拉莫三嗪添加治疗小儿难

拉莫三嗪添加治疗小儿难治性癫癎50例临床分析,四川大学华西第二医院儿科 肖侠明(610041),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:,临床资料,性别：50例中，男性16人(32%)，女性34人(68%)。2. 年龄：小于3岁2人(4%)， 17岁6人(12%)， 12岁24人(48%)， 18岁18人(36%)。,3. 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，10人(20)在5-10年。,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)。,4. 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/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。,5. 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。,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。,Discussion,癫癎80发病于14岁以下儿童,癫癎发作有自发性(spontaneous)、突发性(sudden)、丛集性(cluster)、阵发性(paroxysmal)、反复性(recurrent)、不规则性(irregular)、难以预测性(unpredictable)诸特点，且发作频率(frequency)和程度(severity)很不一致，因此要长期观察(long term observation)，择机(timing)作脑电图复查，停药前必须脑电图完全正常。,2. 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%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）。,3. 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。为改善预后应尽量设法治疗,特别是病因治疗。,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。,4. 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。,难治性癫癎多药治疗,应根据癫癎发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)。,5. 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 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)。,Lamotrigine,is an antiepileptic agent which blocks 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.,LEV,Lamotrigine comes as a regular 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.,Lamotrigine,was effective for the adjunctive treatment of focal seizures in children and demonstrated an acceptable safety profile.(3) Adjunctive lamotrigine 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,lamotrigine,(4) lamotrigine is a welcome addition to the available treatments for refractory childhood epilepsy, particularly Lennox-Gastaut syndrome.(5) Lamotrigine was well tolerated in children and adults.,AEDs- 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 reason for treatment discontinuation. Valproate sodium are associated with an increased risk of rash.,Lamotrigine. 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 with lamotrigine monotherapy was 1.8%; the rate with polytherapy with valproic acid was 10%; and polytherapy without valproic acid was 4.3%.,GO ON,The most recent International Lamotrigine Pregnancy Registry showed that among 414 first-trimester exposures to lamotrigine monotherapy, there were 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 syndromic cleft lip without cleft palate in infants from 564 first-trimester lamotrigine monotherapy exposures, giving a rate of 8.9 per 1,000.,Lamotrigine adjunctive therapy,among children and adolescents with primary generalized tonic-clonic seizures. Pediatrics. 2006 Aug;118(2):e371-8. Epub 2006 Jul 17.,CONCLUSIONS,Adjunctive lamotrigine therapy seems effective in controlling primary generalized tonic-clonic seizures among patients 2 to 20 years of age.,Lamotrigine extended-release,as adjunctive therapy for focal seizures. Neurology. 2007 Oct 16;69(16):1610-8.,To evaluate the efficacy and tolerability,of once-daily adjunctive lamotrigine extended-release (XR) for focal seizures in ep