Drug Resistance in Epilepsy: Which Prospect to Tame its Stubbornness?
Main Article Content
Abstract
Epilepsy is a major health problem, it being among the most common chronic neurologic pathologies. Its basic therapy is via anti-seizure drugs (ASDs), of which nearly two dozen are currently available for symptomatic treatment of epileptic seizures. But, notwithstanding the increasing ASD options, about one-third of epileptic patients remain drug-refractory, and this fraction did not diminish over decades. This paper reviews the subject of drug resistance in epilepsy (DRE), in view of exploring the prospect to overcome its persistence. The survey of various hypotheses about DRE origin and mechanisms notices that any of them alone does not fully account the DRE, their multitude deriving from the lack of solution to this bad medical need. The non-pharmacological (neurosurgical, brain stimulation, focal treatments and dietary) approaches of drug-intractable epilepsy are also surveyed, with the sober conclusion that, in a predictable future, the mainstay of epilepsy therapy will likely remain the drugs. The vast multiplicity of molecular changes associated with DRE suggests that its pharmacological resolution might arise only from integrative, systemic approaches, beyond the reductionist single-target paradigm that dominated the ASD discovery, in the last several decades. A conceivable lessening of DRE might be brought about by precision (personalized) medicine, assisted by complex systems biology description of individual epileptic pathology. In a longer run, the emergent network pharmacology might led to genuine innovative multi-potent antiepileptic drugs, able to treat distinct subpopulations of current refractory patients.
Keywords:
mechanisms of drug resistance, non-pharmacological antiepileptic treatments, precision medicine, network pharmacology, multi-potent drug
Article Details
How to Cite
MARGINEANU, Doru Georg.
Drug Resistance in Epilepsy: Which Prospect to Tame its Stubbornness?.
Medical Research Archives, [S.l.], v. 9, n. 8, aug. 2021.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2514>. Date accessed: 27 apr. 2024.
doi: https://doi.org/10.18103/mra.v9i8.2514.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt J, Sander JV, Newton CR. Incidence of epilepsy : a systematic review and meta-analysis. Neurology 2011;77(10):1005–1012.
2. Kaculini CM, Tate-Looney AJ, Seifi A. The history of epilepsy: from ancient mystery to modern misconception. Cureus 2021; 13(3): e13953. Doi: 10.7759/cureus.13953.
3. Magiorkinis E, Sidiropoulou K, Diamantis A. Hallmarks in the history of epilepsy: epilepsy in antiquity. Epilepsy Behav. 2010;17(1),103–108.
4. Kinnier Wilson JV, Reynolds EH. Translation and analysis of a cuneiform text forming part of a Babylonian treatise on epilepsy. Med Hist. 1990;34(2):185–198.
5. Reynolds EH. Milestones in epilepsy. Epilepsia 2009;50(3):338–342.
6. Lai CW, Lai YHC. History of epilepsy in Chinese traditional medicine. Epilepsia 1991;32(3):299-302.
7. Magiorkinis E, Diamantis A, Sidiropoulou K, Panteliadis C. Highlights in the history of epilepsy: the last 200 years. Epilepsy Res Treat. 2014, Article ID 582039. Doi: http://dx.doi.org/10.1155/2014/582039
8. Reynolds EH, Rodin E. The clinical concept of epilepsy. Epilepsia 2009;50(3):2–7.
9. Golyala A, Kwan P. Drug development for refractory epilepsy: the past 25 years and beyond. Seizure Jan 2017;44:147–156.
10. Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev. 2020;72(3):606–638.
11. Fisher RS, van Emde Boas W, Blume W, Elger C., Genton P., Lee P., Engel J., Jr. Epileptic seizures and epilepsy: definitions proposed by the ILAE and the IBE. Epilepsia 2005;46(4):470–472.
12. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55(4):475–482.
13. Fiest KM, Sauro KM, Wiebe S, Patten SB, Kwon CS, Dykeman J, Pringsheim T, Lorenzetti DL, Jetté N. Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies. Neurology 2017;88(3):296–303.
14. Brodie M.J., Kwan P. Staged approach to epilepsy management. Neurology 2002;58(8, Suppl 5):S2–S8.
15. Schmidt D, Löscher W. Drug resistance in epilepsy: putative neurobiologic and clinical mechanisms. Epilepsia 2005;46(6):858–877.
16. Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology 2012;78(20):1548–1554.
17. Berg AT. Identification of pharmacoresistant epilepsy. Neurol Clin. 2009;27(4):1003–1013.
18. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshé SL, Perucca E, Wiebe S, French J. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51(6):1069–1077.
19. Elger CE. Pharmacoresistance: modern concept and basic data derived from human brain tissue. Epilepsia 2003;44(Suppl 5):9–15.
20. Neligan A, Bell GS, Sander JW, Shorvon SD. How refractory is refractory epilepsy? Patterns of relapse and remission in people with refractory epilepsy. Epilepsy Res. 2011;96(3):225–230.
