耐药性癫痫的研究进展_Journal of Epilepsy

Authors：

李志强 ,  张鸿

中国医科大学附属盛京医院神经内科（沈阳 110004）;

Corresponding author：

张鸿, Email: hongzhang@cmu.edu.com

Keywords：

耐药性癫痫; 定义; 流行病学; 潜在机制; 预警因子; 治疗

DOI：

10.7507/2096-0247.202201004

Video：

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耐药性癫痫（Drug-resistant epilepsy，DRE）患者约占全部癫痫患者 30%，尽管引入了各种新的抗癫痫发作药物（Anti-seizure medications，ASMs），部分癫痫患者仍无法控制发作。这类患者过早死亡、受伤、心理社会功能障碍的风险增加，生活质量降低，因此临床迫切需要开发更有效的治疗方法。然而，由于各种类型的癫痫和癫痫发作和时间模式复杂化，尤其是耐药机制尚未完全了解，耐药仍是癫痫治疗中的一项艰巨挑战。现就近年来有关DRE的研究进展，包括定义、流行病学、潜在机制、预警因子和治疗等做一综述，以期对疾病的早期临床诊断、治疗和预后提供新思路。

Citation： 李志强, 张鸿. 耐药性癫痫的研究进展. Journal of Epilepsy, 2022, 8(4): 342-347. doi: 10.7507/2096-0247.202201004 Copy

