嬰兒痙攣癥的治療和預(yù)后研究進(jìn)展

陳 瑩 綜述 張?jiān)氯A 審校

1 治療

1.1 ACTH和糖皮質(zhì)激素 自Sorel和Dusaucy(1958)報(bào)道ACTH 治療IS有效以來，一直是治療IS的首選藥物之一。雖然ACTH和糖皮質(zhì)激素被廣泛使用，但方案并不一致。大量臨床研究表明[10～13]：ACTH大劑量(120～160 U)和小劑量(20～40 U)在控制痙攣發(fā)作、改善EEG高峰節(jié)律紊亂、降低復(fù)發(fā)率及改善認(rèn)知功能等方面并無差異，但長期隨訪表明，在改善認(rèn)知功能方面小劑量優(yōu)于大劑量[10，11]，隨著ACTH劑量增加，其不良反應(yīng)風(fēng)險(xiǎn)也不斷增加。目前，中國、日本和芬蘭多采用小劑量ACTH治療。

芬蘭Heiskala等[14]推薦的方案：先予維生素B6150～200 mg，3～4 d，后予ACTH 3 U·kg-1·d-1，如果反應(yīng)良好，2周后逐漸減停，癥狀性IS患兒應(yīng)用4周后再逐漸減停；如果反應(yīng)不好，無論隱源性抑或癥狀性IS，2周后加量至6 U·kg-1·d-1，如仍無效，2周后加量至12 U·kg-1·d-1，此劑量維持2周后逐漸減量，每隔1周，減量一半。Heiskala等[14]用此方案治療30例IS患兒，應(yīng)用ACTH小劑量2～3周，6例隱源性及8例癥狀性IS患兒的痙攣發(fā)作緩解， 4/8例僅對(duì)大劑量ACTH有反應(yīng)，總有效率60%，但該項(xiàng)研究未提供長期隨訪的結(jié)果。

中國推薦方案[15]：ACTH 20 U·d-1，肌內(nèi)注射或靜脈注射，應(yīng)用2周，如果癥狀完全控制，改用潑尼松2 mg·kg-1·d-1，連用2周。如對(duì)ACTH無反應(yīng)，ACTH可加量至30～40 U·d-1，再用4周。北京大學(xué)第一醫(yī)院兒科2007年以前采用的方案為：ACTH 25 U·d-1，靜脈注射，應(yīng)用2周，癥狀無緩解，則加量至40 U·d-1，再用2周；若有效，則維持原量再用2周，ACTH總療程為4周，隨后改用潑尼松1.5～2 mg·kg-1·d-1，口服，2周后漸減量至停藥，應(yīng)用潑尼松的總療程為2個(gè)月。陳國利等[16]用此方法治療50例患兒，ACTH治療有效者32例(64.0%)；完全緩解18例(36.0%)。2007年以后，為減少ACTH的不良反應(yīng)，應(yīng)用ACTH的方案更新為[14，17]：ACTH 1 U·kg-1·d-1，靜脈注射，應(yīng)用2周，若無效，則加量至25 U·d-1，再用2周；若有效，則維持原量再用2周，ACTH總療程為4周，隨后改用潑尼松，口服，用量及療程同前。小劑量ACTH的療效與2007年以前的方案相當(dāng)，且不良反應(yīng)發(fā)生率較低。

日本Ito 等[17]推薦方案：ACTH 0.2～0.59 U·kg-1·d-1，用1～4周后逐漸減停。短期內(nèi)痙攣發(fā)作緩解率為75.0%(55/73例)，長期隨訪痙攣發(fā)作緩解率為59.2%(32/54例)，智力運(yùn)動(dòng)發(fā)育正常者占9.3%(5/54例)。Oguni等[13]報(bào)道31例IS患兒，予ACTH 0.2 U·kg-1·d-1治療2周，其中17例(54.8%)痙攣發(fā)作及EEG高峰失律完全緩解；1例痙攣發(fā)作緩解，2例EEG高峰失律緩解；8例無效患兒ACTH加量至1.0 U·kg-1·d-1，再用2周，其中2/8例完全緩解。提示小劑量ACTH治療IS同樣可取得較好的療效。

