Author's Accepted Manuscript
Pacemaker implantation for treatment of symptomatic atrioventricular conduction block caused by a vagus nerve stimulator Yun Lin MD, Jianming Li PhD, MD, FHRS, Huagui Li MD, PhD
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(14)00551-7 http://dx.doi.org/10.1016/j.hrthm.2014.05.020 HRTHM5783
To appear in:
Heart Rhythm
Cite this article as: Yun Lin MD, Jianming Li PhD, MD, FHRS, Huagui Li MD, PhD, Pacemaker implantation for treatment of symptomatic atrioventricular conduction block caused by a vagus nerve stimulator, Heart Rhythm, http://dx.doi.org/10.1016/j. hrthm.2014.05.020 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pacemaker implantation for treatment of symptomatic atrioventricular conduction block caused by a vagus nerve stimulator
Yun, Lin*, MD, Jianming Li**, PhD, MD, FHRS, Huagui Li***, MD, PhD *Capital Medical University, Anzhen Hospital, Beijing, P. R. China; **Minneapolis Veterans Medical Center, Minneapolis, MN; ***Fairview Southdale Hospital, Edina, MN
Running title: AV block caused by vagus nerve stimulator Conflict of interest disclosure: none
Address for correspondence: Huagui Li, MD, PhD 6405 France Avenue South, Suite W200 Edina, MN 55435 Telephone: 952-836-3700 Fax:952-836-3950 Email: [email protected]
Key Words: Vagus nerve stimulator, seizure, pacemaker, atrioventricular block, atrial fibrillation Word count: 2073
1
Introduction: Vagus nerve stimulator (VNS) is an effective therapy for drug-refractory seizures(1). The most common adverse effects of VNS use are hoarseness, throat pain, and cough(1,2). Occasional cases of bradycardia have been observed during the VNS implantation test(3-5). In a rare case, when late-onset atrioventricular (AV) block induced by VNS was observed, the bradycardia symptoms resolved after discontinuation of the VNS therapy(6). However, aggravation of recurrent seizures after discontinuation of the VNS therapy may pose a therapeutic challenge for patients whose only effective therapy for seizure is VNS. Recently, the use of VNS has been investigated for treatment of advanced heart failure(7,8). For seizure disorders, the stimulation electrodes of the VNS are placed around the left vagus nerve, distal to the cervical cardiac branches(4). In contrast, for treatment of heart failure, the stimulation electrodes of the VNS are placed around the right vagus nerve, proximal to the superior cervical cardiac branches(8). The above difference of the VNS electrode placement may have profoundly different cardiovascular effects. It is apparent that the number of patients with different types of VNS will likely to grow significantly in the near future. This will certainly get the attention of physicians about the potential adverse cardiovascular effects of VNS. We hereby report a case of VNS-induced symptomatic 2nd degree AV block that was successfully treated with implantation of a dual chamber pacemaker system.
2
Case Report:
A 55 year-old white female suffered from frequent, drug-refractory seizure as the result of brain injury from an explosion about 30 years ago. She had a VNS (Model 103, Cyberonics, Houston, TX) implanted, with the stimulating electrodes placed around the left vagus near the lower neck, at another institution in 2008. Afterwards, her seizure frequency was reduced from the average of 10 to 4 episodes per month, and the episode duration was reduced from the average of 40 to 10 minutes. However, she reported feeling “horse kick”, “eye giggling”, dizziness and palpitation intermittently since the VNS implantation. Her symptoms seemed to be correlated with the VNS stimulation (output current 1.75 mA, pulse width 130 microseconds, frequency 20 Hertz, for 30 seconds every 5 minutes) but multiple device program changes of the VNS failed to improve the symptoms. At one point, when the VNS output was reduced, her seizure frequency increased. The patient left her first neurologist because she was frustrated by the physician’s inability to manage her symptoms after years of effort.
On one occasion, when she presented to the emergency room for nose bleeding after a fall resulting from recurrent seizure, she was found to have frequent episodes of atrial fibrillation (AF) on the ECG telemetry. The emergency room physician ordered a Holter monitor which detected not only many short episodes of AF but also frequent episodes of sinus bradycardia associated with 2:1 AV block. She was thus referred for cardiology consultation at Fairview Southdale Hospital. Her other
3
medical problems include hypertension and hypothyroidism. Her oral medications included losartan 100 mg daily, divalproex 100 mg twice a day, temazepam 30 mg at bedtime daily, and levothyroxine 175 mg daily.
