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Intractable Generalized Epilepsy: Therapeutic Approaches

  • Epilepsy (C. W. Bazil, Section Editor)
  • Published:
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Abstract

Purpose of Review

To summarize recent developments in therapeutic options, both medical and surgical, for patients with drug-resistant generalized epilepsy syndromes, which continue to be a multifaceted challenge for patients and physicians.

Recent Findings

Newer generation pharmaceutical options are now available, such as brivaracetam, rufinamide, lacosamide, perampanel, and cannabidiol. Less restrictive dietary options appear to be nearly as effective as classic ketogenic diet for amelioration of seizures. The latest implantable devices include responsive neurostimulation and deep brain stimulation. Corpus callosotomy is an effective treatment for some seizure types, and newer and less invasive approaches are being explored. Resective surgical options have demonstrated success in carefully selected patients despite generalized electrographic findings on electroencephalogram.

Summary

The current literature reflects a widening range of clinical experience with newer anticonvulsant medications including cannabinoids, dietary therapies, surgical approaches, and neurostimulation devices for patients with intractable generalized epilepsy.

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References

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  1. Camfield P, Camfield C. Incidence, prevalence and aetiology of seizures and epilepsy in children. Epileptic Disord. 2015;17:117–23.

    PubMed  Google Scholar 

  2. • Falco-Walter JJ, Scheffer IE, Fisher RS. The new definition and classification of seizures and epilepsy. Epilepsy Res. 2018;139:73–9 A summary of the new ILAE classification scheme for seizures and epileptic syndromes.

    Article  Google Scholar 

  3. Beghi E, Camfield PR, Camfield CS. Epidemiologic aspects: lost in transition. Epilepsia. 2014;55(Suppl 3):3–7.

    Article  Google Scholar 

  4. Gomez-Ibañez A, McLachlan RS, Mirsattari SM, Diosy DC, Burneo JG. Prognostic factors in patients with refractory idiopathic generalized epilepsy. Epilepsy Res. 2017;130:69–73.

    Article  Google Scholar 

  5. Voll A, Hernández-Ronquillo L, Buckley S, Téllez-Zenteno JF. Predicting drug resistance in adult patients with generalized epilepsy: a case-control study. Epilepsy Behav. 2015;53:126–30.

    Article  Google Scholar 

  6. Yacubian EM. Juvenile myoclonic epilepsy: challenges on its 60th anniversary. Seizure. 2017;44:48–52.

    Article  Google Scholar 

  7. Camfield P, Camfield C. Long-term prognosis for symptomatic (secondarily) generalized epilepsies: a population-based study. Epilepsia. 2007;48:1128–32.

    Article  Google Scholar 

  8. Ostendorf AP, Ng Y-T. Treatment-resistant Lennox-Gastaut syndrome: therapeutic trends, challenges and future directions. Neuropsychiatr Dis Treat. 2017;13:1131–40.

    Article  CAS  Google Scholar 

  9. Chiron C, Helias M, Kaminska A, Laroche C, de Toffol B, Dulac O, et al. Do children with Dravet syndrome continue to benefit from stiripentol for long through adulthood? Epilepsia. 2018;59:1705–17.

    Article  CAS  Google Scholar 

  10. Nabbout R, Andrade DM, Bahi-Buisson N, Cross H, Desquerre I, Dulac O, et al. Outcome of childhood-onset epilepsy from adolescence to adulthood: transition issues. Epilepsy Behav. 2017;69:161–9.

    Article  CAS  Google Scholar 

  11. Wiemer-Kruel A, Haberlandt E, Hartmann H, Wohlrab G, Bast T. Modified Atkins diet is an effective treatment for children with Doose syndrome. Epilepsia. 2017;58:657–62.

    Article  CAS  Google Scholar 

  12. Akman CI, Yu J, Alter A, Engelstad K, De Vivo DC. Diagnosing glucose transporter 1 deficiency at initial presentation facilitates early treatment. J Pediatr. 2016;171:220–6.

    Article  CAS  Google Scholar 

  13. Helbig KL, Farwell Hagman KD, Shinde DN, Mroske C, Powis Z, Li S, et al. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med. 2016;18:898–905.

    Article  CAS  Google Scholar 

  14. Somerville ER. Some treatments cause seizure aggravation in idiopathic epilepsies (especially absence epilepsy). Epilepsia. 2009;50:31–6.

