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Evidence-based Guideline Update: Vagus Nerve Stimulation for the Treatment of Epilepsy Report of the Evidence-based Guideline Update: Vagus Nerve Stimulation for the Treatment of Epilepsy Report of the Guideline Development Subcommittee of the American Academy of Neurology © 2013 American Academy of Neurology

Authors § George L. Morris III, MD, FAAN § David Gloss, MD § Jeffrey Authors § George L. Morris III, MD, FAAN § David Gloss, MD § Jeffrey Buchhalter, MD, FAAN § Kenneth J. Mack, MD, Ph. D, FAAN § Katherine Nickels, MD § Cynthia Harden, MD © 2013 American Academy of Neurology

Sharing this information § The AAN develops these presentation slides as educational tools for Sharing this information § The AAN develops these presentation slides as educational tools for neurologists and other health care practitioners. You may download and retain a single copy for your personal use. Please contact [email protected] com to learn about options for sharing this content beyond your personal use. © 2013 American Academy of Neurology

Endorsement § This guideline was endorsed by the American Epilepsy Society. © 2013 American Endorsement § This guideline was endorsed by the American Epilepsy Society. © 2013 American Academy of Neurology

Presentation Objectives § To present the evidence since 1999 regarding efficacy and safety of Presentation Objectives § To present the evidence since 1999 regarding efficacy and safety of vagus nerve stimulation (VNS) for epilepsy, currently approved as adjunctive therapy for partial-onset seizures in patients > 12 years. § To present evidence-based recommendations © 2013 American Academy of Neurology

Overview § Background § Gaps in care § American Academy of Neurology (AAN) guideline Overview § Background § Gaps in care § American Academy of Neurology (AAN) guideline § § process Analysis of evidence, conclusions, recommendations Recommendations for future research © 2013 American Academy of Neurology

Background § In 1997, the US Food and Drug Administration § (FDA) approved VNS Background § In 1997, the US Food and Drug Administration § (FDA) approved VNS as adjunctive therapy for reducing the frequency of seizures in patients > 12 years with partial-onset seizures refractory to antiepileptic medications. 1 A 1999 AAN technology assessment concluded that VNS is indicated for patients > 12 years with medically intractable partial seizures who are not candidates for potentially curative surgical resections such as lesionectomies or mesial temporal lobectomies. 2 © 2013 American Academy of Neurology

Background, cont. § The authors also recommended that patients undergo a thorough epilepsy evaluation Background, cont. § The authors also recommended that patients undergo a thorough epilepsy evaluation to rule out nonepileptic conditions or treatable symptomatic epilepsies before implantation of a vagus nerve stimulator. At that time, evidence was insufficient to recommend VNS for epilepsy in young children or for seizures associated with Lennox-Gastaut syndrome (LGS). © 2013 American Academy of Neurology

Background, cont. § Since the 1999 AAN assessment, the FDA has § approved VNS Background, cont. § Since the 1999 AAN assessment, the FDA has § approved VNS for the adjunctive long-term treatment of chronic or recurrent depression in patients > 18 years who are experiencing a major depressive episode and have not had an adequate response to 4 or more adequate antidepressant treatments. 1 There are new reports of long-term efficacy and VNS use in pediatric epilepsy and other seizure types and syndromes. We evaluated this evidence using the AAN guideline methodology. © 2013 American Academy of Neurology

Clinical Questions 1. In children with epilepsy, is using adjunctive VNS 2. 3. 4. Clinical Questions 1. In children with epilepsy, is using adjunctive VNS 2. 3. 4. therapy for seizure frequency reduction better than not using adjunctive VNS therapy for seizure frequency reduction? In patients with LGS, is using adjunctive VNS therapy for seizure frequency reduction better than not using adjunctive VNS therapy for seizure frequency reduction? In patients with epilepsy, is using VNS associated with mood improvement? In patients with epilepsy, is VNS use associated with reduced seizure frequency over time? © 2013 American Academy of Neurology

Clinical Questions, cont. 5. In patients undergoing VNS therapy, does rapid 6. 7. 8. Clinical Questions, cont. 5. In patients undergoing VNS therapy, does rapid 6. 7. 8. stimulation (usual VNS settings are 7 seconds “on” and 30 seconds “off”) improve seizure frequency more often than standard stimulation settings (30 seconds “on” and 300 seconds “off”)? In patients undergoing VNS therapy, does using additional magnet-activated stimulation trains for auras or at seizure onset interrupt seizures relative to not using additional magnet-induced stimulation trains for auras or at seizure onset? In patients undergoing VNS therapy, have new safety concerns emerged since the last assessment? In children undergoing VNS therapy, do adverse effects (AEs) differ from those in adults? © 2013 American Academy of Neurology