Review of the Holter tracings revealed more episodes of sinus bradycardia with 2:1 AV block during the night time than the day time. In contrast, there were more episodes of AF during the day time than the night time. Analysis of the Holter tracings (Figure 1) suggested possible correlation of the arrhythmias with VNS stimulation because of the intermittent nature of the arrhythmias. The patient adamantly declined further alteration to her VNS.
After extensive discussion of the management options, an agreement was reached to implant a pacemaker because of the well-documented symptomatic bradycardia. A dual chamber pacemaker (Adapta DL, Medtronic, Minneapolis, MN) was implanted in 2011 (Figure 2). During the device interaction test of the pacemaker implantation, the patient’s ECG was monitored while the VNS was turned on and off repeatedly (Figure 3). Whenever the VNS was turned on, the patient’s pacemaker changed from sensing of normal sinus rhythm to A-V sequential pacing. The above observation remained persistent with different outputs of the VNS. There was no pacemaker inhibition at maximal stimulation output of the VNS.
Since the pacemaker implantation, all of her previous symptoms except for palpitation resolved. Her palpitation was confirmed to be correlated with AF through pacemaker interrogation and was significantly improved by oral flecainide 75 mg 4
twice daily.
Discussion:
The therapeutic mechanism of VNS in seizure disorder is not well understood. The intended effect of VNS stimulation is to affect the afferent fibers of the vagus nerve to the brain. One possible effect of VNS stimulation is to activate the locus coeruleus for release of norepinephrine, which in turn increases the seizure threshold(9). Apparent adverse cardiac effect of VNS is relatively uncommon, with an estimated incidence of 0.1%(5).
Stimulation of the right vagus nerve predominantly affects the sinus node whereas stimulation of the left vagus nerve mainly affects the AV node(10) . For treatment of seizure disorders, the VNS electrodes are placed around the left vagus nerve in the neck of the patient. Because the electrodes are placed distal to the origin of the superior and inferior cervical cardiac branches of the vagus nerve, direct stimulation of the cardiac vagal fibers can usually be avoided(4), which may explain the low incidence of bradycardia in seizure patients on VNS therapy. It has been speculated that the occasional occurrence of VNS-induced bradycardia may be related to inadvertent placement of the electrodes around the cardiac branches of the vagus nerve, or an aberrant anatomy of the vagus nerve with lower than expected branching of the cardiac fibers, or collateral stimulation of the cardiac branches(4,5).
Severe bradycardia has been observed during the VNS implantation test in a small number of patients(3-5). Tatum et al(3) reported a series of 4 cases with severe 5
bradycardia (complete AV block was specifically mentioned in 1 patient) induced by the VNS during the implantation test. The VNS therapy was abandoned in 3 of the 4 patients. Asconape et al(4) also observed a case of asystole induced by the VNS that required temporary chest compression during the implantation test and the VNS implantation was aborted. Ali et al(5) reported 3 cases of VNS-induced complete AV block during the implantation test and the VNS was removed in 2 patients. Interestingly, the two patients (one from Tatum et al(3) and another from Ali et al(5)) who received the VNS implantation despite bradycardia during the implantation test did not have subsequent bradycardia during follow up. Ardesch et al(11) observed 3 cases of VNS-induced bradycardia who had spontaneous resolution during the implantation procedure. None of the 3 patients had postoperative bradycardia during the follow-up.
In the current case, the patient had unexplained symptoms for years after the VNS implantation although she had significant improvement of her seizure disorder. Cardiac evaluation was not sought, presumably because the VNS implantation testing did not show adverse cardiac effects. Analysis of the relationship among her intermittent symptoms, cardiac arrhythmias and VNS stimulation suggested the potential side effects of VNS stimulation. Removal or deactivation of the VNS was not feasible because of the high frequency of seizures. Therefore, we proceeded with pacemaker implantation because the patient had been frustrated for years and VNS reprogramming had failed to make a change. During the pacemaker implantation, we confirmed that her VNS stimulation was the real cause of sinus bradycardia and AV 6
block. Her unexplained symptoms were eliminated by the pacemaker therapy. Unfortunately, she continued to be bothered by intermittent AF but achieved significant relief from flecainide. Although we cannot prove the direct relationship between VNS stimulation and AF, we think that is very likely, based on the intermittent nature of AF. AF predominantly observed during the day time might be related to a combined effect of vagus stimulation in the presence of increased sympathetic activities while the patient was awake. The potential risk of vagal stimulation-induced AF needs to be investigated when VNS is to be used for heart failure treatment.
