儿童癫痫的精准治疗

doi:10.12372/jcp.2022.21e1721

摘要/Abstract

摘要：

癫痫是儿童时期最常见且危害最大的神经系统疾病之一,抗癫痫药是主要的治疗方法,但在过去几十年,人们对癫痫的病因了解不多,因此主要是根据癫痫发作类型进行选药,治标不治本。近年来随着检测工具和手段的进步,越来越多的癫痫患儿能够找到癫痫病因,针对病因进行治疗能达到标本兼治的目的,儿童癫痫的治疗正步入精准治疗时代。文章根据2017年国际抗癫痫联盟新的癫痫病因分类,总结不同病因的检测方法以及相应的精准治疗,以期提高癫痫的治疗效果。

关键词: 癫痫, 儿童, 病因, 精准治疗

Abstract:

Epilepsy is one of the commonest and the most devastating neurological diseases in childhood, and antiepileptic drugs are the main treatment method. In the past few decades, because the causes of epilepsy were not well understood, drug selection was largely based on the type of seizure, treating only the symptoms rather than the root causes. In recent years, with new tools and means, the diagnosis of the cause of epilepsy has dramatically improved, and the treatment for the cause can achieve the purpose of treating both the symptoms and root causes. The treatment of childhood epilepsy is entering the era of precision treatment. According to the new classification of epilepsy causes published in 2017 by International League Against Epilepsy (ILAE), this paper summarizes new available tests for making diagnoses in each of the etiological categories in the ILAE classification and the corresponding precision treatment.

Key words: epilepsy, childhood, etiology, precision treatment

石秀玉, 胡琳燕, 韩芳, 邹丽萍. 儿童癫痫的精准治疗[J]. 临床儿科杂志, 2022, 40(3): 170-176.

SHI Xiuyu, HU Linyan, HAN Fang, ZOU Liping. Precision treatment in pediatric epilepsy[J]. Journal of Clinical Pediatrics, 2022, 40(3): 170-176.

