三重刺激技術定量評價多系統萎縮患者重復經顱磁刺激治療效果二例分析

王含 王悅 崔麗英

三重刺激技術定量評價多系統萎縮患者重復經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，初級運動皮質予重復經顱磁刺激可以改善皮質脊髓束損害。本研究采用三重刺激技術定量評價2例以帕金森綜合征為主要表現的多系統萎縮（MSA?P）患者重復經顱磁刺激前后皮質脊髓束功能變化，探討重復經顱磁刺激對皮質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，均接受重復經顱磁刺激，采用小指展肌三重刺激技術波幅比和統一多系統萎縮評價量表第二部分（UMSARSⅡ）評價治療前后皮質脊髓束功能和運動功能。結果2例MSA?P型患者治療前小指展肌三重刺激技術波幅比為28.30%和69.10%，UMSARSⅡ評分22和20分；治療后即刻小指展肌三重刺激技術波幅比為58.40%和71.70%，UMSARSⅡ評分16和12分，其中例1隨訪至重復經顱磁刺激后2個月，治療后1和2個月小指展肌三重刺激技術波幅比分別為90.70%和50.70%，UMSARSⅡ評分17和23分。結論采用三重刺激技術可以定量評價重復經顱磁刺激對MSA?P型患者皮質脊髓束損害的改善作用。

誘發電位； 多系統萎縮； 經顱磁刺激

三重刺激技術（TST）是一種可以精確定量評價皮質脊髓束完整性的方法，有應用于多發性硬化（MS）［1?2］、肌萎縮側索硬化癥（ALS）［3?4］和腦卒中［2，5］的文獻報道。研究顯示，三重刺激技術評價脫髓鞘或神經退行性變致皮質脊髓束損害的靈敏度是傳統經顱磁刺激（TMS）的 2.75 倍［1，6］。三重刺激技術波幅比可以反映激活的脊髓運動神經元比例，既往研究顯示其正常值≥90%［6］。晚近研究顯示，三重刺激技術在評價多系統萎縮（MSA）［6］和血管性帕金森綜合征［7］患者皮質脊髓束損害方面具有重要價值，但此方面的研究仍十分有限。重復經顱磁刺激（rTMS）用于治療帕金森病（PD）始于1994年［8］，目前越來越多的證據顯示，該項技術具有一定治療效果［9?10］，但其作用機制尚不明確。我們課題小組既往對以帕金森綜合征為主要表現的多系統萎縮（MSA?P）的研究顯示，重復經顱磁刺激可能對刺激局部和功能相關皮質或皮質下區域（包括皮質脊髓束）產生可塑性影響［11］。鑒于此，本研究采用三重刺激技術［12?13］對符合很可能 MSA?P 型診斷標準［14］的2例MSA?P型患者重復經顱磁刺激前后皮質脊髓束功能進行定量評價，以探討重復經顱磁刺激對皮質脊髓束損害的改善作用。

