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Treating Drug-resistant Epilepsy – Why are we Waiting?

European Neurological Review, 2015;10(2):171–5 DOI:


Drug-resistant epilepsy (DRE) has been defined by the ad hoc Task Force of the International League Against Epilepsy (ILAE) Commission on Therapeutic Strategies as the failure of two appropriately chosen and tolerated anti-epileptic drugs (AEDs) (whether as monotherapy or in combination) to control seizures when used for an adequate period of time. The difference between the number of patients with DRE and the number of these patients who do not get access to adequate treatment is defined as the ‘treatment gap’, which is considered to be substantial. There are multiple possible causes that underlie the treatment gap in DRE: economic costs, natural history of epilepsy, deficiencies in health service provision, social stigma and other as yet unidentified causes. Factors affecting quality of life in DRE include depression and anxiety, raised risk of mortality and morbidity, increased healthcare utilisation and increased risk of adverse events with long- term use of AEDs, cognitive and memory impairment, seizure-related injuries, impaired ability to achieve educational and vocational goals, to drive, establish families and benefit from social relationships. Among the reasons for the greater risk of premature death are the raised risk of suicide in those patients with comorbid psychiatric disease and the increased incidence of sudden unexpected death among those with epilepsy. Managing epilepsy well involves more than just seizure reduction and when freedom from seizures cannot be achieved, addressing quality of life is likely to be more beneficial than interventions aimed at seizure reduction alone. Options exist for patients with DRE who are not candidates for epilepsy surgery, including dietary treatments, further attempts with AEDs and non-pharmacological interventions with devices. Further, non-invasive modalities are emerging, creating a more hopeful picture that the treatment gap for patients with DRE may be narrowed or even closed.
Keywords: Drug-resistant epilepsy, vagus nerve stimulation, deep brain stimulation, epilepsy surgery, closed loop neurostimulation, AspireSR®
Disclosure: Paul Boon has received support from Cyberonics, Medtronic, Sorin and UCB for lecture and consultancy fees and for educational grants through his institution. Philippe Ryvlin have received speaker or consulting fees from Cyberonics, UCB Pharma and Eisai Pharmaceuticals. James W Wheless has received grants from NIH, Shainberg Foundation, Questcor, Novartis, GW Pharma and INSYS Inc. He has received a grant, is on the speaker’s bureau and is a consultant for Lundbeck. He is on the speaker’s bureau for Cyberonics. He is on the speaker’s bureau and is a consultant for Eisai and Supernus. He has received a grant from, and is a consultant for Upsher- Smith, and is a consultant for UCB. Kensuke Kawai has received lecture honorarium from Cyberonics, Nihon Koden, Otsuka Pharmaceutical, and GlaxoSmithKline.
Acknowledgments: Editorial assistance was provided by Catherine Amey at Touch Medical Media, London and funded by Cyberonics BVBA. This article reports the proceedings of a sponsored satellite symposium and as such has not been subject to the journal’s usual peer-review process
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Received: November 03, 2015 Accepted: December 04, 2015
Correspondence: Paul Boon, Sint-Pietersnieuwstraat 25, Ghent, B-9000, Belgium. E:
Support: The publication of this article was supported by Cyberonics (Subsidiary of Livanova PLC). The views and opinions expressed are those of the authors and not necessarily those of Cyberonics.

Epilepsy is one of the most common serious neurological conditions, has no geographic, social or racial boundaries and can affect people of all ages.1 It is frequently associated with co-morbidities, not just seizures, and is a condition that is linked with a high rate of premature death compared with that in the general population.1 The consensus proposal by the ad hoc Task Force of the International League Against Epilepsy (ILAE) Commission on Therapeutic Strategies defined drugresistant epilepsy (DRE) as the failure of two appropriately chosen and tolerated anti-epileptic drugs (AEDs) (whether as monotherapy or in combination) to control seizures when used for an adequate period of time.2,3 The ideal goal for treating newly diagnosed epilepsy is to eliminate seizures while having minimal side-effects; however, in DRE, the treatment goals are required to be more modest.2,4,5 These involve: optimizing long-term seizure control, maximising quality of life (QoL), minimising side effects, maximising adherence and decreasing seizure severity and the postictal period.