21. Gorter JA, Potschka H. Drug Resistance. In: Noebels JL, Avoli M, Rogawski MA et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US) 2012; Drug Resistance - Jasper's Basic Mechanisms of the Epilepsies - NCBI Bookshelf (nih.gov)
22. Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy: multiple hypotheses, few answers. Front Neurol. 2017;8:301. Doi: 10.3389/fneur.2017.00301
23. Pérez-Pérez D, Frías-Soria CL, Rocha L. Drug-resistant epilepsy: from multiple hypotheses to an integral explanation using preclinical resources. Epilepsy Behav. Aug 2019;106430 https://doi.org/10.1016/j.yebeh.2019.07.031.
24. Margineanu DG, Klitgaard H. Mechanisms of drug resistance in epilepsy: relevance for antiepileptic drug discovery. Expert Opin Drug Disc. 2009;4(1):23–32.
25. Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci. 2005; 6(8):591–602.
26. Baltes S, Fedrowitz M, Luna Tortos C, Potschka H, Löscher W. Valproic acid is not a substrate for P-glycoprotein or multidrug resistance proteins 1 and 2 in a number of in vitro and in vivo transport assays. J Pharmacol Exp Ther. 2007;320(1):331–343.
27. Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Löscher W. Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacol. 2007;52(2):333–346.
28. Remy S, Gabriel S, Urban BW, Dietrich D, Lehmann TN, Elger CE, Heinemann U, Beck H. A novel mechanism underlying drug resistance in chronic epilepsy. Ann Neurol. 2003;53(4):469–479.
29. Remy S, Beck H. Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain 2006;129(1):18-35.
30. Remy S, Urban BW, Elger CE, Beck H. Anticonvulsant pharmacology of voltage-gated Na+ channels in hippocampal neurons of control and chronically epileptic rats. Eur J Neurosci. 2003;17(12):2648–2658.
31. Rogawski MA, Johnson MR. Intrinsic severity as a determinant of antiepileptic drug refractoriness. Epilepsy Curr. 2008;8(5):127–130.
32. Rogawski MA. The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs. Epilepsia 2013;54(Suppl 2):33–40.
33. Schmidt D, Löscher W. New developments in antiepileptic drug resistance: an integrative view. Epilepsy Curr. 2009;9(2):47–52.
34. Lazarowski A, Czornyj L, Lubienieki F, Girardi E, Vazquez S, D’Giano C. ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy. Epilepsia 2007;48 (Suppl 5):140–149.
35. Fang M, Xi ZQ, Wu Y, Wang XF. A new hypothesis of drug refractory epilepsy: neural network hypothesis. Med Hypotheses 2011;76(6):871–876.
36. Scheffer IE, Berkovic SF. The genetics of human epilepsy. Trends Pharmacol Sci. 2003;24(8):428–433.
37. Pal DK, Strug LJ, Greenberg DA. Evaluating candidate genes in common epilepsies and the nature of evidence. Epilepsia 2008;49(3):386–392.
38. Helbig I, Heinzen EL, Mefford HC on behalf of the ILAE Genetics Commission. The building blocks of epilepsy genetics. Epilepsia 2016;57(6):861–868.
39. Balestrini S, Sisodiya SM. Pharmacogenomics in epilepsy. Neurosci Lett. Feb 2018;667:27–39.
40. Koeleman BPC. What do genetic studies tell us about the heritable basis of common epilepsy? Polygenic or complex epilepsy? Neurosci Lett. Feb 2018;667:10–16.
41. Cardenas‑Rodriguez N, Carmona‑Aparicio L, Pérez-Lozano DL et al. Genetic variations associated with pharmacoresistant epilepsy. Molec Med Rep. 2020;21(4):1685–1701.
42. Sisodiya SM. Genetics of drug resistance. Epilepsia 2005;46(Suppl 10):33–38.
43. Kobow K, Blümcke I. Epigenetics in epilepsy. Neurosci Lett. Feb 2018;667:40–46.
44. Kobow K, El-Osta A, Blümcke I. The methylation hypothesis of pharmacoresistance in epilepsy. Epilepsia 2013;54(Suppl 2):41–47.
45. Roopra A, Dingledine R, Hsieh J. Epigenetics and epilepsy. Epilepsia 2012;53(Suppl 9):2–10.
46. Navarrete-Modesto V, Orozco-Suárez S, Feria-Romero IA, Rocha L. The molecular hallmarks of epigenetic effects mediated by antiepileptic drugs. Epilepsy Res. Jan 2019;149:53–65.
47. Schultzberg M, Lindberg C, Forslin Aronsson Å et al. Inflammation in the nervous system – Physiological and pathophysiological aspects. Physiol Behav. 2007;92(1-2):121–128.
