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Chapter 20 - Stimulation Treatment for Medication-Resistant Epilepsy

Published online by Cambridge University Press:  20 August 2020

Edited by
John M. Stern ,
Raman Sankar  and
Michael Sperling
John M. Stern
Affiliation:
Geffen School of Medicine at UCLA, Los Angeles, CA
Raman Sankar
Affiliation:
Geffen School of Medicine at UCLA, Los Angeles, CA
Michael Sperling
Affiliation:
Jefferson Hospital for Neurosciences, Philadelphia, PA
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Summary

The vagus nerve performs many different functions in the human body. Understanding these functions helps inform the potential side effects of vagus nerve stimulation (VNS). The nerve consists of 80% afferent fibres [1,2]. These include visceral sensory and taste fibres which travel primarily to the nucleus of the tractus solitarius, as well as cutaneous sensation fibres from the external auditory meatus which project to the spinal nucleus of the trigeminal nerve. The efferent component includes branchial motor fibres from the nucleus ambiguus, parasympathetic fibres primarily from the dorsal nucleus of the vagus and parasympathetic fibres from the nucleus ambiguus to the heart. The motor fibres innervate skeletal muscles in the head and neck involved in speech production and swallowing, while the parasympathetic fibres innervate most of the viscera serving to control heart rate, respiration, gastrointestinal motility and many other autonomic functions. The majority of fibres in the vagus nerve consist of unmyelinated C fibres, but commensurate with its wide variety of functions, it also contains larger and faster-conducting A- and B-type fibres. The brainstem nuclei that receive vagal inputs integrate homeostatic information, provide commensurate adjustments to autonomic functions and also send this information to other brainstem nuclei projecting widely throughout the brain.

Type
Chapter
Information
Medication-Resistant Epilepsy
Diagnosis and Treatment
 , pp. 219 - 240
Publisher: Cambridge University Press
Print publication year: 2020

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References

References

Krahl, SE. Vagus nerve stimulation for epilepsy : a review of the peripheral mechanisms. Surg Neurol Int 2012;3:47–52CrossRefGoogle ScholarPubMed
Yuan, H, Silberstein, SD. Vagus Nerve and vagus nerve stimulation, a comprehensive review. Headache 2016; 56(1):71–78CrossRefGoogle ScholarPubMed
Krahl, SE, Senanayake, SS, Handforth, A. Destruction of peripheral c-fibers does not alter subsequent vagus nerve stimulation-induced seizure suppression in rats. Epilepsia 2001;42(5):586–589CrossRefGoogle Scholar
Krahl, SE, Clark, KB. Vagus nerve stimulation for epilepsy: a review of central mechanisms. Surg Neurol Int 2012;3(Suppl 4):S255-S259Google Scholar
Krahl, SE, Clark, KB, Smith, DC, Browning, RA. Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia 1998;39(7):709–714Google Scholar
Kuba, R, Guzaninova, M, Brazdil, M, et al. Effect of chronic vagal nerve stimulation on interictal epileptiform discharges. Epilepsia 2002;43(10):1181–1188Google Scholar
Panebianco, M, Rigby, A, Weston, J, Marson, AG. Vagus nerve stimulation for partial seizures. Cochrane Database Syst Rev 2015;(4)CD002896Google Scholar
Cyberonics VNS Therapy® System Physician’s Manual, 2015.Google Scholar
Morris, GL, Mueller, WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy: the Vagus Nerve Stimulation Study Group E01–E05. Neurology 1999;53(8):1731–1735CrossRefGoogle Scholar
Kuba, R, Brázdil, M, Kalina, M, et al. Vagus nerve stimulation: longitudinal follow-up of patients treated for 5 years. Seizure 2009;18(4):269–274CrossRefGoogle ScholarPubMed
Elliott, RE, Morsi, A, Kalhorn, SP, et al. Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: long-term outcomes and predictors of response. Epilepsy Behav 2011;20(1):57–63CrossRefGoogle ScholarPubMed
Morris, GL, Gloss, D, Buchhalter, J, et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy. Report of the guideline development subcommittee of the American Academy of Neurology. Neurology 2013;81(16):1453–1459CrossRefGoogle Scholar
Ng, M, Devinsky, O. Vagus nerve stimulation for refractory idiopathic generalised epilepsy. Seizure 2004;13(3):176–178Google Scholar
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(5):340–345Google Scholar
Morris, GL, Gloss, D, Buchhalter, J, et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy. Report of the guideline development subcommittee of the American Academy of Neurology. Epilepsy Curr 2013;13(6):297–303CrossRefGoogle Scholar
Heck, C, Helmers, SL, DeGiorgio, CM. Vagus nerve stimulation therapy, epilepsy, and device parameters: scientific basis and recommendations for use. Neurology 2002;59(6 Suppl 4):S31–S37Google Scholar
Degiorgio, CM, Thompson, J, Lewis, P, et al. Vagus nerve stimulation: analysis of device parameters in 154 patients during the long-term XE5 study. Epilepsia 2001;42(8):1017–1020CrossRefGoogle ScholarPubMed
DeGiorgio, C, Heck, C, Bunch, S, et al. Vagus nerve stimulation for epilepsy: randomized comparison of three stimulation paradigms. Neurology 2005;65(2 Suppl 1):317–319Google Scholar
Scherrmann, J, Hoppe, C, Kral, T, Schramm, J, Elger, CE. Vagus nerve stimulation clinical experience in a large patient series. J Clin Neurophysiol 2001;18(5):408–414Google Scholar
Labar, D. Vagus nerve stimulation for 1 year in 269 patients on unchanged antiepileptic drugs. Seizure 2004:392–398Google Scholar
Fanselow, EE, Reid, AP, Nicolelis, MA. Reduction of pentylenetetrazole-induced seizure activity in awake rats by seizure-triggered trigeminal nerve stimulation. J Neurosci 2000;20(21):8160–8168Google Scholar
DeGiorgio, CM, Soss, J, Cook, IA, et al. Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy. Neurology 2013;80(9):786–791Google Scholar
Soss, J, Heck, C, Murray, D, et al. A prospective long-term study of external trigeminal nerve stimulation for drug-resistant epilepsy. Epilepsy Behav 2015;42:44–47Google Scholar