    Article  CAS  Google Scholar 

  15. Asadi-Pooya AA. Lennox-Gastaut syndrome: a comprehensive review. Neurol Sci. 2018;39:403–14.

    Article  Google Scholar 

  16. Coppola G, Piccorossi A, Operto FF, Verrotti A. Anticonvulsant drugs for generalized tonic-clonic epilepsy. Expert Opin Pharmacother. 2017;18:925–36.

    Article  CAS  Google Scholar 

  17. • French JA, Krauss GL, Wechsler RT, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy A randomized trial. Neurology. 2015;85:950–7 Important recent RCT data on this recently approved medication for generalized epilepsy.

    Article  CAS  Google Scholar 

  18. • French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388:2153–63 Important recent RCT data on this recently approved medication for seizures associated with TSC.

    Article  CAS  Google Scholar 

  19. Bergey GK. Evidence-based treatment of idiopathic generalized epilepsies with new antiepileptic drugs. Epilepsia. 2005;46(Suppl 9):161–8.

    Article  CAS  Google Scholar 

  20. Wechsler RT, Yates SL, Messenheimer J, Leroy R, Beller C, Doty P. Lacosamide for uncontrolled primary generalized tonic-clonic seizures: an open-label pilot study with 59-week extension. Epilepsy Res. 2017;130:13–20.

    Article  CAS  Google Scholar 

  21. Nevitt SJ, Marson AG, Weston J, Smith CT. Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures: an individual participant data review. Cochrane Database Syst Rev. 2016. https://doi.org/10.1002/14651858.cd001769.pub3.

  22. Giri VP, Giri OP, Khan FA, Kumar N, Kumar A, Haque A. Valproic acid versus lamotrigine as first-line monotherapy in newly diagnosed idiopathic generalized tonic-clonic seizures in adults—a randomized controlled trial. J Clin Diagn Res. 2016;10:FC01–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. • Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369:1016–26 One of the few comparative studies of anticonvulsants for generalized epilepsy.

    Article  CAS  Google Scholar 

  24. Delanty N, Jones J, Tonner F. Adjunctive levetiracetam in children, adolescents, and adults with primary generalized seizures: open-label, noncomparative, multicenter, long-term follow-up study. Epilepsia. 2012;53:111–9.

    Article  CAS  Google Scholar 

  25. Biton V, Montouris GD, Ritter F, Riviello JJ, Reife R, Lim P, et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group. Neurology. 1999;52:1330–7.

    Article  CAS  Google Scholar 

  26. Kothare SV, Valencia I, Khurana DS, Hardison H, Melvin JJ, Legido A. Efficacy and tolerability of zonisamide in juvenile myoclonic epilepsy. Epileptic Disord. 2004;6:267–70.

    PubMed  Google Scholar 

  27. Abou-Khalil BW. Antiepileptic drugs. Continuum. 2016;22:132–56.

    PubMed  Google Scholar 

  28. Villanueva V, Montoya J, Castillo A, Mauri-Llerda JÁ, Giner P, López-González FJ, et al. Perampanel in routine clinical use in idiopathic generalized epilepsy: the 12-month GENERAL study. Epilepsia. 2018;59:1740–52.

    Article  Google Scholar 

  29. Sake J-K, Hebert D, Isojärvi J, Doty P, De Backer M, Davies K, et al. A pooled analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant antiepileptic drugs. CNS Drugs. 2010;24:1055–68.

    Article  CAS  Google Scholar 

  30. • Kwan P, Trinka E, Van Paesschen W, Rektor I, Johnson ME, Lu S. Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial. Epilepsia. 2014;55:38–46 Important recent RCT data on this recently approved medication for epilepsy.

    Article  CAS  Google Scholar 

  31. Pellock JM, Faught E, Leppik IE, Shinnar S, Zupanc ML. Felbamate: consensus of current clinical experience. Epilepsy Res. 2006;71:89–101.

    Article  Google Scholar 

  32. Brodie MJ, Chung S, Wade A, Quelen C, Guiraud-Diawara A, François C, et al. Clobazam and clonazepam use in epilepsy: results from a UK database incident user cohort study. Epilepsy Res. 2016;123:68–74.

