难治性癫痫：治疗与展望_Journal of Epilepsy

Authors：

王新艳 ,  强烈应 , 杜韫

首都医科大学三博脑科医院药剂科（北京 100089）;

Corresponding author：

强烈应, Email: qianglieying@126.com

Keywords：

难治性癫痫; 抗癫痫发作药物; 治疗; 进展

DOI：

10.7507/2096-0247.202208004

Video：

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癫痫是由于大脑神经元过度兴奋，突然异常反复放电，导致大脑功能障碍所引发的临床表现复杂多样的慢性神经系统疾病。经药物或手术治疗后仍无法得到有效控制可发展为难治性癫痫，其机制复杂。不受控制的癫痫发作是危险的，不仅可导致认知、行为退化，还会增加死亡的风险。近年来关于难治性癫痫治疗的研究已取得一定成果。本文将对近年来有关难治性癫痫的相关药物和非药物治疗方法进行综述，以期为临床诊治提供新思路。

Citation： 王新艳, 强烈应, 杜韫. 难治性癫痫：治疗与展望. Journal of Epilepsy, 2023, 9(2): 128-133. doi: 10.7507/2096-0247.202208004 Copy

1.	WHO. Epilepsy Factsheet. WHO Webpage, 2020.
2.	Beghi E, Giussani G, Nichols E, et al. Global, regional, and national burden of epilepsy, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol, 2019, 18(4): 357–375.
3.	Desli E, Spilioti M, Evangeliou A, et al. The efficacy and safety of ketogenic diets in drug-resistant epilepsy in children and adolescents: a systematic review of randomized controlled trials. Current nutrition reports, 2022, 11(2): 102-116.
4.	Beghi E, Camfield PR, Camfield CS. Epidemiologic aspects: lost intransition. Epilepsia, 2014, 55(Suppl 3): 3–7.
5.	Gomez-Ibañez A, McLachlan RS, Mirsattari SM, et al. Prognostic factors in patients with refractory idiopathic generalized epilepsy. Epilepsy Res, 2017, 130(2): 69-73.
6.	Shuli L, Xing F, Ming Z, et al. Clinical practice guidelines for the diagnosis and treatment of adult diffuse glioma‐related epilepsy. Cancer Medicine, 2019, 8(10): 4527-4535.
7.	Hwang ST, Stevens SJ, Fu AX, et al. Intractable generalized epilepsy: therapeutic approaches. Curr Neurol Neurosci Rep, 2019, 19(4): 16.
8.	Kramer U, Chi CS, Lin KL, et al. Febrile infection-related epilepsy syndrome (FIRES): Pathogenesis, treatment, and outcome: a multicenter study on 77 children. Epilepsia, 2011, 52(11): 1956-1965.
9.	Xin T, Qianyun C, Dezhi G, et al. Chinese expert recommendations on ketogenic diet therapy for super-refractory status epilepticus. Acta Epileptologica, 2022, 4(1): 1-11.
10.	Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE commissionfor classification and terminology. Epilepsia, 2017, 58(4): 522-530.
11.	Lowenstein DH. Seizures and epilepsy(20th ed). Harrison’s Principles of Internal Medicine, 2018: 3050-3068.
12.	Löscher 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.
13.	Peng J, Pang N, Wang Y, et al. Next-generation sequencing improves treatment efficacy and reduces hospitalization in children with drug-resistant epilepsy. CNS Neurosci Ther, 2019, 25(1): 14-20.
14.	Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr, 2016, 16(1): 48-61.
15.	Vossler DG, Bainbridge JL, Boggs JG, et al. Treatment of refractory convulsive status epilepticus: a comprehensive review by the American Epilepsy Society Treatments Committee. Epilepsy Curr, 2020, 20(5): 245-264.
16.	Eldufani J, Nekoui A, Blaise G. Non-anesthetic effects of ketamine. Journal of Health & Medical Informatics, 2018, 9(2): 1-6.
17.	Alkhachroum, A, Der-Nigoghossian, C, Mathews, E, et al. Ketamine to treat super-refractory status epilepticus. Neurology, 2020, 95(16): e2286-e2294.
18.	Rosati, A, De Masi, S, Guerrini, R. Ketamine for refractory status epilepticus: a systematic review. CNS Drugs, 2018, 32(11): 997-1009.
19.	Petra Opić, Raoul Sutter. The unease when using anesthetics for treatment-refractory status epilepticus: still far too many questions. Journal of Clinical Neurophysiology, 2020, 37(5): 399-405.
20.	AG Marta, SF Ivan, MS Wainwright, et al. Novel drugs and early polypharmacotherapy in status epilepticus. Seizure, 2019, 68: 79-88.