1.	Devinsky O, Vezzani A, O'Brien TJ, et al. Epilepsy. Nat Rev Dis Primers, 2018, 4: 18024.
2.	Ngugi AK, Bottomley C, Kleinschmidt I, et al. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia, 2010, 51(5): 883-890.
3.	Kalilani L, Sun X, Pelgrims B, et al. The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia, 2018, 59(12): 2179-2193.
4.	Laxer KD, Trinka E, Hirsch LJ, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav, 2014, 37: 59-70.
5.	Kwan P, Arzimanoglou A, Berg AT, 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): 1069-1077.
6.	Bell GS, Neligan A, Sander JW. An unknown quantity-the worldwide prevalence of epilepsy. Epilepsia, 2014, 55(7): 958-962.
7.	Janmohamed M, Brodie MJ, Kwan P. Pharmacoresistance - epidemiology, mechanisms, and impact on epilepsy treatment. Neuropharmacology, 2020, 168: 107790.
8.	Sultana B, Panzini MA, Veilleux Carpentier A, et al. Incidence and Prevalence of drug-resistant epilepsy: a systematic review and meta-analysis. Neurology, 2021, 96(17): 805-817.
9.	Remy S, Beck H. Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain, 2006, 129(Pt 1): 18-35.
10.	Remy S, Gabriel S, Urban BW, et al. A novel mechanism underlying drug resistance in chronic epilepsy. Ann Neurol, 2003, 53(4): 469-479.
11.	Naylor DE, Liu H, Wasterlain CG. Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci, 2005, 25(34): 7724-7733.
12.	Ben-Ari Y, Khalilov I, Kahle KT, et al. The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist, 2012, 18(5): 467-486.
13.	Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy: multiple hypotheses, few answers. Front Neurol, 2017, 8: 301.
14.	Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci, 2005, 6(8): 591-602.
15.	Saunders NR, Habgood MD, Møllgård K, et al. The biological significance of brain barrier mechanisms: help or hindrance in drug delivery to the central nervous system? F1000Res, 2016, 5.
16.	Brandt C, Bethmann K, Gastens AM, et al. The multidrug transporter hypothesis of drug resistance in epilepsy: proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol Dis, 2006, 24(1): 202-211.
17.	Fromm MF. Importance of P-glycoprotein at blood-tissue barriers. Trends Pharmacol Sci, 2004, 25(8): 423-429.
18.	Löscher W. Animal models of seizures and epilepsy: past, present, and future role for the discovery of antiseizure drugs. Neurochem Res, 2017, 42(7): 1873-1888.
19.	Lazarowski A, Czornyj L, Lubienieki F, et al. ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy. Epilepsia, 2007, 48 Suppl 5: 140-149.
20.	Fang M, Xi ZQ, Wu Y, et al. A new hypothesis of drug refractory epilepsy: neural network hypothesis. Med Hypotheses, 2011, 76(6): 871-876.
21.	Schmidt D, Löscher W. Drug resistance in epilepsy: putative neurobiologic and clinical mechanisms. Epilepsia, 2005, 46(6): 858-877.
22.	Wiebe S, Jette N. Pharmacoresistance and the role of surgery in difficult to treat epilepsy. Nat Rev Neurol, 2012, 8(12): 669-677.
23.	Rogawski MA, Johnson MR. Intrinsic severity as a determinant of antiepileptic drug refractoriness. Epilepsy Curr, 2008, 8(5): 127-130.
24.	Rogawski MA. The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs. Epilepsia, 2013, 54 Suppl 2: 33-40.
25.	Loscher W, Klotz U, Zimprich F, et al. The clinical impact of pharmacogenetics on the treatment of epilepsy. Epilepsia, 2009, 50(1): 1-23.
26.	Tate SK, Depondt C, Sisodiya SM, et al. Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proc Natl Acad Sci U S A, 2005, 102(15): 5507-5512.
27.	Loscher W, Potschka H, Sisodiya SM, et al. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev, 2020, 72(3): 606-638.
28.	Kobow K, El-Osta A, Blümcke I. The methylation hypothesis of pharmacoresistance in epilepsy. Epilepsia, 2013, 54 Suppl 2: 41-47.
29.	Pitkänen A, Löscher W, Vezzani A, et al. Advances in the development of biomarkers for epilepsy. The Lancet Neurology, 2016, 15(8): 843-856.
30.	Gururaj A, Sztriha L, Hertecant J, et al. Clinical predictors of intractable childhood epilepsy. J Psychosom Res, 2006, 61(3): 343-347.
31.	Zhang L, Zhu X, Peng A, et al. Predictors of drug-resistance in epilepsy with auditory features. Epilepsy Res, 2020, 164: 106353.
32.	Orozco-Hernandez JP, Quintero-Moreno JF, Marin-Medina DS, et al. Multivariable prediction model of drug resistance in adult patients with generalized epilepsy from Colombia: a case-control study. Epilepsy Behav, 2018, 88: 176-180.
33.	Boonluksiri P, Visuthibhan A, Katanyuwong K. Clinical prediction rule of drug resistant epilepsy in children. J Epilepsy Res, 2015, 5(2): 84-88.
34.	Yildiz EP, Gunes D, Bektas G, et al. Predictive factors of drug-resistant epilepsy in children presenting under 2 years of age: experience of a tertiary center in Turkey. Acta Neurol Belg, 2018, 118(1): 71-75.
35.	Voll A, Hernandez-Ronquillo L, Buckley S, et al. Predicting drug resistance in adult patients with generalized epilepsy: A case-control study. Epilepsy Behav, 2015, 53: 126-130.
36.	Vezzani A, French J, Bartfai T, et al. The role of inflammation in epilepsy. Nat Rev Neurol, 2011, 7(1): 31-40.
37.	Ouedraogo O, Rebillard RM, Jamann H, et al. Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug-resistant epilepsy. Epilepsia, 2021, 62(1): 176-189.
38.	Walker LE, Frigerio F, Ravizza T, et al. Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy. J Clin Invest, 2019, 129(5): 2166.
39.	van Vliet EA, Aronica E, Vezzani A, et al. Neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies. Neuropathol Appl Neurobiol, 2018, 44(1): 91-111.
40.	He X, Li Y, Liu Z, et al. The association between CCL2 polymorphisms and drug-resistant epilepsy in Chinese children. Epileptic Disord, 2013, 15(3): 272-277.
41.	Pollard JR, Eidelman O, Mueller GP, et al. The TARC/sICAM5 ratio in patient plasma is a candidate biomarker for drug resistant epilepsy. Front Neurol, 2012, 3: 181.
42.	Zhang HL, Lin YH, Qu Y, et al. The effect of miR-146a gene silencing on drug-resistance and expression of protein of P-gp and MRP1 in epilepsy. Eur Rev Med Pharmacol Sci, 2018, 22(8): 2372-2379.
43.	Leontariti M, Avgeris M, Katsarou MS, et al. Circulating miR-146a and miR-134 in predicting drug-resistant epilepsy in patients with focal impaired awareness seizures. Epilepsia, 2020, 61(5): 959-970.
44.	Asadi-Pooya AA, Sperling MR. Epidemiology of psychogenic nonepileptic seizures. Epilepsy Behav, 2015, 46: 60-65.
45.	Brodie MJ, Barry SJ, Bamagous GA, et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology, 2012, 78(20): 1548-1554.
46.	Moshé SL, Perucca E, Ryvlin P, et al. Epilepsy: new advances. The Lancet, 2015, 385(9971): 884-898.
47.	Arnold S. Cenobamate: new hope for treatment-resistant epilepsy. The Lancet Neurology, 2020, 19(1): 23-24.
48.	Zaccara G, Schmidt D. Antiepileptic Drugs in clinical development: differentiate or die? Curr Pharm Des, 2017, 23(37): 5593-5605.
49.	Engel J, Jr. What can we do for people with drug-resistant epilepsy? The 2016 Wartenberg Lecture. Neurology, 2016, 87(23): 2483-2489.
50.	Nabbout R, Kuchenbuch M. Impact of predictive, preventive and precision medicine strategies in epilepsy. Nat Rev Neurol, 2020, 16(12): 674-688.