References

Kwan, P, Schachter, SC, Brodie, MJ. Drug-resistant epilepsy. N Engl J Med 2011;365(10):919–926Google Scholar
Wiebe, S. Epilepsy: outcome patterns in epilepsy surgery – the long-term view. Nat Rev Neurol 2012;8(3):123–124Google Scholar
Englot, DJ, Chang, EF. Rates and predictors of seizure freedom in resective epilepsy surgery: an update. Neurosurg Rev 2014;37(3):389–405Google Scholar
Bergey, GK. Neurostimulation in the treatment of epilepsy. Exp Neurol 2013;244:87–95Google Scholar
Duncan, JS. Selecting patients for epilepsy surgery: synthesis of data. Epilepsy Behav 2011;20(2):230–232Google Scholar
Sironi, VA. Origin and evolution of deep brain stimulation. Front Integr Neurosci 2011;5:42CrossRefGoogle ScholarPubMed
Fisher, R, Salanova, V, Witt, T, et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 2010;51(5):899–908Google Scholar
Salanova, V, Witt, T, Worth, R, et al. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology 2015;84(10):1017–1025CrossRefGoogle ScholarPubMed
Morel, A, Magnin, M, Jeanmonod, D. Multiarchitectonic and stereotactic atlas of the human thalamus. J Comp Neurol 1997;387(4):588–630Google Scholar
Jankowski, MM, Ronnqvist, KC, Tsanov, M, et al. The anterior thalamus provides a subcortical circuit supporting memory and spatial navigation. Front Syst Neurosci 2013;7:45Google Scholar
Vertes, RP, Albo, Z, Di Prisco, GV. Theta-rhythmically firing neurons in the anterior thalamus: implications for mnemonic functions of Papez’s circuit. Neuroscience 2001;104(3):619–625Google Scholar
Child, ND, Benarroch, EE. Anterior nucleus of the thalamus: functional organization and clinical implications. Neurology 2013;81(21):1869–1876Google Scholar
Kusske, JA, Ojemann, GA, Ward, AA. Effects of lesions in ventral anterior thalamus on experimental focal epilepsy. Exp Neurol 1972;34(2):279–90Google Scholar
Mirski, MA, Ferrendelli, JA. Interruption of the mammillothalamic tract prevents seizures in guinea pigs. Science 1984;226(4670):72–74Google Scholar
Mirski, MA, Ferrendelli, JA. Anterior thalamic mediation of generalized pentylenetetrazol seizures. Brain Res 1986;399(2):212–223Google Scholar
Mirski, MA, Ferrendelli, JA. Interruption of the connections of the mammillary bodies protects against generalized pentylenetetrazol seizures in guinea pigs. J Neurosci 1987;7(3):662–670Google Scholar
Mirski, MA, Rossell, LA, Terry, JB, Fisher, RS. Anticonvulsant effect of anterior thalamic high frequency electrical stimulation in the rat. Epilepsy Research 1997;28(2):89–100CrossRefGoogle ScholarPubMed
Mirski, MA, Ferrendelli, JA. Anterior thalamic mediation of generalized pentylenetetrazol seizures. Brain Res 1986;399(2):212–223CrossRefGoogle ScholarPubMed
Hamani, C, Ewerton, FIS, Bonilha, SM, et al. Bilateral anterior thalamic nucleus lesions and high-frequency stimulation are protective against pilocarpine-induced seizures and status epilepticus. Neurosurgery 2003;54(1):191–195Google Scholar
Covolan, L, de Almeida, AC, Amorim, B, et al. Effects of anterior thalamic nucleus deep brain stimulation in chronic epileptic rats. PLoS ONE 2014;9(6):e97618Google Scholar
Jou, SB, Kao, IF, Yi, PL, Chang, FC. Electrical stimulation of left anterior thalamic nucleus with high-frequency and low-intensity currents reduces the rate of pilocarpine-induced epilepsy in rats. Seizure 2013;22(3):221–229CrossRefGoogle ScholarPubMed