48. Vezzani A, Granata T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 2005;46(11):1724–1743.
49. Marchi N, Granata T, Freri E, Ciusani E, Ragona F et al. Efficacy of anti-inflammatory therapy in a model of acute seizures and in a population of pediatric drug resistant epileptics. PLoS ONE 2011;6(3): e18200. DOI: 10.1371/journal.pone.0018200
50. Eid T, Williamson A, Lee TS, Petroff OA, de Lanerolle NC. Glutamate and astrocytes—key players in human mesial temporal lobe epilepsy? Epilepsia 2008;49(Suppl 2):42–52.
51. Oberheim NA, Tian G-F, Han X, PengW, Takano T, Ransom B, et al. Loss of astrocytic domain organization in the epileptic brain. J Neurosci. 2008;28(13):3264–3276.
52. Steinhäuser C, Seifert G. Astrocyte dysfunction in epilepsy. In: Noebels JL, Avoli M, Rogawski MA et al, editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US); 2012 Astrocyte dysfunction in epilepsy - Jasper's Basic Mechanisms of the Epilepsies - NCBI Bookshelf (nih.gov)
53. Margineanu DG. Systems biology, complexity, and the impact on antiepileptic drug discovery. Epilepsy Behav. Sep 2014;38:131–142.
54. Löscher W, Schmidt D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 2011;52(4):657–678.
55. Dawit, S.; Crepeau, A.Z. When drugs do not work: alternatives to antiseizure medications. Curr Neurol Neurosci Rep. Jul 2020;20(9):37. DOI: 10.1007/s11910-020-01061-3
56. Stacey WC, Litt B. Technology insight: neuroengineering and epilepsy – designing devices for seizure control. Nat Clin Pract Neurol. 2008;4(4):190–201.
57. Téllez-Zenteno JF, Dhar R, Hernandez-Ronquillo L, Wiebe S. Long-term outcomes in epilepsy surgery: antiepileptic drugs, mortality, cognitive and psychosocial aspects. Brain 2007;130(2):334-345.
58. Rugg-Gunn, Fergus, Miserocchi A, McEvoy A. Epilepsy surgery. Pract Neurol. 2020;20(1):4–14
59. Romanelli P, Anschel DJ. Radiosurgery for epilepsy. Lancet Neurol. 2006;5(7):613–620.
60. Margineanu DG. Epileptic hypersynchrony revisited. Neuroreport 2010;21(15):963–967.
61. Theodore WH, Fisher RS. Brain stimulation for epilepsy. Lancet Neurol. 2004;3(2):111–118.
62. Fisher RS, Velasco AL. Electrical brain stimulation for epilepsy. Nat Rev Neurol. 2014; 10(5):261–270.
63. Edwards CA, Kouzani A, Lee KH, Ross EK. Neurostimulation devices for the treatment of neurologic disorders. Mayo Clin Proc. 2017;92(9):1427–1444.
64. Bouwens van der Vlis TAM, Schijns OEMG, Schaper FLWVJ et al. Deep brain stimulation of the anterior nucleus of the thalamus for drug-resistant epilepsy. Neurosurg Rev. 2019;42(2):287–296.
65. Skarpaas TL, Jarosiewicz B, Morrell MJ. Brain-responsive neurostimulation for epilepsy (RNS® System). Epilepsy Res. Jul 2019;153:68–70.
66. Kremen V, Brinkmann BH, Kim I et al. Integrating brain implants with local and distributed computing devices: a next generation epilepsy management system. IEEE J Transl Eng Health Med. Sep 2018;6:2500112. DOI: 10.1109/JTEHM.2018.2869398
67. Tsuboyama M, Kaye HL, Rotenberg A. Biomarkers obtained by transcranial magnetic stimulation of the motor cortex in epilepsy. Front Integr Neurosci. Oct 2019;13:57. doi: 10.3389/fnint.2019.00057
68. Tsuboyama M, Kaye HL, Rotenberg A. Review of transcranial magnetic stimulation in epilepsy. Clin Ther. 2020;42(7):1155–1168.
69. Nilsen KE, Cock HR. Focal treatment for refractory epilepsy: hope for the future? Brain Res Rev. 2004;44(2-3):141–153.
70. Gernert M, Feja M. Bypassing the blood-brain barrier: direct intracranial drug delivery in epilepsies. Pharmaceutics 2020;12(12):1134; doi: 10.3390/pharmaceutics12121134
71. Stein AG, Eder HG, Blum DE et al. An automated drug delivery system for focal epilepsy. Epilepsy Res. 2000;39(2):103–114.
72. Cook M, Murphy M, Bulluss K et al. Anti-seizure therapy with a long-term, implanted intra-cerebroventricular delivery system for drug-resistant epilepsy: a first-in-man study. EClinicalMedicine May 2020;22:100326 DOI: 10.1016/j.eclinm.2020.100326
73. Freese A, Kaplitt MG, O'Connor WM et al. Direct gene transfer into human epileptogenic hippocampal tissue with an adeno-associated virus vector: implications for a gene therapy approach to epilepsy. Epilepsia 1997;38(7):759–766.
