拉莫三嗪添加治療小兒難

1、拉莫三嗪添加治療小兒難治性癲癎50例臨床分析,四川大學(xué)華西第二醫(yī)院兒科 肖俠明(610041),一待無熱驚厥發(fā)作2次以上(extract:癲癎持續(xù)狀態(tài)-status epilepticus, SE),就應(yīng)早期診斷癲癎并早期正規(guī)治療。我院小兒神經(jīng)?？崎T診每年有新發(fā)癲癎病兒1000人就診，其中半數(shù)常用丙戊酸，半數(shù)常用托吡酯(妥泰), 發(fā)作減少75%顯效率80%;半年無效(ineffective)改藥(丙戊酸/托吡酯);

2、1年無效(占20%)用丙戊酸添加托吡酯1年, 仍無效, 屬難治性癲癎。我院于2006年至2007年底，2年中用拉莫三嗪( lamotrigine, LTG)添加治療小兒難治性癲癎50例,現(xiàn)分析如下:,臨床資料,性別：50例中，男性16人(32%)，女性34人(68%)。2. 年齡：小于3歲2人(4%)， 1－7歲6人(12%)， －12歲24人(48%)， －18歲18人(36%)。,3. 癲癎發(fā)作類型：,全身強(qiáng)直痙攣

3、發(fā)作（GTCS）：20人(占40%)，局灶性發(fā)作繼發(fā)全身性發(fā)作23人(46%)，嬰兒痙攣2人(4%)，失神發(fā)作4人(8%)，和Lennox－Gastaut綜合征1人(2%)。病程40人(80％)在3-5年以內(nèi)，10人(20％)在5-10年。,局灶性發(fā)作,23例(46%)局灶性發(fā)作繼發(fā)全身性發(fā)作中， 證實(shí)有腦CT,MRI異常,諸如：大腦發(fā)育不全5例，缺氧缺血性腦(HIE) 4例, 小頭畸型4例，顳葉癲癎3例，蛛網(wǎng)膜下腔出血2例,灰質(zhì)

4、異位2例，結(jié)節(jié)性硬化2例,胼胝體發(fā)育不全1例等。60%合并智能低下(MR)。,4. 拉莫三嗪添加治療及結(jié)果,拉莫三嗪片,50mg/片。添加治療常規(guī)起始量劑量（initiating dose）常5mg睡前服一次，以后-6.25-12.5-25-50-100mg，每2周增加，直至無發(fā)作療程2年以上(小兒:0.15 mg/kg,1/d 1~2wks,0.3 mg/kg,1/d,1~`2 wks, up to 2~15 mg/(kg·

5、d)。LTG與VPA/TPM合用,療效良好>半年, 停一藥(VPA or TPM), 用VPA+LTG or TPM+LTG。結(jié)果拉莫三嗪添加治療后, 半年完全無發(fā)作率18例(36%);1年完全無發(fā)作率15例(30%);但1年后仍有17人(34%)發(fā)作無改善。,5. 拉莫三嗪藥物不良反應(yīng)(ADRs),以頭暈,嗜睡為主， 5例（占10%），食欲減退次之4例(8%)，有1 例有認(rèn)知障礙(注意力不集中,記憶力減退),皮疹0例。總的來

6、說，副作用大多仍能耐受。未發(fā)現(xiàn)服藥后發(fā)作加重者。,綜上,Standard and New Antiepileptic Drugs ( SANAD,2007)研究支持局灶性癲癇發(fā)作治療應(yīng)首選拉莫三嗪,證明拉莫三嗪可以替代卡馬西平,成為局灶性癲癇發(fā)作治療的新標(biāo)準(zhǔn)。拉莫三嗪抗癲癎的療效是肯定的，添加治療難治性癲癎療效好, 單藥治療各型癲癎初治病人療效亦好,可以作為各型癲癎第一線藥用于初始病例。,Discussion,癲癎80％發(fā)病于14歲以

7、下兒童,癲癎發(fā)作有自發(fā)性(spontaneous)、突發(fā)性(sudden)、叢集性(cluster)、陣發(fā)性(paroxysmal)、反復(fù)性(recurrent)、不規(guī)則性(irregular)、難以預(yù)測性(unpredictable)諸特點(diǎn)，且發(fā)作頻率(frequency)和程度(severity)很不一致，因此要長期觀察(long term observation)，擇機(jī)(timing)作腦電圖復(fù)查，停藥前必須腦電圖完全正常。,2.

