王含 王悅 崔麗英

三重刺激技術(shù)定量評(píng)價(jià)多系統(tǒng)萎縮患者重復(fù)經(jīng)顱磁刺激治療效果二例分析

王含 王悅 崔麗英

研究背景既往研究顯示，初級(jí)運(yùn)動(dòng)皮質(zhì)予重復(fù)經(jīng)顱磁刺激可以改善皮質(zhì)脊髓束損害。本研究采用三重刺激技術(shù)定量評(píng)價(jià)2例以帕金森綜合征為主要表現(xiàn)的多系統(tǒng)萎縮（MSA?P）患者重復(fù)經(jīng)顱磁刺激前后皮質(zhì)脊髓束功能變化，探討重復(fù)經(jīng)顱磁刺激對(duì)皮質(zhì)脊髓束損害的改善作用。方法2例MSA?P型患者（1例為62歲男性，1例為44歲女性），病程1年，均接受重復(fù)經(jīng)顱磁刺激，采用小指展肌三重刺激技術(shù)波幅比和統(tǒng)一多系統(tǒng)萎縮評(píng)價(jià)量表第二部分（UMSARSⅡ）評(píng)價(jià)治療前后皮質(zhì)脊髓束功能和運(yùn)動(dòng)功能。結(jié)果2例MSA?P型患者治療前小指展肌三重刺激技術(shù)波幅比為28.30%和69.10%，UMSARSⅡ評(píng)分22和20分；治療后即刻小指展肌三重刺激技術(shù)波幅比為58.40%和71.70%，UMSARSⅡ評(píng)分16和12分，其中例1隨訪至重復(fù)經(jīng)顱磁刺激后2個(gè)月，治療后1和2個(gè)月小指展肌三重刺激技術(shù)波幅比分別為90.70%和50.70%，UMSARSⅡ評(píng)分17和23分。結(jié)論采用三重刺激技術(shù)可以定量評(píng)價(jià)重復(fù)經(jīng)顱磁刺激對(duì)MSA?P型患者皮質(zhì)脊髓束損害的改善作用。

誘發(fā)電位； 多系統(tǒng)萎縮； 經(jīng)顱磁刺激

三重刺激技術(shù)（TST）是一種可以精確定量評(píng)價(jià)皮質(zhì)脊髓束完整性的方法，有應(yīng)用于多發(fā)性硬化（MS）［1?2］、肌萎縮側(cè)索硬化癥（ALS）［3?4］和腦卒中［2，5］的文獻(xiàn)報(bào)道。研究顯示，三重刺激技術(shù)評(píng)價(jià)脫髓鞘或神經(jīng)退行性變致皮質(zhì)脊髓束損害的靈敏度是傳統(tǒng)經(jīng)顱磁刺激（TMS）的 2.75 倍［1，6］。三重刺激技術(shù)波幅比可以反映激活的脊髓運(yùn)動(dòng)神經(jīng)元比例，既往研究顯示其正常值≥90%［6］。晚近研究顯示，三重刺激技術(shù)在評(píng)價(jià)多系統(tǒng)萎縮（MSA）［6］和血管性帕金森綜合征［7］患者皮質(zhì)脊髓束損害方面具有重要價(jià)值，但此方面的研究仍十分有限。重復(fù)經(jīng)顱磁刺激（rTMS）用于治療帕金森?。≒D）始于1994年［8］，目前越來(lái)越多的證據(jù)顯示，該項(xiàng)技術(shù)具有一定治療效果［9?10］，但其作用機(jī)制尚不明確。我們課題小組既往對(duì)以帕金森綜合征為主要表現(xiàn)的多系統(tǒng)萎縮（MSA?P）的研究顯示，重復(fù)經(jīng)顱磁刺激可能對(duì)刺激局部和功能相關(guān)皮質(zhì)或皮質(zhì)下區(qū)域（包括皮質(zhì)脊髓束）產(chǎn)生可塑性影響［11］。鑒于此，本研究采用三重刺激技術(shù)［12?13］對(duì)符合很可能 MSA?P 型診斷標(biāo)準(zhǔn)［14］的2例MSA?P型患者重復(fù)經(jīng)顱磁刺激前后皮質(zhì)脊髓束功能進(jìn)行定量評(píng)價(jià)，以探討重復(fù)經(jīng)顱磁刺激對(duì)皮質(zhì)脊髓束損害的改善作用。

