Accepted Manuscript Cardioneuroablation in ictal asystole - new treatment method Bor Antolic, MD, PhD, Veronika Rutar Gorisek, MD, PhD, Gal Granda, MD, Bogdan Lorber, MD, Msc, Prof Matjaz Sinkovec, MD, PhD, David Zizek, MD, PhD PII: S2214-0271(18)30186-6 DOI: 10.1016/j.hrcr.2018.07.018 Reference: HRCR 578 To appear in: HeartRhythm Case Reports Received Date: 15 June 2018 Revised Date: 26 July 2018 Accepted Date: 31 July 2018 Please cite this article as: Antolic B, Rutar Gorisek V, Granda G, Lorber B, Sinkovec M, Zizek D, Cardioneuroablation in ictal asystole - new treatment method, HeartRhythm Case Reports (2018), doi: 10.1016/j.hrcr.2018.07.018. 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 proof before it is published in its final 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. ACCEPTED MANUSCRIPT 1 TITLE PAGE 2 Title: Cardioneuroablation in ictal asystole - new treatment method 4 Short title: Cardioneuroablation in ictal asystole 5 RI PT 3 Authors: 7 1. Bor Antolic1, MD, PhD, email: email@example.com 8 2. Veronika Rutar Gorisek2, MD, PhD, email: firstname.lastname@example.org 9 3. Gal Granda, MD2, email: email@example.com SC 6 4. Bogdan Lorber, MD2, Msc, email: firstname.lastname@example.org 11 5. Prof. Matjaz Sinkovec1, MD, PhD, email: email@example.com 12 6. David Zizek, MD, PhD1, email: firstname.lastname@example.org M AN U 10 13 14 1 15 1000 Ljubljana, Slovenia 16 2 17 Ljubljana, Slovenia TE D EP University Medical Center Ljubljana, Department of Neurology, Zaloska 7, AC C 18 University Medical Center Ljubljana, Department of Cardiology, Zaloska 7, 19 Financial support/funding: This research did not receive any specific grant 20 from funding agencies in the public, commercial, or not-for-profit sectors. 21 Conflicts of interest: the authors report no conflicts of interest. 22 Informed consent: informed consent was obtained from the patient before 23 performing the procedure. 24 Word count: 1948 25 1 ACCEPTED MANUSCRIPT 26 27 Corresponding author: 29 Bor Antolic, MD, PhD 30 Department of Cardiology 31 University Medical Centre Ljubljana 32 Zaloška 7 33 1000 Ljubljana 34 Slovenia 35 email: email@example.com 36 tel: +386 1 522 2844, +386 1 522 8539, +386 41 325 796 37 fax: +386 1 522 2828 SC M AN U 38 RI PT 28 Keywords: cardioneuroablation; syncope; ictal asystole; vagal denervation; 40 parasympathetic denervation EP AC C 41 TE D 39 2 ACCEPTED MANUSCRIPT INTRODUCTION 43 We describe a case of successful parasympathetic denervation of the sinus 44 node using cardioneuroablation in a patient with right temporal lobe epilepsy 45 and prolonged ictal asystole. The procedure abolished seizure-induced 46 bradyarrhythmia occurrence and converted patient's dramatic seizures with 47 severe cerebral hypoperfusion into short focal seizures with minimal motor 48 signs. To the best of our knowledge, this is the first report of successful 49 cardioneuroablation procedure to potentially treat ictal asystole. SC RI PT 42 50 CASE REPORT 52 43-year old right-handed male patient with pharmacoresistant focal epilepsy 53 was admitted to Department of Neurology for evaluation before potential 54 epilepsy surgery. He had an extensive focal cortical dysplasia in the right 55 temporal lobe and mild left-sided spastic hemiparesis. Seizures were resistant 56 to several antiepileptic drugs, including levetiracetam and carbamazepine in 57 maximal dosages he was taking before the admission. For the past five years, 58 almost every seizure resulted in loss of consciousness, falls, and on several 59 occasions, in traumatic injuries. During long-term video- 60 electroencephalography (EEG) monitoring, the antiepileptic drugs were 61 temporarily withdrawn, and nine epileptic seizures were recorded. The 62 seizures manifested with ictal pouting (‘chapeau de gendarme’), right leg 63 automatisms and subtle pelvic movements, dystonic left hand posturing, 64 followed by unresponsiveness, upward gaze deviation and posturing 65 resembling decerebration pattern. In EEG, focal ictal activity started in the 66 right temporal region, quickly evolving over both hemispheres and was then AC C EP TE D M AN U 51 3 ACCEPTED MANUSCRIPT followed by postictal EEG slowing over the right hemisphere. Unexpectedly, in 68 late postictal period, we observed generalized EEG flattening and slowing, 69 indicative of cerebral hypoperfusion. Simultaneously, in ECG sinus heart rate 70 slowing with asystole lasting up to 25 seconds was recorded, resulting in 71 patient's syncope (Figure 1, upper panel; see supplementary video). 