Zhang, Q, Wu, ZC, Yu, JT, et al. Mode-dependent effect of high-frequency electrical stimulation of the anterior thalamic nucleus on amygdala-kindled seizures in rats. Neuroscience 2012;217:113–122CrossRefGoogle ScholarPubMed
Zhang, Q, Wu, ZC, Yu, JT, et al. Anticonvulsant effect of unilateral anterior thalamic high frequency electrical stimulation on amygdala-kindled seizures in rats. Brain Res Bull 2012;87(2–3):221–226Google Scholar
Upton, AR, Cooper, IS, Springman, M, Amin, I. Suppression of seizures and psychosis of limbic system origin by chronic stimulation of anterior nucleus of the thalamus. Int J Neurol 1985–1986;19–20:223–230Google ScholarPubMed
Cooper, IS, Upton, AR. Therapeutic implications of modulation of metabolism and functional activity of cerebral cortex by chronic stimulation of cerebellum and thalamus. Biol Psychiatry 1985;20(7):811–813CrossRefGoogle ScholarPubMed
Elliott, RE, Rodgers, SD, Bassani, L, et al. Vagus nerve stimulation for children with treatment-resistant epilepsy: a consecutive series of 141 cases. J Neurosurg Pediatr 2011;7(5):491–500Google Scholar
Bergey, GK, Morrell, MJ, Mizrahi, EM, et al. Long-term treatment with responsive brain stimulation in adults with refractory partial seizures. Neurology 2015;84(8):810–817Google Scholar
Sprengers, M, Vonck, K, Carrette, E, Marson, AG, Boon, P. Deep Brain and Cortical Stimulation for Epilepsy, Boon, P, (ed.) Chichester, UK: John Wiley & Sons, Ltd; 1996.Google Scholar
Park, EH, Barreto, E, Gluckman, BJ, Schiff, SJ, So, P. A model of the effects of applied electric fields on neuronal synchronization. J Comput Neurosci 2005;19(1):53–70Google Scholar
Bikson, M, Lian, J, Hahn, PJ, et al. Suppression of epileptiform activity by high frequency sinusoidal fields in rat hippocampal slices. J Physiol 2004;531(1):181–191Google Scholar
Koubeissi, MZ. Between the pulse generator and the anterior thalamic nucleus: the light at the end of the tunnel. Epilepsy Curr 2015;15(4):183–184Google Scholar
Upton, AR, Amin, I, Garnett, S, et al. Evoked metabolic responses in the limbic-striate system produced by stimulation of anterior thalamic nucleus in man. Pacing Clin Electrophysiol 1987;10(1 Pt 2):217–225Google Scholar
Andrade, DM, Zumsteg, D, Hamani, C, et al. Long-term follow-up of patients with thalamic deep brain stimulation for epilepsy. Neurology 2006;66(10):1571–1573CrossRefGoogle ScholarPubMed
Kerrigan, JF, Litt, B, Fisher, RS, et al. Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy. Epilepsia 2004;45(4):346–354CrossRefGoogle ScholarPubMed
Sussman, NM GHJR, Goldman, HW SNJR. Anterior thalamus stimulation in medically intractable epilepsy, part II: preliminary clinical results. Epilepsia 1988;29:677Google Scholar
Hodaie, M, Wennberg, RA, Dostrovsky, JO, Lozano, AM. Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia 2002;43(6):603–608Google Scholar
Osorio, I, Overman, J, Giftakis, J, Wilkinson, SB. High frequency thalamic stimulation for inoperable mesial temporal epilepsy. Epilepsia 2007;48(8):1561–1571Google Scholar
Lim, SN, Lee, ST, Tsai, YT, et al. Electrical stimulation of the anterior nucleus of the thalamus for intractable epilepsy: a long-term follow-up study. Epilepsia 2007;48(2):342–347Google Scholar

