小儿癫痫治疗的安全性课件

小儿抗癫痫药物治疗的安全性 Adverse Effects of Antiepileptic Drugs in Children,临床流行病学,全球 9岁 4550 / 10万 年发病 35 million 80%发展中国家 新生儿惊厥: 足月 0.5%, 早产 22.2%,Renzo Guerrini, Lancet 2006; 367: 499524,预后 - benign epilepsies 20-30% - pharmacosensitive epilepsies 30% - pharmacodependent epilepsies 20% - pharmacoresistant epilepsies 13-20% 长期缓解: 早期（3M）对药物治疗有效 原发性/隐原性:症状性=3:1,Forsgren L. Epilepsy in children, 2nd edn. London: Arnold, 2004: 2125. Hauser WA,. Epilepsia. 1993; 34: 45368. Tsuboi T. Epilepsia. 1988; 29: 10310.,Determinants of outcome in childhood epilepsy P. Wolf, Acta Neurol Scand 2005: 112 (Suppl. 182): 58,决定儿童癫痫预后的因素 综合征诊断 病因 发作类型 癫痫严重程度 伴发疾病 对治疗的反应 治疗与管理质量,Acta Neurologica Scandinavica 112 (s181), 52-56. 2005,儿童癫痫综合征,Cognitive problems related to epilepsy syndromes, especially malignant epilepsies. K. van Rijckevorsel Seizure (2006) 15, 227234,1840 1860 1880 1900 1920 1940 1960 1980 2000,Antiepileptic Drug,抗癫痫药物的发展,20,15,10,5,Bromide,Phenobarbital,Phenytoin,Primidone,Ethosuximide,Benzodiazepines,Carbamazepine,Sodium Valproate,Vigabatrin,Zonisamide,Lamotrigine,Falbamate,Gabapentin,Topiramate,Fosphenytoin,Tiagabine,Oxcarbazepine,Levetiracetam,pregabalin,理想的抗癫痫药物 Idea AED,广谱 broad-spectrum,安全 safe,无药物之间相互作用 No drug-drug interaction,长半衰期 Long half-life,无认知不良影响 No cognitive side effects,成本-效益高 Good cost-effectiveness,改变自然病程 Alter the nature history of epilepsy,顺应作用机制 Use-dependent mechanism,Renzo Guerrini, Lancet 2006; 367: 499524,Tracy Glauser, Epilepsia, 47(7):10941120, 2006,AEDs不良反应的分类 Table 1 A classification of adverse effects caused by AEDs,Adverse effects of antiepileptic drugs. Acta Neurologica Scandinavica 112 (s181), 30-35.2005.,Table 2 Examples of adverse effects of AEDs in the first three categories,AEDs的不良反应分类举例,中枢神经系统介导的不良反应 非中枢性不良反应 皮肤、结缔组织 造血系统 肝脏与消化系统 肾脏 代谢 内分泌 周围神经系统,FDA guidelines: Adverse reactions are classified as frequent ( 1/100), infrequent ( 1/100), or rare ( 1/1000).,皮肤与结缔组织 Integument and Connective Tissue Effects,皮疹 AED 高敏综合征 Stevens-Johnson Syndrome 中毒性表皮坏死松解 其他,皮 疹 Benign Skin Rashes,轻的麻疹样斑疹,PHT, CBZ : 7% to 12% ； LTG: 8% to 10% 常发生于开始用药的 3 8 周 加量快时易发 多发生在芳香类AEDs: PHT,CBZ,PB, LTG 少见：VPA、TPM、GBP,高敏综合征 AED Hypersensitivity Syndrome,发生率：1/3000， 10% 致死性 多在开始用药后的 2 6 周 常伴有发热和颜面肿胀 还可伴有淋巴结病、肝炎、肾炎、心脏炎、嗜伊红细胞增多,Stevens-Johnson Syndrome,SJS由用药（50%）、病毒感染、恶性肿瘤等引起的严重免疫反应，引起黏膜损害、大疱形成 缺损部位10%体表面积 往往于用药后13周出现，之前伴有发热、咽喉痛、寒战不适， 皮疹常为紫癜样斑疹伴小疱，继而产生大疱，破溃后可感染 角膜瘢痕形成、呼吸道或消化道黏膜受累,中毒性表皮松解坏死 Toxic Epidermal Necrolysis,严重剥脱坏死性皮疹，常分布体表面积的 80%以上由药物引起，30%为致死性 常于用药后13周出现,其他皮肤及结缔组织 Other Skin and Connective Tissue Disorders,PHT：儿童青少年可引起牙龈增生，面容粗糙，多毛症 