72 Immediate surgical treatment of epilepsy was not feasible and also, 73 considering the extensive nature of the presumed epileptogenic lesion, 74 chances of favourable epilepsy surgery outcome were estimated to be low. 75 The cardiology team was consulted. Since asystole after the seizure onset 76 was suggestive of an increased direct vagal stimulation of the cardiac 77 conduction system we decided to try cardioneuroablation as an alternative to 78 permanent pacemaker implantation. M AN U SC RI PT 67 79 After patient’s consent, the cardioneuroablation procedure was performed 81 using mild sedation with midazolam and additional fentanyl boluses. Mapping 82 and ablations were performed using a 3,5 mm irrigated tip catheter (Navistar 83 Thermocool SmartTouch, Biosense Webster, Diamond Bar, CA, USA). Initially, 84 three-dimensional virtual anatomy of the right (RA) and left atrium (LA) was 85 created using CARTO 3 fast anatomical mapping system (Biosense Webster, 86 Diamond Bar, CA, USA), facilitated by intracardiac echocardiography 87 (AcuNav, Siemens Medical Solutions, USA). Tagging the phrenic nerve 88 capture points on the lateral RA allowed us to map the nerve course (Figure 89 2). Afterwards, the electrogram fractionations indicative of epicardial ganglia 90 presence1 were mapped and tagged in the anatomic areas where epicardial 91 parasympathetic ganglia for sinus and AV node innervation are located AC C EP TE D 80 4 ACCEPTED MANUSCRIPT (anteriorly and superiorly to the right superior pulmonary vein (RSPV) and 93 anteriorly to the right inferior pulmonary vein in LA). These locations 94 correspond to locations on the posterior septal side of the RA, where 95 fractionated electrograms were also mapped and tagged. Multiple ablations 96 (power control, 25W in RA, 30W in LA, target contact force 10-30 g, duration 97 up to 40s, temperature limit 43 °C, total RF time 1 544s) were performed in 98 target areas from both the LA and RA with care taken to avoid ablations in the 99 proximity of the mapped course of the phrenic nerve. We aimed to achieve SC RI PT 92 local electrogram attenuation and ablation index (Biosense Webster, Diamond 101 Bar, CA, USA) of 350 to 500. During initial ablations anteriorly to the RSPV 102 increase in heart rate was noticed indicating parasympathetic denervation of 103 the sinus node. Later ablations more inferiorly along the posterior interatrial 104 septum from the LA and RA were anatomically guided. After no additional 105 increase in heart rate was achieved with further ablations and target 106 anatomical area were sufficiently densely ablated the procedure was 107 terminated. Atropine test (3mg of atropine sulphate given intravenously; dose 108 calculated as 0,04mg/kg body weight, maximal dose 3mg) at the end of 109 procedure resulted in only 7% sinus rate increase (from 117 bpm to 125 bpm), 110 which according to published data2 suggests successful denervation of the 111 sinus node. The procedure duration was 200 min, fluoroscopy time was 6,8 112 min (dose-area product - DAP 560 µGym2). 113 To evaluate the impact of cardioneuroablation on bradyarrhythmia occurrence 114 an implantable loop recorder (ILR; Reveal Linq, Medtronic) was implanted. 115 The patient resumed antiepileptic drugs and was released from the hospital. AC C EP TE D M AN U 100 116 5 ACCEPTED MANUSCRIPT One month after the procedure, patient had a seizure without loss of 118 consciousness, reporting only lightheadedness and stiffness of his left arm. 119 Interrogation of ILR showed no bradyarrhythmias at the time of the seizure. 