Vagus nerve stimulation and late-onset bradycardia and asystole: Case report

Abstract

•This is a case of syncope after more than one year of VNS generator replacement.•Bradycardia and asystole are likely related to VNS, but the mechanism is obscured.•Clinicians must be vigilant for rare, late-onset bradyarrhythmia with VNS use. Vagus nerve stimulation (VNS) therapy is approved in the United States by the FDA in 1997 for medically refractory partial epilepsy in patients of ages 12 years and above. The most common stimulation-associated side effects are voice alteration, hoarseness, throat and neck pain, headache, cough, and dyspnea. Four patients with VNS had late-onset bradycardia and asystole, attributed to VNS stimulation. Their ages were 13, 17, 47, and 55. Cardiac symptoms were noted after 2.33–9 years post-implantation [1Åmark P. Stödberg T. Wallstedt L. Late onset bradyarrhythmia during vagus nerve stimulation.Epilepsia. 2007; 48: 1023-1025Crossref PubMed Scopus (56) Google Scholar, 2Iriarte J. Urrestarazu E. Alegre M. Macías A. Gómez A. Amaro P. et al.Late-onset periodic asystolia during vagus nerve stimulation.Epilepsia. 2009; 50: 928-932Crossref PubMed Scopus (49) Google Scholar, 3Borusiak P. Zilbauer M. Cagnoli S. Heldmann M. Jenke A. Late-onset cardiac arrhythmia associated with vagus nerve stimulation.J Neurol. 2009; 256: 1578-1580Crossref PubMed Scopus (17) Google Scholar, 4Shankar R. Olotu V.O. Cole N. Sullivan H. Jory C. Case report: vagal nerve stimulation and late onset asystole.Seizure. 2013; 22: 312-314Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. Three cases had symptoms correlated with stimulation, monitored by electrocardiogram [1Åmark P. Stödberg T. Wallstedt L. Late onset bradyarrhythmia during vagus nerve stimulation.Epilepsia. 2007; 48: 1023-1025Crossref PubMed Scopus (56) Google Scholar, 2Iriarte J. Urrestarazu E. Alegre M. Macías A. Gómez A. Amaro P. et al.Late-onset periodic asystolia during vagus nerve stimulation.Epilepsia. 2009; 50: 928-932Crossref PubMed Scopus (49) Google Scholar, 4Shankar R. Olotu V.O. Cole N. Sullivan H. Jory C. Case report: vagal nerve stimulation and late onset asystole.Seizure. 2013; 22: 312-314Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. This new case report highlights cardiac syncope with very similar clinical presentation as previous four cases, and raises the concern for cardiac symptoms, even many years after VNS implantation. A 56-year-old man with medically refractory partial epilepsy and anxiety, started having partial seizures, associated with staring, lips turning blue, and hands wringing, at age nine. He started having partial seizures, associated with staring, lips turning blue, and hands wringing, at age nine. He started having several secondary convulsions at age 16. After failing numerous anti-epileptic drugs (AEDs) and ruling out epilepsy surgery therapy, VNS was implanted at age 42. It had completely eliminated seizures with secondary convulsion, and significantly decreased the frequency of his partial seizures, with average of one per month. He underwent pulse generator replacement with VNS model 104 at age 54. Routine intraoperative lead testing result is unknown. After 1 year and 11 months post-implantation, he experienced recurrent syncope, associated with lightheadedness, difficulty breathing, and complete loss of consciousness, lasting up to 10 s. He had no postictal confusion. His stimulation parameters (21 s on-time, 3.2 min off-time, 2.75 mA output current, 25 Hz signal frequency, and 500 μ s pulse width) were unchanged for five months prior to syncope. He was on levetiracetam 4000 mg/day and topiramate 600 mg/day, with the last change in dose more than one year prior to syncope. He had been on both AEDs for more than 10 years. He was on stable dose of anxiolytic alprazolam 1 mg/day for one year. His seizure frequency was unchanged for many years. Immediately before hospitalization, his sister, who was a registered nurse, had observed heart rate in the 40 s during his syncope, occurring every 3–4 min. Similar observation