腦深部電刺激術(shù)治療帕金森病的進(jìn)展與展望

吳 曦， 胡小吾

海軍軍醫(yī)大學(xué)附屬長海醫(yī)院神經(jīng)外科，上海 200433

·專題報(bào)道·

腦深部電刺激術(shù)治療帕金森病的進(jìn)展與展望

吳 曦， 胡小吾*

海軍軍醫(yī)大學(xué)附屬長海醫(yī)院神經(jīng)外科，上海 200433

腦深部電刺激術(shù)(deep brain stimulation, DBS)目前已成為國內(nèi)外認(rèn)可的帕金森病重要治療方案。隨著腦科學(xué)、手術(shù)方法、磁共振成像技術(shù)的不斷發(fā)展，以及大量臨床循證醫(yī)學(xué)證據(jù)的逐漸完善，DBS治療帕金森病在手術(shù)時(shí)機(jī)、靶點(diǎn)選擇、癥狀控制、治療機(jī)制、設(shè)備改進(jìn)等方面均取得了較大的進(jìn)展。但是，其在中軸運(yùn)動(dòng)癥狀和非運(yùn)動(dòng)癥狀的控制方面尚存在一些不足，設(shè)備、程控設(shè)置等方面也有待改進(jìn)。

帕金森?。荒X深部電刺激；設(shè)備

如果說左旋多巴是帕金森病(Parkinson disease, PD)藥物治療的金標(biāo)準(zhǔn)，那么腦深部電刺激術(shù)(deep brain stimulation, DBS)是PD輔助藥物治療的外科首選方法。DBS治療PD自1999年獲得我國國家食品藥品監(jiān)督管理總局(CFDA)批準(zhǔn)上市以來，已得到長足發(fā)展。目前，我國已有超過100家中心開展該手術(shù)，全國年手術(shù)量超過4 000例，并研制出了我國自己的DBS系列產(chǎn)品。該療法涉及了神經(jīng)內(nèi)科、神經(jīng)外科、神經(jīng)調(diào)控、神經(jīng)影像、神經(jīng)生物工程等諸多領(lǐng)域，本文對近年來DBS治療PD的主要進(jìn)展進(jìn)行了總結(jié)及展望。

1 DBS治療PD的療效與不足

1.1 核心運(yùn)動(dòng)癥狀 長期隨訪結(jié)果[1-9]顯示，隨著手術(shù)方式和步驟的逐步改良，DBS術(shù)安全性逐步提高，目前手術(shù)死亡率約0.1%。如果患者適應(yīng)證好、電極植入準(zhǔn)確以及刺激參數(shù)設(shè)置適當(dāng)，無論是丘腦底核(subthalamic nucleus, STN)刺激還是蒼白球內(nèi)側(cè)部(internal globus pallidus, GPi)刺激，都可以長期顯著改善中晚期PD患者的震顫、僵直、少動(dòng)等核心運(yùn)動(dòng)癥狀。STN-DBS可以顯著減少PD患者的藥物用量，并減少藥物引起的多種不良反應(yīng)。國內(nèi)手術(shù)安全性及治療效果的長期隨訪研究結(jié)果與國外同期研究[10-12]結(jié)果相仿，但目前還缺少術(shù)后10年以上的長期隨訪結(jié)果。

1.2 軸性運(yùn)動(dòng)癥狀 關(guān)于STN-DBS是否可以改善步態(tài)、吞咽、語言和平衡等軸性癥狀目前存在爭議[13-14]。近期1篇meta分析[15]顯示，STN-DBS確實(shí)可以在患者電極植入48個(gè)月內(nèi)改善藥物關(guān)期狀態(tài)下的步態(tài)(步長、步速等)和凍結(jié)步態(tài)，但是上述癥狀仍會(huì)隨著時(shí)間延長而逐漸惡化，不如核心癥狀改善持久。其原因可能是靶點(diǎn)核團(tuán)參與情感、感覺與運(yùn)動(dòng)，而DBS的電刺激對不同神經(jīng)網(wǎng)絡(luò)的調(diào)控效果有差異。不同神經(jīng)網(wǎng)絡(luò)的神經(jīng)遞質(zhì)、下游重要神經(jīng)節(jié)點(diǎn)的數(shù)量、距電極觸點(diǎn)的距離等差異導(dǎo)致其對電刺激的反應(yīng)不同。如高頻STN-DBS對吞咽能力的改善作用有限，甚至有負(fù)面作用[16]。因此，通過調(diào)整DBS的激活觸點(diǎn)、激活域、刺激參數(shù)來改善軸性運(yùn)動(dòng)癥狀，進(jìn)而提高患者生活質(zhì)量，是目前研究的熱點(diǎn)。