PB，PHT： Dupuytrens挛缩四肢肌腱缩短,造血系统作用 Hemopoietic System Effects,骨髓抑制 发生率 1/1000 再生障碍性贫血致死率 20% to 30% FEM：1/ 4000 to 5000 病例，是普通人群发病率（2/百万）的100倍 常发生于开始用药后的530周 CBZ：可出现再生障碍性贫血和粒性白血球缺乏症等特异质反应，发病率是普通人群发病的58倍；也可出现轻中度白细胞减少和中性粒细胞减少 当不明原因的发热、有出血倾向、口腔溃疡、瘀点时应警惕,骨髓抑制少见：PHT，PB，VPA VPA：血小板减少、抑制血小板聚集、降低纤维蛋白原等，与剂量相关 血小板减少的危险因素：VPA血药浓度： 110 mg/L in women 134 mg/L in men 急性脑损伤时应用i.v VPA 死亡率 i.v PHT,肝脏与消化系统 Hepatic and Digestive System Effects,CBZ: N= 786 AST升高 2 3 倍占14%，黄疸 9%, 均无临床症状 VPA：剂量相关性AST异常占20% -GT可在50%应用AEDs的患者中出现增高，但常为实验室异常，无肝毒性证据,芳香类AEDs（CBZ，PHT，PB）可引起严重肝毒性，但少见（1/3000），多在高敏综合征时 VPA或VPA与其他AEDs合并使用时，注意高氨血 CBZ，FEM，ESX，VPA恶心、呕吐、消化不良通常与剂量有关，常出现在开始用药初期,肾脏影响 Renal Effects,CBZ，OXZ：轻度无症状性低血钠在 5% to 40%的病人，与改变下丘脑渗透压感受器的敏感性有关，与剂量无关 TPM：肾结石发生率1.5%（是普通人群的2-4倍），男性好发；为碳酸酐酶抑制剂，可通过减少柠檬酸排泄和改变尿PH而促进肾石形成，也可出现味觉障碍、味觉反常或感觉异常,代谢、内分泌影响 Metabolic and Endocrine Effects,PHT，PB，CBZ：酶诱导剂；TGB，TPM，LTG：轻度酶诱导作用；VPA，GBP，BZD：无肝酶诱导作用 酶诱导剂可将活性维生素D转化为非活性而影响骨代谢，但骨软化少见；在癫痫母亲的孩子，特别是早产儿中，能减少维生素K的循环水平而有出血倾向；可因诱导肝微粒体酶可减少血清叶酸水平PHT，CBZ：减少T3、T4水平 (60% - 74%) 除VGB，GBP外，所有AEDs均可加剧卟啉病 VPA：体重增加（30-50%），GBP、LTG、VGB轻微 TPM，FBM，：体重减轻或食欲减退 ，TPM(7% 13%), FEM (75%). VPA轻度 VPA：PCOS和月经失调,周围神经系统 Peripheral Nervous System Effects,PTH：长期服用可发生感觉末梢神经病，感觉神经电活动幅度减低，可无症状 TPM：肢体感觉异常（15%），症状短暂而轻微,French JA et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new-onset epilepsy. Neurology 2004;62:125260. *Children only or predominantly children.,Comparison of the efficacy and tolerability of new antiepileptic drugs: what can we learn from long-term studies? Zaccara G, Acta Neurol Scand 2006: 114: 157168.,Studies published in English, Italian, French, or Spanish from 1966 up to May 2005. n=506 GBP LTG LEV OXC PGB TGB TPM ZNS 73 148 52 48 7 47 100 31 criteria open-label studies performed in drug-resistant epileptic patients in whom a new drug was added to a previous treatment, adult patients (or at least 90% aged over 18 years) studies which included only patients affected by generalized seizures were excluded the duration of the study allowed for the evaluation of our outcome measures,Sander JW. Acta Neurol Scand 2005: 112 (Suppl. 181): 2629,Topiramate: a review of its use in childhood epilepsy Database of Abstracts of Reviews of Effects. Issue 3, 2006.,RCT=5, pilot studies=2, non-comparative studie=6 efficacy in Children with partial seizures: one RCT n=86 children(2 to 16 ys) with six or more partial seizures over the 8-week baseline period; treatment duration was 16 weeks. Topiramate: 25 mg/day 125 to 400 mg/day over 8 weeks. seizure frequency reduction: topiramate placebo partial: 33.1% 10.5% secondarily generalised seizures 31.6% 10.6% .,托吡酯在儿童癫痫中的应用研究,Children