VNS implant. In particular, increased BP values were recorded throughout the entire wake period (zenith between h.16:31 and 17:30) while, compared to pre-implant values, nadir increase of the same parameters was observed at night. The results obtained were independent by those correlated to the VNS antiseizure activity (Table 1), given that they had been replicated in all subjects, included the patients without substantial statistical variations in seizure regimen. Moreover, the variation of cardiovascular parameters cannot be attributed to modifications in AEDs, as already considered in other studies (Ansakorpi et al., 2000; Isojarvi et al., 1998), given that the therapeutic regimen was kept stable after VNS implant. Although the variations detected in BP are well below possible age-related risk parameters, the present study suggests that VNS modulation in cardiovascular functions may be viewed in a different perspective to a merely theoretical functional neutrality, thus ruling out the ‘‘null hypothesis’’ of VNS-induced cardio-dynamic effects. Accordingly, the increase in BP may be construed as one of the mani-
Cardiovascular modulation during vagus nerve stimulation therapy
Figure 1
Systolic blood pressure at baseline (Pre) and after VNS device implant (Post).
Figure 2
Diastolic blood pressure at baseline (Pre) and after VNS device implant (Post).
fold VNS effects mediated by a central modulation [in both its systolic and diastolic components (Figs. 1 and 2)] uncorrelated to antiepileptic effects. The characteristics of BP spectra and in particular the circadian peak values sug-
Table 3
149
gest that cardiac responses reflect the complex interplay of somato-autonomic, visceral, and sensory afferences which accomplish their integration and modulation at central level (Cechetto, 1987; Jänig, 1996).
HRV analysis. Pre-VNS
Time domain parameters (12 h night-time) SDNN 100.66 SDNN index (ms) 31.18 SDANN (ms) 94.00 rMSSD (ms) 23.96 SDSD (ms) 16.36 pNN50 (%) 1.90 TINN (ms) 318.76 Power-spectrum parameters (24 h) LF HF LF/HF
± ± ± ± ± ± ±
Post-VNS 48.84 14.16 46.38 10.69 7.35 0.39 160.87
49.2 ± 7.1 35.8 ± 6.8 2.1 ± 0.8
Power-spectrum parameters at the blood pressure zenith LF 51.8 ± 4.6 HF 29.7 ± 3.6 LF/HF 2.3 ± 0.3
93.98 32.72 88.86 26.62 18.07 2.93 421.9
± ± ± ± ± ± ±
44.40 14.07 46.06 12.01 8.14 0.8 189.00
P ns ns ns P < 0.05 P < 0.01 P < 0.05 ns
50.8 ± 7.9 36.3 ± 7.2 1.9 ± 0.7
ns ns ns
47.6 ± 4.2 37.3 ± 4.5 1.7 ± 0.3
P < 0.05 P < 0.0001 P < 0.0005
Abbreviations: SDNN: standard deviation of all normal sinus RR intervals over 24 h; SDNN index: mean of the standard deviations of all normal sinus RR intervals for all 5-min segments; SDANN: standard deviation of the averaged normal sinus RR intervals for all segments; rMSSD: root-mean-square of successive normal sinus RR interval difference; SDSD: standard deviation of successive normal sinus RR interval difference; pNN50: proportion of NN intervals differing more than 50 ms to the total number of NN intervals; TINN: triangular index, the integral of the density distribution of the number of all NN intervals plotted in a histogram divided by the maximum of the density distribution; LF, low frequency; HF, high frequency; LF/HF: low frequency and high frequency ratio.