The consequences of DRE have significant QoL implications for patients. These include: depression and anxiety;5–7 raised risk of mortality and morbidity;6,8–10 increased healthcare utilisation;4,11,14 more adverse events (AEs) with long-term use of AEDs;5–7,13 cognitive and memory impairment;6,7,14 seizure-related injuries;6,7 and impaired ability to obtain educational and work goals; to drive; establish families; and develop and maintain social relations.7,13 Out of a population in Europe of 850 million people, a conservative estimate of people with active epilepsy is 6 million (prevalence of 8.2/1000).15 Of these 6 million people, epilepsy is well controlled with AEDs in 70 %.15 In the remaining 30 % with DRE, onequarter to one-third (450 000–600 000 people) are potential candidates for epilepsy surgery.15 Two-thirds to three-quarters of the people with DRE (approximately 1.4 million) are candidates for other therapies such as vagus nerve stimulation (VNS) Therapy, ketogenic diet, deep brain stimulation (DBS) or experimental AEDs. According to a recent survey of epilepsy clinicians who were asked about the DRE treatment gap, around 40 % of DRE patients have undergone a comprehensive evaluation and, of this 40 %, the proportion who had not received VNS Therapy or epilepsy surgery was 83 %.16

1. de Boer HM, Mula M, Sander JW. The global burden and stigma of epilepsy. Epilepsy Behav. 2008;12(4):540-6.
2. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069-77.
3. Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy: response to sequential treatment schedules. Eur J Neurol 2006;13(3):277-82.
4. Faught RE, Weiner JR, Guerin A, et al. Impact of nonadherence to antiepileptic drugs on health care utilization and costs: findings from the RANSOM study. Epilepsia. 2009;50(3):501-9.
5. Gilliam F. Optimizing health outcomes in active epilepsy. Neurology. 2002;58(8 Suppl 5):S9-20.
6. Schmidt D. The clinical impact of new antiepileptic drugs after a decade of use in epilepsy. Epilepsy Res. 2002;50(1-2):21-32.
7. Fisher RS, Vickrey BG, Gibson P, et al. The impact of epilepsy from the patient’s perspective I. Descriptions and subjective perceptions. Epilepsy Res. 2000;41(1):39-51.
8. Lhatoo SD, Langan Y, Sander JW. Sudden unexpected death in epilepsy. Postgrad Med J. 1999;75(890):706-9.
9. Annegers JF, Coan SP, Hauser WA, et al. Epilepsy, vagal nerve stimulation by the NCP system, mortality, and sudden, unexpected, unexplained death. Epilepsia. 1998;39(2):206-12.
10. Van Ness PC. Therapy for the epilepsies. Arch Neurol. 2002;59(5):732-5.
11. Labiner DM, Paradis PE, Manjunath R, et al. Generic antiepileptic drugs and associated medical resource utilization in the United States. Neurology. 2010;74(20):1566-74.
12. Helmers SL, Paradis PE, Manjunath R, et al. Economic burden associated with the use of generic antiepileptic drugs in the United States. Epilepsy Behav. 2010;18(4):437-44.
13. Wheless JW. Intractable epilepsy: A survey of patients and caregivers. Epilepsy Behav. 2006;8(4):756-64.
14. Meador KJ. Cognitive outcomes and predictive factors in epilepsy. Neurology. 2002;58(8 Suppl 5):S21-6.
15. International Bureau for Epilepsy. EPILEPSY IN THE WHO EUROPEAN REGION: Fostering Epilepsy Care in Europe. EPILEPSY out of the Shadows. Available at: http://www. (Accessed 13 November 2015).
16. Data on file. Cybertronics Inc., Houston, TX, USA.
17. Jacoby A, Baker GA, Steen N, et al. The clinical course of epilepsy and its psychosocial correlates: findings from a U.K. Community study. Epilepsia. 1996;37(2):148-61.
18. Kanner AM. Can antiepileptic drugs unmask a susceptibility to psychiatric disorders? Nat Clin Pract Neurol. 2009;5(3):132-3.
19. Lambert MV, Robertson MM. Depression in epilepsy: etiology, phenomenology, and treatment. Epilepsia. 1999;40 Suppl 10:S21-47.
20. Indaco A, Carrieri PB, Nappi C, et al. Interictal depression in epilepsy. Epilepsy Res. 1992;12(1):45-50.
21. Baker GA, Jacoby A, Chadwick DW. The associations of psychopathology in epilepsy: a community study. Epilepsy Res. 1996;25(1):29-39.
22. Edeh J, Toone B. Relationship between interictal psychopathology and the type of epilepsy. Results of a survey in general practice. Br J Psychiatry. 1987;151:95-101.
23. Mendez MF, Cummings JL, Benson DF. Depression in epilepsy. Significance and phenomenology. Arch Neurol 1986;43(8):766-70.