and adults with generalised tonic-clonic seizures: RCT=2 , 160 patients, at least 3 poorly controlled, primary generalised tonic clonic seizures over the 8-week baseline period treatment duration= 20 weeks. The topiramate dose was titrated over 8 weeks to a target dose, 5.2 to 9.3 mg/kg/d 25 to 43 mg/kg/d One RCT (80 patients, drop-out rate 11%) topiramate placebo 56.7% 9%, The other RCT (80 patients, drop-out rate 25%, 57.1% 32.2,Lennox-Gastout Syndrome: RCT=1, 98 adults and children (mean age 11.2 years; age range: 2 to 42); treatment duration 11 weeks. The median topiramate dose was 5.8 mg/kg/d per day during the 8-week maintenance period. reduced drop attacks: topiramate placebo 14.8% 5.1% improved global parental evaluation of seizure severity (P=0.037).,Children with the West Syndrome: pilot study=2, n=21 children(3 to 25 months) One study (11 children) in children who had failed at least two courses of conventional therapy 9/11: spasm frequency was reduced 50% 5 children spasm free with no EEG evidence of typical hypsarrhythmia The other study (10 newly diagnosed children) 5/10 seizure frequency was reduced 50% 1/10 spasm free, but no EEG changes,Children and adults with newly diagnosed epilepsy of all types: RCT=1, n= 613 patients (age range: 6 to at least 64 years) topiramate carbamazepine valproic acid 100-200mg 600 mg 1,250 mg There was no significant difference between the three treatments in efficacy or tolerability A subgroup analysis n=119 children (6 to 16 years) topiramate carbamazepine valproic acid 100 200mg 600 mg 1,250 mg seizure free 63% 59% 39% 53% ( 6 ms),Adverse events: withdrawal rate due to adverse events 4.8% (8 / 106 children) RCT=4; Seven different neuropsychiatric adverse events and weight loss (199 children) were more common (greater than 5%) with topiramate than with placebo. The most frequent adverse effects : weight loss, memory, aggressive behaviour, concentration or attention problems, nervousness, fatigue, anorexia and somnolence.,conclusions : Topiramate was effective as an adjunctive treatment for treating partial or generalised seizures in children. Adverse events that may limit the dose can occur, but can be managed by slow titration,AEDs触发或加剧某些癫痫综合征,Practitioner Review: Use of antiepileptic drugs in children. Journal of Child Psychology and Psychiatry 47 (2), 115-126,TABLE 1. Potential Psychotropic Effects of Antiepileptic Drugs Psychotropic Effects of Antiepileptic Drugs. Epilepsy Currents 5 (5), 176-1812005.,AEDs对精神心理的影响,N=39, No AED (N= 13) ,CBZ monotherapy(N= 13),VPA monotherapy (N= 13),K. Eriksson et