21.	Snoeren A, Majoie MHJM, Fasen KCFM, et al. Brivaracetam for the treatment of refractory epilepsy in patients with prior exposure to levetiracetam: a retrospective outcome analysis. Seizure, 2022, 96: 102-107.
22.	Simona L, Cana-foglia L, Paola-Canevini M, et al. Adjunctive brivaracetam in older patients with focal seizures: evidence from the brivaracetam add-on first italian network study (BRIVAFIRST). Drugs & Aging, 2022, 39(4): 297-304.
23.	Kouji F, Motohiro O. Brivaracetam and levetiracetam suppress astroglial l-glutamate release through hemichannel via inhibition of synaptic vesicle protein. International Journal of Molecular Sciences, 2022, 23(9): 4473-4473.
24.	Nakamura M, Cho JH, Shin H, et al. Effects of cenobamate (YKP3089), a newly developed anti-epileptic drug, on voltage-gated sodium channels in rat hippocampal CA3 neurons. Eur J Pharmacol, 2019, Jul,855: 175-182.
25.	Zaccara G, Lattanzi S, Leo A, et al. Critical appraisal of cenobamate as adjunctive treatment of focal seizures in adults. Neuropsychiatric disease and treatment, 2021, 17: 3447-3457.
26.	Steinhoff BJ, Rosenfeld WE, Serratosa JM, et al. Practical guidance for the management of adults receiving adjunctive cenobamate for the treatment of focal epilepsy-expert opinion. Epilepsy & Behavior, 2021, 123: 108270.
27.	Reena E, Emily Z, Pamela C, et al. Cenobamate treatment of focal-onset seizures: Quality of life and outcome during up to eight years of treatment. Epilepsy & Behavior, 2021, 116: 107796.
28.	Robin VT, Yash SD, Shefali K, et al. Adjunctive use of cenobamate for pediatric refractory focal-onset epilepsy: a single-center retrospective study. Epilepsy & Behavior, 2022, 130: 108679.
29.	Amin MR, Ali DW. Pharmacology of medical cannabis. Springer Nature, 2019, 1162: 151-165.
30.	Maria MB, Marta Z. Use of cannabidiol in the treatment of epilepsy. Neurologia I Neurochirurgia Polska, 2022, 56(1): 14-20.
31.	Gray RA, Whalley BJ. The proposed mechanisms of action of CBD in epilepsy. Epileptic Disord, 2020, 22(S1): 10-15.
32.	Klotz K A, Grob D, Schönberger J, et al. Effect of cannabidiol on interictal epileptiform activity and sleep architecture in children with intractable epilepsy: a prospective open-label study. CNS Drugs, 2021, 35(11): 1207-1215.
33.	Caraballo R, Reyes G, Demirdjian G, et al. Long-term use of cannabidiol-enriched medical cannabis in a prospective cohort of children with drug-resistant developmental and epileptic encephalopathy. Seizure, 2022, 95: 56-63.
34.	Harte S, Singh Y, Malone S, et al. Wallace G. Cannabidiol and refractory epilepsy:parental and caregiver perspectives of participation in a compassionate access scheme. BMC Health Services Research, 2022, 22(1): 173-173.
35.	Brodie MJ, Ben-Menachem E. Cannabinoids for epilepsy: what do we know and where do we go? Epilepsia, 2018, 59(2): 291-296.
36.	Von Wrede R, Helmstaedter C, Surges R. Cannabidiol in the treatment of epilepsy. Clinical Drug Investigation, 2021, 41(3): 211-220.
37.	Gaston TE, Bebin EM, Cutter GR, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia, 2017, 58(9): 1586-1592.
38.	Marchese F, Vari MS, Verrotti A, et al. An Open retrospective study of a standardized cannabidiol based-oil in treatment-resistant epilepsy. Cannabis and Cannabinoid Research, 2022, 7(2): 199-206.
39.	Carla M, Maria G. Novel treatments in epilepsy guided by genetic diagnosis. British journal of clinical pharmacology, 2021, 88(6): 2539-2551.
40.	Janmohamed M, Martin J, Kwan P. Pharmacoresistance – epidemiology, mechanisms, and impact on epilepsy treatment. Neuropharmacology, 2020, 168: 107790.