24. Hitiris N, Mohanraj R, Norrie J, et al. Predictors of pharmacoresistant epilepsy. Epilepsy Res. 2007;75(2-3):192-6.
25. Kanner AM. Can neurobiological pathogenic mechanisms of depression facilitate the development of seizure disorders? Lancet Neurol. 2012;11(12):1093-102.
26. Catena-Dell’Osso M, Caserta A, Baroni S, et al. The relationship between epilepsy and depression: an update. Curr Med Chem. 2013;20(23):2861-7.
27. Epps SA, Weinshenker D. Rhythm and blues: animal models of epilepsy and depression comorbidity. Biochem Pharmacol 2013;85(2):135-46.
28. Cramer JA, Mintzer S, Wheless J, Mattson RH. Adverse effects of antiepileptic drugs: a brief overview of important issues. Expert Rev Neurother. 2010;10(6):885-91.
29. Gilliam FG, Barry JJ, Hermann BP, et al. Rapid detection of major depression in epilepsy: a multicentre study. Lancet Neurol 2006;5(5):399-405.
30. Helmstaedter C, Kurthen M, Lux S, et al. Chronic epilepsy and cognition: a longitudinal study in temporal lobe epilepsy. Ann Neurol. 2003;54(4):425-32.
31. Levy RH. Antiepileptic Drugs. 5th edition ed. Philadelphia, PA, USA: Lippincott Williams & Wilkins; 2002.
32. Boshuisen K, van Schooneveld MM, Uiterwaal CS, et al. Intelligence quotient improves after antiepileptic drug withdrawal following pediatric epilepsy surgery. Ann Neurol 2015;78(1):104-14.
33. Tellez-Zenteno JF, Hunter G, Wiebe S. Injuries in people with self-reported epilepsy: a population-based study. Epilepsia. 2008;49(6):954-61.
34. Fazel S, Wolf A, Langstrom N, et al. Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study. Lancet. 2013;382(9905):1646-54.
35. Ding D, Wang W, Wu J, et al. Premature mortality in people with epilepsy in rural China: a prospective study. Lancet Neurol. 2006;5(10):823-7.
36. Christensen J, Vestergaard M, Mortensen PB, et al. Epilepsy and risk of suicide: a population-based case-control study. Lancet Neurol. 2007;6(8):693-8.
37. Thurman DJ, Hesdorffer DC, French JA. Sudden unexpected death in epilepsy: assessing the public health burden. Epilepsia. 2014;55(10):1479-85.
38. Tellez-Zenteno JF, Ronquillo LH, Wiebe S. Sudden unexpected death in epilepsy: evidence-based analysis of incidence and risk factors. Epilepsy Res. 2005;65(1-2):101-15.
39. Sillanpaa M, Shinnar S. Long-term mortality in childhoodonset epilepsy. N Engl J Med .2010;363(26):2522-9.
40. Ryvlin P, Gilliam FG, Nguyen DK, et al. The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial. Epilepsia. 2014;55(6):893-900.
41. Jobst BC, Cascino GD. Resective epilepsy surgery for drugresistant focal epilepsy: a review. JAMA. 2015;313(3):285-93.
42. Engel J, Jr., McDermott MP, Wiebe S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial. JAMA. 2012;307(9):922-30.
43. Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345(5):311-8.
44. Elsharkawy AE, Thorbecke R, Ebner A, May TW. Determinants of quality of life in patients with refractory focal epilepsy who were not eligible for surgery or who rejected surgery. Epilepsy Behav. 2012;24(2):249-55.
45. Faught E, Duh MS, Weiner JR, Guerin A, Cunnington MC. Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM Study. Neurology. 2008;71(20):1572-8.
46. Hovinga CA, Asato MR, Manjunath R, et al. Association of non-adherence to antiepileptic drugs and seizures, quality of life, and productivity: survey of patients with epilepsy and physicians. Epilepsy Behav. 2008;13(2):316-22.
47. Asato MR, Manjunath R, Sheth RD, CA, et al. Adolescent and caregiver experiences with epilepsy. J Child Neurol. 2009;24(5):562-71.
48. Modi AC, Rausch JR, Glauser TA. Early pediatric antiepileptic drug nonadherence is related to lower long-term seizure freedom. Neurology. 2014;82(8):671-3.
49. Davis KL, Candrilli SD, Edin HM. Prevalence and cost of nonadherence with antiepileptic drugs in an adult managed care population. Epilepsia. 2008;49(3):446-54.
50. Helmers SL, Duh MS, Guerin A, et al. Clinical outcomes, quality of life, and costs associated with implantation of vagus nerve stimulation therapy in pediatric patients with drug-resistant epilepsy. Eur J Paediatr Neurol. 2012;16(5):449-58.