120 The patient was then readmitted for follow-up video-EEG monitoring and the 121 antiepileptic drugs were again withdrawn. Five seizures were recorded. All of 122 the recorded seizures ended with a short postictal EEG slowing over the right 123 hemisphere, followed by rapid restoration of normal background activity 124 (Figure 1, lower panel). There were no bradyarrhythmias recorded during the 125 seizures. He is still under evaluation for epilepsy surgery, but at present, his 126 seizures have a minor impact on his quality of life. During 6 months follow-up 127 period the patient reported no syncope and there were no bradyarrhythmias 128 recorded by the ILR. M AN U SC RI PT 117 129 DISCUSSION 131 Seizure-induced asystole, or ictal asystole, is caused by spread of ictal activity 132 to loci where it intervenes with central autonomic networks which can result in 133 direct vagal stimulation of the cardiac conduction system. This rare, but 134 devastating condition is a feature of focal, most commonly temporal and 135 mesial frontal lobe epilepsy involving insula, cingulate gyrus and other parts of 136 central autonomic network.3-6 It is estimated that only 0.27% of epileptic 137 patients suffer from the condition, which is hypothesized as one of many 138 potential mechanisms of sudden unexpected death in epilepsy (SUDEP).7-10 139 Several approaches are proposed to treat ictal asystole, including adjustment 140 of antiepileptic drugs, epilepsy surgery for medically refractory patients, and 141 only recently permanent pacemaker implantation.8 However, despite the AC C EP TE D 130 6 ACCEPTED MANUSCRIPT technological development of implantable electronic cardiac devices, 143 complication incidence in modern pacing therapy is still substantial. Although 144 most adverse events occur in the early postimplantation period (lead-related), 145 complications rates during long-term follow-up are not scarce, ranging from 146 7.5% to almost 10% of the patients.11,12 147 Pachon et al.13 first described cardioneuroablation in 2005 as a new treatment 148 modality for neurocardiogenic syncope, functional sinus node dysfunction and 149 functional atrioventricular block. The technique is based on radiofrequency 150 ablation of main epicardial parasympathetic ganglia in the heart. With this 151 procedure partial parasympathetic denervation of the sinus and/or AV node is 152 achieved and consequently the adverse parasympathetic influence on the 153 heart diminished. Long term follow-up2 of patients undergoing 154 cardioneuroablation procedure for cardioinhibitory neurocardiogenic syncope 155 showed very promising results, with only 3 patients out of 43 experienced 156 recurrent syncope. In addition, post procedure 24-hour Holter ECGs and 157 stress tests showed no major abnormalities except mildly elevated basal heart 158 rate. SC M AN U TE D EP AC C 159 RI PT 142 160 Although cardioneuroablation procedure considerably diminished patient’s 161 seizure presentation longer follow-up and close monitoring of the patient is 162 required to detect possible recurrence of bradyarrhythmias and worsening of 163 seizures. Consequently, pharmacoresistant epilepsy merits constant 164 evaluation for potential surgical treatment. 165 166 CONCLUSIONS 7 ACCEPTED MANUSCRIPT Cardioneuroablation might represent a new treatment modality in select 168 pharmacoresistant patients with ictal asystole. In addition, with this treatment 169 option permanent pacemaker implantation could be avoided and device- 170 related complications prevented. Further research is warranted to evaluate 171 this treatment option. RI PT 167 172 173 References SC 174 1. Lellouche N, Buch E, Celigoj A, Siegerman C, Cesario D, De Diego C, 176 Mahajan A, Boyle NG, Wiener I, Garfinkel A, Shivkumar K. Functional 177 characterization of atrial electrograms in sinus rhythm delineates sites 178 of parasympathetic innervation in patients with paroxysmal atrial 179 fibrillation. J Am Coll Cardiol. 2007;50:1324-1331. doi: 180 10.1016/j.jacc.2007.03.069 TE D 181 M AN U 175 2. Pachon JC, Pachon EI, Cunha Pachon MZ, Lobo TJ, Pachon JC, Santillana TG. Catheter ablation of severe neurally meditated reflex 183 (neurocardiogenic or vasovagal) syncope: cardioneuroablation long- 184 term results. Europace. 2011;13:1231-1242. doi: 186 187 AC C 185 EP 182 10.1093/europace/eur163 3. Schuele SU, Bermeo AC, Alexopoulos AV, Locatelli ER, Burgess RC, Dinner DS, Foldvary-Schaefer N. Video-electrographic and clinical 188 features in patients with ictal asystole. Neurology. 2007;69:434-441. 189 doi: 10.1212/01.wnl.0000266595.77885.7f 8 ACCEPTED MANUSCRIPT 190 4. Ghearing GR, Munger TM, Jaffe AS, Benarroch EE, Britton JW. 191 Clinical cues for detecting ictal asystole. Clin Auton Res. 2007;17:221- 192 226. doi: 10.1007/s10286-007-0429-9 5. Rocamora R, Kurthen M, Lickfett L, Von Oertzen J, Elger CE. Cardiac 194 asystole in epilepsy: clinical and neurophysiologic features. Epilepsia. 