41.	Pérez-Pérez D , Frías-Soria CL , Rocha L. Drug-resistant epilepsy: from multiple hypotheses to an integral explanation using preclinical resources. Epilepsy & Behavior, 2021, 121(Pt B): 106430.
42.	Parker WE, Orlova KA, Parker WH, et al. Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder. Sci Transl Med, 2013, 5(182): 53.
43.	Gage M, Putra M, Wachter L, et al. Saracatinib, a src tyrosine kinase inhibitor, as a disease modifier in the rat dfp model: sex differences, neurobehavior, gliosis, neurodegeneration, and nitro-oxidative stress. Antioxidants, 2021, 11(1): 61.
44.	李欣, 陈嘉诚, 乔月朋, 等. 基于网络药理学的柴胡治疗癫痫有效活性成分、作用靶基因筛选及靶基因生物学功能分析. 山东医药, 2022, 62(9): 57-62.
45.	周娇娇, 张青萍, 吴成挺, 等. “钩藤 - 黄芩” 药对治疗癫痫的潜在作用机制探讨. 中医药临床杂志, 2022, 34(3): 498-504.
46.	Yamanaka G, Ishida Y, Kanou K, et al. Towards a treatment for neuroinflammation in epilepsy: interleukin-1 receptor antagonist, anakinra, as a potential treatment in intractable epilepsy. International Journal of Molecular Sciences, 2021, 22(12): 1-12.
47.	Dilena R, Mauri E, Aronica E, et al. Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection–related epilepsy syndrome. Epilepsia Open, 2019, 4(2): 344-350.
48.	Jun JS, Lee ST, Kim R, et al. Tocilizumab treatment for new onset refractory status epilepticus. Ann Neurol, 2018, 84(6): 940-945.
49.	Cantarín-Extremera V, Jiménez-Legido M, Duat-Rodríguez M, et al. Tocilizumab in pediatric refractory status epilepticus and acute epilepsy: experience in two patients. Journal of Neuroimmunology, 2020, 340: 577142.
50.	Kossof EH, Zupec-Kania BA, Auvin S, 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(2): 175-192.
51.	Barry D, Ellul S, Watters L, et al. The ketoenic diet in disease and development. International Journal of Developmental Neuroscience, 2018, 68: 53-58.
52.	Dressler A, Trimmel-Schwahofer P. The ketogenic diet for infants: How long can you go? Epilepsy Res, 2020, 164: 106339.
53.	Wells J, Swaminathan A, Paseka J, et al. Efficacy and safety of a ketogenic diet in children and adolescents with refractory epilepsy—a review. Nutrients, 2020, 12(6): 1809.
54.	Xiangjun D, Xiaoke X, Tingting M, et al. Evaluation of the seizure control and the tolerability of ketogenic diet in Chinese children with structural drug-resistant epilepsy. Seizure, 2022, 94: 43-51.
55.	方雨. 生酮饮食在基因突变所致难治性癫痫中应用及疗效的研究进展. 国际儿科学杂志, 2022, 49(1): 39-43.
56.	Paketci C, Edem P, Hiz S, et al. Successful treatment of intractable epilepsy with ketogenic diet therapy in twins with ALG3 -CDG. Brain and Development, 2020, 42(7): 539-545.
57.	Kaul N, Nation J, Laing J, et al. Modified low ratio ketogenic therapy in the treatment of adults with super refractory status epilepticus. Journal of Parenteral and Enteral Nutrition, 2022, 13: 1-9.
58.	陈婷, 陈娅, 张海青, 等. 肠道微生态与癫痫的相关性研究进展. 中华神经医学志, 2019, 18(4): 413-416.
59.	Arulsamy A, Tan QY, Balasubramaniam V, et al. Gut microbiota and epilepsy: a systematic review on their relationship and possible therapeutics. ACS Chem Neurosci, 2020, 11(21): 3488-3498.
60.	Mengoni F, Salari V, Kosenkova I, et al, Gut microbiota modulates seizure susceptibility. Epilepsia, 2021 , 62(9): e153-e157.
61.	Kızılaslan N, Sumbul O, Aygun H. The benefcial efect of probiotics supplementation on penicillin-induced focal seizure in rats. Neurochemical Research, 2022, 47(5): 1395-1404.
62.	Holmes M, Flaminio Z, Vardhan M, et al. Cross talk between drug-resistant epilepsy and the gut microbiome. Epilepsia, 2020, 61(12): 2619-2628.
63.	Olson CA, Iñiguez AJ, Yang GE, et al. Alterations in the gut microbiota contribute to cognitive impairment induced by the ketogenic diet and hypoxia. Cell Host & Microbe, 2021, 29(9): 1378-1392.