74. Löscher W, Ebert U, Lehmann H et al. Seizure suppression in kindling epilepsy by grafts of fetal GABAergic neurons in rat substantia nigra. J Neurosci Res. 1998;51(2):196–209.
75. Boison D. Cell and gene therapies for refractory epilepsy. Curr Neuropharmacol. 2007;5(2):115–125.
76. Loscher W, Gernert M, Heinemann U. Cell and gene therapies in epilepsy – promising avenues or blind alleys? Trends Neurosci. 2008;31(2):62–73.
77. Dudek FE. Commentary: a skeptical view of experimental gene therapy to block epileptogenesis. Neurotherapeutics 2009;6(2):319–322.
78. Riban V, Fitzsimons HL, During MJ. Gene therapy in epilepsy. Epilepsia 2009;50(1):24–32.
79. Naegele JR, Maisano X, Yang J et al. Recent advancements in stem cell and gene therapies for neurological disorders and intractable epilepsy. Neuropharmacol. 2010;58(6):855–864.
80. Ess KC. Patient heal thyself: modeling and treating neurological disorders using patient-derived stem cells. Exp Biol Med. (Maywood) 2013;238(3):308–314.
81 Simonato M. Gene therapy for epilepsy. Epilepsy Behav. Sep 2014;38:125–130.
82. Lybrand ZR, Goswami S, Hsieh J. Stem cells: A path towards improved epilepsy therapies. Neuropharmacol. May 2020;168:107781. doi: 10.1016/j.neuropharm.2019.107781
83. Wheless JW. History of the ketogenic diet. Epilepsia 2008;49(Suppl 8):3–5.
84. Kossoff EH, Dorward JL. The modified Atkins diet. Epilepsia 2008;49(Suppl 8):37–41.
85. Neal EG, Chaffe H, Schwartz RH et al. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia 2009;50(5):1109–1117.
86. Masino SA, Rho JM. Mechanisms of ketogenic diet action. In: Noebels JL.Avoli M, Rogawski MA et al., editors: Jasper’s Basic Mechanisms of the Epilepsies [Internet] 4th ed. Bethesda (MD): National Center for Biotechnology Information (US) 2012; Mechanisms of Ketogenic Diet Action - Jasper's Basic Mechanisms of the Epilepsies - NCBI Bookshelf (nih.gov)
87. Boison D. New insights into the mechanisms of the ketogenic diet. Curr Opin Neurol. 2017;30(2):187–192.
88. Hartman AL, Vining EP. Clinical aspects of the ketogenic diet. Epilepsia 2007;48(1):31–42.
89. Devinsky O, Vezzani A, O’Brien TJ et al. Epilepsy. Nat Rev Dis Primers 2018;3 doi: 10.1038/nrdp.2018.24.
90. Beyenburg S, Stavem K, Schmidt D. Placebo-corrected efficacy of modern antiepileptic drugs for refractory epilepsy: systematic review and meta-analysis. Epilepsia 2010;51(1):7–26.
91. Berkovic SF, Scheffer IE, Petrou S et al. A road map for precision medicine in the epilepsies. Lancet Neurol. 2015;14(12):1219–1228.
92. Myers CT, Mefford HC. Advancing epilepsy genetics in the genomic era. Genome Med. 2015;7(1):91 DOI 10.1186/s13073-015-0214-7.
93. Chen R, Snyder M. Systems biology: personalized medicine for the future? Curr Opin Pharmacol. 2012;12(5):623–628.
94. Stéphanou A, Fanchon E, Innominato PF, Ballesta A. Systems biology, systems medicine, systems pharmacology: the what and the why. Acta Biotheor. May 2018 https://doi.org/10.1007/s10441-018-9330-2
95. Kitano H. Systems biology: a brief overview. Science 2002;295(5560):1662–1664.
96. Tavassoly I, Goldfarb J, Iyengar R. Systems biology primer: the basic methods and approaches. Essays Biochem. 2018;62(4):487–500.
97. Schadt EE, Friend SH, Shaywitz DA. A network view of disease and compound screening. Nat Rev Drug Discov. 2009;8(4):286–295.
98. Margineanu DG. Systems biology impact on antiepileptic drug discovery. Epilepsy Res. 2012;98(2-3):104–115.
99. Naimo GD, Guarnaccia M, Sprovieri T et al. A systems biology approach for personalized medicine in refractory epilepsy. Int J Mol Sci. 2019 Jul;20(15):3717. doi: 10.3390/ijms20153717
100. Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008;4(11):682–690.
101. Loeb JA. Identifying targets for preventing epilepsy using systems biology. Neurosci Lett. 2011;497(3):205–212.
102. Löscher W, Klitgaard H, Twyman RE, Schmidt D. New avenues for antiepileptic drug discovery and development. Nat Rev Drug Discov. 2013;12(10):757–776.