51. Helmers SL, Duh MS, Guerin A, et al. Clinical and economic impact of vagus nerve stimulation therapy in patients with drug-resistant epilepsy. Epilepsy Behav. 2011;22(2):370-5.
52. Kanner AM. The complex epilepsy patient: intricacies of assessment and treatment. Epilepsia. 2003;44 Suppl 5:3-8.
53. Moser D, Pablik E, Aull-Watschinger S, et al. Depressive symptoms predict the quality of sleep in patients with partial epilepsy--A combined retrospective and prospective study. Epilepsy Behav. 2015;47:104-10.
54. Gomez-Arias B, Crail-Melendez D, Lopez-Zapata R, Martinez- Juarez IE. Severity of anxiety and depression are related to a higher perception of adverse effects of antiepileptic drugs. Seizure. 2012;21(8):588-94.
55. Panelli RJ, Kilpatrick C, Moore SM, et al. The Liverpool Adverse Events Profile: relation to AED use and mood. Epilepsia. 2007;48(3):456-63.
56. Mula M, Cock HR. More than seizures: improving the lives of people with refractory epilepsy. Eur J Neurol 2015;22(1):24-30.
57. Luoni C, Bisulli F, Canevini MP, et al. Determinants of healthrelated quality of life in pharmacoresistant epilepsy: results from a large multicenter study of consecutively enrolled patients using validated quantitative assessments. Epilepsia. 2011;52(12):2181-91.
58. Kale R. Global Campaign Against Epilepsy:the treatment gap. Epilepsia. 2002;43 Suppl 6:31-3.
59. Vonck K, Boon P. Epilepsy: closing the loop for patients with epilepsy. Nat Rev Neurol. 2015;11(5):252-4.
60. 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):899-908.
61. 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):1017-25.
62. Sun FT, Morrell MJ, Wharen RE, Jr. Responsive cortical stimulation for the treatment of epilepsy. Neurotherapeutics. 2008;5(1):68-74.
63. 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):810-7.
64. Stefan H, Kreiselmeyer G, Kerling F, et al. Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: a proof of concept trial. Epilepsia. 2012;53(7):e115-8.
65. DeGiorgio CM, Soss J, Cook IA, et al. Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy. Neurology. 2013;80(9):786-91.
66. DeGiorgio CM, Murray D, Markovic D, Whitehurst T. Trigeminal nerve stimulation for epilepsy: long-term feasibility and efficacy. Neurology. 2009;72(10):936-8.
67. 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(4):447-55.
68. Nitsche MA, Paulus W. Transcranial direct current stimulation-- update 2011. Restor Neurol Neurosci. 2011;29(6):463-92.
69. Varga ET, Terney D, Atkins MD, et al. Transcranial direct current stimulation in refractory continuous spikes and waves during slow sleep: a controlled study. Epilepsy Res. 2011;97(1-2):142-5.
70. Auvichayapat N, Rotenberg A, Gersner R, et al. Transcranial direct current stimulation for treatment of refractory childhood focal epilepsy. Brain Stimul. 2013;6(4):696-700.
71. Leutmezer F, Schernthaner C, Lurger S, et al. Electrocardiographic changes at the onset of epileptic seizures. Epilepsia. 2003;44(3):348-54.
72. Boon P, Vonck K, van Rijckevorsel K, et al. A prospective, multicenter study of cardiac-based seizure detection to activate vagus nerve stimulation. Seizure. 2015;32:52-61
73. Novy J, Bartolini E, Bell GS, et al. Long-term retention of lacosamide in a large cohort of people with medically refractory epilepsy: a single centre evaluation. Epilepsy Res. 2013;106(1-2):250-6.
74. Catarino CB, Bartolini E, Bell GS, et al. The long-term retention of zonisamide in a large cohort of people with epilepsy at a tertiary referral centre. Epilepsy Res. 2011;96(1-2):39-44.
75. Lhatoo SD, Wong IC, Polizzi G, Sander JW. Long-term retention rates of lamotrigine, gabapentin, and topiramate in chronic epilepsy. Epilepsia. 2000;41(12):1592-6.
76. Depondt C, Yuen AW, Bell GS, et al. The long term retention of levetiracetam in a large cohort of patients with epilepsy. J Neurol Neurosurg Psychiatry 2006;77(1):101-3..
Keywords: Drug-resistant epilepsy, vagus nerve stimulation, deep brain stimulation, epilepsy surgery, closed loop neurostimulation, AspireSR®