臨床資料

例1 男性，62歲，因頭暈、行動(dòng)遲緩1年余，于2009年2月9日至神經(jīng)科門(mén)診就診?；颊?年前無(wú)明顯誘因出現(xiàn)間斷性頭暈，無(wú)天旋地轉(zhuǎn)感，無(wú)頭痛，站立和行走時(shí)顯著、平臥時(shí)減輕，自覺(jué)肢體僵硬，伴頸背部疼痛；癥狀進(jìn)行性加重，逐漸出現(xiàn)運(yùn)動(dòng)遲緩、雙手靜止性震顫、講話時(shí)嘴唇震顫，伴雙下肢浮腫、排尿不盡和便秘（1次/5～8 d），反復(fù)出現(xiàn)肺部感染（具體不詳）。患者自發(fā)病以來(lái)，睡眠欠佳，時(shí)有夢(mèng)魘和手足舞動(dòng)，打鼾，偶有睡眠呼吸障礙；飲食、精神尚可，體重?zé)o明顯變化。既往史、個(gè)人史及家族史：約3年前開(kāi)始出現(xiàn)尿頻、排尿不盡，逐漸進(jìn)展至尿失禁，未予特殊處理；2年前行經(jīng)尿道前列腺電切術(shù)，術(shù)后癥狀無(wú)明顯改善；間斷飲酒20年、500 g/次，吸煙約5年（約5支/d），目前已經(jīng)戒煙10余年；家族史無(wú)特殊。門(mén)診體格檢查：臥位血壓125/80 mm Hg（1 mm Hg=0.133 kPa）、立位 90/70 mm Hg；神志清楚，語(yǔ)言欠清晰，聲音低沉，表情淡漠；雙側(cè)瞳孔等大、等圓，直徑約3 mm，對(duì)光反射靈敏，雙眼水平眼動(dòng)充分、垂直眼動(dòng)受限，Horner征陰性，咽反射減弱，其余腦神經(jīng)檢查未見(jiàn)明顯異常；四肢肌力5級(jí)，右上肢肌張力增高，呈“鉛管”樣，余肢體肌張力正常；感覺(jué)系統(tǒng)未見(jiàn)異常，雙手快復(fù)輪替動(dòng)作緩慢，指鼻試驗(yàn)穩(wěn)準(zhǔn)，可見(jiàn)雙手姿勢(shì)性震顫；腱反射對(duì)稱活躍，雙側(cè)Babinski征陽(yáng)性，歡呼征可疑陽(yáng)性，腦膜刺激征陰性。實(shí)驗(yàn)室檢查各項(xiàng)指標(biāo)均于正常值范圍。頭部MRI顯示，腦橋和小腦欠飽滿。睡眠期腦電圖顯示，快速眼動(dòng)睡眠期（REM）肌肉遲緩障礙，符合快速眼動(dòng)睡眠期行為障礙（RBD）。臨床診斷為很可能MSA?P型，左旋多巴治療無(wú)效，于2010年9月行重復(fù)經(jīng)顱磁刺激，刺激頻率5 Hz，脈沖次數(shù)1000次/d，刺激強(qiáng)度80%靜息運(yùn)動(dòng)閾值（RMT），間隔時(shí)間40 s，每天1次、每周5 d，連續(xù)2周。治療前小指展肌三重刺激技術(shù)波幅比為28.30%（圖1a），統(tǒng)一多系統(tǒng)萎縮評(píng)價(jià)量表第二部分（UMSARSⅡ）評(píng)分為20分；治療后即刻、1個(gè)月和2個(gè)月小指展肌三重刺激技術(shù)波幅比分別為58.40%，90.70%和50.70%（圖1b～1d），UMSARSⅡ評(píng)分分別為16、17和23分。