1.3 非運(yùn)動(dòng)癥狀 目前認(rèn)為非運(yùn)動(dòng)癥狀較運(yùn)動(dòng)癥狀更影響患者的生活質(zhì)量。術(shù)后1～3年，DBS可以部分改善某些非運(yùn)動(dòng)癥狀，如睡眠質(zhì)量[17]、便秘[17]、肌張力障礙性疼痛[18]、胃脹感[19]、膀胱激惹癥狀[20]。研究[21]顯示，STN-DBS可以改善多種類型的非運(yùn)動(dòng)癥狀，但該研究病例數(shù)較少，且隨訪時(shí)間較短。隨著對非運(yùn)動(dòng)癥狀認(rèn)識(shí)的深入、非運(yùn)動(dòng)癥狀量表設(shè)計(jì)與評估方法的改進(jìn)，DBS改善PD患者非運(yùn)動(dòng)癥狀的長期隨訪結(jié)果將逐漸增多。

1.4 精神心理、認(rèn)知與高級(jí)神經(jīng)功能 由于STN參與邊緣系統(tǒng)的神經(jīng)通路，PD患者在STN-DBS術(shù)后減少藥量過程中會(huì)出現(xiàn)撤藥反應(yīng)，導(dǎo)致心理或精神改變[22]。臨床中需要鑒別STN-DBS術(shù)后精神癥狀是病程進(jìn)展結(jié)果、撤藥反應(yīng)或是電刺激引起的不良反應(yīng)。大部分精神心理癥狀可通過調(diào)整刺激參數(shù)或輔助藥物治療改善。

DBS對絕大部分PD患者的認(rèn)知能力影響較小[23]。但是，DBS術(shù)后電刺激對額葉有抑制作用[24]，可能導(dǎo)致患者認(rèn)知功能輕微下降，主要表現(xiàn)在視覺空間感覺[25]、語言流暢性[26]、對他人語言理解力、注意力、沖突協(xié)調(diào)力[27]、執(zhí)行力下降。上述癥狀與術(shù)前認(rèn)知功能下降有關(guān)尚無定論[28-29]。STN-DBS對PD患者高級(jí)神經(jīng)功能的影響可能成為STN功能的一個(gè)研究熱點(diǎn)。

1.5 不良反應(yīng) DBS術(shù)中如電極位置不佳或刺激參數(shù)設(shè)置不當(dāng)，除治療效果不佳外，可能刺激周圍神經(jīng)傳導(dǎo)束，引起多種類型的運(yùn)動(dòng)癥狀、感覺癥狀、精神癥狀等[30-31]。因此，通過對手術(shù)時(shí)機(jī)、靶點(diǎn)選擇的進(jìn)一步研究，設(shè)備的改進(jìn)，刺激參數(shù)的探索，可進(jìn)一步提高療效、減少刺激引起的不良反應(yīng)。

2 DBS治療PD研究進(jìn)展

目前DBS治療PD研究主要集中于以下幾個(gè)方面：(1)手術(shù)時(shí)機(jī)的選擇；(2)靶點(diǎn)的選擇和應(yīng)用；(3)定位方法的改進(jìn)和顱內(nèi)電極位置的確認(rèn)；(4)顱內(nèi)電極、脈沖發(fā)生器等電刺激設(shè)備的改進(jìn)；(5)刺激參數(shù)(程控)探索；(6)刺激域的模擬及可視化程控。