1. WHO. Epilepsy Factsheet. WHO Webpage, 2020.
2. Beghi E, Giussani G, Nichols E, et al. Global, regional, and national burden of epilepsy, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol, 2019, 18(4): 357–375.
3. Desli E, Spilioti M, Evangeliou A, et al. The efficacy and safety of ketogenic diets in drug-resistant epilepsy in children and adolescents: a systematic review of randomized controlled trials. Current nutrition reports, 2022, 11(2): 102-116.
4. Beghi E, Camfield PR, Camfield CS. Epidemiologic aspects: lost intransition. Epilepsia, 2014, 55(Suppl 3): 3–7.
5. Gomez-Ibañez A, McLachlan RS, Mirsattari SM, et al. Prognostic factors in patients with refractory idiopathic generalized epilepsy. Epilepsy Res, 2017, 130(2): 69-73.
6. Shuli L, Xing F, Ming Z, et al. Clinical practice guidelines for the diagnosis and treatment of adult diffuse glioma‐related epilepsy. Cancer Medicine, 2019, 8(10): 4527-4535.
7. Hwang ST, Stevens SJ, Fu AX, et al. Intractable generalized epilepsy: therapeutic approaches. Curr Neurol Neurosci Rep, 2019, 19(4): 16.
8. Kramer U, Chi CS, Lin KL, et al. Febrile infection-related epilepsy syndrome (FIRES): Pathogenesis, treatment, and outcome: a multicenter study on 77 children. Epilepsia, 2011, 52(11): 1956-1965.
9. Xin T, Qianyun C, Dezhi G, et al. Chinese expert recommendations on ketogenic diet therapy for super-refractory status epilepticus. Acta Epileptologica, 2022, 4(1): 1-11.
10. Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE commissionfor classification and terminology. Epilepsia, 2017, 58(4): 522-530.
11. Lowenstein DH. Seizures and epilepsy(20th ed). Harrison’s Principles of Internal Medicine, 2018: 3050-3068.
12. Löscher 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.
13. Peng J, Pang N, Wang Y, et al. Next-generation sequencing improves treatment efficacy and reduces hospitalization in children with drug-resistant epilepsy. CNS Neurosci Ther, 2019, 25(1): 14-20.
14. Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr, 2016, 16(1): 48-61.
15. Vossler DG, Bainbridge JL, Boggs JG, et al. Treatment of refractory convulsive status epilepticus: a comprehensive review by the American Epilepsy Society Treatments Committee. Epilepsy Curr, 2020, 20(5): 245-264.
16. Eldufani J, Nekoui A, Blaise G. Non-anesthetic effects of ketamine. Journal of Health & Medical Informatics, 2018, 9(2): 1-6.
17. Alkhachroum, A, Der-Nigoghossian, C, Mathews, E, et al. Ketamine to treat super-refractory status epilepticus. Neurology, 2020, 95(16): e2286-e2294.
18. Rosati, A, De Masi, S, Guerrini, R. Ketamine for refractory status epilepticus: a systematic review. CNS Drugs, 2018, 32(11): 997-1009.
19. Petra Opić, Raoul Sutter. The unease when using anesthetics for treatment-refractory status epilepticus: still far too many questions. Journal of Clinical Neurophysiology, 2020, 37(5): 399-405.
20. AG Marta, SF Ivan, MS Wainwright, et al. Novel drugs and early polypharmacotherapy in status epilepticus. Seizure, 2019, 68: 79-88.
21. Snoeren A, Majoie MHJM, Fasen KCFM, et al. Brivaracetam for the treatment of refractory epilepsy in patients with prior exposure to levetiracetam: a retrospective outcome analysis. Seizure, 2022, 96: 102-107.
22. Simona L, Cana-foglia L, Paola-Canevini M, et al. Adjunctive brivaracetam in older patients with focal seizures: evidence from the brivaracetam add-on first italian network study (BRIVAFIRST). Drugs & Aging, 2022, 39(4): 297-304.