例2 女性，44歲，因進(jìn)行性動(dòng)作遲緩1年余，于2010年3月23日至神經(jīng)科門(mén)診就診。患者1年余前無(wú)明顯誘因逐漸出現(xiàn)行走緩慢，雙腿沉重感、抬起費(fèi)力，進(jìn)行性加重，行走距離逐漸縮短，伴輕度前傾；此后出現(xiàn)雙上肢動(dòng)作遲緩、笨拙，寫(xiě)字和解紐扣等精細(xì)動(dòng)作遲緩，語(yǔ)言緩慢，生活尚能自理，可以自行上下樓梯、做飯；1個(gè)月后出現(xiàn)啟動(dòng)困難，尤以轉(zhuǎn)身或跨越障礙時(shí)顯著，坐位站起困難；此后1個(gè)月偶出現(xiàn)持物時(shí)雙手顫抖，無(wú)靜止性震顫，不能翻身，生活不能自理，自覺(jué)右側(cè)肢體略沉重；病程中無(wú)認(rèn)知功能障礙?；颊呓?年出汗減少，怕熱；近1年頸部和背部酸痛，尿不盡，曾發(fā)生3～4次尿失禁，便秘。既往史、個(gè)人史及家族史：貧血30余年（具體不詳）；28年前（1982年）曾發(fā)生一氧化碳中毒，意識(shí)障礙，自行緩解，未影響認(rèn)知功能；1年前出現(xiàn)支氣管擴(kuò)張（具體不詳）；個(gè)人史及家族史無(wú)特殊。門(mén)診體格檢查：臥位血壓90/60 mm Hg、立位60/40 mm Hg，皮膚黏膜蒼白；神志清楚，語(yǔ)言緩慢，表情淡漠，腦神經(jīng)檢查未見(jiàn)異常；四肢肌力5級(jí)、肌張力增高，深淺感覺(jué)對(duì)稱存在，雙手快復(fù)輪替動(dòng)作緩慢，指鼻試驗(yàn)和跟?膝?脛試驗(yàn)欠穩(wěn)準(zhǔn)；Romberg征可疑陽(yáng)性，慌張步態(tài)，雙側(cè)腱反射對(duì)稱活躍，雙側(cè)Hoffman征陽(yáng)性、Babinski征可疑陽(yáng)性、Chaddock征陽(yáng)性，腦膜刺激征呈陰性。簡(jiǎn)易智能狀態(tài)檢查量表（MMSE）評(píng)分30分。實(shí)驗(yàn)室檢查：血常規(guī)血紅蛋白113 g/L（110～150 g/L）；血清轉(zhuǎn)鐵蛋白飽和度（TS）0.18（0.25～0.35），血清鐵7.34 μmol/L（12.53 ～ 26.85 μmol/L）；血液涂片無(wú)異常。頭部MRI檢查未見(jiàn)異常。肌電圖和神經(jīng)傳導(dǎo)速度（NCV）未見(jiàn)異常。肛門(mén)括約肌肌電圖呈神經(jīng)源性損害，膀胱殘余尿量240 ml。臨床診斷為很可能MSA?P型，左旋多巴治療無(wú)效，遂于2010年9月行重復(fù)經(jīng)顱磁刺激，刺激頻率5 Hz，脈沖次數(shù)1000次/d，刺激強(qiáng)度為80%靜息運(yùn)動(dòng)閾值，間隔時(shí)間40 s，每天1次、每周5 d，連續(xù)2周。治療前小指展肌三重刺激技術(shù)波幅比為69.10%（圖2a）、UMSARSⅡ評(píng)分為20分；治療后即刻小指展肌三重刺激技術(shù)波幅比為71.70%（圖2b）、UMSARSⅡ評(píng)分為12分。由于患者在外地不方便隨診，未能客觀評(píng)價(jià)遠(yuǎn)期三重刺激技術(shù)波幅比和UMSARSⅡ評(píng)分。

圖1 小指展肌三重刺激技術(shù)所見(jiàn) 1a 治療前三重刺激技術(shù)波幅比為28.30% 1b 治療后即刻三重刺激技術(shù)波幅比為58.40% 1c 治療后1個(gè)月三重刺激技術(shù)波幅比為90.70% 1d 治療后2個(gè)月三重刺激技術(shù)波幅比為50.70%Figure 1 TST findings at abductor digiti minimi The TST amplitude ratio before rTMS(Panel 1a),immediately after rTMS(Panel 1b),one month after rTMS(Panel 1c)and 2 months after rTMS(Panel 1d)was 28.30%,58.40%,90.70%and 50.70%,respectively.