2.1 手術(shù)時(shí)機(jī)的選擇 以往認(rèn)為，DBS是中晚期PD患者在藥物治療效果不佳的時(shí)候不得不用的備選方案。但后來研究發(fā)現(xiàn)中期(≤3年)患者出現(xiàn)運(yùn)動(dòng)癥狀時(shí)進(jìn)行DBS干預(yù)后，生活質(zhì)量得到很大改善[32]，這一結(jié)果可能促使治療窗前移。研究[33]報(bào)道了DBS在更早期患者的應(yīng)用，發(fā)現(xiàn)病程僅2年的患者也可以很好地耐受DBS，且DBS患者藥物服用量較單用藥物組更少。目前，美國FDA正在進(jìn)行早期PD患者STN-DBS治療的3期臨床試驗(yàn)，如果結(jié)果良好并獲得批準(zhǔn)，DBS手術(shù)時(shí)機(jī)選擇范圍將更寬。

2.2 靶點(diǎn)的選擇和應(yīng)用 國內(nèi)目前最常用的PD治療靶點(diǎn)為STN。其改善運(yùn)動(dòng)癥狀的效果與選擇GPi相仿[34-35]，但是可以減少藥物的使用，且耗電較少。近期一項(xiàng)入組128例手術(shù)患者的前瞻性研究[36-37]顯示，STN-DBS較GPi-DBS可以更好地改善運(yùn)動(dòng)癥狀(46%vs26%)，兩者對非運(yùn)動(dòng)癥狀和精神癥狀的改善有差異。但是，GPi-DBS對PD異動(dòng)癥的直接抑制效果優(yōu)于STN-DBS，通過STN對PD異動(dòng)癥的治療主要依賴減少藥物用量。因此，對于有異動(dòng)癥的患者，應(yīng)該根據(jù)疾病特點(diǎn)選擇適宜的靶點(diǎn)。

腳橋核(pedunculopontine nucleus, PPN)是中腦運(yùn)動(dòng)區(qū)的重要組成部分，與步的啟動(dòng)和步態(tài)的調(diào)節(jié)密切相關(guān)。在PD發(fā)病過程中累及此核團(tuán)，因此其也是神經(jīng)調(diào)控治療PD的一個(gè)熱點(diǎn)。PPN低頻電刺激可改善患者的步態(tài)障礙[38]。但是由于單獨(dú)PPN-DBS對于震顫、僵直、動(dòng)作遲緩等核心運(yùn)動(dòng)癥狀的改善并不理想，目前多與STN-DBS的聯(lián)合進(jìn)行。國內(nèi)也有中心嘗試進(jìn)行STN與PPN的聯(lián)合刺激，但是該研究樣本量較小，且未發(fā)表論文。目前，STN與PPN聯(lián)合刺激對DBS的療效尚未明確。

STN聯(lián)合齒狀核-紅核-丘腦束電刺激對藥物難治性震顫型PD患者的療效優(yōu)于單純STN-DBS[39]。此外，刺激紅核外側(cè)、STN內(nèi)側(cè)、內(nèi)側(cè)丘系前的丘系前輻射也可改善PD相關(guān)震顫、僵直[40]。因此，應(yīng)進(jìn)一步研究STN-DBS取得的治療效果是通過刺激哪些結(jié)構(gòu)獲得的，以及今后對電極的設(shè)計(jì)是否可以使其“一箭多星”。

2.3 定位方法的改進(jìn)和顱內(nèi)電極位置的確認(rèn) 既往根據(jù)可視核團(tuán)的MRI與帶框架下CT掃描融合后進(jìn)行的核團(tuán)坐標(biāo)，計(jì)算電極植入的位置，術(shù)中通過單通道或多通道微電極電生理記錄和微刺激確定靶點(diǎn)。隨著MRI核團(tuán)可視化水平的不斷提高，有學(xué)者認(rèn)為只根據(jù)MRI提供的解剖信息即可確定植入電極的位置[41-43]。而術(shù)中磁共振(intraoperative MRI, iMRI)的出現(xiàn)使植入電極過程中可以根據(jù)iMRI提供的腦移位信息來進(jìn)行電極的動(dòng)態(tài)調(diào)整，而不是根據(jù)電生理監(jiān)測結(jié)果。由于術(shù)中腦移位具有不可預(yù)測性[44]，iMRI監(jiān)測下的靶點(diǎn)植入較常規(guī)方法更為準(zhǔn)確，其中期治療效果較好[45-46]。在iMRI未普及的情況下，患者術(shù)中佩戴立體定向儀復(fù)查MRI不失為一種較好選擇，其也可以直接顯示電極位置和STN，如電極位置有偏差可在術(shù)中直接調(diào)整。

