1、拉莫三嗪添加治疗小儿拉莫三嗪添加治疗小儿难治性难治性癫癎癫癎50例临床分析例临床分析 四川大学华西第二医院儿科四川大学华西第二医院儿科 肖侠明肖侠明(610041)拉莫三嗪添加治疗小儿难1一待无热惊厥发作2次以上(extract:癫癎持续状态-status epilepticus,SE)就应早期诊断癫癎并早期正规治疗。我院小儿神经专科门诊每年有新发癫癎病儿1000人就诊，其中半数常用丙戊酸，半数常用托吡酯(妥泰),发作减少75%显效率80%;半年无效(ineffective)改药(丙戊酸/托吡酯);1年无效(占20%)用丙戊酸添加托吡酯1年,仍无效,属难治性癫癎。我院于2006年至2007年底
2、，2年中用拉莫三嗪(lamotrigine,LTG)添加治疗小儿难治性癫癎50例,现分析如下:拉莫三嗪添加治疗小儿难2临床资料临床资料1.1.性别：性别：50例中，男性16人(32%)，女性34人(68%)。2.年龄年龄：小于3岁2人(4%)，1.17岁6人(12%)，2.12岁24人(48%)，3.18岁18人(36%)。拉莫三嗪添加治疗小儿难33.癫癎发作类型癫癎发作类型：全身强直痉挛发作（GTCS）：20人(占40%)，局灶性发作继发全身性发作23人(46%)，婴儿痉挛2人(4%)，失神发作4人(8%)，和LennoxGastaut综合征1人(2%)。病程40人(80)在3-5年以内，1
3、0人(20)在5-10年。拉莫三嗪添加治疗小儿难4局灶性发作23例(46%)局灶性发作继发全身性发作中，证实有脑CT,MRI异常,诸如：大脑发育不全5例，缺氧缺血性脑(HIE)4例,小头畸型4例，颞叶癫癎3例，蛛网膜下腔出血2例,灰质异位2例，结节性硬化2例,胼胝体发育不全1例等。60%合并智能低下(MR)。拉莫三嗪添加治疗小儿难54.拉莫三嗪添加治疗及结果拉莫三嗪添加治疗及结果拉莫三嗪片,50mg/片。添加治疗常规起始量剂量（initiating dose）常5mg睡前服一次，以后-6.25-12.5-25-50-100mg，每2周增加，直至无发作疗程2年以上(小儿:0.15 mg/kg,1
4、/d 12wks,0.3 mg/kg,1/d,12 wks,up to 215 mg/(kgd)。LTG与VPA/TPM合用,疗效良好半年,停一药(VPA or TPM),用VPA+LTG or TPM+LTG。结果拉莫三嗪添加治疗后,半年完全无发作率18例(36%);1年完全无发作率15例(30%);但1年后仍有17人(34%)发作无改善。拉莫三嗪添加治疗小儿难65.拉莫三嗪药物不良反应拉莫三嗪药物不良反应(ADRs)以头晕,嗜睡为主，5例（占10%），食欲减退次之4例(8%)，有1 例有认知障碍(注意力不集中,记忆力减退),皮疹0例。总的来说，副作用大多仍能耐受。未发现服药后发作加重者。拉
5、莫三嗪添加治疗小儿难7综上综上Standard and New Antiepileptic Drugs(SANAD,2007)研究支持局灶性癫痫发作治疗应首选拉莫三嗪,证明拉莫三嗪可以替代卡马西平,成为局灶性癫痫发作治疗的新标准。拉莫三嗪抗癫癎的疗效是肯定的，添加治疗难治性癫癎疗效好,单药治疗各型癫癎初治病人疗效亦好,可以作为各型癫癎第一线药用于初始病例。拉莫三嗪添加治疗小儿难8Discussion1.1.癫癎癫癎80发病于发病于14岁以下儿童岁以下儿童,癫癎发癫癎发作有自发性作有自发性(spontaneous)、突发性、突发性(sudden)、丛集性、丛集性(cluster)、阵发性、阵发性
6、(paroxysmal)、反复性、反复性(recurrent)、不、不规则性规则性(irregular)、难以预测性、难以预测性(unpredictable)诸特点，且发作频率诸特点，且发作频率(frequency)和程度和程度(severity)很不一致，很不一致，因 此 要 长 期 观 察因 此 要 长 期 观 察(l o n g t e r m observation)，择机，择机(timing)作脑电图作脑电图复查，停药前必须脑电图完全正常。复查，停药前必须脑电图完全正常。拉莫三嗪添加治疗小儿难92.癫癎自然发作史癫癎自然发作史对未与治疗的330例癫癎(EP)病人进行长期观察，结果66
7、%发作频率增加，25%发作频率不变，10%发作频率自然减少。两次发作之间的间隔期平均3.6月，70%有癫癎持续状态及丛发（Paurannik）。拉莫三嗪添加治疗小儿难103.下列病况者易发难治性癫癎诸如年龄小发病于2岁以下，有频繁全身性发作尤其婴儿痉挛发作,失张力发作，有脑损伤基础疾病或脑结构畸形(如灰质异位，小头畸形),颞叶癫癎，癫癎性脑病(如大田原综合征,IS,LGS)，或为特殊癫癎综合征(Rasmussen综合征);伴有智力低下，脑性瘫痪者，脑电图明显不对称、不同步性异常,且长期无好转者，多药耐药(multidrugs-resistant,MDR)以及有心理，行为障碍，生活质量低下等。为
8、改善预后应尽量设法治疗,特别是病因治疗。拉莫三嗪添加治疗小儿难11患者癫癎发作长期不能控制的原因没有按癫癎发作类型选药;用量不够;多药联用,急于多药联用;治疗不专一,药物更换频繁;停药太快;不规律服药;有部分癫癎患者因为有先天脑发育异常、后天脑软化或者有遗传因素，也是造成长期不能控制的原因。拉莫三嗪添加治疗小儿难124.难治性癫癎多药治疗难治性癫癎多药治疗癫癎有慢性反复发作的特点，20%(15%25%)的癫癎病人经3种AEDs正规治疗2年以上,仍每月发作1次以上，可归为难治性(intractable)或顽固性(refractory)癫癎。拉莫三嗪添加治疗小儿难13难治性癫癎多药治疗应根据癫癎发
9、作类型和癫癎综合征正确选择抗癫痫药。先选用正确的抗癫痫药单药治疗,二种单药疗效不佳时,再二药联用;如一线(first line drugs)2种(3种)单药、6个月治疗无效,须加用(add-on)另1种2种抗癫癎药,以不超过3种为宜。一、二线药已有十余种，要科学地、艺术性地、个别化地联合用药(scientific,artic,individual combination medication)。拉莫三嗪添加治疗小儿难145.疗效判断疗效判断服药后第一次发作时间(time to first seizure)，6个月(or 24wks)，12个月(or 48wks),5年缓解率(rates of
10、remission)，无发作比例(seizure-free)。服药后发作次数减少50%表明有效(Sz-reduction rates decreased 50%-effective)，减少75%表明显效(excellent,well-controlled Sz)，减少100%表明发作完全控制(complete controlled)，发作减少不足50%表明无效(ineffective)，可改药(change drug)或添加治疗(added-on treatment)。拉莫三嗪添加治疗小儿难15Lamotrigineis an antiepileptic agent which blocks