of bradycardia on cardiac rhythm strip was seen, with VNS stimulation felt by the patient. He had sinus bradycardia, with heart rate of low 30 s, which instantaneously resolved when the VNS was deactivated. When diagnostic testing was attempted, he had immediate syncope after VNS was reactivated, associated with sinus bradycardia and eight-second asystole. Thus, VNS was again deactivated, without any further bradycardia or syncope. His comprehensive metabolic panel was normal. X-ray ruled out lead breakage. Cardiologist had recommended placement of temporary transvenous pacemaker backup when testing the integrity of the VNS and its effect on cardiac conduction system and blood pressure, but the patient and his family chose to leave the VNS deactivated. One month after VNS deactivation, a 48-h Holter monitor showed normal heart rate and rhythm. A transthoracic echocardiogram at four months was normal. There was a great concern for worsening of his convulsion, but after six months, his seizure frequency had remained stable, without any convulsion. This case raises the concern for late-onset bradyarrhythmia after VNS implantation. Though rarely observed in patients with VNS, it is a serious and potentially fatal complication. In our case, the observed syncope and bradycardia coincided with VNS activation, every 3–4 min versus 3.2 min, respectively. Bradyarrhythmia and syncope instantly reappeared when the VNS was reactivated, and never recurred when the device was again deactivated. Cardiac and metabolic causes were ruled out. Our patient had no prior history of cardiac problems. The role of VNS is obscured, however. As pointed out in a preceding case, VNS is not expected to cause efferent stimulation of the vagus nerve cardiac fibers, hence bradycardia and asystole are unusual adverse effect [[1]Åmark P. Stödberg T. Wallstedt L. Late onset bradyarrhythmia during vagus nerve stimulation.Epilepsia. 2007; 48: 1023-1025Crossref PubMed Scopus (56) Google Scholar]. Previous cases had raised possible contribution of newly added levetiracetam for status epilepticus [[2]Iriarte J. Urrestarazu E. Alegre M. Macías A. Gómez A. Amaro P. et al.Late-onset periodic asystolia during vagus nerve stimulation.Epilepsia. 2009; 50: 928-932Crossref PubMed Scopus (49) Google Scholar], and worsening seizure and changes in AED [[3]Borusiak P. Zilbauer M. Cagnoli S. Heldmann M. Jenke A. Late-onset cardiac arrhythmia associated with vagus nerve stimulation.J Neurol. 2009; 256: 1578-1580Crossref PubMed Scopus (17) Google Scholar]. In our case, VNS parameters, seizure frequency, and AED regimen were unchanged for relatively long period of time. Also, X-ray had ruled out lead breakage. Unfortunately, a limitation of this report is the absence of device diagnostics, to ensure device proper functioning. The bradyarrythmia was most likely related to VNS, but the ultimate cause remains unclear. Anatomic variation of vagus nerve innervation of the heart could not be ruled out. However, this would be a more likely explanation if symptom onset was seen earlier, during or closely after initial device placement or generator replacement. Alternatively, a change in either the sensitivity of cardiac mechanoreceptors or the function of nucleus tractus soltarius in the medulla might have occurred, due to chronic vagus nerve stimulation by the device. On the other hand, underlying new conduction system disease seems less plausible, but could not be ruled out. Lastly, it is uncertain to why this case's seizure control did not change after VNS deactivation. It can only be hypothesized that the continuing control may be related to a change of vagus nerve function due to chronic nerve stimulation, any prior AED changes made after initial VNS placement, or the natural history of his epilepsy. In conclusion, clinicians should be vigilant for rare bradycardia and asystole in patients with VNS, even years after device implantation. Dr. Pascual has served as the principal investigator for two clinical drug trials, sponsored by Eisai, Inc. and Upsher-Smith Laboratories, Inc.