腦深部電刺激術治療帕金森病的進展與展望

吳 曦， 胡小吾

海軍軍醫大學附屬長海醫院神經外科，上海 200433

·專題報道·

腦深部電刺激術治療帕金森病的進展與展望

吳 曦， 胡小吾*

海軍軍醫大學附屬長海醫院神經外科，上海 200433

腦深部電刺激術(deep brain stimulation, DBS)目前已成為國內外認可的帕金森病重要治療方案。隨著腦科學、手術方法、磁共振成像技術的不斷發展，以及大量臨床循證醫學證據的逐漸完善，DBS治療帕金森病在手術時機、靶點選擇、癥狀控制、治療機制、設備改進等方面均取得了較大的進展。但是，其在中軸運動癥狀和非運動癥狀的控制方面尚存在一些不足，設備、程控設置等方面也有待改進。

帕金森病；腦深部電刺激；設備

如果說左旋多巴是帕金森病(Parkinson disease, PD)藥物治療的金標準，那么腦深部電刺激術(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督管理總局(CFDA)批準上市以來，已得到長足發展。目前，我國已有超過100家中心開展該手術，全國年手術量超過4 000例，并研制出了我國自己的DBS系列產品。該療法涉及了神經內科、神經外科、神經調控、神經影像、神經生物工程等諸多領域，本文對近年來DBS治療PD的主要進展進行了總結及展望。

1 DBS治療PD的療效與不足

1.1 核心運動癥狀 長期隨訪結果[1-9]顯示，隨著手術方式和步驟的逐步改良，DBS術安全性逐步提高，目前手術死亡率約0.1%。如果患者適應證好、電極植入準確以及刺激參數設置適當，無論是丘腦底核(subthalamic nucleus, STN)刺激還是蒼白球內側部(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、少動等核心運動癥狀。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。國內手術安全性及治療效果的長期隨訪研究結果與國外同期研究[10-12]結果相仿，但目前還缺少術后10年以上的長期隨訪結果。

1.2 軸性運動癥狀 關于STN-DBS是否可以改善步態、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確實可以在患者電極植入48個月內改善藥物關期狀態下的步態(步長、步速等)和凍結步態，但是上述癥狀仍會隨著時間延長而逐漸惡化，不如核心癥狀改善持久。其原因可能是靶點核團參與情感、感覺與運動，而DBS的電刺激對不同神經網絡的調控效果有差異。不同神經網絡的神經遞質、下游重要神經節點的數量、距電極觸點的距離等差異導致其對電刺激的反應不同。如高頻STN-DBS對吞咽能力的改善作用有限，甚至有負面作用[16]。因此，通過調整DBS的激活觸點、激活域、刺激參數來改善軸性運動癥狀，進而提高患者生活質量，是目前研究的熱點。

1.3 非運動癥狀 目前認為非運動癥狀較運動癥狀更影響患者的生活質量。術后1～3年，DBS可以部分改善某些非運動癥狀，如睡眠質量[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動癥狀，但該研究病例數較少，且隨訪時間較短。隨著對非運動癥狀認識的深入、非運動癥狀量表設計與評估方法的改進，DBS改善PD患者非運動癥狀的長期隨訪結果將逐漸增多。

1.4 精神心理、認知與高級神經功能 由于STN參與邊緣系統的神經通路，PD患者在STN-DBS術后減少藥量過程中會出現撤藥反應，導致心理或精神改變[22]。臨床中需要鑒別STN-DBS術后精神癥狀是病程進展結果、撤藥反應或是電刺激引起的不良反應。大部分精神心理癥狀可通過調整刺激參數或輔助藥物治療改善。

DBS對絕大部分PD患者的認知能力影響較小[23]。但是，DBS術后電刺激對額葉有抑制作用[24]，可能導致患者認知功能輕微下降，主要表現在視覺空間感覺[25]、語言流暢性[26]、對他人語言理解力、注意力、沖突協調力[27]、執行力下降。上述癥狀與術前認知功能下降有關尚無定論[28-29]。STN-DBS對PD患者高級神經功能的影響可能成為STN功能的一個研究熱點。

1.5 不良反應 DBS術中如電極位置不佳或刺激參數設置不當，除治療效果不佳外，可能刺激周圍神經傳導束，引起多種類型的運動癥狀、感覺癥狀、精神癥狀等[30-31]。因此，通過對手術時機、靶點選擇的進一步研究，設備的改進，刺激參數的探索，可進一步提高療效、減少刺激引起的不良反應。

2 DBS治療PD研究進展

目前DBS治療PD研究主要集中于以下幾個方面：(1)手術時機的選擇；(2)靶點的選擇和應用；(3)定位方法的改進和顱內電極位置的確認；(4)顱內電極、脈沖發生器等電刺激設備的改進；(5)刺激參數(程控)探索；(6)刺激域的模擬及可視化程控。

2.1 手術時機的選擇 以往認為，DBS是中晚期PD患者在藥物治療效果不佳的時候不得不用的備選方案。但后來研究發現中期(≤3年)患者出現運動癥狀時進行DBS干預后，生活質量得到很大改善[32]，這一結果可能促使治療窗前移。研究[33]報道了DBS在更早期患者的應用，發現病程僅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正在進行早期PD患者STN-DBS治療的3期臨床試驗，如果結果良好并獲得批準，DBS手術時機選擇范圍將更寬。