AAN Guideline Process § Clinical Question § Evidence § Conclusions § Recommendations © 2013 AAN Guideline Process § Clinical Question § Evidence § Conclusions § Recommendations © 2013 American Academy of Neurology

Literature Search/Review § Rigorous, Comprehensive, Transparent Search Review abstracts Review full text Relevant © Literature Search/Review § Rigorous, Comprehensive, Transparent Search Review abstracts Review full text Relevant © 2013 American Academy of Neurology Select articles

AAN Classification of Evidence § All studies meeting inclusion/exclusion criteria defined a priori rated AAN Classification of Evidence § All studies meeting inclusion/exclusion criteria defined a priori rated Class I, III, or IV § Five different classification systems • Therapeutic üRandomization, control, blinding • Diagnostic üComparison with reference standard • Prognostic • Screening • Causation © 2013 American Academy of Neurology

AAN Level of Recommendations § A = Established as effective, ineffective, or harmful § AAN Level of Recommendations § A = Established as effective, ineffective, or harmful § § § (or established as useful/predictive or not useful/predictive) for the given condition in the specified population B = Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven § Note that recommendations can be positive or negative © 2013 American Academy of Neurology

Translating Class to Recommendations § A = Requires at least two consistent Class I Translating Class to Recommendations § A = Requires at least two consistent Class I § § § studies* B = Requires at least one Class I study or two consistent Class II studies C = Requires at least one Class II study or two consistent Class III studies U = Assigned in cases of only one Class III study, only Class IV studies, or evidence that is conflicting and cannot be reconciled * In exceptional cases, one convincing Class I study may suffice for an “A” recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome > 5 and the lower limit of the confidence interval [CI] is > 2) © 2013 American Academy of Neurology

Applying the Process to the Issue § We will now turn our attention to Applying the Process to the Issue § We will now turn our attention to the guideline. © 2013 American Academy of Neurology

Methods § Literature searches of MEDLINE, EMBASE and § § Web of Science (1996 Methods § Literature searches of MEDLINE, EMBASE and § § Web of Science (1996 to February 2012) were performed using the key words “seizures, ” “epilepsy, ” “mood disorder, ” “depressive disorder, ” “vagus nerve stimulation, ” and “neurostimulation. ” Authors reviewed each article for inclusion. Risk of bias was determined using the classification of evidence scheme for therapeutic articles. Strength of recommendations was linked directly to evidence levels. Conflicts of interest were disclosed. © 2013 American Academy of Neurology

Literature Search/Review § Rigorous, Comprehensive, Transparent 1, 274 abstracts Inclusion criteria: - Articles using Literature Search/Review § Rigorous, Comprehensive, Transparent 1, 274 abstracts Inclusion criteria: - Articles using the patient as his or her own control only if the patient’s assessment of seizures (e. g. , seizure diary) was independent of the assessing physician’s. Exclusion criteria: - Reviews and Class IV reports, except for case reports of serious safety concerns. 216 articles © 2013 American Academy of Neurology

AAN Classification of Evidence for Therapeutic Studies § Class I: A randomized, controlled clinical AAN Classification of Evidence for Therapeutic Studies § Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are also required: a. b. c. d. Concealed allocation Primary outcome(s) clearly defined Exclusion/inclusion criteria clearly defined Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias. © 2013 American Academy of Neurology

AAN Classification of Evidence for Therapeutic Studies, cont. e. For noninferiority or equivalence trials AAN Classification of Evidence for Therapeutic Studies, cont. e. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*: üThe authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority. üThe standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e. g. , for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective). üThe inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment. üThe interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers. © 2013 American Academy of Neurology

AAN Classification of Evidence for Therapeutic Studies, cont. § Class II: A randomized controlled AAN Classification of Evidence for Therapeutic Studies, cont. § Class II: A randomized controlled clinical trial of the § intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement. ** © 2013 American Academy of Neurology