103. Brodie MJ, Sills GJ. Combining AEDs – rational polytherapy? Seizure 2011;20(5):369–375.
104. Margineanu DG. Neuropharmacology beyond reductionism – a likely prospect. Biosystems Mar 2016;141:1–9.
105. Csermely P, Korcsmáros T, Kiss HJM, London G, Nussinov R. Structure and dynamics of molecular networks: a novel paradigm of drug discovery. Pharmacol Ther. 2013;138(3):333–408.
106. Talevi A. Computational approaches for innovative antiepileptic drug discovery. Expert Opin Drug Discov. 2016;11(10):1001–1016.
107. Glicksberg BS, Li L, Chen R, Dudley J, Chen B. Leveraging big data to transform drug discovery. Methods Mol Biol. 2019;1939:91–118. DOI: 10.1007/978-1-4939-9089-4_6.
108. Muhammad J, Khan A, Ali A, Fang L et al. Network pharmacology: exploring the resources and methodologies. Curr Top Med Chem. 2018;18(12):949–964.
2. Kaculini CM, Tate-Looney AJ, Seifi A. The history of epilepsy: from ancient mystery to modern misconception. Cureus 2021; 13(3): e13953. Doi: 10.7759/cureus.13953.
3. Magiorkinis E, Sidiropoulou K, Diamantis A. Hallmarks in the history of epilepsy: epilepsy in antiquity. Epilepsy Behav. 2010;17(1),103–108.
4. Kinnier Wilson JV, Reynolds EH. Translation and analysis of a cuneiform text forming part of a Babylonian treatise on epilepsy. Med Hist. 1990;34(2):185–198.
5. Reynolds EH. Milestones in epilepsy. Epilepsia 2009;50(3):338–342.
6. Lai CW, Lai YHC. History of epilepsy in Chinese traditional medicine. Epilepsia 1991;32(3):299-302.
7. Magiorkinis E, Diamantis A, Sidiropoulou K, Panteliadis C. Highlights in the history of epilepsy: the last 200 years. Epilepsy Res Treat. 2014, Article ID 582039. Doi: http://dx.doi.org/10.1155/2014/582039
8. Reynolds EH, Rodin E. The clinical concept of epilepsy. Epilepsia 2009;50(3):2–7.
9. Golyala A, Kwan P. Drug development for refractory epilepsy: the past 25 years and beyond. Seizure Jan 2017;44:147–156.
10. Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev. 2020;72(3):606–638.
11. Fisher RS, van Emde Boas W, Blume W, Elger C., Genton P., Lee P., Engel J., Jr. Epileptic seizures and epilepsy: definitions proposed by the ILAE and the IBE. Epilepsia 2005;46(4):470–472.
12. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014;55(4):475–482.
13. Fiest KM, Sauro KM, Wiebe S, Patten SB, Kwon CS, Dykeman J, Pringsheim T, Lorenzetti DL, Jetté N. Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies. Neurology 2017;88(3):296–303.
14. Brodie M.J., Kwan P. Staged approach to epilepsy management. Neurology 2002;58(8, Suppl 5):S2–S8.
15. Schmidt D, Löscher W. Drug resistance in epilepsy: putative neurobiologic and clinical mechanisms. Epilepsia 2005;46(6):858–877.
16. Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Patterns of treatment response in newly diagnosed epilepsy. Neurology 2012;78(20):1548–1554.
17. Berg AT. Identification of pharmacoresistant epilepsy. Neurol Clin. 2009;27(4):1003–1013.
18. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshé SL, Perucca E, Wiebe S, French J. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51(6):1069–1077.
19. Elger CE. Pharmacoresistance: modern concept and basic data derived from human brain tissue. Epilepsia 2003;44(Suppl 5):9–15.
20. Neligan A, Bell GS, Sander JW, Shorvon SD. How refractory is refractory epilepsy? Patterns of relapse and remission in people with refractory epilepsy. Epilepsy Res. 2011;96(3):225–230.
21. Gorter JA, Potschka H. Drug Resistance. In: Noebels JL, Avoli M, Rogawski MA et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US) 2012; Drug Resistance - Jasper's Basic Mechanisms of the Epilepsies - NCBI Bookshelf (nih.gov)
22. Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy: multiple hypotheses, few answers. Front Neurol. 2017;8:301. Doi: 10.3389/fneur.2017.00301
23. Pérez-Pérez D, Frías-Soria CL, Rocha L. Drug-resistant epilepsy: from multiple hypotheses to an integral explanation using preclinical resources. Epilepsy Behav. Aug 2019;106430 https://doi.org/10.1016/j.yebeh.2019.07.031.
24. Margineanu DG, Klitgaard H. Mechanisms of drug resistance in epilepsy: relevance for antiepileptic drug discovery. Expert Opin Drug Disc. 2009;4(1):23–32.
25. Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci. 2005; 6(8):591–602.