195 2003;44:179-185. doi: 10.1046/j.1528-1157.2003.15101.x 196 RI PT 193 6. Lanz M, Oehl B, Brandt A, Schulze-Bonhage A. Seizure induced cardiac asystole in epilepsy patients undergoing long term video-EEG 198 monitoring. Seizure. 2011;20:167-172. doi: 199 10.1016/j.seizure.2010.11.017 M AN U 200 SC 197 7. Velagapudi P, Turagam M, Laurence T, Kocheril A. Cardiac arrhythmias and sudden unexpected death in epilepsy (SUDEP). 202 Pacing Clin Electrophysiol. 2012;35:363-370. doi: 10.1111/j.1540- 203 8159.2011.03276.x 204 TE D 201 8. Wittekind SG, Lie O, Hubbard S, Viswanathan MN. Ictal asystole: an indication for pacemaker implantation and emerging cause of sudden 206 death. Pacing Clin Electrophysiol. 2012;35:e193-196. doi: 207 10.1111/j.1540-8159.2011.03179.x 209 210 AC C 208 EP 205 9. Nashef L, Hindocha N, Makoff A. Risk factors in sudden death in epilepsy (SUDEP): the quest for mechanisms. Epilepsia. 2007;48:859871. doi: 10.1111/j.1528-1167.2007.01082.x 211 10. Scorza FA, Arida RM, Cysneiros RM, Terra VC, Sonoda EY, de 212 Albuquerque M, Cavalheiro EA. The brain-heart connection: 213 implications for understanding sudden unexpected death in epilepsy. 214 Cardiol J. 2009;16:394-399. 9 ACCEPTED MANUSCRIPT 215 11. Ellenbogen KA, Hellkamp AS, Wilkoff BL, Camunãs JL, Love JC, 216 Hadjis TA, Lee KL, Lamas GA. Complications arising after implantation 217 of DDD pacemakers: the MOST experience. Am J Cardiol. 218 2003;92:740-741. doi:10.1016/S0002-9149(03)00844-0 12. Udo EO, Zuithoff NP, van Hemel NM, de Cock CC, Hendriks T, RI PT 219 Doevendans PA, Moons KG. Incidence and predictors of short- and 221 long-term complications in pacemaker therapy: the FOLLOWPACE 222 study. Heart Rhythm. 2012;9:728-735. doi: 223 10.1016/j.hrthm.2011.12.014 13. Pachon JC, Pachon EI, Pachon JC, Lobo TJ, Pachon MZ, Vargas RN, M AN U 224 SC 220 225 Jatene AD. "Cardioneuroablation"--new treatment for neurocardiogenic 226 syncope, functional AV block and sinus dysfunction using catheter RF- 227 ablation. Europace. 2005;7:1-13. doi: 10.1016/j.eupc.2004.10.003 AC C EP TE D 228 10 M AN U SC RI PT ACCEPTED MANUSCRIPT 229 230 Figure 1 232 Electroencephalography (EEG) and electrocardiography (ECG) changes 233 occurring 35 seconds after the start of the seizure before (upper panel A) and 234 after (lower panel B) cardioneuroablation procedure. A) Before the procedure, 235 single-channel ECG demonstrated sinus rhythm slowing followed by asystole 236 (23 seconds) and then slow return to normal sinus rhythm. In postictal EEG 237 with slow activity over right hemisphere, the cerebral hypoperfusion resulted 238 in generalized slow activity, followed by a 'flat' EEG (22 seconds) and then 239 generalized slow activity. B) After the procedure, single-channel ECG 240 demonstrated normal sinus rhythm. In EEG, postictal slow activity over right 241 hemisphere abruptly returned to normal background activity. AC C EP TE D 231 242 243 11 244 EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT Figure 2 246 A posterolateral view of three-dimensional constructed virtual anatomy of the 247 left and right atrium. Red dots designate radiofrequency ablation lesions on 248 the interatrial septum. Violet dots show the phrenic nerve course. 249 LA left atrium, LIPV left inferior pulmonary vein, LSPV let superior pulmonary 250 vein, RA right atrium, RIPV right inferior pulmonary vein, RSPV right superior 251 pulmonary vein, SVC superior vena cava AC C 245 12 ACCEPTED MANUSCRIPT Key teaching points • Seizure-induced (ictal) asystole is caused by direct vagal stimulation of the cardiac conduction system. It is estimated that only 0.27% of epileptic patients suffer from the condition, which is hypothesized as one of many potential • RI PT mechanisms of sudden unexpected death in epilepsy. Several approaches are proposed to treat ictal asystole, including adjustment of antiepileptic drugs, epilepsy surgery, and only recently permanent Cardioneuroablation – parasympathetic denervation of the sinus node - might M AN U represent a new treatment option in select patients with ictal asystole. In addition, with this treatment option permanent pacemaker implantation could EP TE D be avoided and device-related complications prevented. AC C • SC pacemaker implantation.