An important question of pacemaker therapy in a patient with VNS is the potential device-device interaction. Caeres et al(12) reported a seizure patient who received pacemaker implantation for post-ictal transient AV block. No adverse inter-device interaction was observed when this patient subsequently had a VNS implanted. There was no adverse inter-device interaction either in our case. However, careful testing for any potential inter-device interaction during the implantation procedure should always be conducted whenever a patient with a VNS needs pacemaker or a pacemaker patient needs a VNS.
Our case indicates that in patients with VNS and unexplained symptoms, cardiac adverse effects of VNS stimulation should be considered even if the implantation test does not show apparent cardiac effects. In those with VNS-induced symptomatic bradycardia that cannot be managed by VNS reprogramming, pacemaker implantation
7
is a reasonable option.
With the increasing number of patients with implanted VNS, the potential adverse cardiac side effects of VNS deserve serious attention by the medical community. Most importantly, with the strong interest in pursuing heart failure treatment by using the VNS, the potential adverse effects of bradycardia and AF from the VNS use need to be carefully studied. The preliminary study of De Ferrari et al(8) seemed to show good safety and tolerance in patients on VNS therapy for heart failure.
8
References: 1. Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active control trial. Neurology 1998;51:48-55.
2. Ben-Menachem E. Vagus nerve stimulation: side effects and long-term safety. J Clin Neurophysiol 2001;18:415-8. 3. Tatum WO IV, Moore DB, Stecker MM, Baltuch GH, French JA, Ferreira JA, Carney PM, Labar DR, Vale FL. Ventricular asystole during vagus nerve stimulation for epilepsy in humans. Neurology 1999;52:1267-9.
4. Asconape JJ, Moore DD, Zipes DP, Hartman LM, Duffell WH Jr. Bradycardia and asystole with the use of vagus nerve stimulation for treatment of epilepsy: a rare complication of intraoperative device testing. Epilepsia 1999;40:1452-4. 5. Ali II, Pirzada NA, Kanjwal Y, Wannamaker B, Medhkour A, Koltz MT, Vaughn BV. Complete heart block with ventricular asystole during left vagus nerve stimulation for epilepsy. Epilepsy Behav 2004;5:768-71. 6. Iriarte J, Urrestarazu E, Alegre M, Macías A, Gómez Asier, Amaro P, Artieda J, Viteri C. Late-onset bradyarrhythmia during vagus nerve stimulation. Epilepsia 2009;50:928-32.
7. Schwartz PJ, De Ferrari GM, Sanzo A, Landolina M, Rordorf R, Raineri C,
9
Campana C, Revera M, Ajmone-Marsan N, Tavazzi L, Odero A. Long-term vagal stimulation in patients with advanced heart failure: first experience in man. Eur J Heart Fail 2008;10:884-91.
8. De Ferrari GM, CrijinsH, Borggrefe M, et al. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Hear J 2011;32:847-55.
9. Krahl SE, Clark KB, Smith DC, Browning RA. Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulatin. Epilepsia 1998;39:709-14.
10. Cohn A. On the differences in the effects of stimulation of the two vagus nerves on rate and conduction of the dog’s heart. J Exp Med 1912;16:732-757.
11. Ardesch JJ, Buschman HP, van der Burgh PH, Wagener-Schimmel LJ, van der Aa HE, Hagema G. Cardiac responses of vagus nerve stimulation: intraoperative bradycardia and subsequent chronic stimulation. Clin Neurol Neurosurg 2007;109:848-52.
12. Caceres R, Richter J, Safstrom K, Landtblom AM. Application of a vagus nerve stimulator in an epilepsy patient with cardiac pacemaker after post-ictal cardiac arrest. Acta Neurol Scan 2009;120:139-142.
10
Figure legends: Figure 1. Tracings of the electrocardiogram from Holter monitoring. A, continuous (large arrow) recording of transient 2:1 AV block with sinus bradycardia. B, short episode of atrial fibrillation. Numbers below the baseline indicate P-P (small arrows) intervals.
11
Figure 2. Chest x-ray image showing the VNS on the left side and dual chamber pacemaker on the right side. The arrow points to the electrodes of VNS which were placed at the level of the lower cervical spine.
12
Figure 3. Surface electrocardiogram recording during the pacemaker implantation test. Arrows indicate timing of VNS stimulation.