References

Velasco, AL, Velasco, M, Velasco, F et al. Subacute and chronic electrical stimulation of the hippocampus on intractable temporal lobe seizures: preliminary report. Arch Med Res 2000;31:316–328Google Scholar
Peters, TE, Bhavaraju, NC, Frei, MG, et al. Network system for automated seizure detection and contingent delivery of therapy. J Clin Neurophysiol 2001;18:545–549Google Scholar
RNS System in Epilepsy Study Group, Morrell, MJ. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 2011;77:1295–1304CrossRefGoogle ScholarPubMed
Bergey, GK, Morrell, MJ, Mizrahi, EM, et al. Long-term treatment with responsive brain stimulation in adults with refractory partial seizures. Neurology 2015;84:810–817Google Scholar
Penfield, W, Jasper, H. Epilepsy and the Functional Anatomy of the Human Brain. Boston, MA: Little, Brown and Company, 1954:239.Google Scholar
Lesser, RP, Kim, SH, Beyderman, L et al. Brief bursts of pulse stimulation terminate afterdischarges caused by cortical stimulation. Neurology 1999;53:2073–2081CrossRefGoogle ScholarPubMed
Motamedi, GK, Lesser, RP, Miglioretti, DL, et al. Optimizing parameters for terminating cortical afterdischarges with pulse stimulation. Epilepsia 2002;43:836–846Google Scholar
Harding, GW. An automated seizure monitoring system for patients with indwelling recording electrodes. Electroencephalogr Clin Neurophysiol 1993;86:428–437CrossRefGoogle ScholarPubMed
Kossoff, EH, Ritzl, EK, Politsky, JM, et al. Effect of an external responsive neurostimulator on seizures and electrographic discharges during subdural electrode monitoring. Epilepsia 2004;45:1560–1567Google Scholar
Fisher, R, Salanova, V, Witt, T, et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 2010;51:899–908Google Scholar
Meador, KJ, Kapur, R, Loring, DW, et al. Quality of life and mood in patients with medically intractable epilepsy treated with targeted responsive neurostimulation. Epilepsy Behav 2015;45:242–247Google Scholar
Loring, DW, Kapur, R, Meador, KJ, et al. Differential neuropsychological outcomes following targeted responsive neurostimulation for partial-onset epilepsy. Epilepsia 2015;56:1836–1844Google Scholar
Cook, MJ, Karoly, PJ, Freestone, DR, et al. Human focal seizures are characterized by populations of fixed duration and interval. Epilepsia 2016;57(3):359–368Google Scholar
Davis, KA, Ung, H, Wulsin, D, et al. Mining continuous intracranial EEG in focal canine epilepsy: relating interictal bursts to seizure onsets. Epilepsia 2016;57:89–98CrossRefGoogle ScholarPubMed
Fisher, RS, Blum, DE, DiVentura, B, et al. Seizure diaries for clinical research and practice: limitations and future prospects. Epilepsy Behav 2012;24:304–310Google Scholar
Quigg, M, Sun, F, Fountain, NB, et al. Interrater reliability in interpretation of electrocorticographic seizure detections of the responsive neurostimulator. Epilepsia 2015;56:968–971Google Scholar
Durazzo, TS, Spencer, SS, Duckrow, RB, et al. Temporal distributions of seizure occurrence from various epileptogenic regions. Neurology 2008;70:1265–1271CrossRefGoogle ScholarPubMed
Anderson, CT, Tcheng, TK, Sun, FT, et al. Day-night patterns of epileptiform activity in 65 patients with long-term ambulatory electrocorticography. J Clin Neurophysiol 2015;32:406–412CrossRefGoogle ScholarPubMed
Engel, J, Jr, Wiebe, S, French, J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Report of the Quality Standards Subcommittee of the American Academy of Neurology, in association with the American Epilepsy Society and the American Association of Neurological Surgeons. Neurology 2003;60:538–547Google Scholar
Struck, AF, Cole, AJ, Cash, SS, et al. The number of seizures needed in the EMU. Epilepsia 2015;56:1753–1759CrossRefGoogle ScholarPubMed
King-Stephens, D, Mirro, E, Weber, PB, et al. Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography. Epilepsia 2015;56:959–967CrossRefGoogle ScholarPubMed
DiLorenzo, DJ, Mangubat, EZ, Rossi, MA, et al. Chronic unlimited recording electrocorticography-guided resective epilepsy surgery: technology-enabled enhanced fidelity in seizure focus localization with improved surgical efficacy. J Neurosurg 2014;120:1402–1414Google Scholar
Lozano, AM, Lipsman, N. Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron 2013;77:406–424Google Scholar
Hess, CW, Vaillancourt, DE, Okun, MS. The temporal pattern of stimulation may be important to the mechanism of deep brain stimulation. Exp Neurol 2013; 247:296–302Google Scholar
Jensen, AL, Durand, DM. High frequency stimulation can block axonal conduction. Exp Neurol 2009;220:57–70Google Scholar
McIntyre, CC, Hahn, PJ. Network perspectives on the mechanisms of deep brain stimulation. Neurobiol Dis 2010;38:329–337Google Scholar

