全淑燕 張伶俐 王 凌 蔣學(xué)華 楊春松 劉 丹 蔣璐燦 胡志強(qiáng)
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·論著·
托吡酯對(duì)兒童認(rèn)知功能影響的系統(tǒng)評(píng)價(jià)和Meta分析
全淑燕1,2張伶俐2王 凌1蔣學(xué)華1楊春松2劉 丹1,2蔣璐燦1,2胡志強(qiáng)1,2
系統(tǒng)評(píng)價(jià); 托吡酯; 認(rèn)知功能; 不良事件; 兒童; Meta分析
1.1 文獻(xiàn)納入標(biāo)準(zhǔn) ①研究類型包括RCT、隊(duì)列研究、病例對(duì)照研究和病例系列報(bào)告;②中文和英文文獻(xiàn);③研究對(duì)象年齡0~18歲;④予托吡酯治療的劑量和療效不限。
1.2 文獻(xiàn)排除標(biāo)準(zhǔn) ①接受托吡酯治療前存在認(rèn)知功能障礙;②托吡酯與其他藥物聯(lián)合治療;③重復(fù)發(fā)表的文獻(xiàn);④無(wú)法提取本文結(jié)局指標(biāo)的文獻(xiàn)。
1.3 結(jié)局指標(biāo)
1.3.1 主要結(jié)局指標(biāo) 認(rèn)知不良事件發(fā)生率,根據(jù)美國(guó)FDA的定義,將常見的認(rèn)知不良事件分為3類:①認(rèn)知相關(guān)的功能紊亂:困惑焦慮、精神運(yùn)動(dòng)性障礙、注意力難以集中、記憶力降低、語(yǔ)言障礙和感覺異常;②精神行為紊亂:情緒異常和攻擊行為;③疲倦和嗜睡[3]。
1.3.2 次要結(jié)局指標(biāo) 使用不同的認(rèn)知功能測(cè)量工具測(cè)量的效應(yīng)指標(biāo)。
1.4 文獻(xiàn)檢索策略 計(jì)算機(jī)檢索PubMed、The Cochrane Library、EMBASE(Ovid)、中國(guó)生物醫(yī)學(xué)文獻(xiàn)數(shù)據(jù)庫(kù)、中國(guó)知網(wǎng)、萬(wàn)方數(shù)據(jù)庫(kù)和維普數(shù)據(jù)庫(kù),檢索起止時(shí)間均從建庫(kù)至2014年9月15日,同時(shí)回溯納入文獻(xiàn)的參考文獻(xiàn)。中文檢索詞:認(rèn)知、覺知、認(rèn)知不協(xié)調(diào)、意識(shí)、直覺、理解力、認(rèn)知障礙、聽覺障礙、杭廷頓病、亨廷頓病、譫妄、癡呆、閱讀障礙、托吡酯、妥泰;英文檢索詞:topiramate、topamax、epitomax、qnexa、cognition、awareness、cognitive dissonance、cognitive reserve、comprehension、consciousness、imagination、intuition、cognition disorders、auditory perceptual disorders、huntington disease、mild cognitive impairment、cognitive difficulty、cognitive impairment和cognitive decline。英文檢索年齡限定在18歲以下,中文檢索年齡不限定。以PubMed數(shù)據(jù)庫(kù)為例,檢索策略如下。
#1 Topiramate [text word]
#2 Topamax [text word]
#3 Epitomax [text word]
#4 Qnexa [text word]
#5 #1 OR #2 OR #3 OR #4
#6 Cognition [mesh terms]
#7 Awareness[mesh terms]
#8 Cognitive dissonance[mesh terms]
#9 Cognitive reserve[mesh terms]
#10 Comprehension[mesh terms]
#11 Consciousness[mesh terms]
#12 Imagination[mesh terms]
#13 Intuition[mesh terms]
#14 Cognition disorders[mesh terms]
#15 Auditory perceptual disorders[mesh terms]
#16 Huntington disease[mesh terms]
#17 Mild cognitive impairment[mesh terms]
#18 Cognition[text word]
#19 Awareness[text word]
#20 Cognitive dissonance[text word]
#21 Cognitive reserve[text word]
#22 Comprehension[text word]
#23 Consciousness[text word]