13
Pacemaker implantation for treatment of symptomatic atrioventricular conduction block caused by a vagus nerve stimulator Yun Lin MD, Jianming Li PhD, MD, FHRS, Huagui Li MD, PhD
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(14)00551-7 http://dx.doi.org/10.1016/j.hrthm.2014.05.020 HRTHM5783
To appear in:
Heart Rhythm
Cite this article as: Yun Lin MD, Jianming Li PhD, MD, FHRS, Huagui Li MD, PhD, Pacemaker implantation for treatment of symptomatic atrioventricular conduction block caused by a vagus nerve stimulator, Heart Rhythm, http://dx.doi.org/10.1016/j. hrthm.2014.05.020 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pacemaker implantation for treatment of symptomatic atrioventricular conduction block caused by a vagus nerve stimulator
Yun, Lin*, MD, Jianming Li**, PhD, MD, FHRS, Huagui Li***, MD, PhD *Capital Medical University, Anzhen Hospital, Beijing, P. R. China; **Minneapolis Veterans Medical Center, Minneapolis, MN; ***Fairview Southdale Hospital, Edina, MN
Running title: AV block caused by vagus nerve stimulator Conflict of interest disclosure: none
Address for correspondence: Huagui Li, MD, PhD 6405 France Avenue South, Suite W200 Edina, MN 55435 Telephone: 952-836-3700 Fax:952-836-3950 Email: [email protected]
Key Words: Vagus nerve stimulator, seizure, pacemaker, atrioventricular block, atrial fibrillation Word count: 2073
1
Introduction: Vagus nerve stimulator (VNS) is an effective therapy for drug-refractory seizures(1). The most common adverse effects of VNS use are hoarseness, throat pain, and cough(1,2). Occasional cases of bradycardia have been observed during the VNS implantation test(3-5). In a rare case, when late-onset atrioventricular (AV) block induced by VNS was observed, the bradycardia symptoms resolved after discontinuation of the VNS therapy(6). However, aggravation of recurrent seizures after discontinuation of the VNS therapy may pose a therapeutic challenge for patients whose only effective therapy for seizure is VNS. Recently, the use of VNS has been investigated for treatment of advanced heart failure(7,8). For seizure disorders, the stimulation electrodes of the VNS are placed around the left vagus nerve, distal to the cervical cardiac branches(4). In contrast, for treatment of heart failure, the stimulation electrodes of the VNS are placed around the right vagus nerve, proximal to the superior cervical cardiac branches(8). The above difference of the VNS electrode placement may have profoundly different cardiovascular effects. It is apparent that the number of patients with different types of VNS will likely to grow significantly in the near future. This will certainly get the attention of physicians about the potential adverse cardiovascular effects of VNS. We hereby report a case of VNS-induced symptomatic 2nd degree AV block that was successfully treated with implantation of a dual chamber pacemaker system.
2
Case Report:
A 55 year-old white female suffered from frequent, drug-refractory seizure as the result of brain injury from an explosion about 30 years ago. She had a VNS (Model 103, Cyberonics, Houston, TX) implanted, with the stimulating electrodes placed around the left vagus near the lower neck, at another institution in 2008. Afterwards, her seizure frequency was reduced from the average of 10 to 4 episodes per month, and the episode duration was reduced from the average of 40 to 10 minutes. However, she reported feeling “horse kick”, “eye giggling”, dizziness and palpitation intermittently since the VNS implantation. Her symptoms seemed to be correlated with the VNS stimulation (output current 1.75 mA, pulse width 130 microseconds, frequency 20 Hertz, for 30 seconds every 5 minutes) but multiple device program changes of the VNS failed to improve the symptoms. At one point, when the VNS output was reduced, her seizure frequency increased. The patient left her first neurologist because she was frustrated by the physician’s inability to manage her symptoms after years of effort.
On one occasion, when she presented to the emergency room for nose bleeding after a fall resulting from recurrent seizure, she was found to have frequent episodes of atrial fibrillation (AF) on the ECG telemetry. The emergency room physician ordered a Holter monitor which detected not only many short episodes of AF but also frequent episodes of sinus bradycardia associated with 2:1 AV block. She was thus referred for cardiology consultation at Fairview Southdale Hospital. Her other
3
medical problems include hypertension and hypothyroidism. Her oral medications included losartan 100 mg daily, divalproex 100 mg twice a day, temazepam 30 mg at bedtime daily, and levothyroxine 175 mg daily.