26. Baltes S, Fedrowitz M, Luna Tortos C, Potschka H, Löscher W. Valproic acid is not a substrate for P-glycoprotein or multidrug resistance proteins 1 and 2 in a number of in vitro and in vivo transport assays. J Pharmacol Exp Ther. 2007;320(1):331–343.
27. Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Löscher W. Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacol. 2007;52(2):333–346.
28. Remy S, Gabriel S, Urban BW, Dietrich D, Lehmann TN, Elger CE, Heinemann U, Beck H. A novel mechanism underlying drug resistance in chronic epilepsy. Ann Neurol. 2003;53(4):469–479.
29. Remy S, Beck H. Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain 2006;129(1):18-35.
30. Remy S, Urban BW, Elger CE, Beck H. Anticonvulsant pharmacology of voltage-gated Na+ channels in hippocampal neurons of control and chronically epileptic rats. Eur J Neurosci. 2003;17(12):2648–2658.
31. Rogawski MA, Johnson MR. Intrinsic severity as a determinant of antiepileptic drug refractoriness. Epilepsy Curr. 2008;8(5):127–130.
32. Rogawski MA. The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs. Epilepsia 2013;54(Suppl 2):33–40.
33. Schmidt D, Löscher W. New developments in antiepileptic drug resistance: an integrative view. Epilepsy Curr. 2009;9(2):47–52.
34. Lazarowski A, Czornyj L, Lubienieki F, Girardi E, Vazquez S, D’Giano C. ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy. Epilepsia 2007;48 (Suppl 5):140–149.
35. Fang M, Xi ZQ, Wu Y, Wang XF. A new hypothesis of drug refractory epilepsy: neural network hypothesis. Med Hypotheses 2011;76(6):871–876.
36. Scheffer IE, Berkovic SF. The genetics of human epilepsy. Trends Pharmacol Sci. 2003;24(8):428–433.
37. Pal DK, Strug LJ, Greenberg DA. Evaluating candidate genes in common epilepsies and the nature of evidence. Epilepsia 2008;49(3):386–392.
38. Helbig I, Heinzen EL, Mefford HC on behalf of the ILAE Genetics Commission. The building blocks of epilepsy genetics. Epilepsia 2016;57(6):861–868.
39. Balestrini S, Sisodiya SM. Pharmacogenomics in epilepsy. Neurosci Lett. Feb 2018;667:27–39.
40. Koeleman BPC. What do genetic studies tell us about the heritable basis of common epilepsy? Polygenic or complex epilepsy? Neurosci Lett. Feb 2018;667:10–16.
41. Cardenas‑Rodriguez N, Carmona‑Aparicio L, Pérez-Lozano DL et al. Genetic variations associated with pharmacoresistant epilepsy. Molec Med Rep. 2020;21(4):1685–1701.
42. Sisodiya SM. Genetics of drug resistance. Epilepsia 2005;46(Suppl 10):33–38.
43. Kobow K, Blümcke I. Epigenetics in epilepsy. Neurosci Lett. Feb 2018;667:40–46.
44. Kobow K, El-Osta A, Blümcke I. The methylation hypothesis of pharmacoresistance in epilepsy. Epilepsia 2013;54(Suppl 2):41–47.
45. Roopra A, Dingledine R, Hsieh J. Epigenetics and epilepsy. Epilepsia 2012;53(Suppl 9):2–10.
46. Navarrete-Modesto V, Orozco-Suárez S, Feria-Romero IA, Rocha L. The molecular hallmarks of epigenetic effects mediated by antiepileptic drugs. Epilepsy Res. Jan 2019;149:53–65.
47. Schultzberg M, Lindberg C, Forslin Aronsson Å et al. Inflammation in the nervous system – Physiological and pathophysiological aspects. Physiol Behav. 2007;92(1-2):121–128.
48. Vezzani A, Granata T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 2005;46(11):1724–1743.
49. Marchi N, Granata T, Freri E, Ciusani E, Ragona F et al. Efficacy of anti-inflammatory therapy in a model of acute seizures and in a population of pediatric drug resistant epileptics. PLoS ONE 2011;6(3): e18200. DOI: 10.1371/journal.pone.0018200
50. Eid T, Williamson A, Lee TS, Petroff OA, de Lanerolle NC. Glutamate and astrocytes—key players in human mesial temporal lobe epilepsy? Epilepsia 2008;49(Suppl 2):42–52.
51. Oberheim NA, Tian G-F, Han X, PengW, Takano T, Ransom B, et al. Loss of astrocytic domain organization in the epileptic brain. J Neurosci. 2008;28(13):3264–3276.
52. Steinhäuser C, Seifert G. Astrocyte dysfunction in epilepsy. In: Noebels JL, Avoli M, Rogawski MA et al, editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US); 2012 Astrocyte dysfunction in epilepsy - Jasper's Basic Mechanisms of the Epilepsies - NCBI Bookshelf (nih.gov)
53. Margineanu DG. Systems biology, complexity, and the impact on antiepileptic drug discovery. Epilepsy Behav. Sep 2014;38:131–142.