11、voltage-dependent sodium channels,thereby preventing excitatory neurotransmitter release.Lamotrigine is completely absorbed following oral administration,and the bioavailability is approximately 98%.In general,the pharmacokinetics of lamotrigine are linear.拉莫三嗪添加治疗小儿难16LEVLamotrigine comes as a regu
12、lar tablet and a chewable dispersible(can be chewed or dissolved in liquid)tablet to take by mouth.It is usually taken once or twice a day.拉莫三嗪添加治疗小儿难17Lamotriginewas effective for the adjunctive treatment of focal seizures in children and demonstrated an acceptable safety profile.(3)Adjunctive lamo
13、trigine is effective in the treatment of primary generalized tonic-clonic seizures and has a favorable tolerability profile.Total seizure frequency was reduced by 17 to 59%compared with placebo,拉莫三嗪添加治疗小儿难18lamotrigine(4)lamotrigine is a welcome addition to the available treatments for refractory ch
14、ildhood epilepsy,particularly Lennox-Gastaut syndrome.(5)Lamotrigine was well tolerated in children and adults.拉莫三嗪添加治疗小儿难19AEDs-skin rash(6)Maculopapular or erythematous skin rash,occurred in approximately 10%of paediatric patients(aged 16 years)treated with lamotrigine and was the most common reas
15、on for treatment discontinuation.Valproate sodium are associated with an increased risk of rash.拉莫三嗪添加治疗小儿难20Lamotrigine.From a registry of 334 pregnancies(7)there were different rates of major structural birth defects depending on whether lamotrigine was used in monotherapy or polytherapy.The rate
16、with lamotrigine monotherapy was 1.8%;the rate with polytherapy with valproic acid was 10%;and polytherapy without valproic acid was 4.3%.拉莫三嗪添加治疗小儿难21GO ONThe most recent International Lamotrigine Pregnancy Registry showed that among 414 first-trimester exposures to lamotrigine monotherapy,there we
17、re 12 outcomes with major birth defects reported,ie,2.9%,similar to that in the general population.Although there have been suggestions that lamotrigine may be less teratogenic than older antiepileptic drugs,recently report 3 cases of isolated,non syndromic cleft palate and 2 cases of isolated,non s
18、yndromic cleft lip without cleft palate in infants from 564 first-trimester lamotrigine monotherapy exposures,giving a rate of 8.9 per 1,000.拉莫三嗪添加治疗小儿难22Lamotrigine adjunctive therapyamong children and adolescents with primary generalized tonic-clonic s e i z u r e s.P e d i a t r i c s.2 0 0 6 Aug
19、;118(2):e371-8.Epub 2006 Jul 17.拉莫三嗪添加治疗小儿难23CONCLUSIONS Adjunctive lamotrigine therapy seems effective in controlling primary generalized tonic-clonic seizures among patients 2 to 20 years of age.拉莫三嗪添加治疗小儿难24Lamotrigine extended-releaseas adjunctive therapy for focal seizures.Neurology.2007 Oct 16
20、;69(16):1610-8.拉莫三嗪添加治疗小儿难25To evaluate the efficacy and tolerabilityof once-daily adjunctive lamotrigine extended-release(XR)for focal seizures in epilepsy.CONCLUSIONS:Once-daily adjunctive lamotrigine extended-release compared with placebo effectively reduced focal seizure frequency and was well tolerated in this double-blind study.Results support the clinical utility of this new once-daily formulation.拉莫三嗪添加治疗小儿难26That is allThank you.拉莫三嗪添加治疗小儿难27