應(yīng)用糖皮質(zhì)激素治療IS的方案也不盡相同。目前中國多采用潑尼松作為停用ACTH后的序貫治療?？蓱?yīng)用潑尼松1～3 mg·kg-1·d-1，每日或隔日分3次口服2周，以后10周內(nèi)減量維持。Kossoff等[20]報(bào)道，口服潑尼松40～60 mg·d-1治療15例IS患兒，10例在2周內(nèi)痙攣發(fā)作控制，且價(jià)格便宜，不良反應(yīng)發(fā)生率較低。Hancock等[21]通過12項(xiàng)小樣本RCT(<60例)和2項(xiàng)大樣本RCT(>100例)，共觀察了681例IS患兒，考察了9種不同的藥物的療效，研究顯示高劑量潑尼松可有效控制痙攣發(fā)作，而且可能改善長期預(yù)后。Mytinger等[22]治療105例IS患兒，應(yīng)用甲潑尼龍20 mg·kg-1·d-1，靜脈注射，連用3 d，之后口服潑尼松減量維持治療2個(gè)月，治療2～6 d有50%痙攣發(fā)作控制，研究指出靜脈注射甲潑尼龍和(或)口服皮質(zhì)類固醇可控制痙攣發(fā)作，且不良反應(yīng)發(fā)生率較低。

ACTH的不良反應(yīng)包括：高血壓、感染、電解質(zhì)紊亂、腎上腺皮質(zhì)功能減退、下丘腦-垂體功能減退、骨質(zhì)疏松、消化性潰瘍、肥厚型心肌病、腦水腫、腦萎縮、硬膜下積液及硬膜下血腫等[23]。目前對(duì)肥厚型心肌病的認(rèn)識(shí)仍不夠，對(duì)發(fā)生高血壓的患者應(yīng)行超聲心動(dòng)圖檢查，有心血管不良反應(yīng)者應(yīng)減量。ATCH最危險(xiǎn)的不良反應(yīng)是腎上腺皮質(zhì)功能減退，曾有腎上腺皮質(zhì)功能減退合并嚴(yán)重電解質(zhì)紊亂而死亡的病例報(bào)道。

降低ACTH不良反應(yīng)發(fā)生率可采取以下措施：①采用最小的有效劑量和較短的療程；②緩慢減量；③ACTH治療結(jié)束后給予足量的皮質(zhì)醇替代物。在使用ACTH治療時(shí)每例患兒的不良反應(yīng)不盡相同，應(yīng)采取適當(dāng)?shù)念A(yù)防措施。

1.2 維生素B6治療 大劑量維生素B6治療IS在日本應(yīng)用較廣泛，10%～30% IS患兒應(yīng)用大劑量維生素B6治療有效，其起效迅速，常在用藥2周內(nèi)起效，隱源性IS較癥狀性IS療效好[5]。對(duì)于吡哆醇依賴癥的患兒作為首選治療。

維生素B6的應(yīng)用劑量：有學(xué)者[24]采用20～30 mg·kg-1·d-1，依據(jù)治療反應(yīng)和耐受情況3～4 d 后加量至40～50 mg·kg-1·d-1，13.3%(6/45例)癥狀性IS患者痙攣發(fā)作完全控制[24]；也有學(xué)者[25]應(yīng)用100 mg·kg-1·d-1，分3次口服，6 d內(nèi)加量至300 mg·kg-1·d-1，有效率為29.4%。

Miyajima 等[26]報(bào)道大劑量維生素B6(40～50 mg·kg-1·d-1)與小劑量ACTH(0.4 U·kg-1·d-1)聯(lián)合治療IS患兒17例，療程1個(gè)月，取得良好效果，有效率為80%，患兒的智力發(fā)育較好。Imai等[27]報(bào)道維生素B6與丙戊酸聯(lián)合治療IS較單用丙戊酸療效好。