54. Löscher W, Schmidt D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 2011;52(4):657–678.
55. Dawit, S.; Crepeau, A.Z. When drugs do not work: alternatives to antiseizure medications. Curr Neurol Neurosci Rep. Jul 2020;20(9):37. DOI: 10.1007/s11910-020-01061-3
56. Stacey WC, Litt B. Technology insight: neuroengineering and epilepsy – designing devices for seizure control. Nat Clin Pract Neurol. 2008;4(4):190–201.
57. Téllez-Zenteno JF, Dhar R, Hernandez-Ronquillo L, Wiebe S. Long-term outcomes in epilepsy surgery: antiepileptic drugs, mortality, cognitive and psychosocial aspects. Brain 2007;130(2):334-345.
58. Rugg-Gunn, Fergus, Miserocchi A, McEvoy A. Epilepsy surgery. Pract Neurol. 2020;20(1):4–14
59. Romanelli P, Anschel DJ. Radiosurgery for epilepsy. Lancet Neurol. 2006;5(7):613–620.
60. Margineanu DG. Epileptic hypersynchrony revisited. Neuroreport 2010;21(15):963–967.
61. Theodore WH, Fisher RS. Brain stimulation for epilepsy. Lancet Neurol. 2004;3(2):111–118.
62. Fisher RS, Velasco AL. Electrical brain stimulation for epilepsy. Nat Rev Neurol. 2014; 10(5):261–270.
63. Edwards CA, Kouzani A, Lee KH, Ross EK. Neurostimulation devices for the treatment of neurologic disorders. Mayo Clin Proc. 2017;92(9):1427–1444.
64. Bouwens van der Vlis TAM, Schijns OEMG, Schaper FLWVJ et al. Deep brain stimulation of the anterior nucleus of the thalamus for drug-resistant epilepsy. Neurosurg Rev. 2019;42(2):287–296.
65. Skarpaas TL, Jarosiewicz B, Morrell MJ. Brain-responsive neurostimulation for epilepsy (RNS® System). Epilepsy Res. Jul 2019;153:68–70.
66. Kremen V, Brinkmann BH, Kim I et al. Integrating brain implants with local and distributed computing devices: a next generation epilepsy management system. IEEE J Transl Eng Health Med. Sep 2018;6:2500112. DOI: 10.1109/JTEHM.2018.2869398
67. Tsuboyama M, Kaye HL, Rotenberg A. Biomarkers obtained by transcranial magnetic stimulation of the motor cortex in epilepsy. Front Integr Neurosci. Oct 2019;13:57. doi: 10.3389/fnint.2019.00057
68. Tsuboyama M, Kaye HL, Rotenberg A. Review of transcranial magnetic stimulation in epilepsy. Clin Ther. 2020;42(7):1155–1168.
69. Nilsen KE, Cock HR. Focal treatment for refractory epilepsy: hope for the future? Brain Res Rev. 2004;44(2-3):141–153.
70. Gernert M, Feja M. Bypassing the blood-brain barrier: direct intracranial drug delivery in epilepsies. Pharmaceutics 2020;12(12):1134; doi: 10.3390/pharmaceutics12121134
71. Stein AG, Eder HG, Blum DE et al. An automated drug delivery system for focal epilepsy. Epilepsy Res. 2000;39(2):103–114.
72. Cook M, Murphy M, Bulluss K et al. Anti-seizure therapy with a long-term, implanted intra-cerebroventricular delivery system for drug-resistant epilepsy: a first-in-man study. EClinicalMedicine May 2020;22:100326 DOI: 10.1016/j.eclinm.2020.100326
73. Freese A, Kaplitt MG, O'Connor WM et al. Direct gene transfer into human epileptogenic hippocampal tissue with an adeno-associated virus vector: implications for a gene therapy approach to epilepsy. Epilepsia 1997;38(7):759–766.
74. Löscher W, Ebert U, Lehmann H et al. Seizure suppression in kindling epilepsy by grafts of fetal GABAergic neurons in rat substantia nigra. J Neurosci Res. 1998;51(2):196–209.
75. Boison D. Cell and gene therapies for refractory epilepsy. Curr Neuropharmacol. 2007;5(2):115–125.
76. Loscher W, Gernert M, Heinemann U. Cell and gene therapies in epilepsy – promising avenues or blind alleys? Trends Neurosci. 2008;31(2):62–73.
77. Dudek FE. Commentary: a skeptical view of experimental gene therapy to block epileptogenesis. Neurotherapeutics 2009;6(2):319–322.
78. Riban V, Fitzsimons HL, During MJ. Gene therapy in epilepsy. Epilepsia 2009;50(1):24–32.
79. Naegele JR, Maisano X, Yang J et al. Recent advancements in stem cell and gene therapies for neurological disorders and intractable epilepsy. Neuropharmacol. 2010;58(6):855–864.