AAN Classification of Evidence for Therapeutic Studies, cont. § Class IV: Studies not meeting AAN Classification of Evidence for Therapeutic Studies, cont. § Class IV: Studies not meeting Class I, II, or III criteria including consensus or expert opinion. *Note that numbers 1 3 in Class I, item 5 are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III. **Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e. g. , blood tests, administrative outcome data). © 2013 American Academy of Neurology

Clinical Question 1 § In children with epilepsy, is using adjunctive VNS therapy for Clinical Question 1 § In children with epilepsy, is using adjunctive VNS therapy for seizure frequency reduction better than not using adjunctive VNS therapy for seizure frequency reduction? © 2013 American Academy of Neurology

Clinical Question 1, cont. Conclusion § Based on data from 14 Class III studies, Clinical Question 1, cont. Conclusion § Based on data from 14 Class III studies, VNS is possibly effective in achieving > 50% seizure frequency reduction (responder rate). • In the pooled analysis of 481 children, the responder rate was 55% (95% CI 51%– 59%), but there was significant heterogeneity in the data. • Two of the 16 studies 3, 4 were not included in the analysis because either they did not provide information about responder rate or they included a significant number (> 20%) of adults in their population. The pooled seizure freedom rate was 7% (95% CI 5%– 10%). © 2013 American Academy of Neurology

Clinical Question 1, cont. Recommendation § VNS may be considered as adjunctive treatment for Clinical Question 1, cont. Recommendation § VNS may be considered as adjunctive treatment for children with partial or generalized epilepsy (Level C). Clinical Context § VNS may be considered a possibly effective option after a child with medication-resistant epilepsy has been declared a poor surgical candidate or has had unsuccessful surgery. © 2013 American Academy of Neurology

Clinical Question 2 § In patients with LGS, is using adjunctive VNS therapy for Clinical Question 2 § In patients with LGS, is using adjunctive VNS therapy for seizure frequency reduction better than not using adjunctive VNS therapy for seizure frequency reduction? © 2013 American Academy of Neurology

Clinical Question 2, cont. Conclusion § Based on data from 4 Class III studies, Clinical Question 2, cont. Conclusion § Based on data from 4 Class III studies, VNS is possibly effective in achieving > 50% seizure frequency reduction in patients with LGS. • The pooled analysis of 113 patients with LGS (including data from articles with multiple seizure types where LGS data were parsed out 5 7) yielded a 55% (95% CI 46%– 64%) responder rate. Recommendation § VNS may be considered in patients with LGS (Level C). © 2013 American Academy of Neurology

Clinical Question 2, cont. Clinical Context § The responder rate for patients with LGS Clinical Question 2, cont. Clinical Context § The responder rate for patients with LGS does not appear to differ from that of the general population of patients with medication-resistant epilepsy. © 2013 American Academy of Neurology

Clinical Question 3 § In patients with epilepsy, is using VNS associated with mood Clinical Question 3 § In patients with epilepsy, is using VNS associated with mood improvement? © 2013 American Academy of Neurology

Clinical Question 3, cont. Conclusion § Based on data from 2 Class III studies, Clinical Question 3, cont. Conclusion § Based on data from 2 Class III studies, VNS is possibly effective for mood improvement in adults with epilepsy. Recommendation § In adult patients receiving VNS for epilepsy, improvement in mood may be an additional benefit (Level C). © 2013 American Academy of Neurology

Clinical Question 3, cont. Clinical Context § Depression is a common comorbidity for people Clinical Question 3, cont. Clinical Context § Depression is a common comorbidity for people with epilepsy. § VNS may provide an additional benefit by improving mood in some patients; however, the potential for mood improvement should be considered a secondary rather than a primary reason for VNS implantation. § The evidence does not clearly support an independent effect on mood in this complex population. © 2013 American Academy of Neurology

Clinical Question 4 § In patients with epilepsy, is VNS use associated with reduced Clinical Question 4 § In patients with epilepsy, is VNS use associated with reduced seizure frequency over time? © 2013 American Academy of Neurology

Clinical Question 4, cont. Conclusion §Based on data from 2 Class III studies, VNS Clinical Question 4, cont. Conclusion §Based on data from 2 Class III studies, VNS is possibly associated with an increase in ≥ 50% seizure frequency reduction rates of 7% from 1 to 5 years postimplantation. Recommendation §VNS may be considered progressively effective in patients over multiple years of exposure (Level C). © 2013 American Academy of Neurology