#24 Imagination[text word]
#25 Intuition[text word]
#26 Cognition disorders[text word]
#27 Auditory perceptual disorders[text word]
#28 Huntington disease[text word]
#29 Mild cognitive impairment[text word]
#30 Cognitive difficulty[text word]
#31 Cognitive impairment[text word]
#32 Cognitive decline[text word]
#33 #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32
#34 #5 AND #33
#35 children aged less than 18 years
1.5 文獻(xiàn)篩選、資料提取與質(zhì)量評(píng)價(jià) 由全淑燕和楊春松按照納入和排除標(biāo)準(zhǔn)獨(dú)立完成文獻(xiàn)篩選、資料提取和文獻(xiàn)質(zhì)量評(píng)價(jià),如遇分歧則由劉丹決定,若數(shù)據(jù)缺失則聯(lián)系原始研究作者獲得。資料提取主要內(nèi)容包括:①研究基本信息(作者、國(guó)家、年份);②研究設(shè)計(jì)類型,受試者信息(年齡、性別、診斷),干預(yù)措施(劑量、療程),對(duì)照措施和隨訪時(shí)間;③認(rèn)知功能測(cè)量工具及測(cè)量結(jié)果,認(rèn)知不良事件發(fā)生頻率和失訪人數(shù)。
文獻(xiàn)偏倚風(fēng)險(xiǎn)評(píng)估工具包括:①RCT采用Cochrane 系統(tǒng)評(píng)價(jià)員手冊(cè)5.1.0推薦的 RCT 偏倚風(fēng)險(xiǎn)評(píng)估工具[6];②隊(duì)列研究和病例對(duì)照研究采用紐卡斯?fàn)?渥太華量表(NOS)[7];③病例系列報(bào)告采用英國(guó)國(guó)家優(yōu)化衛(wèi)生與保健研究所(NICE)推薦的病例系列評(píng)價(jià)量表[8]。
1.6 統(tǒng)計(jì)學(xué)方法 統(tǒng)計(jì)分析采用Cochrane協(xié)作網(wǎng)提供的RevMan 5.1軟件。認(rèn)知不良事件發(fā)生率采用無(wú)對(duì)照二分類數(shù)據(jù)的Meta分析[9]:?jiǎn)纹嘉墨I(xiàn)觀察對(duì)象總例數(shù)和不良事件發(fā)生率分別用n和p表示,當(dāng)n×p和n×(1-p)均>5時(shí),Meta分析結(jié)果即為最終結(jié)果;當(dāng)不滿足n×p和n×(1-p)均>5時(shí),Meta分析結(jié)果需經(jīng)過(guò)轉(zhuǎn)換,轉(zhuǎn)換得到的不良事件發(fā)生率及其95%CI上下限分別用pf、LL、UL表示,pf=OR/(1+OR),LL=LLOR/(1+LLOR),UL=ULOR/(1+ULOR)。采用χ2檢驗(yàn)分析不同文獻(xiàn)間的異質(zhì)性,采用I2值衡量異質(zhì)性的大??;若異質(zhì)性無(wú)統(tǒng)計(jì)學(xué)意義(P>0.1,I2<50%),采用固定效應(yīng)模型分析,若異質(zhì)性有統(tǒng)計(jì)學(xué)意義(P≤0.1,I2≥50%),采用隨機(jī)效應(yīng)模型合并結(jié)果。文獻(xiàn)量>10篇時(shí)采用漏斗圖評(píng)價(jià)發(fā)表偏倚。
2.1 納入文獻(xiàn)基本情況 初檢獲得676篇相關(guān)文獻(xiàn),符合納入和排除標(biāo)準(zhǔn)的9篇文獻(xiàn)進(jìn)入系統(tǒng)評(píng)價(jià)(圖1),其中RCT 文獻(xiàn)3篇[4,5,10]、病例系列報(bào)告6篇[1,11~15],未檢到隊(duì)列研究和病例對(duì)照研究。表1顯示,9篇文獻(xiàn)共納入1 240例患兒。研究來(lái)自中國(guó)[1,4,14,15]、美國(guó)[5]、韓國(guó)[10,13]、德國(guó)[11]和荷蘭[12]。3篇RCT文獻(xiàn)的試驗(yàn)組均予托吡酯治療,對(duì)照組分別予空白對(duì)照[5]、卡馬西平[10]和丙戊酸鈉[4]。6篇病例系列報(bào)告均為前瞻性設(shè)計(jì),多中心研究2篇[11,13]。4篇文獻(xiàn)均接受了同一制藥公司的資金支持[5,10,11,13]。各納入文獻(xiàn)的病例數(shù)、年齡、診斷、前期用藥、藥物用法用量及隨訪時(shí)間如表1所示。
圖1 文獻(xiàn)篩選流程圖
