脑深部电刺激术治疗帕金森病的进展与展望

吴 曦， 胡小吾

海军军医大学附属长海医院神经外科，上海 200433

·专题报道·

脑深部电刺激术治疗帕金森病的进展与展望

吴 曦， 胡小吾*

海军军医大学附属长海医院神经外科，上海 200433

脑深部电刺激术(deep brain stimulation, DBS)目前已成为国内外认可的帕金森病重要治疗方案。随着脑科学、手术方法、磁共振成像技术的不断发展，以及大量临床循证医学证据的逐渐完善，DBS治疗帕金森病在手术时机、靶点选择、症状控制、治疗机制、设备改进等方面均取得了较大的进展。但是，其在中轴运动症状和非运动症状的控制方面尚存在一些不足，设备、程控设置等方面也有待改进。

帕金森病；脑深部电刺激；设备

如果说左旋多巴是帕金森病(Parkinson disease, PD)药物治疗的金标准，那么脑深部电刺激术(deep brain stimulation, DBS)是PD辅助药物治疗的外科首选方法。DBS治疗PD自1999年获得我国国家食品药品监督管理总局(CFDA)批准上市以来，已得到长足发展。目前，我国已有超过100家中心开展该手术，全国年手术量超过4 000例，并研制出了我国自己的DBS系列产品。该疗法涉及了神经内科、神经外科、神经调控、神经影像、神经生物工程等诸多领域，本文对近年来DBS治疗PD的主要进展进行了总结及展望。

1 DBS治疗PD的疗效与不足

1.1 核心运动症状 长期随访结果[1-9]显示，随着手术方式和步骤的逐步改良，DBS术安全性逐步提高，目前手术死亡率约0.1%。如果患者适应证好、电极植入准确以及刺激参数设置适当，无论是丘脑底核(subthalamic nucleus, STN)刺激还是苍白球内侧部(internal globus pallidus, GPi)刺激，都可以长期显著改善中晚期PD患者的震颤、僵直、少动等核心运动症状。STN-DBS可以显著减少PD患者的药物用量，并减少药物引起的多种不良反应。国内手术安全性及治疗效果的长期随访研究结果与国外同期研究[10-12]结果相仿，但目前还缺少术后10年以上的长期随访结果。

1.2 轴性运动症状 关于STN-DBS是否可以改善步态、吞咽、语言和平衡等轴性症状目前存在争议[13-14]。近期1篇meta分析[15]显示，STN-DBS确实可以在患者电极植入48个月内改善药物关期状态下的步态(步长、步速等)和冻结步态，但是上述症状仍会随着时间延长而逐渐恶化，不如核心症状改善持久。其原因可能是靶点核团参与情感、感觉与运动，而DBS的电刺激对不同神经网络的调控效果有差异。不同神经网络的神经递质、下游重要神经节点的数量、距电极触点的距离等差异导致其对电刺激的反应不同。如高频STN-DBS对吞咽能力的改善作用有限，甚至有负面作用[16]。因此，通过调整DBS的激活触点、激活域、刺激参数来改善轴性运动症状，进而提高患者生活质量，是目前研究的热点。

1.3 非运动症状 目前认为非运动症状较运动症状更影响患者的生活质量。术后1～3年，DBS可以部分改善某些非运动症状，如睡眠质量[17]、便秘[17]、肌张力障碍性疼痛[18]、胃胀感[19]、膀胱激惹症状[20]。研究[21]显示，STN-DBS可以改善多种类型的非运动症状，但该研究病例数较少，且随访时间较短。随着对非运动症状认识的深入、非运动症状量表设计与评估方法的改进，DBS改善PD患者非运动症状的长期随访结果将逐渐增多。

1.4 精神心理、认知与高级神经功能 由于STN参与边缘系统的神经通路，PD患者在STN-DBS术后减少药量过程中会出现撤药反应，导致心理或精神改变[22]。临床中需要鉴别STN-DBS术后精神症状是病程进展结果、撤药反应或是电刺激引起的不良反应。大部分精神心理症状可通过调整刺激参数或辅助药物治疗改善。

DBS对绝大部分PD患者的认知能力影响较小[23]。但是，DBS术后电刺激对额叶有抑制作用[24]，可能导致患者认知功能轻微下降，主要表现在视觉空间感觉[25]、语言流畅性[26]、对他人语言理解力、注意力、冲突协调力[27]、执行力下降。上述症状与术前认知功能下降有关尚无定论[28-29]。STN-DBS对PD患者高级神经功能的影响可能成为STN功能的一个研究热点。

1.5 不良反应 DBS术中如电极位置不佳或刺激参数设置不当，除治疗效果不佳外，可能刺激周围神经传导束，引起多种类型的运动症状、感觉症状、精神症状等[30-31]。因此，通过对手术时机、靶点选择的进一步研究，设备的改进，刺激参数的探索，可进一步提高疗效、减少刺激引起的不良反应。