    Article  CAS  Google Scholar 

  33. Conry JA, Ng Y-T, Kernitsky L, Mitchell WG, Veidemanis R, Drummond R, et al. Stable dosages of clobazam for Lennox-Gastaut syndrome are associated with sustained drop-seizure and total-seizure improvements over 3 years. Epilepsia. 2014;55:558–67.

    Article  CAS  Google Scholar 

  34. Wheless JW, Phelps SJ. Clobazam: a newly approved but well-established drug for the treatment of intractable epilepsy syndromes. J Child Neurol. 2013;28:219–29.

    Article  Google Scholar 

  35. Ohtsuka Y, Yoshinaga H, Shirasaka Y, Takayama R, Takano H, Iyoda K. Long-term safety and seizure outcome in Japanese patients with Lennox-Gastaut syndrome receiving adjunctive rufinamide therapy: an open-label study following a randomized clinical trial. Epilepsy Res. 2016;121:1–7.

    Article  CAS  Google Scholar 

  36. Willmore LJ, Abelson MB, Ben-Menachem E, Pellock JM, Shields WD. Vigabatrin: 2008 update. Epilepsia. 2009;50:163–73.

    Article  CAS  Google Scholar 

  37. Foroozan R. Vigabatrin: lessons learned from the United States experience. J Neuroophthalmol. 2018;38:442–50.

    PubMed  Google Scholar 

  38. • Chiron C, Marchand MC, Tran A, Rey E, d’Athis P, Vincent J, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. Lancet. 2000;356:1638–42 Important recent RCT data on this newer medication for Dravet syndrome.

    Article  CAS  Google Scholar 

  39. Elliott J, DeJean D, Clifford T, Coyle D, Potter BK, Skidmore B, et al. Cannabis-based products for pediatric epilepsy: a systematic review. Epilepsia. 2018;60:6–19. https://doi.org/10.1111/epi.14608.

    Article  PubMed  Google Scholar 

  40. •• Devinsky O, Helen Cross J, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011–20 Important recent RCT data supporting the use of cannabidiol in Dravet syndrome.

    Article  CAS  Google Scholar 

  41. •• Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391:1085–96 Important recent RCT data supporting the use of cannabidiol in Lennox Gastaut syndrome.

    Article  CAS  Google Scholar 

  42. Vining EP, Freeman JM, Ballaban-Gil K, Camfield CS, Camfield PR, Holmes GL, et al. A multicenter study of the efficacy of the ketogenic diet. Arch Neurol. 1998;55:1433–7.

    Article  CAS  Google Scholar 

  43. • Kossoff EH, Zupec-Kania BA, Auvin S, Ballaban-Gil KR, Christina Bergqvist AG, Blackford R, et al. Optimal clinical management of children receiving dietary therapies for epilepsy: updated recommendations of the international ketogenic diet study group. Epilepsia Open. 2018;3:175–92 An excellent review of dietary therapies.

    Article  Google Scholar 

  44. Wirrell E, Eckert S, Wong-Kisiel L, Payne E, Nickels K. Ketogenic diet therapy in infants: efficacy and tolerability. Pediatr Neurol. 2018;82:13–8.

    Article  Google Scholar 

  45. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, et al. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia. 2009;50:1109–17.

    Article  Google Scholar 

  46. Gulati S. Dietary therapies: emerging paradigms in therapy of drug resistant epilepsy in children: based on 6th Dr. I. C. Verma excellence in research award oration. Indian J Pediatr. 2018;85:1000–5.

    Article  Google Scholar 

  47. Rho JM. How does the ketogenic diet induce anti-seizure effects? Neurosci Lett. 2017;637:4–10.

    Article  CAS  Google Scholar 

  48. Zhang Y, Xu J, Zhang K, Yang W, Li B. The anticonvulsant effects of ketogenic diet on epileptic seizures and potential mechanisms. Curr Neuropharmacol. 2018;16:66–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kverneland M, Selmer KK, Nakken KO, Iversen PO, Taubøll E. A prospective study of the modified Atkins diet for adults with idiopathic generalized epilepsy. Epilepsy Behav. 2015;53:197–201.

    Article  Google Scholar 

  50. Elia M, Klepper J, Leiendecker B, Hartmann H. Ketogenic diets in the treatment of epilepsy. Curr Pharm Des. 2017;23:5691–701.