Clinical Question 4, cont. Clinical Context § The loss of medication efficacy over time Clinical Question 4, cont. Clinical Context § The loss of medication efficacy over time is a challenging aspect of epilepsy management. § The evidence of maintained efficacy in the long term and the trend toward improvement over time make VNS an option. © 2013 American Academy of Neurology

Clinical Question 5 § In patients undergoing VNS therapy, does rapid stimulation (usual VNS Clinical Question 5 § In patients undergoing VNS therapy, does rapid stimulation (usual VNS settings are 7 seconds “on” and 30 seconds “off”) improve seizure frequency more often than standard stimulation settings (30 seconds “on” and 300 seconds “off”)? © 2013 American Academy of Neurology

Clinical Question 5, cont. Conclusion § These 3 Class III studies were underpowered to Clinical Question 5, cont. Conclusion § These 3 Class III studies were underpowered to detect a difference in efficacy between rapid stimulation (7 seconds “on, ” 30 seconds “off”) used either after standard stimulation (30 seconds “on, ” 300 seconds “off”) was unsuccessful or as an initial treatment setting. Recommendation § Optimal VNS settings are still unknown, and the evidence is insufficient to support a recommendation for the use of standard stimulation vs rapid stimulation to reduce seizure occurrence (Level U). © 2013 American Academy of Neurology

Clinical Question 5, cont. Clinical Context § Rapid cycling increases the duty cycle and Clinical Question 5, cont. Clinical Context § Rapid cycling increases the duty cycle and hastens the need for battery replacement; therefore, when used, the efficacy of rapid cycling should be carefully assessed. © 2013 American Academy of Neurology

Clinical Question 6 § In patients undergoing VNS therapy, does using additional magnetactivated stimulation Clinical Question 6 § In patients undergoing VNS therapy, does using additional magnetactivated stimulation trains for auras or at seizure onset interrupt seizures relative to not using additional magnet-induced stimulation trains for auras or at seizure onset? © 2013 American Academy of Neurology

Clinical Question 6, cont. Conclusion § Based on data from 2 Class III studies, Clinical Question 6, cont. Conclusion § Based on data from 2 Class III studies, seizure abortion with magnet-activated stimulation is possibly associated with overall response to VNS therapy. § Based on 3 Class III studies, magnet-activated stimulation may be expected to abort seizures one-fourth to two-thirds of the time when used during seizure auras (one Class III study omitted because it was not generalizable). © 2013 American Academy of Neurology

Clinical Question 6, cont. Recommendation § Patients may be counseled that VNS magnet activation Clinical Question 6, cont. Recommendation § Patients may be counseled that VNS magnet activation may be associated with seizure abortion when used at the time of seizure auras (Level C) and that seizure abortion with magnet use may be associated with overall response to VNS treatment (Level C). © 2013 American Academy of Neurology

Clinical Question 7 § In patients undergoing VNS therapy, have new safety concerns emerged Clinical Question 7 § In patients undergoing VNS therapy, have new safety concerns emerged since the last assessment? • During the literature review, we identified several case reports regarding complications related to VNS use. 8– 27 • This information is detailed in table e-3 of the published guideline. © 2013 American Academy of Neurology

Clinical Question 7, cont. Clinical Context § Current physician attention to intraoperative rhythm disturbances Clinical Question 7, cont. Clinical Context § Current physician attention to intraoperative rhythm disturbances from VNS use need not be changed. • The paroxysmal nature of epilepsy poses a challenge for identifying a cardiac rhythm disturbance as device-related rather than as an additional seizure manifestation. § Video-EEG and ECG monitoring of new-onset events that might be cardiac-related would be warranted to exclude this possibility in what is likely to be a small number of patients. © 2013 American Academy of Neurology

Clinical Question 7, cont. Clinical Context § Reduced sudden unexpected death in epilepsy (SUDEP) Clinical Question 7, cont. Clinical Context § Reduced sudden unexpected death in epilepsy (SUDEP) rates over time is an important finding associated with VNS therapy. • In a cohort of 1, 819 individuals followed 3, 176. 3 person-years from VNS implantation, the SUDEP rate was 5. 5 per 1, 000 over the first 2 years but only 1. 7 per 1, 000 thereafter. 28 § The clinical importance of the effect of VNS on sleep apnea and treatment is unclear, but caution regarding VNS use in this setting is suggested. © 2013 American Academy of Neurology