23. Kouji F, Motohiro O. Brivaracetam and levetiracetam suppress astroglial l-glutamate release through hemichannel via inhibition of synaptic vesicle protein. International Journal of Molecular Sciences, 2022, 23(9): 4473-4473.
24. Nakamura M, Cho JH, Shin H, et al. Effects of cenobamate (YKP3089), a newly developed anti-epileptic drug, on voltage-gated sodium channels in rat hippocampal CA3 neurons. Eur J Pharmacol, 2019, Jul,855: 175-182.
25. Zaccara G, Lattanzi S, Leo A, et al. Critical appraisal of cenobamate as adjunctive treatment of focal seizures in adults. Neuropsychiatric disease and treatment, 2021, 17: 3447-3457.
26. Steinhoff BJ, Rosenfeld WE, Serratosa JM, et al. Practical guidance for the management of adults receiving adjunctive cenobamate for the treatment of focal epilepsy-expert opinion. Epilepsy & Behavior, 2021, 123: 108270.
27. Reena E, Emily Z, Pamela C, et al. Cenobamate treatment of focal-onset seizures: Quality of life and outcome during up to eight years of treatment. Epilepsy & Behavior, 2021, 116: 107796.
28. Robin VT, Yash SD, Shefali K, et al. Adjunctive use of cenobamate for pediatric refractory focal-onset epilepsy: a single-center retrospective study. Epilepsy & Behavior, 2022, 130: 108679.
29. Amin MR, Ali DW. Pharmacology of medical cannabis. Springer Nature, 2019, 1162: 151-165.
30. Maria MB, Marta Z. Use of cannabidiol in the treatment of epilepsy. Neurologia I Neurochirurgia Polska, 2022, 56(1): 14-20.
31. Gray RA, Whalley BJ. The proposed mechanisms of action of CBD in epilepsy. Epileptic Disord, 2020, 22(S1): 10-15.
32. Klotz K A, Grob D, Schönberger J, et al. Effect of cannabidiol on interictal epileptiform activity and sleep architecture in children with intractable epilepsy: a prospective open-label study. CNS Drugs, 2021, 35(11): 1207-1215.
33. Caraballo R, Reyes G, Demirdjian G, et al. Long-term use of cannabidiol-enriched medical cannabis in a prospective cohort of children with drug-resistant developmental and epileptic encephalopathy. Seizure, 2022, 95: 56-63.
34. Harte S, Singh Y, Malone S, et al. Wallace G. Cannabidiol and refractory epilepsy:parental and caregiver perspectives of participation in a compassionate access scheme. BMC Health Services Research, 2022, 22(1): 173-173.
35. Brodie MJ, Ben-Menachem E. Cannabinoids for epilepsy: what do we know and where do we go? Epilepsia, 2018, 59(2): 291-296.
36. Von Wrede R, Helmstaedter C, Surges R. Cannabidiol in the treatment of epilepsy. Clinical Drug Investigation, 2021, 41(3): 211-220.
37. Gaston TE, Bebin EM, Cutter GR, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia, 2017, 58(9): 1586-1592.
38. Marchese F, Vari MS, Verrotti A, et al. An Open retrospective study of a standardized cannabidiol based-oil in treatment-resistant epilepsy. Cannabis and Cannabinoid Research, 2022, 7(2): 199-206.
39. Carla M, Maria G. Novel treatments in epilepsy guided by genetic diagnosis. British journal of clinical pharmacology, 2021, 88(6): 2539-2551.
40. Janmohamed M, Martin J, Kwan P. Pharmacoresistance – epidemiology, mechanisms, and impact on epilepsy treatment. Neuropharmacology, 2020, 168: 107790.
41. Pérez-Pérez D , Frías-Soria CL , Rocha L. Drug-resistant epilepsy: from multiple hypotheses to an integral explanation using preclinical resources. Epilepsy & Behavior, 2021, 121(Pt B): 106430.
42. Parker WE, Orlova KA, Parker WH, et al. Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder. Sci Transl Med, 2013, 5(182): 53.