用術(shù)中CT(intraoperative CT, iCT)技術(shù)在全麻下植入DBS時(shí)，需要將其與術(shù)前MRI融合，但融合結(jié)果無法糾正腦移位造成的誤差，加之融合技術(shù)本身也存在一定缺陷，因此電極植入誤差沒有較常規(guī)方法減小[47-48]，應(yīng)用前景可能較iMRI差。

我國有少數(shù)單位嘗試應(yīng)用無框架定位系統(tǒng)。有研究認(rèn)為，無框架定位系統(tǒng)的電極植入精度與傳統(tǒng)框架技術(shù)相似[49]，臨床療效也差不多[50]。但近期一項(xiàng)較大樣本量臨床研究[51]顯示，無框架定位系統(tǒng)電極植入位置與傳統(tǒng)框架相差約0.5 mm。因此，該系統(tǒng)的應(yīng)用應(yīng)謹(jǐn)慎。

2.4 電刺激設(shè)備的進(jìn)展 將足夠刺激強(qiáng)度的激活域控制在預(yù)期靶點(diǎn)周圍的預(yù)定空間內(nèi)，是確保電刺激療效和避免電刺激不良反應(yīng)的基礎(chǔ)。為克服環(huán)形觸點(diǎn)電刺激產(chǎn)生的類球形激活域帶來的不良反應(yīng)，多種方向性電極應(yīng)運(yùn)而生，并且取得了更好的臨床效果[52]。如32觸點(diǎn)電極(Medtronic, Eindhoven, The Netherlands)療效較傳統(tǒng)電極更優(yōu)，同時(shí)還可以記錄電刺激時(shí)其他觸點(diǎn)的局部場電位(local field potential, LFP)[53-55]。其與感知反饋式DBS設(shè)備聯(lián)用，顯示廣闊的應(yīng)用前景。另一種3個(gè)方向觸點(diǎn)結(jié)合傳統(tǒng)環(huán)形觸點(diǎn)的電極(Aleva, Lausanne, Switzerland)顯示減少刺激不良反應(yīng)的優(yōu)勢[56]。

感知反饋式DBS設(shè)備也稱閉環(huán)式DBS(closed-loop DBS)設(shè)備或自適應(yīng)DBS(adaptive DBS systems)設(shè)備，與既往的開環(huán)式DBS設(shè)備有明顯的不同。該設(shè)備根據(jù)感知到的患者電極周圍核團(tuán)內(nèi)神經(jīng)元形成的LFP(如β振蕩)[57]，分析是否需要或進(jìn)行何種類型、何種刺激強(qiáng)度的電刺激，從而根據(jù)患者實(shí)時(shí)腦電信號(hào)自動(dòng)調(diào)整電刺激參數(shù)[58-60]。從理論上講，感知反饋式DBS在減少電刺激誘發(fā)的不良反應(yīng)、減少癥狀波動(dòng)、提高刺激療效方面較開環(huán)式DBS有著明顯的優(yōu)勢。但是對于解讀觸點(diǎn)記錄到的LFP的要求也高，我國多個(gè)中心的學(xué)者在此方面進(jìn)行了大量的動(dòng)物和臨床研究[61]。該設(shè)備的臨床療效較傳統(tǒng)DBS效果更佳[62]，并可進(jìn)一步應(yīng)用于腦科學(xué)研究，進(jìn)而指導(dǎo)臨床工作。該設(shè)備可在感知不同LFP信號(hào)后，采用多種刺激模式發(fā)揮綜合、更優(yōu)的治療效果。隨著對腦電信號(hào)解讀水平的提高，這類設(shè)備將有較大的發(fā)展?jié)摿蛻?yīng)用前景。