臨床資料

例1 男性，62歲，因頭暈、行動遲緩1年余，于2009年2月9日至神經科門診就診。患者1年前無明顯誘因出現間斷性頭暈，無天旋地轉感，無頭痛，站立和行走時顯著、平臥時減輕，自覺肢體僵硬，伴頸背部疼痛；癥狀進行性加重，逐漸出現運動遲緩、雙手靜止性震顫、講話時嘴唇震顫，伴雙下肢浮腫、排尿不盡和便秘（1次/5～8 d），反復出現肺部感染（具體不詳）。患者自發病以來，睡眠欠佳，時有夢魘和手足舞動，打鼾，偶有睡眠呼吸障礙；飲食、精神尚可，體重無明顯變化。既往史、個人史及家族史：約3年前開始出現尿頻、排尿不盡，逐漸進展至尿失禁，未予特殊處理；2年前行經尿道前列腺電切術，術后癥狀無明顯改善；間斷飲酒20年、500 g/次，吸煙約5年（約5支/d），目前已經戒煙10余年；家族史無特殊。門診體格檢查：臥位血壓125/80 mm Hg（1 mm Hg=0.133 kPa）、立位 90/70 mm Hg；神志清楚，語言欠清晰，聲音低沉，表情淡漠；雙側瞳孔等大、等圓，直徑約3 mm，對光反射靈敏，雙眼水平眼動充分、垂直眼動受限，Horner征陰性，咽反射減弱，其余腦神經檢查未見明顯異常；四肢肌力5級，右上肢肌張力增高，呈“鉛管”樣，余肢體肌張力正常；感覺系統未見異常，雙手快復輪替動作緩慢，指鼻試驗穩準，可見雙手姿勢性震顫；腱反射對稱活躍，雙側Babinski征陽性，歡呼征可疑陽性，腦膜刺激征陰性。實驗室檢查各項指標均于正常值范圍。頭部MRI顯示，腦橋和小腦欠飽滿。睡眠期腦電圖顯示，快速眼動睡眠期（REM）肌肉遲緩障礙，符合快速眼動睡眠期行為障礙（RBD）。臨床診斷為很可能MSA?P型，左旋多巴治療無效，于2010年9月行重復經顱磁刺激，刺激頻率5 Hz，脈沖次數1000次/d，刺激強度80%靜息運動閾值（RMT），間隔時間40 s，每天1次、每周5 d，連續2周。治療前小指展肌三重刺激技術波幅比為28.30%（圖1a），統一多系統萎縮評價量表第二部分（UMSARSⅡ）評分為20分；治療后即刻、1個月和2個月小指展肌三重刺激技術波幅比分別為58.40%，90.70%和50.70%（圖1b～1d），UMSARSⅡ評分分別為16、17和23分。

例2 女性，44歲，因進行性動作遲緩1年余，于2010年3月23日至神經科門診就診。患者1年余前無明顯誘因逐漸出現行走緩慢，雙腿沉重感、抬起費力，進行性加重，行走距離逐漸縮短，伴輕度前傾；此后出現雙上肢動作遲緩、笨拙，寫字和解紐扣等精細動作遲緩，語言緩慢，生活尚能自理，可以自行上下樓梯、做飯；1個月后出現啟動困難，尤以轉身或跨越障礙時顯著，坐位站起困難；此后1個月偶出現持物時雙手顫抖，無靜止性震顫，不能翻身，生活不能自理，自覺右側肢體略沉重；病程中無認知功能障礙。患者近2年出汗減少，怕熱；近1年頸部和背部酸痛，尿不盡，曾發生3～4次尿失禁，便秘。既往史、個人史及家族史：貧血30余年（具體不詳）；28年前（1982年）曾發生一氧化碳中毒，意識障礙，自行緩解，未影響認知功能；1年前出現支氣管擴張（具體不詳）；個人史及家族史無特殊。門診體格檢查：臥位血壓90/60 mm Hg、立位60/40 mm Hg，皮膚黏膜蒼白；神志清楚，語言緩慢，表情淡漠，腦神經檢查未見異常；四肢肌力5級、肌張力增高，深淺感覺對稱存在，雙手快復輪替動作緩慢，指鼻試驗和跟?膝?脛試驗欠穩準；Romberg征可疑陽性，慌張步態，雙側腱反射對稱活躍，雙側Hoffman征陽性、Babinski征可疑陽性、Chaddock征陽性，腦膜刺激征呈陰性。簡易智能狀態檢查量表（MMSE）評分30分。實驗室檢查：血常規血紅蛋白113 g/L（110～150 g/L）；血清轉鐵蛋白飽和度（TS）0.18（0.25～0.35），血清鐵7.34 μmol/L（12.53 ～ 26.85 μmol/L）；血液涂片無異常。頭部MRI檢查未見異常。肌電圖和神經傳導速度（NCV）未見異常。肛門括約肌肌電圖呈神經源性損害，膀胱殘余尿量240 ml。臨床診斷為很可能MSA?P型，左旋多巴治療無效，遂于2010年9月行重復經顱磁刺激，刺激頻率5 Hz，脈沖次數1000次/d，刺激強度為80%靜息運動閾值，間隔時間40 s，每天1次、每周5 d，連續2周。治療前小指展肌三重刺激技術波幅比為69.10%（圖2a）、UMSARSⅡ評分為20分；治療后即刻小指展肌三重刺激技術波幅比為71.70%（圖2b）、UMSARSⅡ評分為12分。由于患者在外地不方便隨診，未能客觀評價遠期三重刺激技術波幅比和UMSARSⅡ評分。