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

腳橋核(pedunculopontine nucleus, PPN)是中腦運動區的重要組成部分，與步的啟動和步態的調節密切相關。在PD發病過程中累及此核團，因此其也是神經調控治療PD的一個熱點。PPN低頻電刺激可改善患者的步態障礙[38]。但是由于單獨PPN-DBS對于震顫、僵直、動作遲緩等核心運動癥狀的改善并不理想，目前多與STN-DBS的聯合進行。國內也有中心嘗試進行STN與PPN的聯合刺激，但是該研究樣本量較小，且未發表論文。目前，STN與PPN聯合刺激對DBS的療效尚未明確。

STN聯合齒狀核-紅核-丘腦束電刺激對藥物難治性震顫型PD患者的療效優于單純STN-DBS[39]。此外，刺激紅核外側、STN內側、內側丘系前的丘系前輻射也可改善PD相關震顫、僵直[40]。因此，應進一步研究STN-DBS取得的治療效果是通過刺激哪些結構獲得的，以及今后對電極的設計是否可以使其“一箭多星”。

2.3 定位方法的改進和顱內電極位置的確認 既往根據可視核團的MRI與帶框架下CT掃描融合后進行的核團坐標，計算電極植入的位置，術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。隨著MRI核團可視化水平的不斷提高，有學者認為只根據MRI提供的解剖信息即可確定植入電極的位置[41-43]。而術中磁共振(intraoperative MRI, iMRI)的出現使植入電極過程中可以根據iMRI提供的腦移位信息來進行電極的動態調整，而不是根據電生理監測結果。由于術中腦移位具有不可預測性[44]，iMRI監測下的靶點植入較常規方法更為準確，其中期治療效果較好[45-46]。在iMRI未普及的情況下，患者術中佩戴立體定向儀復查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中直接調整。

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

我國有少數單位嘗試應用無框架定位系統。有研究認為，無框架定位系統的電極植入精度與傳統框架技術相似[49]，臨床療效也差不多[50]。但近期一項較大樣本量臨床研究[51]顯示，無框架定位系統電極植入位置與傳統框架相差約0.5 mm。因此，該系統的應用應謹慎。

2.4 電刺激設備的進展 將足夠刺激強度的激活域控制在預期靶點周圍的預定空間內，是確保電刺激療效和避免電刺激不良反應的基礎。為克服環形觸點電刺激產生的類球形激活域帶來的不良反應，多種方向性電極應運而生，并且取得了更好的臨床效果[52]。如32觸點電極(Medtronic, Eindhoven, The Netherlands)療效較傳統電極更優，同時還可以記錄電刺激時其他觸點的局部場電位(local field potential, LFP)[53-55]。其與感知反饋式DBS設備聯用，顯示廣闊的應用前景。另一種3個方向觸點結合傳統環形觸點的電極(Aleva, Lausanne, Switzerland)顯示減少刺激不良反應的優勢[56]。

感知反饋式DBS設備也稱閉環式DBS(closed-loop DBS)設備或自適應DBS(adaptive DBS systems)設備，與既往的開環式DBS設備有明顯的不同。該設備根據感知到的患者電極周圍核團內神經元形成的LFP(如β振蕩)[57]，分析是否需要或進行何種類型、何種刺激強度的電刺激，從而根據患者實時腦電信號自動調整電刺激參數[58-60]。從理論上講，感知反饋式DBS在減少電刺激誘發的不良反應、減少癥狀波動、提高刺激療效方面較開環式DBS有著明顯的優勢。但是對于解讀觸點記錄到的LFP的要求也高，我國多個中心的學者在此方面進行了大量的動物和臨床研究[61]。該設備的臨床療效較傳統DBS效果更佳[62]，并可進一步應用于腦科學研究，進而指導臨床工作。該設備可在感知不同LFP信號后，采用多種刺激模式發揮綜合、更優的治療效果。隨著對腦電信號解讀水平的提高，這類設備將有較大的發展潛力和應用前景。

2.5 刺激參數設置(程控) STN-DBS在高頻(≥100 Hz)刺激時，可能引起凍結步態、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度時，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時間可能因人而異，無法持久，且部分患者的核心運動癥狀可能加重，可通過以下幾點預測低頻刺激效果[64]：(1)術后1年左旋多巴對軸性癥狀改善顯著；(2)術后高頻電刺激使軸性癥狀加重；(3)高頻電刺激導致服藥后藥效減退。為了兼顧高頻對核心運動癥狀的治療效果以及低頻對中軸癥狀的治療效果，清華大學國家神經調控重點實驗室研發了變頻電刺激技術，初步臨床應用顯示其達到了預期的治療效果、減少了不良反應[65-66]，大樣本臨床研究正在進行。低頻刺激或變頻刺激改善中軸癥狀的機制有待進一步研究。

脈寬在刺激參數設置中的調整幅度往往不大，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。對于這一參數的設置，可能還需要進行更多的調整和試驗。

交叉電脈沖刺激技術是可以在同一根電極上的不同觸點，給予兩套獨立刺激參數的新技術。該技術可以通過分別調節不同激活觸點的激活域，在增強治療效果的同時，避免電刺激引起的不良反應[68-69]。

3 DBS治療PD的展望

隨著PD神經網絡研究的進展、對疾病發生的神經電生理機制認識的加深及電極植入準確性的提高，對患者群和靶點的選擇、新型DBS設備和方向性電極的使用、多樣性刺激參數的設置更加精確。電刺激設備的更新和升級，必然增加程控醫師工作量，因此可視化程控[70-71]或者計算機自動化癥狀評估與程控[72-73]會得到推廣，進而進一步提高PD療效并減少電刺激不良反應。目前國內關于數字化評估患者運動癥狀的研究已較多且較深入[74]，但是還需要進一步研發智能程控系統，并增強醫工協作能力。

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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

國家重點研發計劃“數字診療裝備研發”試點專項課題(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