Fig 1 Flow chart of aricle screening and selection process
表1 納入9篇文獻(xiàn)的一般情況
Notes RCT:randomized controlled trial; NR:not report; TPM:topiramate; CBZ:carbamazepine; ESX:ethosuximide;LTG:lamotrigine;OXC:oxcarbazepine;VPA:valproate; CZP:clonazepam; PB:phenobarbital; m: months
2.2 納入文獻(xiàn)偏倚風(fēng)險(xiǎn)評(píng)價(jià) 2篇RCT文獻(xiàn)[5,10]描述了隨機(jī)序列的產(chǎn)生、分配隱藏,1篇RCT文獻(xiàn)[4]未描述隨機(jī)方法和分配隱藏;文獻(xiàn)[5]采用雙盲法,文獻(xiàn)[4,10]未描述盲法的實(shí)施情況;文獻(xiàn)[5,10]結(jié)果數(shù)據(jù)具完整性,3篇RCT文獻(xiàn)均未選擇性報(bào)告研究結(jié)果,其他偏倚來(lái)源均為低度。6篇病例系列報(bào)告[1,11~15]均在研究目的描述、納入排除標(biāo)準(zhǔn)定義、資料收集、研究結(jié)果描述表現(xiàn)為低偏倚風(fēng)險(xiǎn);其中5篇文獻(xiàn)[1,11~14]在結(jié)局指標(biāo)定義表現(xiàn)為低偏倚風(fēng)險(xiǎn),文獻(xiàn)[15]表現(xiàn)為中度偏倚風(fēng)險(xiǎn);4篇文獻(xiàn)[11~13,15]在結(jié)局分層分析表現(xiàn)為低偏倚風(fēng)險(xiǎn),2篇文獻(xiàn)[1,14]表現(xiàn)為高偏倚風(fēng)險(xiǎn)。
2.3 系統(tǒng)評(píng)價(jià)和Meta分析結(jié)果
2.3.1 認(rèn)知不良事件發(fā)生率Meta分析結(jié)果 表2顯示,困惑焦慮、精神運(yùn)動(dòng)性障礙、注意力難以集中、感覺異常、情緒異常、疲倦、嗜睡等認(rèn)知不良事件的發(fā)生率均有統(tǒng)計(jì)學(xué)意義(P均<0.05);記憶力降低、語(yǔ)言障礙發(fā)生率無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。
表2 托吡酯認(rèn)知不良事件發(fā)生率的Meta分析
Notesn/N:the numbers of AEDs/total patients; 1) adjusted meta-analysis results
本文系統(tǒng)評(píng)價(jià)共納入9篇原始研究,包含3篇RCT和6篇病例系列報(bào)告。2篇RCT文獻(xiàn)的偏倚風(fēng)險(xiǎn)為低度,1篇RCT文獻(xiàn)存在高度風(fēng)險(xiǎn)偏倚。6篇病例系列報(bào)告偏倚風(fēng)險(xiǎn)均為低度,其中2篇為多中心研究。因納入文獻(xiàn)量不多未行發(fā)表偏倚檢驗(yàn)。4篇文獻(xiàn)接受了同一制藥企業(yè)的資金資助,可能存在利益沖突。本文系統(tǒng)評(píng)價(jià)的證據(jù)強(qiáng)度為中度。
認(rèn)知是一種人類心理活動(dòng),認(rèn)知功能由多個(gè)域組成,包括記憶、計(jì)算、時(shí)間和空間定向、結(jié)構(gòu)能力、執(zhí)行能力、語(yǔ)言理解、語(yǔ)言表達(dá)及應(yīng)用等方面[16]。WHO不良反應(yīng)術(shù)語(yǔ)(WHO-ART)包括的認(rèn)知功能不良事件有:激動(dòng)、攻擊行為、厭食、焦慮、冷漠、虛弱、昏迷、困惑、記憶力降低、抑郁、頭暈、注意力難以集中、情緒不穩(wěn)定性、疲勞、嗜睡、失眠、語(yǔ)言障礙、情緒失常、緊張、眼球震顫、感覺異常、精神運(yùn)動(dòng)性障礙、嗜睡、語(yǔ)言障礙[5]。本文采用的是美國(guó)FDA的認(rèn)知不良事件分類方法 , 雖較WHO-ART條
目有所簡(jiǎn)化,但基本涵蓋了認(rèn)知不良的主要表現(xiàn),且受臨床關(guān)注。本文采用的無(wú)對(duì)照二分類變量的Meta分析方法是描述不良事件發(fā)生率的較好方法,結(jié)果提示絕大多數(shù)認(rèn)知不良事件的發(fā)生率有統(tǒng)計(jì)學(xué)意義,但總體發(fā)生率不高(0.03~0.12);但由于納入的文獻(xiàn)量不多,置信區(qū)間較寬,結(jié)果存在一定的不精確性;有待補(bǔ)充研究進(jìn)一步考察。對(duì)于記憶力降低、語(yǔ)言障礙的發(fā)生率無(wú)統(tǒng)計(jì)學(xué)意義,納入文獻(xiàn)均未報(bào)道攻擊行為的不良事件。