1. Devinsky O, Vezzani A, O'Brien TJ, et al. Epilepsy. Nat Rev Dis Primers, 2018, 4: 18024.
2. Ngugi AK, Bottomley C, Kleinschmidt I, et al. Estimation of the burden of active and life-time epilepsy: a meta-analytic approach. Epilepsia, 2010, 51(5): 883-890.
3. Kalilani L, Sun X, Pelgrims B, et al. The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia, 2018, 59(12): 2179-2193.
4. Laxer KD, Trinka E, Hirsch LJ, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav, 2014, 37: 59-70.
5. Kwan P, Arzimanoglou A, Berg AT, 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): 1069-1077.
6. Bell GS, Neligan A, Sander JW. An unknown quantity-the worldwide prevalence of epilepsy. Epilepsia, 2014, 55(7): 958-962.
7. Janmohamed M, Brodie MJ, Kwan P. Pharmacoresistance - epidemiology, mechanisms, and impact on epilepsy treatment. Neuropharmacology, 2020, 168: 107790.
8. Sultana B, Panzini MA, Veilleux Carpentier A, et al. Incidence and Prevalence of drug-resistant epilepsy: a systematic review and meta-analysis. Neurology, 2021, 96(17): 805-817.
9. Remy S, Beck H. Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain, 2006, 129(Pt 1): 18-35.
10. Remy S, Gabriel S, Urban BW, et al. A novel mechanism underlying drug resistance in chronic epilepsy. Ann Neurol, 2003, 53(4): 469-479.
11. Naylor DE, Liu H, Wasterlain CG. Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci, 2005, 25(34): 7724-7733.
12. Ben-Ari Y, Khalilov I, Kahle KT, et al. The GABA excitatory/inhibitory shift in brain maturation and neurological disorders. Neuroscientist, 2012, 18(5): 467-486.
13. Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy: multiple hypotheses, few answers. Front Neurol, 2017, 8: 301.
14. Löscher W, Potschka H. Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci, 2005, 6(8): 591-602.
15. Saunders NR, Habgood MD, Møllgård K, et al. The biological significance of brain barrier mechanisms: help or hindrance in drug delivery to the central nervous system? F1000Res, 2016, 5.
16. Brandt C, Bethmann K, Gastens AM, et al. The multidrug transporter hypothesis of drug resistance in epilepsy: proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol Dis, 2006, 24(1): 202-211.
17. Fromm MF. Importance of P-glycoprotein at blood-tissue barriers. Trends Pharmacol Sci, 2004, 25(8): 423-429.
18. Löscher W. Animal models of seizures and epilepsy: past, present, and future role for the discovery of antiseizure drugs. Neurochem Res, 2017, 42(7): 1873-1888.
19. Lazarowski A, Czornyj L, Lubienieki F, et al. ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy. Epilepsia, 2007, 48 Suppl 5: 140-149.
20. Fang M, Xi ZQ, Wu Y, et al. A new hypothesis of drug refractory epilepsy: neural network hypothesis. Med Hypotheses, 2011, 76(6): 871-876.
21. Schmidt D, Löscher W. Drug resistance in epilepsy: putative neurobiologic and clinical mechanisms. Epilepsia, 2005, 46(6): 858-877.
22. Wiebe S, Jette N. Pharmacoresistance and the role of surgery in difficult to treat epilepsy. Nat Rev Neurol, 2012, 8(12): 669-677.
23. Rogawski MA, Johnson MR. Intrinsic severity as a determinant of antiepileptic drug refractoriness. Epilepsy Curr, 2008, 8(5): 127-130.
24. Rogawski MA. The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs. Epilepsia, 2013, 54 Suppl 2: 33-40.
25. Loscher W, Klotz U, Zimprich F, et al. The clinical impact of pharmacogenetics on the treatment of epilepsy. Epilepsia, 2009, 50(1): 1-23.
26. Tate SK, Depondt C, Sisodiya SM, et al. Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proc Natl Acad Sci U S A, 2005, 102(15): 5507-5512.
27. Loscher W, Potschka H, Sisodiya SM, et al. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev, 2020, 72(3): 606-638.