    Article  CAS  Google Scholar 

  51. Nei M, Ngo L, Sirven JI, Sperling MR. Ketogenic diet in adolescents and adults with epilepsy. Seizure. 2014;23:439–42.

    Article  Google Scholar 

  52. Ye F, Li X-J, Jiang W-L, Sun H-B, Liu J. Efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy: a meta-analysis. J Clin Neurol. 2015;11:26–31.

    Article  Google Scholar 

  53. Arya R, Rotenberg A. Dietary, immunological, surgical, and other emerging treatments for pediatric refractory status epilepticus. Seizure. 2018. https://doi.org/10.1016/j.seizure.2018.09.002.

  54. Smith G, Press CA. Ketogenic diet in super-refractory status epilepticus. Pediatr Neurol Brief. 2017;31:8.

    Article  Google Scholar 

  55. Gaspard N, Hirsch LJ, Sculier C, Loddenkemper T, van Baalen A, Lancrenon J, et al. New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): state of the art and perspectives. Epilepsia. 2018;59:745–52.

    Article  Google Scholar 

  56. Francis BA, Fillenworth J, Gorelick P, Karanec K, Tanner A. The feasibility, safety and effectiveness of a ketogenic diet for refractory status epilepticus in adults in the intensive care unit. Neurocrit Care. 2018. https://doi.org/10.1007/s12028-018-0653-2.

  57. Cai Q-Y, Zhou Z-J, Luo R, Gan J, Li S-P, Mu D-Z, et al. Safety and tolerability of the ketogenic diet used for the treatment of refractory childhood epilepsy: a systematic review of published prospective studies. World J Pediatr. 2017;13:528–36.

    Article  Google Scholar 

  58. Sharma S, Goel S, Jain P, Agarwala A, Aneja S. Evaluation of a simplified modified Atkins diet for use by parents with low levels of literacy in children with refractory epilepsy: a randomized controlled trial. Epilepsy Res. 2016;127:152–9.

    Article  Google Scholar 

  59. Kim JA, Yoon J-R, Lee EJ, Lee JS, Kim JT, Kim HD, et al. Efficacy of the classic ketogenic and the modified Atkins diets in refractory childhood epilepsy. Epilepsia. 2016;57:51–8.

    Article  Google Scholar 

  60. Rezaei S, Abdurahman AA, Saghazadeh A, Badv RS, Mahmoudi M. Short-term and long-term efficacy of classical ketogenic diet and modified Atkins diet in children and adolescents with epilepsy: a systematic review and meta-analysis. Nutr Neurosci. 2017;25:1–18. https://doi.org/10.1080/1028415X.2017.1387721.

  61. Kasasbeh AS, Smyth MD, Steger-May K, Jalilian L, Bertrand M, Limbrick DD. Outcomes after anterior or complete corpus callosotomy in children. Neurosurgery. 2014;74:17–28.

    Article  Google Scholar 

  62. Paglioli E, Martins WA, Azambuja N, Portuguez M, Frigeri TM, Pinos L, et al. Selective posterior callosotomy for drop attacks: a new approach sparing prefrontal connectivity. Neurology. 2016;87:1968–74.

    Article  Google Scholar 

  63. • Graham D, Tisdall MM, Gill D. Corpus callosotomy outcomes in pediatric patients: a systematic review. Epilepsia. 2016;57:1053–68 An in depth review on the topic of callosotomy from an experienced center.

    Article  Google Scholar 

  64. Luat AF, Asano E, Kumar A, Chugani HT, Sood S. Corpus callosotomy for intractable epilepsy revisited: the Children’s Hospital of Michigan Series. J Child Neurol. 2017;32:624–9.

    Article  Google Scholar 

  65. Stigsdotter-Broman L, Olsson I, Flink R, Rydenhag B, Malmgren K. Long-term follow-up after callosotomy--a prospective, population based, observational study. Epilepsia. 2014;55:316–21.

    Article  Google Scholar 

  66. Lehner KR, Yeagle EM, Argyelan M, Klimaj Z, Du V, Megevand P, et al. Validation of corpus callosotomy after laser interstitial thermal therapy: a multimodal approach. J Neurosurg. 2018;1:1–11. https://doi.org/10.3171/2018.4.JNS172588.