43. Gage M, Putra M, Wachter L, et al. Saracatinib, a src tyrosine kinase inhibitor, as a disease modifier in the rat dfp model: sex differences, neurobehavior, gliosis, neurodegeneration, and nitro-oxidative stress. Antioxidants, 2021, 11(1): 61.
44. 李欣, 陈嘉诚, 乔月朋, 等. 基于网络药理学的柴胡治疗癫痫有效活性成分、作用靶基因筛选及靶基因生物学功能分析. 山东医药, 2022, 62(9): 57-62.
45. 周娇娇, 张青萍, 吴成挺, 等. “钩藤 - 黄芩” 药对治疗癫痫的潜在作用机制探讨. 中医药临床杂志, 2022, 34(3): 498-504.
46. Yamanaka G, Ishida Y, Kanou K, et al. Towards a treatment for neuroinflammation in epilepsy: interleukin-1 receptor antagonist, anakinra, as a potential treatment in intractable epilepsy. International Journal of Molecular Sciences, 2021, 22(12): 1-12.
47. Dilena R, Mauri E, Aronica E, et al. Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection–related epilepsy syndrome. Epilepsia Open, 2019, 4(2): 344-350.
48. Jun JS, Lee ST, Kim R, et al. Tocilizumab treatment for new onset refractory status epilepticus. Ann Neurol, 2018, 84(6): 940-945.
49. Cantarín-Extremera V, Jiménez-Legido M, Duat-Rodríguez M, et al. Tocilizumab in pediatric refractory status epilepticus and acute epilepsy: experience in two patients. Journal of Neuroimmunology, 2020, 340: 577142.
50. Kossof EH, Zupec-Kania BA, Auvin S, 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(2): 175-192.
51. Barry D, Ellul S, Watters L, et al. The ketoenic diet in disease and development. International Journal of Developmental Neuroscience, 2018, 68: 53-58.
52. Dressler A, Trimmel-Schwahofer P. The ketogenic diet for infants: How long can you go? Epilepsy Res, 2020, 164: 106339.
53. Wells J, Swaminathan A, Paseka J, et al. Efficacy and safety of a ketogenic diet in children and adolescents with refractory epilepsy—a review. Nutrients, 2020, 12(6): 1809.
54. Xiangjun D, Xiaoke X, Tingting M, et al. Evaluation of the seizure control and the tolerability of ketogenic diet in Chinese children with structural drug-resistant epilepsy. Seizure, 2022, 94: 43-51.
55. 方雨. 生酮饮食在基因突变所致难治性癫痫中应用及疗效的研究进展. 国际儿科学杂志, 2022, 49(1): 39-43.
56. Paketci C, Edem P, Hiz S, et al. Successful treatment of intractable epilepsy with ketogenic diet therapy in twins with ALG3 -CDG. Brain and Development, 2020, 42(7): 539-545.
57. Kaul N, Nation J, Laing J, et al. Modified low ratio ketogenic therapy in the treatment of adults with super refractory status epilepticus. Journal of Parenteral and Enteral Nutrition, 2022, 13: 1-9.
58. 陈婷, 陈娅, 张海青, 等. 肠道微生态与癫痫的相关性研究进展. 中华神经医学志, 2019, 18(4): 413-416.
59. Arulsamy A, Tan QY, Balasubramaniam V, et al. Gut microbiota and epilepsy: a systematic review on their relationship and possible therapeutics. ACS Chem Neurosci, 2020, 11(21): 3488-3498.
60. Mengoni F, Salari V, Kosenkova I, et al, Gut microbiota modulates seizure susceptibility. Epilepsia, 2021 , 62(9): e153-e157.
61. Kızılaslan N, Sumbul O, Aygun H. The benefcial efect of probiotics supplementation on penicillin-induced focal seizure in rats. Neurochemical Research, 2022, 47(5): 1395-1404.
62. Holmes M, Flaminio Z, Vardhan M, et al. Cross talk between drug-resistant epilepsy and the gut microbiome. Epilepsia, 2020, 61(12): 2619-2628.
63. Olson CA, Iñiguez AJ, Yang GE, et al. Alterations in the gut microbiota contribute to cognitive impairment induced by the ketogenic diet and hypoxia. Cell Host & Microbe, 2021, 29(9): 1378-1392.

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