Clinical Question 8 § In children undergoing VNS therapy, do adverse effects (AEs) differ Clinical Question 8 § In children undergoing VNS therapy, do adverse effects (AEs) differ from those in adults? • Only Class IV evidence was available for analysis with regard to this question. © 2013 American Academy of Neurology

Clinical Question 8, cont. Clinical Context § Children may have greater risk for wound Clinical Question 8, cont. Clinical Context § Children may have greater risk for wound infection than adults due to behaviors more common in children. § Extra vigilance in monitoring for occurrence of site infection in children should be undertaken. © 2013 American Academy of Neurology

Future Research Recommendations § More information is needed on the treatment of primary generalized Future Research Recommendations § More information is needed on the treatment of primary generalized epilepsy in adults. • Only one Class II article 29 addresses this population. § The effectiveness of VNS should be studied in epilepsies other than those discussed here, such as primary generalized syndromes. • Some reports have discussed VNS use in small numbers of patients with juvenile myoclonic epilepsy (JME). • Larger reports would help substantiate whether VNS is appropriate in medically refractory JME. © 2013 American Academy of Neurology

Future Research Recommendations, cont. § More information about parameter settings (e. g. , § Future Research Recommendations, cont. § More information about parameter settings (e. g. , § § cycle time length) would potentially help with better VNS management and use. Techniques to reduce infection risk at the VNS site in children should be developed. Further information is needed on the effects of VNS on sleep apnea. © 2013 American Academy of Neurology

References 1. Cyberonics, Inc. VNS Therapy products manuals and safety alerts. Part I - References 1. Cyberonics, Inc. VNS Therapy products manuals and safety alerts. Part I - Introduction - Indications, 2. 3. 4. 5. 6. 7. 8. 9. 10. Warnings, and Precautions. pdf, p. 7– 13. Available at: http: //dynamic. cyberonics. com/manuals/. Accessed October 1, 2012. Fisher RS, Handforth A. Reassessment: vagus nerve stimulation for epilepsy: a report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology 1999; 53: 666– 669. Colicchio G, Policicchio D, Barbati G, et al. Vagal nerve stimulation for drug-resistant epilepsies in different age, aetiology and duration. Childs Nerv Syst 2010; 26: 811– 819. Wheeler M, De Herdt V, Vonck K, et al. Efficacy of vagus nerve stimulation for refractory epilepsy among patient subgroups: a re-analysis using the Engel classification. Seizure 2011; 20: 331– 335. Kang HC, Hwang YS, Kim DS, Kim HD. Vagus nerve stimulation in pediatric intractable epilepsy: a Korean bicentric study. Acta Neurochir Suppl 2006; 99: 93– 96. Shahwan A, Bailey C, Maxiner W, Harvey AS. Vagus nerve stimulation for refractory epilepsy in children: more to VNS than seizure frequency reduction. Epilepsia 2009; 50: 1220– 1228. Zamponi N, Passamonti C, Cesaroni E, Trignani R, Rychlicki F. Effectiveness of vagal nerve stimulation (VNS) in patients with drop-attacks and different epileptic syndromes. Seizure 2011; 20: 468– 474. Amark P, Stödberg T, Wallstedt L. Late onset bradyarrhythmia during vagus nerve stimulation. Epilepsia 2007; 48: 1023– 1024. Iriarte J, Urrestarazu E, Alegre M, et al. Late-onset periodic asystolia during vagus nerve stimulation. Epilepsia 2009; 50: 928– 932. Borusiak P, Zilbauer M, Cagnoli S, Heldmann M, Jenke A. Late-onset cardiac arrhythmia associated with vagus nerve stimulation. J Neurol 2009; 256: 1578– 1580. © 2013 American Academy of Neurology