維生素B6治療IS機(jī)制尚不十分清楚，可能的機(jī)制為：維生素B6在體內(nèi)轉(zhuǎn)化為吡哆醛-5-磷酸，其作為輔酶在氨基酸的代謝中有許多作用。發(fā)育時(shí)期腦的GABA濃度很高。GABA由谷氨酸在谷氨酸脫羧酶的作用下合成，此反應(yīng)中吡哆醛起輔酶作用，吡哆醇缺乏時(shí)，GABA水平降低，興奮閾值降低，易發(fā)生驚厥，因此，維生素B6的應(yīng)用可提高興奮閾值，輔助控制發(fā)作。

維生素B6的不良反應(yīng)較輕，可表現(xiàn)為：胃腸道癥狀(食欲差、嘔吐、腹瀉、腹脹和便秘)、肝功能異常、消化道出血、多發(fā)神經(jīng)炎和感覺異常等； 減量或停藥可減輕40%～70%消化道癥狀[5]。

唑尼沙胺不良反應(yīng)包括：嗜睡、共濟(jì)失調(diào)、食欲差、胃腸道反應(yīng)、頭暈、皮疹、意識(shí)障礙、體重下降和WBC降低,但均為一過性[29]。

1.4 氨己烯酸 自Chiron等首次應(yīng)用氨己烯酸有效治療難治性IS以來，目前尤其在歐洲國家，已將其作為治療IS的一線藥物[6，7]。隱源性IS療效優(yōu)于癥狀性IS，對(duì)于IS合并有結(jié)節(jié)性硬化者或有局灶性皮質(zhì)損害者療效較好。Granstrion等[7]推薦的方法：首劑量40～100 mg·kg-1·d-1，若10～14 d痙攣發(fā)作未控制，將劑量增至150 mg·kg-1·d-1，若仍有發(fā)作則加用ACTH，初始劑量為3～6 U·kg-1·d-1，肌內(nèi)注射，2周后仍發(fā)作加量至6～12 U·kg-1·d-1或加用丙戊酸，氨己烯酸用至ACTH起效后的6個(gè)月至2年。Elterman等[30]納入221例新診斷的IS患兒，隨機(jī)分為氨己烯酸高劑量組(100～148 mg·kg-1·d-1)和低劑量組(18～36 mg·kg-1·d-1)，用藥14 d內(nèi)行VEEG檢查，高劑量組和低劑量組連續(xù)7 d痙攣發(fā)作停止者分別占15.9%和7.0%。報(bào)道指出氨己烯酸緩解痙攣發(fā)作迅速，不良反應(yīng)小，呈劑量依賴性。

氨己烯酸的主要不良反應(yīng)有嗜睡、多動(dòng)。近年來發(fā)現(xiàn)應(yīng)用該藥可產(chǎn)生不可逆轉(zhuǎn)的視野缺損(VFD)，甚至在停用氨己烯酸后仍可出現(xiàn)。由于檢查技術(shù)及檢查時(shí)患兒不易配合等因素，嬰幼兒VFD的報(bào)道很少，但潛在的VFD不良反應(yīng)限制了其廣泛使用[31，32]。近來有文獻(xiàn)報(bào)道[33]，動(dòng)物實(shí)驗(yàn)發(fā)現(xiàn)VFD與應(yīng)用氨己烯酸后引起牛磺酸缺乏導(dǎo)致的視網(wǎng)膜光毒性損傷有關(guān)，能否通過減少光線暴露和補(bǔ)充牛磺酸來降低VFD的發(fā)生，目前在研究中。