本文部分Meta分析的文獻(xiàn)間具顯著的統(tǒng)計(jì)學(xué)異質(zhì)性,考慮與文獻(xiàn)間人群的年齡、托吡酯劑量分布有差異,也可能與文獻(xiàn)間認(rèn)知不良事件判別和認(rèn)識(shí)存在差別且判斷時(shí)多未采用盲法有關(guān)。因此仍需更多研究明確結(jié)論。
認(rèn)知功能測(cè)量量表的描述性分析顯示,托吡酯對(duì)認(rèn)知功能的影響低于卡馬西平;100 mg·d-1劑量的托吡酯可能會(huì)輕微延長(zhǎng)反應(yīng)時(shí)間,需引起臨床關(guān)注。對(duì)智商的影響,2篇文獻(xiàn)得出的結(jié)論不一致,其中1篇文獻(xiàn)為RCT,另1篇為病例系列報(bào)告,考慮與研究類型和樣本量有關(guān),仍需進(jìn)一步探討。
結(jié)論:托吡酯對(duì)兒童認(rèn)知反應(yīng)不良事件有一定影響,但發(fā)生率較低;托吡酯可引起運(yùn)動(dòng)反應(yīng)時(shí)間輕微延長(zhǎng),但對(duì)記憶力影響不大。
[1]Peng JX(彭建霞), Zhang S, Pang BD, et al. Study on the efficacy and adverse reaction of Topiramate in treatment of children with epilepsy. Modern Preventive Medicine(現(xiàn)代預(yù)防醫(yī)學(xué)),2012,39(8):1917-1918
[2]Holland S, Silberstein SD, Freitag F, et al. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults. Neurology,2012,78(17):1346-1353
[3]FDA. Label for Topamax. 2014-3
[4]Ying XM(應(yīng)小明),Jin A,Ye H, et al.Impact of antiepileptic drugs on cognitive function of epilepsy chilren. Journal of Hebei Medical University(河北醫(yī)科大學(xué)學(xué)報(bào)),2011,32(5):530-532
[5]Gahan J, Seth N, Elena P, et al. Cognitive effects of topiramate in migraine patients aged 12 through 17 years.Pediatr Neurol,2009,42(3):187-195
[6]Julian PTH, Douglas GA. Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0. The Cochrane Collaboration, 2011, Available at: www.cochranehandbook.org
[7]Wells GA, Shea B, O′Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2014, Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
[8]National Institute for Health and Clinical Excellence (NICE), Quality assessment for case series. Available at: http://www.nice.org.uk/nicemedia/live/10919/29075/29075.pdf
[9]Chen YH(陳月紅), Du L, Geng XY, et al. Implement meta-analysis with non-comparative binary data in RevMan softare. Chin J Evid-based Med(中國(guó)循證醫(yī)學(xué)雜志) 2014, 14(7): 889-896
[10]Hoon-Chul K, Baik-Lin E, Chang WL, et al. The effects on cognitive function and behavioral problems of topiramate compared to carbamazepine as monotherapy for children with benign rolandic epilepsy. Epilepsia, 2007,48(9):1716-1723