al. / Epilepsy Research 65 (2005) 189200,K. Eriksson et al. / Epilepsy Research 65 (2005) 189200,K. Eriksson et al. / Epilepsy Research 65 (2005) 189200,no AED N= 12, CBZ, N= 11, VPA, N= 10 (*p = 0.016 VPA group CBZ group, *p = 0.008 CBZ and VPA group no AED group,Fig. 1. Psychiatric disorders in patients with JME treated with VPA and TPM.,Neuropsychiatric profiles of patients with juvenile myoclonic epilepsy treated with valproate or topiramate . G.M. de Araujo Filho et al. / Epilepsy & Behavior 8 (2006) 606609,N=42, VPA=26, TPM=16,抗癫痫药物与致畸 AEDs and teratogenicity,North American AED pregnancy registry: Rate of teratogenicity: n=4274 -LTG 1.8% -VPA 8.6% -PB 12% UK pregnancy registry, n=3000 VPALTGCBZ EURAP pregnancy registry group, n=6500 confounding factors (e.g. maternal age, type of epilepsy, seizure occurrence, family history of malformations, exposure to other teratogens etc).,癫痫孕妇围产期预后前瞻性多因素对照分析（n=179） Epilepsia 47 (1), 186-192.2006,TABLE 4. Major malformations in the children of women with active epilepsy according to the medication used,新的抗癫痫药物的血药浓度监测,Which, When and Why? gabapentin, 70-120 mol/L felbamate, 125-250 mol/L lamotrigine, 10-60 mol/L levetiracetam 35-120 mol/L oxcarbazepine 50-140 mol/L tiagabine 50-250 nmol/L topiramate 15-60 mol/L vigabatrin 6-278 mol/L zonisamide 45-180 mol/L,临床前期在研的新的抗惊厥药物 Epilepsia, 44(s4) 46,卡拉博沙 Carabersat (GlaxoSmithKline) Conantokin-G (Congnetix Inc.) 普加巴林 Pregabalin (Pfizer) 瑞替加滨 Retigabine (Viatris) 卢非酰胺 Rufinamide (Novartis) RWJ 333 369 (Ortho McNeil) Safinamide (Newron) SPM 927 (Schwarz Pharma) SPD 421 (Shire) UCB 34 714 (UCB Pharma) 他仑帕奈 Talampanel (Ivax) 丙戊塞胺 (Valrocemide) (Teva),TABLE 2. Expected changes in plasma levels (concentrations) when an antiepileptic drug (AED) is added to a preexisting AED regimen,Properties of Antiepileptic Drugs in the Treatment of Idiopathic Generalized Epilepsies. Epilepsia 46 (s9), 140-148. 2005,AEDs 间的相互作用,难治性癫痫,特别是在婴幼儿症状性癫痫，将会对发育中的大脑带来严重不良影响： -难治性发作 -药物经济负担 -认知水平下降 -社会心理功能不全 -依赖行为 -生活方式受限 -生命质量下降 -并发症加剧 -死亡率增加：1/200， 3%/6 years 发育中的大脑皮层具有可塑性和功能重建,Vasconcellos et al 2001; Nolan et al 2003; Devlin et al 2003; Jonas et al 2004; Gleissner et al 2005; Jonas et al 2005; Korkman et al 2005; Janszky et al 2005； Curtiss et al 2001; van Empelen et al 2005; deBode et al 2005;,癫痫患者生命质量要素,惊厥seizures,药物不良反应Adverse drug effects,相关的神经系统缺陷Associated neurologic deficits,功能损害Impairment Physical,cognitive, Psychiatric,sedation,etc.,功能缺失Disability Activities of daily living, Psychosocial, Vocational, etc.,残障 Handicap Social, Economic, Vocational, Quality of life,社会/家庭态度与信心 Societal and family at