1.6 拉莫三嗪 拉莫三嗪通過抑制電位相關(guān)性Na+通道，穩(wěn)定神經(jīng)細(xì)胞膜，抑制腦內(nèi)興奮性氨基酸(谷氨酸、天冬氨酸)的釋放而起作用。兒童單藥治療時(shí)初始劑量為2 mg·kg-1·d-1，分2次口服，2周后加量至5 mg·kg-1·d-1，2周后效果不好可繼續(xù)緩慢加量，維持量為5～15 mg·kg-1·d-1[24]。若與丙戊酸合用，則初始劑量為0.2 mg·kg-1·d-1，每2周增加0.5 mg·kg-1·d-1，維持劑量1～5 mg·kg-1·d-1[40]。有文獻(xiàn)報(bào)道在維生素B620～50 mg·kg-1·d-1治療基礎(chǔ)上，加用ACTH 0.4～0.6 U·kg-1·d-1，療程2個(gè)月，與拉莫三嗪聯(lián)合治療IS患兒25例，拉莫三嗪起始劑量0.2 mg·kg-1·d-1，2周后增至0.5 mg·kg-1·d-1，第5周予1 mg·kg-1·d-1，分早晚2次口服，維持量5～10 mg·kg-1·d-1，用此方案治療3個(gè)月時(shí)，22例患兒(88 .0%)的痙攣發(fā)作得到完全控制；隨訪6～30個(gè)月，平均(20±14.1)個(gè)月，9.1%(2/22例)患兒出現(xiàn)復(fù)發(fā)，無演變?yōu)槠渌愋桶l(fā)作者[41]。

拉莫三嗪的不良反應(yīng)主要有困倦、皮疹、嘔吐和發(fā)作頻率增加，還有復(fù)視、共濟(jì)失調(diào)、頭痛、情緒障礙和攻擊行為等。不良反應(yīng)發(fā)生率與加量速度有關(guān)。為了減少皮疹的發(fā)生,推薦的加量方案是通過2個(gè)月的緩慢加量期達(dá)到最小治療量?？紤]到IS患兒需要盡快控制其痙攣發(fā)作,2個(gè)月的時(shí)間達(dá)到最小治療量顯然降低了拉莫三嗪對(duì)嬰兒痙攣癥的治療價(jià)值[42]。

左乙拉西坦對(duì)IS有較好療效及安全性[46，47]。Grosso等[47]報(bào)道17例IS患兒(隱源性7例，癥狀性10例)添加左乙拉西坦治療，3例完全緩解，6例有效。Lawlor等[48]報(bào)道1例癥狀性IS患兒添加左乙拉西坦15 mg·kg-1·d-1達(dá)到完全緩解。Gumus等[49]報(bào)道5例IS患兒采用左乙拉西坦單藥治療，其中2例完全緩解，2例發(fā)作減少≥50%，1例無效，平均劑量為 50 mg·kg-1·d-1。Mikati等[40]報(bào)道添加左乙拉西坦治療IS 7例，5例發(fā)作減少≥50%，其中2例發(fā)作減少≥75%。國內(nèi)有多中心研究發(fā)現(xiàn)[50]，左乙拉西坦治療IS有效，起效劑量及完全緩解劑量較國外報(bào)道的低，且存在較大的個(gè)體差異，提出在中國應(yīng)用左乙拉西坦治療IS可從小劑量開始，以控制發(fā)作為治療目標(biāo)。

Eun等[54]回顧性分析了1995至2004年43例IS患兒生酮飲食治療的資料，53.5%(23/43例)發(fā)作完全控制，62.8%(27/43例)發(fā)作減少> 90%，與EEG改善結(jié)果一致。Hong等[55]回顧性分析了1996至2009年104例IS患兒生酮飲食治療的資料，平均年齡1.2歲，治療6個(gè)月，64%發(fā)作減少，其中37%發(fā)作完全控制，35%EEG改善，29%同時(shí)應(yīng)用AEDs的劑量減少。治療1～2年77%發(fā)作減少。Kossoff 等[56]回顧性對(duì)比分析了13例應(yīng)用生酮飲食和20例應(yīng)用ACTH治療的IS患兒，生酮飲食治療1個(gè)月時(shí)61.5%(8/13例)發(fā)作控制，治療2～5個(gè)月EEG改善；ACTH治療1個(gè)月90%發(fā)作及EEG均改善。認(rèn)為應(yīng)用ACTH治療的患兒EEG正?；杆?，而生酮飲食對(duì)發(fā)作的控制與ACTH相當(dāng)，不良反應(yīng)少于ACTH。目前大多數(shù)學(xué)者認(rèn)為生酮飲食治療有費(fèi)用低廉、風(fēng)險(xiǎn)小和療效肯定等優(yōu)點(diǎn)；缺點(diǎn)是麻煩，兒童正處于迅速發(fā)育階段，應(yīng)保證基本的蛋白質(zhì)攝入量為1 g·kg-1·d-1，還必須保證熱量供應(yīng)；因配出來的飲食口味不佳，往往難于接受。