Review of the Holter tracings revealed more episodes of sinus bradycardia with 2:1 AV block during the night time than the day time. In contrast, there were more episodes of AF during the day time than the night time. Analysis of the Holter tracings (Figure 1) suggested possible correlation of the arrhythmias with VNS stimulation because of the intermittent nature of the arrhythmias. The patient adamantly declined further alteration to her VNS.
After extensive discussion of the management options, an agreement was reached to implant a pacemaker because of the well-documented symptomatic bradycardia. A dual chamber pacemaker (Adapta DL, Medtronic, Minneapolis, MN) was implanted in 2011 (Figure 2). During the device interaction test of the pacemaker implantation, the patient’s ECG was monitored while the VNS was turned on and off repeatedly (Figure 3). Whenever the VNS was turned on, the patient’s pacemaker changed from sensing of normal sinus rhythm to A-V sequential pacing. The above observation remained persistent with different outputs of the VNS. There was no pacemaker inhibition at maximal stimulation output of the VNS.
Since the pacemaker implantation, all of her previous symptoms except for palpitation resolved. Her palpitation was confirmed to be correlated with AF through pacemaker interrogation and was significantly improved by oral flecainide 75 mg 4
twice daily.
Discussion:
The therapeutic mechanism of VNS in seizure disorder is not well understood. The intended effect of VNS stimulation is to affect the afferent fibers of the vagus nerve to the brain. One possible effect of VNS stimulation is to activate the locus coeruleus for release of norepinephrine, which in turn increases the seizure threshold(9). Apparent adverse cardiac effect of VNS is relatively uncommon, with an estimated incidence of 0.1%(5).
Stimulation of the right vagus nerve predominantly affects the sinus node whereas stimulation of the left vagus nerve mainly affects the AV node(10) . For treatment of seizure disorders, the VNS electrodes are placed around the left vagus nerve in the neck of the patient. Because the electrodes are placed distal to the origin of the superior and inferior cervical cardiac branches of the vagus nerve, direct stimulation of the cardiac vagal fibers can usually be avoided(4), which may explain the low incidence of bradycardia in seizure patients on VNS therapy. It has been speculated that the occasional occurrence of VNS-induced bradycardia may be related to inadvertent placement of the electrodes around the cardiac branches of the vagus nerve, or an aberrant anatomy of the vagus nerve with lower than expected branching of the cardiac fibers, or collateral stimulation of the cardiac branches(4,5).
Severe bradycardia has been observed during the VNS implantation test in a small number of patients(3-5). Tatum et al(3) reported a series of 4 cases with severe 5
bradycardia (complete AV block was specifically mentioned in 1 patient) induced by the VNS during the implantation test. The VNS therapy was abandoned in 3 of the 4 patients. Asconape et al(4) also observed a case of asystole induced by the VNS that required temporary chest compression during the implantation test and the VNS implantation was aborted. Ali et al(5) reported 3 cases of VNS-induced complete AV block during the implantation test and the VNS was removed in 2 patients. Interestingly, the two patients (one from Tatum et al(3) and another from Ali et al(5)) who received the VNS implantation despite bradycardia during the implantation test did not have subsequent bradycardia during follow up. Ardesch et al(11) observed 3 cases of VNS-induced bradycardia who had spontaneous resolution during the implantation procedure. None of the 3 patients had postoperative bradycardia during the follow-up.
In the current case, the patient had unexplained symptoms for years after the VNS implantation although she had significant improvement of her seizure disorder. Cardiac evaluation was not sought, presumably because the VNS implantation testing did not show adverse cardiac effects. Analysis of the relationship among her intermittent symptoms, cardiac arrhythmias and VNS stimulation suggested the potential side effects of VNS stimulation. Removal or deactivation of the VNS was not feasible because of the high frequency of seizures. Therefore, we proceeded with pacemaker implantation because the patient had been frustrated for years and VNS reprogramming had failed to make a change. During the pacemaker implantation, we confirmed that her VNS stimulation was the real cause of sinus bradycardia and AV 6
block. Her unexplained symptoms were eliminated by the pacemaker therapy. Unfortunately, she continued to be bothered by intermittent AF but achieved significant relief from flecainide. Although we cannot prove the direct relationship between VNS stimulation and AF, we think that is very likely, based on the intermittent nature of AF. AF predominantly observed during the day time might be related to a combined effect of vagus stimulation in the presence of increased sympathetic activities while the patient was awake. The potential risk of vagal stimulation-induced AF needs to be investigated when VNS is to be used for heart failure treatment.