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参考文献 33

[1]	Fiest KM, Sauro KM, Wiebe S, et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies[J]. Neurology, 2017, 88(3): 296-303. doi: 10.1212/WNL.0000000000003509
[2]	邓小龙, 胡春辉, 孙丹, 等. 精准药物治疗在遗传性癫痫中的应用[J]. 中国医师杂志, 2017, 19(8): 1125-1129.
[3]	臧轲君, 刘学伍, 苏永鑫, 等. 精准医学在癫痫诊疗中的临床应用进展[J]. 精准医学杂志, 2018, 33(4): 374-376.
[4]	田美玲, 谭兰. 癫痫的精准诊疗[J]. 精准医学杂志, 2018, 33(5): 377-379, 384.
[5]	Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology[J]. Epilepsia, 2017, 58(4): 522-530. doi: 10.1111/epi.2017.58.issue-4
[6]	Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology[J]. Epilepsia, 2017, 58(4): 512-521. doi: 10.1111/epi.13709 pmid: 28276062
[7]	Bowdin S, Gilbert A, Bedoukian E, et al. Recom-mendations for the integration of genomics into clinical practice[J]. Genet Med, 2016, 18(11): 1075-1084. doi: 10.1038/gim.2016.17 pmid: 27171546
[8]	Wang Y, Zhou Y, Wang H, et al. Voxel-based automated detection of focal cortical dysplasia lesions using diffusion tensor imaging and T2-weighted MRI data[J]. Epilepsy Behav, 2018, 84: 127-134. doi: 10.1016/j.yebeh.2018.04.005
[9]	Winston GP. The potential role of novel diffusion imaging techniques in the understanding and treatment of epilepsy[J]. Quant Imaging Med Surg, 2015, 5(2): 279-287.
[10]	Moeller F, Stephani U, Siniatchkin M. Simultaneous EEG and fMRI recordings (EEG-fMRI) in children with epilepsy[J]. Epilepsia, 2013, 54(6): 971-982. doi: 10.1111/epi.12197
[11]	Lascano AM, Perneger T, Vulliemoz S, et al. Yield of MRI, high-density electric source imaging (HD-ESI), SPECT and PET in epilepsy surgery candidates[J]. Clin Neurophysiol, 2016, 127(1): 150-155. doi: 10.1016/j.clinph.2015.03.025
[12]	Agarwal N, Krishnan B, Burgess RC, et al. Mag-netoencephalographic characteristics of cortical dysplasia in children[J]. Pediatr Neurol, 2018, 78: 13-19. doi: S0887-8994(17)30582-9 pmid: 29074057
[13]	Garcia-Tarodo S, Funke M, Caballero L, et al. Mag-netoencephalographic recordings in infants: a retrospective analysis of seizure-focus yield and postsurgical outcomes[J]. J Clin Neurophysiol, 2018, 35(6): 454-462. doi: 10.1097/WNP.0000000000000500 pmid: 30004913
[14]	Holmes E, Nicholson JK, Tranter G. Metabonomic characterization of genetic variations in toxicological and metabolic responses using probabilistic neural networks[J]. Chem Res Toxicol, 2001, 14(2): 182-191. pmid: 11258967
[15]	Nicholson JK, Lindon JC, Holmes E. 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data[J]. Xenobiotica, 1999, 29(11): 1181-1189. doi: 10.1080/004982599238047 pmid: 10598751
[16]	Wright CF, FitzPatrick DR, Firth HV. Paediatric genomics: diagnosing rare disease in children[J]. Nat Rev Genet, 2018, 19(5): 253-268. doi: 10.1038/nrg.2017.116
[17]	Wirrell EC, Nabbout R. Recent advances in the drug treatment of Dravet syndrome[J]. CNS Drugs, 2019, 33(9): 867-881. doi: 10.1007/s40263-019-00666-8 pmid: 31549357
[18]	Wolff M, Johannesen KM, Hedrich UBS, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders[J]. Brain, 2017, 140(5): 1316-1336. doi: 10.1093/brain/awx054
[19]	Larsen J, Carvill GL, Gardella E, et al. The phenotypic spectrum of SCN8A encephalopathy[J]. Neurology, 2015, 84(5): 480-489. doi: 10.1212/WNL.0000000000001211 pmid: 25568300
[20]	Johannesen KM, Gardella E, Encinas AC, et al. The spectrum of intermediate SCN8A-related epilepsy[J]. Epilepsia, 2019, 60(5): 830-844. doi: 10.1111/epi.14705 pmid: 30968951
[21]	Weckhuysen S, Ivanovic V, Hendrickx R, et al. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients[J]. Neurology, 2013, 81(19): 1697-1703. doi: 10.1212/01.wnl.0000435296.72400.a1 pmid: 24107868
[22]	Millichap JJ, Park KL, Tsuchida T, et al. KCNQ2 encephalopathy: features, mutational hot spots, and ezogabine treatment of 11 patients[J]. Neurol Genet, 2016, 2(5): e96. doi: 10.1212/NXG.0000000000000096
[23]	Striano P, Minassian BA. From genetic testing to precision medicine in epilepsy[J]. Neurotherapeutics, 2020, 17(2): 609-615. doi: 10.1007/s13311-020-00835-4
[24]	Passey CC, Erramouspe J, Castellanos P, et al. Concurrent quinidine and phenobarbital in the treatment of a patient with 2 KCNT1 mutations[J]. Curr Ther Res Clin Exp, 2019, 90: 106-108. doi: 10.1016/j.curtheres.2019.02.002
[25]	Kuchenbuch M, Barcia G, Chemaly N, et al. KCNT1 epilepsy with migrating focal seizures shows a temporal sequence with poor outcome, high mortality and SUDEP[J]. Brain, 2019, 142(10): 2996-3008. doi: 10.1093/brain/awz240 pmid: 31532509
[26]	Pierson TM, Yuan H, Marsh ED, et al. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine[J]. Ann Clin Transl Neurol, 2014, 1(3): 190-198. doi: 10.1002/acn3.39
[27]	Li D, Yuan H, Ortiz-Gonzalez XR, et al. GRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers[J]. Am J Hum Genet, 2016, 99(4): 802-816. doi: 10.1016/j.ajhg.2016.07.013
[28]	Daci A, Bozalija A, Jashari F, et al. Individualizing treatment approaches for epileptic patients with glucose transporter type1 (GLUT-1) deficiency[J]. Int J Mol Sci, 2018, 19(1): 122-131. doi: 10.3390/ijms19010122
[29]	Kass HR, Winesett SP, Bessone SK, et al. Use of dietary therapies amongst patients with GLUT1 deficiency syndrome[J]. Seizure, 2016, 35: 83-87. doi: 10.1016/j.seizure.2016.01.011
[30]	邹丽萍, 刘玉洁, 庞领玉, 等. 雷帕霉素治疗儿童结节性硬化症合并癫痫的临床效果及安全性观察[J]. 中华儿科杂志, 2014, 52(11): 812-816.
[31]	Dibbens LM, de Vries B, Donatello S, et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci[J]. Nat Genet, 2013, 45(5): 546-551. doi: 10.1038/ng.2599 pmid: 23542697
[32]	Vezzani A, Fujinami RS, White HS, et al. Infections, inflammation and epilepsy[J]. Acta Neuropathol, 2016, 131(2): 211-234. doi: 10.1007/s00401-015-1481-5
[33]	Hermetter C, Fazekas F, Hochmeister S. Systematic review: syndromes, early diagnosis, and treatment in autoimmune encephalitis[J]. Front Neurol, 2018, 9: 706. doi: 10.3389/fneur.2018.00706