  67. Rolston JD, Englot DJ, Wang DD, Garcia PA, Chang EF. Corpus callosotomy versus vagus nerve stimulation for atonic seizures and drop attacks: a systematic review. Epilepsy Behav. 2015;51:13–7.

    Article  Google Scholar 

  68. Wheless JW, Gienapp AJ, Ryvlin P. Vagus nerve stimulation (VNS) therapy update. Epilepsy Behav. 2018;88S:2–10.

    Article  Google Scholar 

  69. Dibué-Adjei M, Fischer I, Steiger H-J, Kamp MA. Efficacy of adjunctive vagus nerve stimulation in patients with Dravet syndrome: a meta-analysis of 68 patients. Seizure. 2017;50:147–52.

    Article  Google Scholar 

  70. Welch WP, Sitwat B, Sogawa Y. Use of Vagus nerve stimulator on children with primary generalized epilepsy. J Child Neurol. 2018;33:449–52.

    Article  Google Scholar 

  71. Englot DJ, Rolston JD, Wright CW, Hassnain KH, Chang EF. Rates and predictors of seizure freedom with vagus nerve stimulation for intractable epilepsy. Neurosurgery. 2016;79:345–53.

    Article  Google Scholar 

  72. Salanova V, Witt T, Worth R, Henry TR, Gross RE, Nazzaro JM, et al. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology. 2015;84:1017–25.

    Article  CAS  Google Scholar 

  73. Valentín A, García Navarrete E, Chelvarajah R, Torres C, Navas M, Vico L, et al. Deep brain stimulation of the centromedian thalamic nucleus for the treatment of generalized and frontal epilepsies. Epilepsia. 2013;54:1823–33.

    Article  Google Scholar 

  74. • Wyllie E, Lachhwani DK, Gupta A, Chirla A, Cosmo G, Worley S, et al. Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings. Neurology. 2007;69:389–97 A paradigm shifting article on the use of surgery in this patient population.

    Article  CAS  Google Scholar 

  75. • Kang JW, Eom S, Hong W, et al. Long-term outcome of resective epilepsy surgery in patients with Lennox-Gastaut syndrome. Pediatrics. 2018. https://doi.org/10.1542/peds.2018-0449 One of a series of articles from this epilepsy center with extensive experience with surgery in this patient population.

  76. Fallah A, Rodgers SD, Weil AG, Vadera S, Mansouri A, Connolly MB, et al. Resective epilepsy surgery for tuberous sclerosis in children: determining predictors of seizure outcomes in a multicenter retrospective cohort Study. Neurosurgery. 2015;77:517–24 discussion 524.

    Article  Google Scholar 

  77. Holthausen H, Pieper T, Kudernatsch M. Towards early diagnosis and treatment to save children from catastrophic epilepsy—focus on epilepsy surgery. Brain Dev. 2013;35:730–41.

    Article  Google Scholar 

  78. Cobourn K, Fayed I, Keating RF, Oluigbo CO. Early outcomes of stereoelectroencephalography followed by MR-guided laser interstitial thermal therapy: a paradigm for minimally invasive epilepsy surgery. Neurosurg Focus. 2018;45:E8.

    Article  Google Scholar 

  79. Fujiwara H, Leach JL, Greiner HM, Holland-Bouley KD, Rose DF, Arthur T, et al. Resection of ictal high frequency oscillations is associated with favorable surgical outcome in pediatric drug resistant epilepsy secondary to tuberous sclerosis complex. Epilepsy Res. 2016;126:90–7.

    Article  Google Scholar 

  80. Tovar-Spinoza Z, Ziechmann R, Zyck S. Single and staged laser interstitial thermal therapy ablation for cortical tubers causing refractory epilepsy in pediatric patients. Neurosurg Focus. 2018;45:E9.

    Article  Google Scholar 

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Correspondence to Sean T. Hwang.

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Sean T. Hwang, Simona V. Proteasa, Aradia X. Fu, and Scott J. Stevens each declare no potential conflicts of interest.

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Hwang, S.T., Stevens, S.J., Fu, A.X. et al. Intractable Generalized Epilepsy: Therapeutic Approaches. Curr Neurol Neurosci Rep 19, 16 (2019). https://doi.org/10.1007/s11910-019-0933-z

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