討 論

多系統(tǒng)萎縮是散發(fā)性神經(jīng)變性病，臨床表現(xiàn)為帕金森綜合征、小腦共濟(jì)失調(diào)和自主神經(jīng)功能障礙的組合，目前尚無(wú)肯定有效的治療方法。皮質(zhì)脊髓束損害是多系統(tǒng)萎縮的臨床表現(xiàn)之一，約28%患者可見(jiàn)病理征，43%可見(jiàn)腱反射亢進(jìn)［15］。Eusebio等［6］采用三重刺激技術(shù)定量分析MSA?P型患者皮質(zhì)脊髓束損害，結(jié)果顯示，50%存在皮質(zhì)脊髓束損害，平均三重刺激技術(shù)波幅比為86.60%。我們的既往研究顯示，MSA?P型患者三重刺激技術(shù)波幅比為（40.70±18.60）%［16］，表明皮質(zhì)脊髓束損害常見(jiàn)。

本組2例MSA?P型患者均行重復(fù)經(jīng)顱磁刺激治療，采用三重刺激技術(shù)定量評(píng)價(jià)療效，結(jié)果顯示，皮質(zhì)脊髓束損害明顯改善（例1小指展肌三重刺激技術(shù)波幅比自28.30%增至90.70%，例2自69.10%增至71.70%），運(yùn)動(dòng)功能明顯提高（例1 UMSARSⅡ評(píng)分自20分降至16分，例2自20分降至12分），表明三重刺激技術(shù)波幅比與臨床癥狀具有相關(guān)性。既往研究顯示，帕金森綜合征患者皮質(zhì)興奮性主要受基底神經(jīng)節(jié)向皮質(zhì)流出異常的影響，并非直接累及皮質(zhì)脊髓束的投射［17］。在本研究中，究竟是由于重復(fù)經(jīng)顱磁刺激對(duì)皮質(zhì)脊髓束的影響逆向改變基底神經(jīng)節(jié)向皮質(zhì)的流出，還是重復(fù)經(jīng)顱磁刺激通過(guò)遠(yuǎn)隔效應(yīng)改變基底神經(jīng)節(jié)向皮質(zhì)的流出，從而達(dá)到改善皮質(zhì)脊髓束的目的，尚待進(jìn)一步深入研究。此外，在本研究中，我們還觀察到重復(fù)經(jīng)顱磁刺激對(duì)三重刺激技術(shù)波幅比的影響相對(duì)持久，治療后1個(gè)月三重刺激技術(shù)波幅比仍持續(xù)升高，同時(shí)伴UMSARSⅡ評(píng)分降低，間接提示三重刺激技術(shù)波幅比與臨床癥狀之間具有相關(guān)性。三重刺激技術(shù)波幅比升高趨勢(shì)于重復(fù)經(jīng)顱磁刺激1個(gè)月后發(fā)生衰退，可能是由于多系統(tǒng)萎縮持續(xù)性進(jìn)展的特征，同時(shí)也為重復(fù)經(jīng)顱磁刺激的治療周期提供參考依據(jù)。

本研究?jī)H是三重刺激技術(shù)定量評(píng)價(jià)重復(fù)經(jīng)顱磁刺激治療效果的初步探討，尚待更大樣本量的研究加以證實(shí)。毋庸置疑的是，對(duì)于多系統(tǒng)萎縮這種缺乏有效治療方法的疾病而言，任何有陽(yáng)性結(jié)果的研究均鼓舞人心，但仍需謹(jǐn)慎求證。

圖2 小指展肌三重刺激技術(shù)所見(jiàn) 2a 治療前的三重刺激技術(shù)波幅比為69.10% 2b 治療后即刻的三重刺激技術(shù)波幅比為71.70%Figure 2 TST findings at abductor digiti minimi The TST amplitude ratio before rTMS(Panel 2a)and immediately after rTMS(Panel 2b)was 69.10%and 71.70%,respectively.

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2017?04?06）

The 23rd World Congress of Neurology

Time:September 16-21,2017

Venue:Kyoto,Japan

Website:www.2017.wcn-neurology.com

The 23rd World Congress of Neurology(WCN 2017)will take place in Kyoto,Japan on September 16-21 2017,cohosted by the Japanese Society of Neurology(JSN),Societas Neurologica Japonica,and Asian and Oceanian Association of Neurology(AOAN).The theme of WCN 2017 will be"Defining the Future of Neurology".