150 Furthermore, as the HF-component of HRV is related to the parasympathetic system while LF band relates to the sympathetic system, the hypothesis whereby VNS and its main afferent NTS may be involved in optimizing the homeostatic balance of sympatho-vagal responses between concurrent autonomic components (Lambertz et al., 1993; Seagard et al., 2001; Boscan et al., 2002) is of particular interest. However, in view of the different protocols applied to the studies performed to assess the effects of VNS stimulation on autonomic function, it is hardly surprisingly that considerably controversial results have been obtained. For instance, some studies have reported a reduction in HF power during the night and no change of sympatho-vagal circadian values (Galli et al., 2003), while another study showed a slight increase in the baroreflex and HF power spectrum during vagal stimulation (Stemper et al., 2008). The latter result is in line with the data obtained in the present study, which shows a slight increase in HF power and LF/HF ratio over a 24-h recording, though the suggestion that responders may reflect a favourable VNS effect on HRV, while non-responders fail to show modulation of cardiac autonomic control, has been recently considered (Ronkainen et al., 2006). Though the mechanism by which VNS-induced BP variations remains to be clarified, the findings of this study suggest that the HRV-related BP increase could be mediated by the baroreflex, a relationship which implies a central modulation (Balan et al., 2004). Moreover, it has been shown that the cardiac sympathetic afferent reflex is inhibited by NTS barosensitive neurons and excited by NTS chemosensitive neurons, suggesting that NTS plays an important role in processing the interactions between these cardiovascular reflexes that contribute towards modulating HRV (Wang et al., 2006). In addition, other experimental studies have proposed that BP regulation, which would appear to be increasingly correlated to physiological circadian fluctuations, may be modulated by NTS pathways impinging on noradrenergic pathways (Silva de Oliveira et al., 2007; Machado, 2001). Accordingly, it has been shown that stimulation of NTS excites putative vasopressin-secreting cells of the supraoptic nucleus via a catecholaminergic projection to the hypothalamus due to activation of a relay projection through A1 noradrenergic cell group of the caudal ventrolateral medulla. Another possible BP regulation by VNS-modulated central mechanisms might be represented by impingement upon the locus coeruleus by NTS (Aston-Jones et al., 1991). It has furthermore been demonstrated that LC not only plays a crucial role in the complex antiepileptic mechanism of VNS (Krahl et al., 1998; Gale, 1992) but also, through its projections, increases norepinephrine content in prefrontal cortex and limbic areas (Follesa et al., 2007), both related to BP regulation (Lovallo, 2005). The role of VNS-driven noradrenergic modulation through NTS either via a complex relay projection through the A1 cell group (Day, 1989) or via locus coeruleus projections (Randich et al., 1990), is largely in line with the findings of the present study. Indeed, the circadian profile of both systolic and diastolic BP suggests that VNS might induce a simple increase in a physiological trend in the hours between 16:00 and 18:00. Indeed, the fact that during the rest of the day it has been recorded only a slight BP increase negligibly persist-
C. Cadeddu et al. ing during the night, is in accordance with the observation that noradrenergic cells exert their lowest activity at night and increase their firing rate during daylight hours (Park, 2002). The report of severe HRV alterations and autonomic (sympathetic—parasympathetic) imbalances in intractable epileptic subjects compared to responders is of considerable interest in focusing the reduced parasympathetic drive to heart function (Mukherjee et al., 2009). Other studies have suggested an enhanced sympathetic tone or relative increase in sympathetic activity (via a decrease of parasympathetic tone) in chronic epileptic patients (Hennessy et al., 2001). The latter observations would appear to suggest an increased risk of sudden unexpected death in epileptic subjects (SUDEP) (Diehl et al., 1997; Hilz et al., 2002; Harnod et al., 2009). Although the subjects at high risk of SUDEP may present a complex clinical profile, as the causes range from a direct effect of seizures on critical neurovegetative areas to apneusic brainstem-modulated reflexes, nonetheless the cardiac autonomic vegetative regulation, whether or not induced by seizure, is likely to play a relevant role in SUDEP pathophysiology (Isojarvi et al., 1998; Tennis et al., 1995). In addition, while the SUDEP risk factor represented by interictal HRV changes, has yet under scrutiny (Surges et al., 2009), it is worthy of mention how in our patients VNS induced a significant reduction of night-time RMMSD and pNN50, a factor potentially supporting the hypothesis of a VNS role in contrasting SUDEP risk (Annegers et al., 2000). The present results, though obtained in a small size of selected patients, add further data to the ongoing debate on the autonomic modulation of VNS as a complex phenomenon and welcome the setting up of more multicentric studies in order to investigate VNS aspects not strictly pertaining to antiseizure activity.
Conflict of interest statement None of the authors has any conflict of interest to disclose.
Acknowledgment Authors warmly thank Veronica Tola for her support in the writing of the text.
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