2.5 刺激參數(shù)設(shè)置(程控) STN-DBS在高頻(≥100 Hz)刺激時(shí)，可能引起凍結(jié)步態(tài)、語言功能下降和吞咽困難等中軸癥狀的加重，而在60～80 Hz刺激且維持等效刺激強(qiáng)度時(shí)，可以一定程度上改善這些癥狀[63]。但是，低頻治療有效的持續(xù)時(shí)間可能因人而異，無法持久，且部分患者的核心運(yùn)動(dòng)癥狀可能加重，可通過以下幾點(diǎn)預(yù)測低頻刺激效果[64]：(1)術(shù)后1年左旋多巴對軸性癥狀改善顯著；(2)術(shù)后高頻電刺激使軸性癥狀加重；(3)高頻電刺激導(dǎo)致服藥后藥效減退。為了兼顧高頻對核心運(yùn)動(dòng)癥狀的治療效果以及低頻對中軸癥狀的治療效果，清華大學(xué)國家神經(jīng)調(diào)控重點(diǎn)實(shí)驗(yàn)室研發(fā)了變頻電刺激技術(shù)，初步臨床應(yīng)用顯示其達(dá)到了預(yù)期的治療效果、減少了不良反應(yīng)[65-66]，大樣本臨床研究正在進(jìn)行。低頻刺激或變頻刺激改善中軸癥狀的機(jī)制有待進(jìn)一步研究。

脈寬在刺激參數(shù)設(shè)置中的調(diào)整幅度往往不大，一般最低為60 μs，有研究[67]顯示低于60 μs脈寬的電刺激可以減少電刺激引起的不良反應(yīng)。對于這一參數(shù)的設(shè)置，可能還需要進(jìn)行更多的調(diào)整和試驗(yàn)。

交叉電脈沖刺激技術(shù)是可以在同一根電極上的不同觸點(diǎn)，給予兩套獨(dú)立刺激參數(shù)的新技術(shù)。該技術(shù)可以通過分別調(diào)節(jié)不同激活觸點(diǎn)的激活域，在增強(qiáng)治療效果的同時(shí)，避免電刺激引起的不良反應(yīng)[68-69]。

3 DBS治療PD的展望

隨著PD神經(jīng)網(wǎng)絡(luò)研究的進(jìn)展、對疾病發(fā)生的神經(jīng)電生理機(jī)制認(rèn)識(shí)的加深及電極植入準(zhǔn)確性的提高，對患者群和靶點(diǎn)的選擇、新型DBS設(shè)備和方向性電極的使用、多樣性刺激參數(shù)的設(shè)置更加精確。電刺激設(shè)備的更新和升級(jí)，必然增加程控醫(yī)師工作量，因此可視化程控[70-71]或者計(jì)算機(jī)自動(dòng)化癥狀評估與程控[72-73]會(huì)得到推廣，進(jìn)而進(jìn)一步提高PD療效并減少電刺激不良反應(yīng)。目前國內(nèi)關(guān)于數(shù)字化評估患者運(yùn)動(dòng)癥狀的研究已較多且較深入[74]，但是還需要進(jìn)一步研發(fā)智能程控系統(tǒng)，并增強(qiáng)醫(yī)工協(xié)作能力。

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Progress and prospect of deep brain stimulation in treating Parkinson disease

WU Xi, HU Xiao-wu*

Department of Neurosurgery, Changhai Hospital, Navy Military Medical University, Shanghai 200433, China

Deep brain stimulation (DBS) has become an important treatment for Parkinson disease (PD) in domestic and abroad. With continuous developments of brain science, surgical methods, MRI technology, and gradual improvement of evidence-based medicine factors, significant progresses have been achieved in timing of operation, target selection, symptom control, treatment mechanism and equipment improvement for DBS in treating PD. However, there are some inadequacies in controlling axial motor symptoms and non-motor symptoms, and the equipment and programmer also need to improve.

Parkinson disease; deep brain stimulation; equipments

2017-01-18接受日期2017-10-09

國家重點(diǎn)研發(fā)計(jì)劃“數(shù)字診療裝備研發(fā)”試點(diǎn)專項(xiàng)課題(2016YFC0105900). Supported by “Digital Equipment of Diagnosis and Treatment” Special Program of National Key Research and Development Plan (2016YFC0105900).

吳 曦, 博士, 講師、主治醫(yī)師. E-mail：wuxi_smmu@sina.com

*通信作者(Corresponding author). Tel: 021-31161789, E-mail: huxiaowu_smmu@sina.com

10.12025/j.issn.1008-6358.2017.20170049

R 742.5

A

[本文編輯] 姬靜芳