项目	检测疾病
血液
氨基酸	氨基酸血症
酰基肉碱谱	线粒体疾病,脂肪酸氧化缺陷和酮体代谢紊乱
乳酸/丙酮酸	能量代谢障碍
溶酶体酶	溶酶体贮积病
过氧化物酶体脂肪酸	过氧化物酶体病
同型半胱氨酸	高同型半胱氨酸血症
生物素酶活性	生物素酶缺乏症
尿液
有机酸	有机酸尿症
氨基酸	氨基酸血症
尿肉碱及酰基肉碱	脂肪酸代谢缺陷病
尿液嘌呤与嘧啶代谢检测	腺苷脱氨酶缺乏症,二氢嘧啶脱氢酶缺乏症,二氢嘧啶分解酶缺乏症,β-脲基丙酸酶缺陷症
肌酸和胍基乙酸	脑肌酸缺乏综合征,肌酸缺乏综合征
硫化半胱氨酸	钼辅因子缺乏症
脑脊液
脑脊液/血液葡萄糖比值	葡萄糖转运体缺陷
甲基四氢叶酸/叶酸受体抗体	脑叶酸缺乏症
氨基酸	非酮症性高血糖,甘氨酸脑病,丝氨酸生物合成缺陷,亚硫酸盐氧化酶缺乏症
乳酸/丙酮酸	能量代谢障碍
神经递质合成与代谢缺陷筛查	3-O-甲基多巴,5-羟基色氨酸,5-羟吲哚乙酸,高香草酸,羟苯乙二醇,5-甲基四氢叶酸
其他
成纤维细胞/白细胞	溶酶体贮积病,线粒体酶活性
肌肉组织	线粒体疾病
骨髓	戈谢病,尼曼匹克病

代谢疾病	基因/病因	精准治疗
原发性脑叶酸缺乏	叶酸受体缺陷或叶酸受体抗体	亚叶酸或甲基叶酸
吡哆醇依赖性癫痫	ALDH7A	吡哆醇和亚叶酸
吡哆醛5'-磷酸依赖性癫痫	PNPO / PNPO酶	吡哆醛5'-磷酸盐
葡萄糖转运体缺陷	SLC2A1 / 葡萄糖转运蛋白1型	生酮饮食
生物素酶缺乏	BTD/生物酶	生物素
生物素硫胺素反应性基底节病	SLCl9A3 /硫胺素转运蛋白	硫胺素和生物素
丝氨酸合成缺陷	PHGDH、PSPH、PSAT	口服L-丝氨酸
肌酸缺乏综合征	SLC6A8 / GAMT	膳食中限制精氨酸,补充肌酸和L鸟氨酸
核黄素转运体缺乏症	SLC52A2 / RFVT2	核黄素
钼辅因子缺乏症A	MOCS1和MOCS2	纯化环吡蝶呤单磷酸

癫痫综合征（#OMIM）	基因	蛋白功能	可能的靶向治疗
伴有语言障碍的局灶性癫痫,有/没有智力低下（#245570）/EIEE27（#616139）	GRIN2A, GRIN2B, GRIN2D	NMDAR亚单位	NMDAR拮抗剂美金刚和右美沙芬,潜在有用(对于GOF变异)
EIEE32（#616366）	KCNA2	电压门控钾通道	对于GOF变异,4-氨基吡啶(4-AP,Kv1通道抑制剂)潜在有效
EIEE7（#613720）;BFNS1（#121200）	KCNQ2	电压门控钾通道	钾通道开启剂(瑞替加滨和依唑加滨治疗LOF变异),钠通道阻滞剂(CBZ)潜在有效
EIEE14（#614959）;夜间额叶癫痫（#615005）	KCNT1	钠活化的钾离子通道	钾通道开启剂（奎尼丁对GOF可能有效）
家族性婴儿惊厥伴阵发性舞蹈症（#602066);BFIS2（#605751）	PRRT2	突触传递调节器	钠通道阻滞剂（卡马西平、奥卡西平）
Dravet综合征（#607208）	SCN1A	电压门控钠通道	避免使用钠通道阻滞剂（卡马西平、苯妥英钠）
EIEE11（#613721);BFIS3（#607745）	SCN2A	电压门控钠通道	GOF变异用钠通道阻滞剂,LOF变异避免钠通道阻滞剂
EIEE13（#614558);BFIS5（#617080）	SCN8A	电压门控钠通道	对于GOF变异用钠通道阻滞剂
FCDII型（#607341）	mTOR, TSC1, TSC2	mTOR通路效应因子/调节因子	雷帕霉素或其他mTOR抑制剂