[11]Brandl U, Kurlemann G, Neubauer B, et al. Seizure and cognitive outcomes in children and adolescents with epilepsy treated with topiramate. Neuropediatrics, 2010, 41:113-120
[12]Femke K, Erica LT, Stenvert LS, et al.Effect of topiramate on cognition in obese children.Neurology,2006,67(1):1307-1308
[13]Da-Eun J, Heung-Dong K, Yun-Jung H, et al. Topiramate on the quality of life in childhood epilepsy. Brain Dev, 2011,33(9):707-712
[14]Li J(李晶), Yan HQ. Curative effect observation of topiramate in childhood epilepsy.China Modern Medicine(中國(guó)當(dāng)代醫(yī)藥),2011,18(23):81-82
[15]Cheng XH(程曉紅),Zhu C, Liu CZ, et al. An open-labeled experience with topiramate in 46 children with epilepsy. Journal of Brain and Nervous Diseases(腦與神經(jīng)疾病雜志),2002,10(6):336-338
[16]Chen SD(陳生弟), Fan DS, Gao XG, et al.中國(guó)防治認(rèn)知功能障礙專家共識(shí). Chin J Intern Med(中華內(nèi)科雜志), 2006, 42(2):171-173
(本文編輯:丁俊杰)
第一屆中國(guó)國(guó)際兒童肥胖和高血壓學(xué)術(shù)會(huì)議征文通知
由中國(guó)高血壓聯(lián)盟、中華預(yù)防醫(yī)學(xué)會(huì)、國(guó)家心血管病中心和北京市兒童成人慢性病防治辦公室聯(lián)合主辦,首都兒科研究所和北京高血壓防治協(xié)會(huì)共同承辦的“第一屆中國(guó)國(guó)際兒童肥胖和高血壓學(xué)術(shù)會(huì)議”將于2015年5月29~31日在北京召開。誠(chéng)摯歡迎全國(guó)相關(guān)領(lǐng)域的同道踴躍投稿,積極參與會(huì)議交流。參會(huì)人員將授予國(guó)家級(jí)繼續(xù)教育Ⅰ類學(xué)分6分。
投稿要求:①稿件要求:兒童肥胖、兒童高血壓及相關(guān)兒童代謝性疾病的流行病學(xué)研究,篩查診斷與健康風(fēng)險(xiǎn)評(píng)估,遺傳與分子生物機(jī)制、宮內(nèi)及生后早期危險(xiǎn)因素、代謝異常與相關(guān)疾病、運(yùn)動(dòng)與膳食、相關(guān)心理健康問(wèn)題和干預(yù)控制與相關(guān)政策等方面的研究;②來(lái)稿未在國(guó)內(nèi)外學(xué)術(shù)期刊發(fā)表及同類學(xué)術(shù)會(huì)議上交流;③提供1 000字以內(nèi)的中文或英文摘要,包括文題、目的、方法、結(jié)論和關(guān)鍵詞;④在文題下注明作者姓名、工作單位和郵政編碼;⑤本次會(huì)議只接受網(wǎng)上投稿,不接受紙質(zhì)和Email投稿,請(qǐng)登陸會(huì)議網(wǎng)站(http://www.ccoh.org.cn)進(jìn)行在線投稿;⑥投稿截止日期:2015年3月31日。被錄用的摘要將編入會(huì)議論文匯編,并有機(jī)會(huì)參與壁報(bào)交流或口頭報(bào)告。
有意參加本次會(huì)議者請(qǐng)登陸會(huì)議網(wǎng)站了解詳細(xì)的會(huì)議信息。聯(lián)系人:鐘德君,漆衛(wèi)芳,吳艷芳,電話010-84766022。
Effect of topiramate on children cognitive function: a systematic review and meta-analysis
QUANShu-yan1,2,ZHANGLing-li2,WANGLing1,JIANGXue-hua1,YANGChun-song2,LIUDan1,2,JIANGLu-can1,2,HUZhi-qiang1,2(1WestChinaSchoolofPharmacy,SichuanUniversity,Chengdu610041; 2DepartmentofPharmacy,WestChinaSecondUniversityHospital,SichuanUniversity,Chengdu610041,China)
WANG Ling,E-mail:rebeccawang312@gmail.com