2 預(yù)后

Ito等[17]對(duì)98 例IS患兒隨訪2 年以上，發(fā)作完全緩解52.0%(51/98例),48.0%(47/98例)的IS患兒仍有發(fā)作。隱源性IS、發(fā)病年齡>3個(gè)月、病程<2個(gè)月、病初發(fā)作控制好及EEG恢復(fù)快患兒的發(fā)作預(yù)后較好,相反則預(yù)后差；而與ACTH 的每日劑量及總劑量無關(guān)。陳國利等[16]對(duì)53例IS患兒隨訪2年以上，發(fā)現(xiàn)臨床發(fā)作預(yù)后與開始應(yīng)用ACTH 治療時(shí)的病程和近期療效有關(guān)；與患兒的起病年齡和病因無關(guān)；病程≤2個(gè)月者、近期療效好的患兒預(yù)后較好。Rijkonen[68]報(bào)道，IS患兒發(fā)作預(yù)后好的因素包括：病因不明，發(fā)病年齡>4個(gè)月，無非典型痙攣和部分性發(fā)作，無EEG異常不對(duì)稱，短期治療具有早期和持續(xù)的治療反應(yīng)。

2.2 智力和運(yùn)動(dòng)發(fā)育轉(zhuǎn)歸 多數(shù)IS患兒痙攣消失后,遺留不同程度智能缺陷和運(yùn)動(dòng)發(fā)育遲滯。IS預(yù)后不良,并非指痙攣發(fā)作本身,而是指其病死率和智能缺陷率較高。長期隨訪研究表明,在存活的IS患兒中,智能和運(yùn)動(dòng)發(fā)育恢復(fù)正常的患兒僅為7.7%～16.0%,而嚴(yán)重智能缺陷和運(yùn)動(dòng)發(fā)育遲滯率為34.5%～68.0%。王藝等[69]對(duì)127例IS患兒隨訪3年,86.6%的患兒(110例)伴智能發(fā)育異常。有研究發(fā)現(xiàn)隱源性IS患兒僅30%～50%存在智力落后，而癥狀性IS患兒80%～95%存在智力落后[70]。IS的病死率為5%～30%，約1/3的患兒在3歲前死亡，50%以上患兒<10歲死亡，常見死亡原因?yàn)楦腥炯霸l(fā)病所致[71]。

2.3 EEG轉(zhuǎn)歸 隨患兒年齡增長，EEG異常程度逐漸節(jié)律化，高峰節(jié)律紊亂消失，代之以正?；蚱渌愋彤惓EG。痙攣發(fā)作終止后約2/3患兒EEG恢復(fù)正常。典型高峰節(jié)律紊亂EEG通常在5歲內(nèi)消失，但EEG的改善并不一定伴隨臨床發(fā)作的改善。

2.4 影響預(yù)后的因素 主要包括：發(fā)病前神經(jīng)系統(tǒng)檢查及發(fā)育情況、病前有無其他發(fā)作形式、起病年齡、病程長短及早期是否有效控制痙攣發(fā)作。提示預(yù)后較好的因素為[72]：發(fā)病前神經(jīng)系統(tǒng)檢查及發(fā)育正常，病前無其他發(fā)作形式，起病年齡較大者，病程短和早期有效控制痙攣發(fā)作者。提示預(yù)后較差的因素為：大腦皮質(zhì)發(fā)育異常、發(fā)病前智力運(yùn)動(dòng)發(fā)育落后者、癥狀性者、復(fù)發(fā)或抽搐持續(xù)存在者。

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