Founded originally in 1902,the JSN has evolved into a large society with 8579 members.Initially a combined neurology and psychiatry association,the current JSN separated in 1959 and continued to flourish ever since.It was the 12th WCN meeting held at Kyoto in 1981 that greatly contributed to the development of JSN and AOAN.Therefore,WCN 2017 which is being held at the very same venue would be a very historic meeting which will again serve as a springboard to strongly advance the Asia Initiative of World Federation of Neurology(WFN)for worldwide advancement of neurology in both scientific and clinical aspects,thus"Defining the Future of Neurology".You can participate in very active discussions and cutting?edge lectures by the world's top scientists and neurologists including three Nobel laureates as well as hear all the advances of scientific and clinical neurology.Gene therapy and stem/induced pluripotent stem(iPS)cell medicine are such examples on the one hand and brain?machine?interface,information technology and robotics in care and rehabilitation on the other.Neurology related to environmental and disaster medicine will also attract many neurologists particularly in rapidly developing counties.

The Local Organizing Committee of JSN in close collaboration with the WFN looks forward to welcoming you in Kyoto for WCN 2017.

The 142nd Annual Meeting of American Neurological Association

Time:October 15-17,2017

Venue:San Diego,California,USA

Website:2017.myana.org

Abstract deadline:September 11,2017

The 142nd Annual Meeting of American Neurological Association(ANA2017)will be held on October 15-17,2017 in San Diego,California,USA.ANA2017 offers exceptional education,career development for all levels of academic neurology and networking opportunities with leaders in the field.Scientific symposia cover broad spectrum of subspecialties.Poster sessions are packed with the latest emerging neuroscience and interactive lunch workshops take breakout sessions to the next level.

ANA2017 will feature five main symposia,which highlight groundbreaking conceptual and therapeutic advances in a variety of neurologic disease states,as well as interactive educational sessions designed to both support career development and provide educational opportunities in sub?specialties.

Triple stimulation technique to evaluate the curative effect of repetitive transcranial magnetic stimulation in patients with multiple system atrophy:two cases report

WANG Han1,WANG Yue1,CUI Li?ying1,2
1Department of Neurology,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100730,China
2Neurosciences Center,Chinese Academy of Medical Sciences,Beijing 100730,China
Corresponding author:WANG Han(Email:wanghanpumch@163.com)

BackgroundPrevious studies suggest that the cortico?spinal tract can be modulated by M1 repetitive transcranial magnetic stimulation(rTMS).However,it is not well investigated in patients with multiple system atrophy(MSA).We discuss 2 cases of MSA with parkinsonism?predominant(MSA?P),who have been evaluated the function of cortico?spinal tract using triple stimulation technique(TST)before and after rTMS,so as to explore the effect of rTMS on improving the damage of cortico?spinal tract.MethodsTwo MSA?P patients(one 62?year?old male,one 44?year?old female)with disease course of one year were examined with TST at abductor digiti minimi.TST amplitude ratio and the motor score of Unified Multiple System Atrophy Rating Scale(UMSARSⅡ)were used to assess the damage of cortico?spinal tract and motor function before and after rTMS treatment.ResultsTST amplitude ratio at abductor drgiti minimi of both patients was 28.30%and 69.10%,and UMSARSⅡscore was 22 and 20 before treatment.Immediately after rTMS the amplitude ratio was 58.40% and 71.70%,and UMSARSⅡscore was 16 and 12,respectively.The improvement sustained in Case one in the next month(TST amplitude ratio 90.70%,UMSARSⅡscore 17)and the second month(TST amplitude ratio 50.70%,UMSARSⅡscore 23).ConclusionsTST can be used to quantitatively evaluate the integrity of cortico?spinal tract after rTMS.

Evoked potentials; Multiple system atrophy; Transcranial magnetic stimulation This study was supported by the National Natural Science Foundation of China(No.30800352).

10.3969/j.issn.1672?6731.2017.06.008

國(guó)家自然科學(xué)基金資助項(xiàng)目（項(xiàng)目編號(hào)：30800352）

100730中國(guó)醫(yī)學(xué)科學(xué)院 北京協(xié)和醫(yī)學(xué)院 北京協(xié)和醫(yī)院神經(jīng)科（王含，王悅，崔麗英）；100730北京，中國(guó)醫(yī)學(xué)科學(xué)院神經(jīng)科學(xué)中心（崔麗英）

王含（Email：wanghanpumch@163.com）