28. Kobow K, El-Osta A, Blümcke I. The methylation hypothesis of pharmacoresistance in epilepsy. Epilepsia, 2013, 54 Suppl 2: 41-47.
29. Pitkänen A, Löscher W, Vezzani A, et al. Advances in the development of biomarkers for epilepsy. The Lancet Neurology, 2016, 15(8): 843-856.
30. Gururaj A, Sztriha L, Hertecant J, et al. Clinical predictors of intractable childhood epilepsy. J Psychosom Res, 2006, 61(3): 343-347.
31. Zhang L, Zhu X, Peng A, et al. Predictors of drug-resistance in epilepsy with auditory features. Epilepsy Res, 2020, 164: 106353.
32. Orozco-Hernandez JP, Quintero-Moreno JF, Marin-Medina DS, et al. Multivariable prediction model of drug resistance in adult patients with generalized epilepsy from Colombia: a case-control study. Epilepsy Behav, 2018, 88: 176-180.
33. Boonluksiri P, Visuthibhan A, Katanyuwong K. Clinical prediction rule of drug resistant epilepsy in children. J Epilepsy Res, 2015, 5(2): 84-88.
34. Yildiz EP, Gunes D, Bektas G, et al. Predictive factors of drug-resistant epilepsy in children presenting under 2 years of age: experience of a tertiary center in Turkey. Acta Neurol Belg, 2018, 118(1): 71-75.
35. Voll A, Hernandez-Ronquillo L, Buckley S, et al. Predicting drug resistance in adult patients with generalized epilepsy: A case-control study. Epilepsy Behav, 2015, 53: 126-130.
36. Vezzani A, French J, Bartfai T, et al. The role of inflammation in epilepsy. Nat Rev Neurol, 2011, 7(1): 31-40.
37. Ouedraogo O, Rebillard RM, Jamann H, et al. Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug-resistant epilepsy. Epilepsia, 2021, 62(1): 176-189.
38. Walker LE, Frigerio F, Ravizza T, et al. Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy. J Clin Invest, 2019, 129(5): 2166.
39. van Vliet EA, Aronica E, Vezzani A, et al. Neuroinflammatory pathways as treatment targets and biomarker candidates in epilepsy: emerging evidence from preclinical and clinical studies. Neuropathol Appl Neurobiol, 2018, 44(1): 91-111.
40. He X, Li Y, Liu Z, et al. The association between CCL2 polymorphisms and drug-resistant epilepsy in Chinese children. Epileptic Disord, 2013, 15(3): 272-277.
41. Pollard JR, Eidelman O, Mueller GP, et al. The TARC/sICAM5 ratio in patient plasma is a candidate biomarker for drug resistant epilepsy. Front Neurol, 2012, 3: 181.
42. Zhang HL, Lin YH, Qu Y, et al. The effect of miR-146a gene silencing on drug-resistance and expression of protein of P-gp and MRP1 in epilepsy. Eur Rev Med Pharmacol Sci, 2018, 22(8): 2372-2379.
43. Leontariti M, Avgeris M, Katsarou MS, et al. Circulating miR-146a and miR-134 in predicting drug-resistant epilepsy in patients with focal impaired awareness seizures. Epilepsia, 2020, 61(5): 959-970.
44. Asadi-Pooya AA, Sperling MR. Epidemiology of psychogenic nonepileptic seizures. Epilepsy Behav, 2015, 46: 60-65.
45. Brodie MJ, Barry SJ, Bamagous GA, et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology, 2012, 78(20): 1548-1554.
46. Moshé SL, Perucca E, Ryvlin P, et al. Epilepsy: new advances. The Lancet, 2015, 385(9971): 884-898.
47. Arnold S. Cenobamate: new hope for treatment-resistant epilepsy. The Lancet Neurology, 2020, 19(1): 23-24.
48. Zaccara G, Schmidt D. Antiepileptic Drugs in clinical development: differentiate or die? Curr Pharm Des, 2017, 23(37): 5593-5605.
49. Engel J, Jr. What can we do for people with drug-resistant epilepsy? The 2016 Wartenberg Lecture. Neurology, 2016, 87(23): 2483-2489.
50. Nabbout R, Kuchenbuch M. Impact of predictive, preventive and precision medicine strategies in epilepsy. Nat Rev Neurol, 2020, 16(12): 674-688.

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