ObjectiveA systematic review was conducted to assess the influence of topiramate on children′s cognitive function to provide high quality evidence for clinical practice.MethodsThe literatures were searched using PubMed, Cochrane Library, EMBASE(Ovid), China Biology Medicine disc(CBM), China National Knowledge Infrastructure (CNKI), WanFang Data, VIP database from establishment until now. Two researchers independently screened the studies using predetermined inclusion and exclusion criteria and assessed the quality of these studies and extracted the data. Quantitative analysis of cognitive-related ADEs was performed using meta-analysis with non-comparative binary data, the outcome measured by different scales was represented.Results676 studies were found and 9 studies were finally included in this systematic review, 3 RCTs and 6 case series, including 1 240 patients. Among 9 experimental studies, 2 RCTs and 6 case series indicated low risk bias, 1 RCT had high risk bias .The incidence and 95% confidence interval of cognitive-related ADEs: confusion 0.03(0.01-0.06) , psychomotor slowing 0.08(0.02-0.26), difficulty with concentration/attention 0.07(0.02-0.21), word-finding difficulties0.07(0.04-0.14), depression or mood problems 0.05(0.02-0.11), fatigue 0.05(0.02-0.10),somnolence 0.12(0.04-0.28), difficulty with memory and speech or language problems were without statistical significance. Cognitive function was worsen treated by TPM than VPA,topiramate 100 mg per day was associated with increases in psychomotor reaction times but memory was unchanged, there were no significant differences between TPM monotherapy and converting monotherapy.ConclusionThe incidence of cognitive-related ADEs was low in children received topiramate treatment. Topiramate was associated with modest increases in psychomotor reaction times. Learning and memory were unchanged in migraine children.
Systematic review; Topiramate; Cognitive function; Adverse drug events; Children; Meta analysis
國(guó)家自然科學(xué)基金:81373381
1 四川大學(xué)華西藥學(xué)院 成都,610041;2 四川大學(xué)華西第二醫(yī)院藥學(xué)部 成都,610041
王凌,E-mail:rebeccawang312@gmail.com
10.3969/j.issn.1673-5501.2015.01.010
2014-12-13
2015-01-17)