圖1 小指展肌三重刺激技術所見 1a 治療前三重刺激技術波幅比為28.30% 1b 治療后即刻三重刺激技術波幅比為58.40% 1c 治療后1個月三重刺激技術波幅比為90.70% 1d 治療后2個月三重刺激技術波幅比為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

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

本組2例MSA?P型患者均行重復經顱磁刺激治療，采用三重刺激技術定量評價療效，結果顯示，皮質脊髓束損害明顯改善（例1小指展肌三重刺激技術波幅比自28.30%增至90.70%，例2自69.10%增至71.70%），運動功能明顯提高（例1 UMSARSⅡ評分自20分降至16分，例2自20分降至12分），表明三重刺激技術波幅比與臨床癥狀具有相關性。既往研究顯示，帕金森綜合征患者皮質興奮性主要受基底神經節向皮質流出異常的影響，并非直接累及皮質脊髓束的投射［17］。在本研究中，究竟是由于重復經顱磁刺激對皮質脊髓束的影響逆向改變基底神經節向皮質的流出，還是重復經顱磁刺激通過遠隔效應改變基底神經節向皮質的流出，從而達到改善皮質脊髓束的目的，尚待進一步深入研究。此外，在本研究中，我們還觀察到重復經顱磁刺激對三重刺激技術波幅比的影響相對持久，治療后1個月三重刺激技術波幅比仍持續升高，同時伴UMSARSⅡ評分降低，間接提示三重刺激技術波幅比與臨床癥狀之間具有相關性。三重刺激技術波幅比升高趨勢于重復經顱磁刺激1個月后發生衰退，可能是由于多系統萎縮持續性進展的特征，同時也為重復經顱磁刺激的治療周期提供參考依據。

本研究僅是三重刺激技術定量評價重復經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。毋庸置疑的是，對于多系統萎縮這種缺乏有效治療方法的疾病而言，任何有陽性結果的研究均鼓舞人心，但仍需謹慎求證。

圖2 小指展肌三重刺激技術所見 2a 治療前的三重刺激技術波幅比為69.10% 2b 治療后即刻的三重刺激技術波幅比為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.

［1］Magistris MR,R?sler KM,Truffert A,Landis T,Hess CW.A clinical study of motor evoked potentials using a triple stimulation technique.Brain,1999,122:265?279.

［2］Groppa S,Oliviero A,Eisen A,Quartarone A,Cohen LG,Mall V,Kaelin?Lang A,Mima T,Rossi S,Thickbroom GW,Rossini PM,Ziemann U,Valls ?Solé J,Siebner HR.A practical guide to diagnostic transcranial magnetic stimulation:report of an IFCN committee.Clin Neurophysiol,2012,123:858?882.

［3］Rosler KM,Truffert A,Hess CW,Magistris MR.Quantification of upper motor neuron loss in amyotrophic lateral sclerosis.Clin Neurophysiol,2000,111:2208?2218.

［4］Grapperon AM,Verschueren A,Duclos Y,Confort?Gouny S,Soulier E,Loundou AD,Guye M,Cozzone PJ,Pouget J,Ranjeva JP,Attarian S.Association between structural and functional corticospinal involvement in amyotrophic lateral sclerosis assessed by diffusion tensor MRI and triple stimulation technique.Muscle Nerve,2014,49:551?557.

［5］Tan F,Wang X,Li HQ,Lu L,Li M,Li JH,Fang M,Meng D,Zheng GQ.A randomized controlled pilot study of the triple stimulation technique in the assessment of electroacupuncture for motor function recovery in patients with acute ischemic stroke.Evid Based Complement Alternat Med,2013:ID431986.

［6］Eusebio A,Azulay JP,Witjas T,Rico A,Attarian S.Assessment of cortico?spinal tract impairment in multiple system atrophy using transcranial magnetic stimulation.Clin Neurophysiol,2007,118:815?823.