8、 癲癎自然發(fā)作史,對未與治療的330例癲癎(EP)病人進(jìn)行長期觀察，結(jié)果66%發(fā)作頻率增加，25%發(fā)作頻率不變，10%發(fā)作頻率自然減少。兩次發(fā)作之間的間隔期平均3.6月，70%有癲癎持續(xù)狀態(tài)及叢發(fā)（Paurannik）。,3. 下列病況者易發(fā)難治性癲癎,諸如年齡小發(fā)病于2歲以下，有頻繁全身性發(fā)作尤其嬰兒痙攣發(fā)作,失張力發(fā)作，有腦損傷基礎(chǔ)疾病或腦結(jié)構(gòu)畸形(如灰質(zhì)異位，小頭畸形),顳葉癲癎，癲癎性腦病(如大田原綜合征,IS,LGS)，或為特

9、殊癲癎綜合征(Rasmussen綜合征);伴有智力低下，腦性癱瘓者，腦電圖明顯不對稱、不同步性異常,且長期無好轉(zhuǎn)者，多藥耐藥(multidrugs-resistant, MDR)以及有心理，行為障礙，生活質(zhì)量低下等。為改善預(yù)后應(yīng)盡量設(shè)法治療,特別是病因治療。,患者癲癎發(fā)作長期不能控制的原因,沒有按癲癎發(fā)作類型選藥;用量不夠;多藥聯(lián)用,急于多藥聯(lián)用;治療不專一,藥物更換頻繁;停藥太快;不規(guī)律服藥;有部分癲癎患者因為有先天腦發(fā)育異常、

10、后天腦軟化或者有遺傳因素，也是造成長期不能控制的原因。,4. 難治性癲癎多藥治療,癲癎有慢性反復(fù)發(fā)作的特點(diǎn)，20%(15%~25%)的癲癎病人經(jīng)3種AEDs正規(guī)治療2年以上,仍每月發(fā)作1次以上，可歸為難治性(intractable)或頑固性(refractory)癲癎。,難治性癲癎多藥治療,應(yīng)根據(jù)癲癎發(fā)作類型和癲癎綜合征正確選擇抗癲癇藥。先選用正確的抗癲癇藥單藥治療,二種單藥療效不佳時,再二藥聯(lián)用;如一線(first line drug

11、s)2種(~3種)單藥、6個月治療無效,須加用(add-on)另1種~2種抗癲癎藥,以不超過3種為宜。一、二線藥已有十余種，要科學(xué)地、藝術(shù)性地、個別化地聯(lián)合用藥(scientific, artic, individual combination medication)。,5. 療效判斷,服藥后第一次發(fā)作時間(time to first seizure)，6個月(or 24wks)，12個月(or 48wks),5年緩解率(rates o

12、f remission)，無發(fā)作比例(seizure-free)。服藥后發(fā)作次數(shù)減少50%表明有效(Sz-reduction rates decreased 50%-effective)，減少75%表明顯效(excellent,well-controlled Sz)，減少100%表明發(fā)作完全控制(complete controlled)，發(fā)作減少不足50%表明無效(ineffective)，可改藥(change drug)或添加治療(

13、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 admini

14、stration, 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 liqu

15、id) 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 lam

16、otrigine 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) lamotr

17、igine 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) Maculopapula

18、r 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 associate

19、d 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.

20、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 sho

21、wed 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 suggestion

22、s 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

23、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 A

24、ug;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

25、 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 epilepsy. CONCLUSI

26、ONS: 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 n