References

Lefaucheur, JP, André-Obadia, N, Antal, A, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophys 2014;125:2150–206. Google Scholar
Tergau, F, Naumann, U, Paulus, W, Steinhoff, BJ. Low-frequency repetitive transcranial magnetic stimulation improves intractable epilepsy. Lancet 1999;353:2209.Google Scholar
Hsu, WY, Cheng, CH, Lin, MW, et al. Antiepileptic effects of low frequency repetitive transcranial magnetic stimulation: a meta-analysis. Epilepsy Res 2011;96:231–40.Google Scholar
Theodore, WH, Hunter, K, Chen, R, et al. Transcranial magnetic stimulation for the treatment of seizures: a controlled study. Neurology 2002;59:560–2.Google Scholar
Cantello, R, Rossi, S, Varrasi, C, et al. Slow repetitive TMS for drug-resistant epilepsy: clinical and EEG findings of a placebo-controlled trial. Epilepsia 2007;48:366–74.Google Scholar
Fregni, F, Otachi, PT, Do Valle, A, et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in patients with refractory epilepsy. Ann Neurol 2006;60:447–55.Google Scholar
Sun, W, Mao, W, Meng, X, et al. Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: a controlled clinical study. Epilepsia 2012;53:1782-9.Google Scholar
Tergau, F, Neumann, D, Rosenow, F, et al. Can epilepsies be improved by repetitive transcranial magnetic sitmulation?--interim analysis of a controlled study. Suppl Clin Neurophysiol 2003;56:400–5.Google Scholar
Joo, EY, Han, SJ, Chung, SH, et al. Antiepileptic effects of low-frequency repetitive transcranial magnetic stimulation by different stimulation durations and locations. Clin Neurophysiol 2007;118:702–8.Google Scholar
Bae, EH, Theodore, WH, Fregni, F, et al. An estimate of placebo effect of repetitive transcranial magnetic stimulation in epilepsy. Epilepsy Beh 2011;20:355–9.Google Scholar
Zeiler, FA, Matuszczak, M, Teitelbaum, J, Gillman, LM, Kazina, CJ. Transcranial magnetic stimulation for status epilepticus. Epilepsy Res Treat 2015;2015:678074:1–10.Google Scholar
Graff-Guerrero, A, Gonzáles-Olvera, J, Ruiz-García, M, et al. rTMS reduces focal brain hyperperfusion in two patients with EPC. Acta Neurol Scand 2004;190:290–6.Google Scholar
Rotenberg, A, Bae, EH, Takeoka, M, et al. Repetitive transcranial magnetic stimulation in the treatment of epilepsia partialis continua. Epilepsy Behav 2009;14:253–7.Google Scholar
Morales, OG, Henry, ME, Nobler, MS, Wassermann, EM, Lisanby, SH. Electroconvulsive therapy and repetitive transcranial magnetic stimulation in children and adolescents: a review and report of two cases of epilepsia partialis continua. Child Adolesc Psychiatr Clin N Am 2005;14:193–210.CrossRefGoogle Scholar
Phillips, B, Ball, C, Sackett D et al. Oxford Center for Evidence-Based Medicine Levels of Evidence. Version 2009. 2015;http://www.cebm.net/?o=1025.Google Scholar
Jaeschke, R, Guyatt, GH, Dellinger, P, et al. Use of GRADE grid tor each decisions on clinical practice guidelines when consensus is elusive. BMJ 2008;337:a744.CrossRefGoogle Scholar
Bae, EH, Schrader, LM, Machii, K, et al. Safety and tolerability of repetitive transcranial magnetic stimulation in patients with epilepsy: a review of the literature. Epilepsy Behav 2007;10:521–8.Google Scholar
Rotenberg, A, Bae, EH, Muller, PA, et al. In-session seizures during low-frequency repetitive transcranial magnetic stimulation in patients with epilepsy. Epilepsy Behav 2009;16:353–5.Google Scholar

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