［7］Jang W,Park J,Kim JS,Youn J,Oh E,Jo KD,Lee MK,Kim HT.Triple stimulation technique findings in vascular Parkinsonism and Parkinson's disease.Clin Neurophysiol,2014,125:1834?1839.

［8］Pascual?Leone A,Valls?Solé J,Brasil?Neto JP,Cammarota A,Grafman J,Hallett M.Akinesia in Parkinson's disease:Ⅱ.Effects ofsubthreshold repetitive transcranialmotorcortex stimulation.Neurology,1994,44:892?898.

［9］Elahi B,Elahi B,Chen R.Effect of transcranial magnetic stimulation on Parkinson motor function:systematic review of controlled clinical trials.Mov Disord,2009,24:357?363.

［10］Shirota Y,Ohtsu H,Hamada M,Enomoto H,Ugawa Y;Research Committee on rTMS Treatment of Parkinson's Disease.Supplementary motor area stimulation for Parkinson disease:a randomized controlled study.Neurology,2013,80:1400?1405.

［11］Chou YH,You H,Wang H,Zhao YP,Hou B,Chen NK,Feng F.Effect of repetitive transcranial magnetic stimulation on fMRI resting?state connectivity in multiple system atrophy.Brain Connect,2015,5:451?459.

［12］Magistris MR,R?sler KM,Truffert A,Myers JP.Transcranial stimulation excites virtually all motor neurons supplying the target muscle:a demonstration and a method improving the study of motor evoked potentials.Brain,1998,121:437?450.

［13］Roth G,Magistris MR.Identification of motor conduction block despite desynchronisation: a method. Electromyogr Clin Neurophysiol,1989,29:305?313.

［14］Gilman S,Wenning GK,Low PA,Brooks DJ,Mathias CJ,Trojanowski JQ,Wood NW,Colosimo C,Dürr A,Fowler CJ,Kaufmann H,Klockgether T,Lees A,Poewe W,Quinn N,Revesz T,Robertson D,Sandroni P,Seppi K,Vidailhet M.Second consensus statement on the diagnosis of multiple system atrophy.Neurology,2008,71:670?676.

［15］K?llensperger M,Geser F,Ndayisaba JP,Boesch S,Seppi K,Ostergaard K,DupontE,CardozoA,TolosaE,AbeleM,Klockgether T,Yekhlef F,Tison F,Daniels C,Deuschl G,Coelho M,Sampaio C,Bozi M,Quinn N,Schrag A,Mathias CJ,Fowler C,Nilsson CF,Widner H,Schimke N,Oertel W,Del Sorbo F,Albanese A,Pellecchia MT,Barone P,Djaldetti R,Colosimo C,Meco G,Gonzalez?Mandly A,Berciano J,Gurevich T,Giladi N,Galitzky M,Rascol O,Kamm C,Gasser T,Siebert U,Poewe W,Wenning GK;EMSA ?SG.Presentation,diagnosis,and management of multiple system atrophy in Europe:final analysis of the European multiple system atrophy registry.Mov Disord,2010,25:2604?2612.

［16］Wang H,Wang Y,Cui LY.Electrophysiological characteristics of cortico?spinaltractimpairmentin patients with atypical parkinsonism:clinicalvalue of triple stimulation technique.Zhonghua Lao Nian Duo Qi Guan Ji Bing Za Zhi,2015,14:655?659［.王含,王悅,崔麗英.不典型帕金森患者皮質脊髓束損害的電生理特點——三重刺激技術研究初探.中華老年多器官疾病雜志,2015,14:655?659.］

［17］Kühn AA,Grosse P,Holtz K,Brown P,Meyer BU,Kupsch A.Patterns ofabnormalmotor cortex excitability in atypical parkinsonian syndromes.Clin Neurophysiol,2004,115:1786?1795.

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

國家自然科學基金資助項目（項目編號：30800352）

100730中國醫學科學院 北京協和醫學院 北京協和醫院神經科（王含，王悅，崔麗英）；100730北京，中國醫學科學院神經科學中心（崔麗英）

王含（Email：wanghanpumch@163.com）