References, cont. 11. 12. 13. 14. 15. 16. 17. 18. 19. Ali II, Pirzada References, cont. 11. 12. 13. 14. 15. 16. 17. 18. 19. Ali II, Pirzada NA, Kanjwal Y, et al. Complete heart block with ventricular asystole during left vagus nerve stimulation for epilepsy. Epilepsy Behav 2004; 5: 768– 771. Asconapé JJ, Moore DD, Zipes DP, Hartman LM, Duffell WH Jr. Bradycardia and asystole with the use of vagus nerve stimulation for the treatment of epilepsy: a rare complication of intraoperative device testing. Epilepsia 1999; 40: 1452– 1454. Schuurman PR, Beukers RJ. Ventricular asystole during vagal nerve stimulation. Epilepsia 2009; 50: 967 – 968. Tatum WO 4 th, Moore DB, Stecker MM, et al. Ventricular asystole during vagus nerve stimulation for epilepsy in humans. Neurology 1999; 52: 1267– 1269. Ardesch JJ, Buschman HP, van der Burgh PH, Wagener-Schimmel LJ, van der Aa HE, Hageman G. Cardiac responses of vagus nerve stimulation: intraoperative bradycardia and subsequent chronic stimulation. Clin Neurol Neurosurg 2007; 109: 849– 852. Sheck L, Meyer HD. Episodic monocular vision loss after implantation of a vagal nerve stimulator. Ann Intern Med 2011; 155: 648– 649. Cukiert A, Mariani PP, Burattini JA, et al. Parkinsonism induced by VNS in a child with double-cortex syndrome. Epilepsia 2009; 50: 2667– 2669. St Louis EK, Faber K. Reversible sleep-related stridor during vagus nerve stimulation. Epileptic Disord 2010; 12: 76– 80. Hajnšek S, Šulentić V, Samaržija M, et al. Bronchoconstriction induced by vagus nerve stimulation for the management of pharmacoresistant epilepsy in a patient with bronchial asthma: case report. Neurologia Croatica 2010; 59: 89– 93. © 2013 American Academy of Neurology

References, cont. 20. El Tahry R, De Herdt V, Raedt R, et al. Evolution References, cont. 20. El Tahry R, De Herdt V, Raedt R, et al. Evolution in VNS therapy for refractory epilepsy, experience with 21. 22. 23. 24. 25. 26. 27. 1. 20. Demipulse devices at Ghent University Hospital. Seizure 2010; 19: 531– 535. Gerson R, Murray E, Price B, Frankel M, Douglass LM, Cunningham M. Mania following vagus nerve stimulation: a case report and review of the literature. Epilepsy Behav 2011; 20: 138– 140. Murr NI, Azar NJ. Severe new seizures after initiation of vagus nerve stimulation therapy. Epilepsy Behav 2011; 22: 398– 400. Spitz MC, Winston KR, Maa EH, Ojemann SG. Insulation discontinuity in a vagus nerve stimulator lead: a treatable cause of intolerable stimulation-related symptoms. J Neurosurg 2010; 112: 829– 831. Marzec M, Edwards J, Sagher O, Fromes G, Malow BA. Effects of vagus nerve stimulation on sleeprelated breathing in epilepsy patients. Epilepsia 2003; 44: 930– 935. Ebben MR, Sethi NK, Conte M, Pollak CP, Labar D. Vagus nerve stimulation, sleep apnea, and CPAP titration. J Clin Sleep Med 2008; 4: 471– 473. Amar AP, De. Giorgio CM, Tarver WB, Apuzzo ML. Long-term multicenter experience with vagus nerve stimulation for intractable partial seizures: results of the XE 5 trial. Stereotact Funct Neurosurg 1999; 73: 104– 108. Kawai K, Shimuzu H, Maehara T, Murakami H. Outcome of long-term vagus nerve stimulation for intractable epilepsy. Neurol Med Chir (Tokyo) 2002; 42: 481– 490. Annegers JF, Coan SP, Hauser WA, Leestma J. Epilepsy, vagal nerve stimulation by the NCP system, allcause mortality, and sudden, unexpected, unexplained death. Epilepsia 2000; 41: 549– 553. Holmes MD, Silbergeld DL, Drouhard D, Wilensky AJ, Ojemann LM. Effect of vagus nerve stimulation on adults with pharmacoresistant generalized epilepsy syndromes. Seizure 2004; 13: 340– 345 © 2013 American Academy of Neurology

References, cont. For a complete list of references, please access the full guideline at References, cont. For a complete list of references, please access the full guideline at www. aan. com/guidelines. © 2013 American Academy of Neurology

Question-and-Answer Period § Questions/comments? © 2013 American Academy of Neurology Question-and-Answer Period § Questions/comments? © 2013 American Academy of Neurology

Closing § To access the complete guideline and related guideline summary tools, visit www. Closing § To access the complete guideline and related guideline summary tools, visit www. aan. com/guidelines. § Thank you for your participation! © 2013 American Academy of Neurology