An important question of pacemaker therapy in a patient with VNS is the potential device-device interaction. Caeres et al(12) reported a seizure patient who received pacemaker implantation for post-ictal transient AV block. No adverse inter-device interaction was observed when this patient subsequently had a VNS implanted. There was no adverse inter-device interaction either in our case. However, careful testing for any potential inter-device interaction during the implantation procedure should always be conducted whenever a patient with a VNS needs pacemaker or a pacemaker patient needs a VNS.
Our case indicates that in patients with VNS and unexplained symptoms, cardiac adverse effects of VNS stimulation should be considered even if the implantation test does not show apparent cardiac effects. In those with VNS-induced symptomatic bradycardia that cannot be managed by VNS reprogramming, pacemaker implantation
7
is a reasonable option.
With the increasing number of patients with implanted VNS, the potential adverse cardiac side effects of VNS deserve serious attention by the medical community. Most importantly, with the strong interest in pursuing heart failure treatment by using the VNS, the potential adverse effects of bradycardia and AF from the VNS use need to be carefully studied. The preliminary study of De Ferrari et al(8) seemed to show good safety and tolerance in patients on VNS therapy for heart failure.
8
References: 1. Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active control trial. Neurology 1998;51:48-55.
2. Ben-Menachem E. Vagus nerve stimulation: side effects and long-term safety. J Clin Neurophysiol 2001;18:415-8. 3. Tatum WO IV, Moore DB, Stecker MM, Baltuch GH, French JA, Ferreira JA, Carney PM, Labar DR, Vale FL. Ventricular asystole during vagus nerve stimulation for epilepsy in humans. Neurology 1999;52:1267-9.
4. Asconape JJ, Moore DD, Zipes DP, Hartman LM, Duffell WH Jr. Bradycardia and asystole with the use of vagus nerve stimulation for treatment of epilepsy: a rare complication of intraoperative device testing. Epilepsia 1999;40:1452-4. 5. Ali II, Pirzada NA, Kanjwal Y, Wannamaker B, Medhkour A, Koltz MT, Vaughn BV. Complete heart block with ventricular asystole during left vagus nerve stimulation for epilepsy. Epilepsy Behav 2004;5:768-71. 6. Iriarte J, Urrestarazu E, Alegre M, Macías A, Gómez Asier, Amaro P, Artieda J, Viteri C. Late-onset bradyarrhythmia during vagus nerve stimulation. Epilepsia 2009;50:928-32.
7. Schwartz PJ, De Ferrari GM, Sanzo A, Landolina M, Rordorf R, Raineri C,
9
Campana C, Revera M, Ajmone-Marsan N, Tavazzi L, Odero A. Long-term vagal stimulation in patients with advanced heart failure: first experience in man. Eur J Heart Fail 2008;10:884-91.
8. De Ferrari GM, CrijinsH, Borggrefe M, et al. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Hear J 2011;32:847-55.
9. Krahl SE, Clark KB, Smith DC, Browning RA. Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulatin. Epilepsia 1998;39:709-14.
10. Cohn A. On the differences in the effects of stimulation of the two vagus nerves on rate and conduction of the dog’s heart. J Exp Med 1912;16:732-757.
11. Ardesch JJ, Buschman HP, van der Burgh PH, Wagener-Schimmel LJ, van der Aa HE, Hagema G. Cardiac responses of vagus nerve stimulation: intraoperative bradycardia and subsequent chronic stimulation. Clin Neurol Neurosurg 2007;109:848-52.
12. Caceres R, Richter J, Safstrom K, Landtblom AM. Application of a vagus nerve stimulator in an epilepsy patient with cardiac pacemaker after post-ictal cardiac arrest. Acta Neurol Scan 2009;120:139-142.
10
Figure legends: Figure 1. Tracings of the electrocardiogram from Holter monitoring. A, continuous (large arrow) recording of transient 2:1 AV block with sinus bradycardia. B, short episode of atrial fibrillation. Numbers below the baseline indicate P-P (small arrows) intervals.
11
Figure 2. Chest x-ray image showing the VNS on the left side and dual chamber pacemaker on the right side. The arrow points to the electrodes of VNS which were placed at the level of the lower cervical spine.
12
Figure 3. Surface electrocardiogram recording during the pacemaker implantation test. Arrows indicate timing of VNS stimulation.
13