80. Ess KC. Patient heal thyself: modeling and treating neurological disorders using patient-derived stem cells. Exp Biol Med. (Maywood) 2013;238(3):308–314.
81 Simonato M. Gene therapy for epilepsy. Epilepsy Behav. Sep 2014;38:125–130.
82. Lybrand ZR, Goswami S, Hsieh J. Stem cells: A path towards improved epilepsy therapies. Neuropharmacol. May 2020;168:107781. doi: 10.1016/j.neuropharm.2019.107781
83. Wheless JW. History of the ketogenic diet. Epilepsia 2008;49(Suppl 8):3–5.
84. Kossoff EH, Dorward JL. The modified Atkins diet. Epilepsia 2008;49(Suppl 8):37–41.
85. Neal EG, Chaffe H, Schwartz RH et al. A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia 2009;50(5):1109–1117.
86. Masino SA, Rho JM. Mechanisms of ketogenic diet action. In: Noebels JL.Avoli M, Rogawski MA et al., editors: Jasper’s Basic Mechanisms of the Epilepsies [Internet] 4th ed. Bethesda (MD): National Center for Biotechnology Information (US) 2012; Mechanisms of Ketogenic Diet Action - Jasper's Basic Mechanisms of the Epilepsies - NCBI Bookshelf (nih.gov)
87. Boison D. New insights into the mechanisms of the ketogenic diet. Curr Opin Neurol. 2017;30(2):187–192.
88. Hartman AL, Vining EP. Clinical aspects of the ketogenic diet. Epilepsia 2007;48(1):31–42.
89. Devinsky O, Vezzani A, O’Brien TJ et al. Epilepsy. Nat Rev Dis Primers 2018;3 doi: 10.1038/nrdp.2018.24.
90. Beyenburg S, Stavem K, Schmidt D. Placebo-corrected efficacy of modern antiepileptic drugs for refractory epilepsy: systematic review and meta-analysis. Epilepsia 2010;51(1):7–26.
91. Berkovic SF, Scheffer IE, Petrou S et al. A road map for precision medicine in the epilepsies. Lancet Neurol. 2015;14(12):1219–1228.
92. Myers CT, Mefford HC. Advancing epilepsy genetics in the genomic era. Genome Med. 2015;7(1):91 DOI 10.1186/s13073-015-0214-7.
93. Chen R, Snyder M. Systems biology: personalized medicine for the future? Curr Opin Pharmacol. 2012;12(5):623–628.
94. Stéphanou A, Fanchon E, Innominato PF, Ballesta A. Systems biology, systems medicine, systems pharmacology: the what and the why. Acta Biotheor. May 2018 https://doi.org/10.1007/s10441-018-9330-2
95. Kitano H. Systems biology: a brief overview. Science 2002;295(5560):1662–1664.
96. Tavassoly I, Goldfarb J, Iyengar R. Systems biology primer: the basic methods and approaches. Essays Biochem. 2018;62(4):487–500.
97. Schadt EE, Friend SH, Shaywitz DA. A network view of disease and compound screening. Nat Rev Drug Discov. 2009;8(4):286–295.
98. Margineanu DG. Systems biology impact on antiepileptic drug discovery. Epilepsy Res. 2012;98(2-3):104–115.
99. Naimo GD, Guarnaccia M, Sprovieri T et al. A systems biology approach for personalized medicine in refractory epilepsy. Int J Mol Sci. 2019 Jul;20(15):3717. doi: 10.3390/ijms20153717
100. Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008;4(11):682–690.
101. Loeb JA. Identifying targets for preventing epilepsy using systems biology. Neurosci Lett. 2011;497(3):205–212.
102. Löscher W, Klitgaard H, Twyman RE, Schmidt D. New avenues for antiepileptic drug discovery and development. Nat Rev Drug Discov. 2013;12(10):757–776.
103. Brodie MJ, Sills GJ. Combining AEDs – rational polytherapy? Seizure 2011;20(5):369–375.
104. Margineanu DG. Neuropharmacology beyond reductionism – a likely prospect. Biosystems Mar 2016;141:1–9.
105. Csermely P, Korcsmáros T, Kiss HJM, London G, Nussinov R. Structure and dynamics of molecular networks: a novel paradigm of drug discovery. Pharmacol Ther. 2013;138(3):333–408.
106. Talevi A. Computational approaches for innovative antiepileptic drug discovery. Expert Opin Drug Discov. 2016;11(10):1001–1016.
107. Glicksberg BS, Li L, Chen R, Dudley J, Chen B. Leveraging big data to transform drug discovery. Methods Mol Biol. 2019;1939:91–118. DOI: 10.1007/978-1-4939-9089-4_6.
108. Muhammad J, Khan A, Ali A, Fang L et al. Network pharmacology: exploring the resources and methodologies. Curr Top Med Chem. 2018;18(12):949–964.