2 DBS治疗PD研究进展

目前DBS治疗PD研究主要集中于以下几个方面：(1)手术时机的选择；(2)靶点的选择和应用；(3)定位方法的改进和颅内电极位置的确认；(4)颅内电极、脉冲发生器等电刺激设备的改进；(5)刺激参数(程控)探索；(6)刺激域的模拟及可视化程控。

2.1 手术时机的选择 以往认为，DBS是中晚期PD患者在药物治疗效果不佳的时候不得不用的备选方案。但后来研究发现中期(≤3年)患者出现运动症状时进行DBS干预后，生活质量得到很大改善[32]，这一结果可能促使治疗窗前移。研究[33]报道了DBS在更早期患者的应用，发现病程仅2年的患者也可以很好地耐受DBS，且DBS患者药物服用量较单用药物组更少。目前，美国FDA正在进行早期PD患者STN-DBS治疗的3期临床试验，如果结果良好并获得批准，DBS手术时机选择范围将更宽。

2.2 靶点的选择和应用 国内目前最常用的PD治疗靶点为STN。其改善运动症状的效果与选择GPi相仿[34-35]，但是可以减少药物的使用，且耗电较少。近期一项入组128例手术患者的前瞻性研究[36-37]显示，STN-DBS较GPi-DBS可以更好地改善运动症状(46%vs26%)，两者对非运动症状和精神症状的改善有差异。但是，GPi-DBS对PD异动症的直接抑制效果优于STN-DBS，通过STN对PD异动症的治疗主要依赖减少药物用量。因此，对于有异动症的患者，应该根据疾病特点选择适宜的靶点。

脚桥核(pedunculopontine nucleus, PPN)是中脑运动区的重要组成部分，与步的启动和步态的调节密切相关。在PD发病过程中累及此核团，因此其也是神经调控治疗PD的一个热点。PPN低频电刺激可改善患者的步态障碍[38]。但是由于单独PPN-DBS对于震颤、僵直、动作迟缓等核心运动症状的改善并不理想，目前多与STN-DBS的联合进行。国内也有中心尝试进行STN与PPN的联合刺激，但是该研究样本量较小，且未发表论文。目前，STN与PPN联合刺激对DBS的疗效尚未明确。

STN联合齿状核-红核-丘脑束电刺激对药物难治性震颤型PD患者的疗效优于单纯STN-DBS[39]。此外，刺激红核外侧、STN内侧、内侧丘系前的丘系前辐射也可改善PD相关震颤、僵直[40]。因此，应进一步研究STN-DBS取得的治疗效果是通过刺激哪些结构获得的，以及今后对电极的设计是否可以使其“一箭多星”。

2.3 定位方法的改进和颅内电极位置的确认 既往根据可视核团的MRI与带框架下CT扫描融合后进行的核团坐标，计算电极植入的位置，术中通过单通道或多通道微电极电生理记录和微刺激确定靶点。随着MRI核团可视化水平的不断提高，有学者认为只根据MRI提供的解剖信息即可确定植入电极的位置[41-43]。而术中磁共振(intraoperative MRI, iMRI)的出现使植入电极过程中可以根据iMRI提供的脑移位信息来进行电极的动态调整，而不是根据电生理监测结果。由于术中脑移位具有不可预测性[44]，iMRI监测下的靶点植入较常规方法更为准确，其中期治疗效果较好[45-46]。在iMRI未普及的情况下，患者术中佩戴立体定向仪复查MRI不失为一种较好选择，其也可以直接显示电极位置和STN，如电极位置有偏差可在术中直接调整。

用术中CT(intraoperative CT, iCT)技术在全麻下植入DBS时，需要将其与术前MRI融合，但融合结果无法纠正脑移位造成的误差，加之融合技术本身也存在一定缺陷，因此电极植入误差没有较常规方法减小[47-48]，应用前景可能较iMRI差。

我国有少数单位尝试应用无框架定位系统。有研究认为，无框架定位系统的电极植入精度与传统框架技术相似[49]，临床疗效也差不多[50]。但近期一项较大样本量临床研究[51]显示，无框架定位系统电极植入位置与传统框架相差约0.5 mm。因此，该系统的应用应谨慎。

2.4 电刺激设备的进展 将足够刺激强度的激活域控制在预期靶点周围的预定空间内，是确保电刺激疗效和避免电刺激不良反应的基础。为克服环形触点电刺激产生的类球形激活域带来的不良反应，多种方向性电极应运而生，并且取得了更好的临床效果[52]。如32触点电极(Medtronic, Eindhoven, The Netherlands)疗效较传统电极更优，同时还可以记录电刺激时其他触点的局部场电位(local field potential, LFP)[53-55]。其与感知反馈式DBS设备联用，显示广阔的应用前景。另一种3个方向触点结合传统环形触点的电极(Aleva, Lausanne, Switzerland)显示减少刺激不良反应的优势[56]。

感知反馈式DBS设备也称闭环式DBS(closed-loop DBS)设备或自适应DBS(adaptive DBS systems)设备，与既往的开环式DBS设备有明显的不同。该设备根据感知到的患者电极周围核团内神经元形成的LFP(如β振荡)[57]，分析是否需要或进行何种类型、何种刺激强度的电刺激，从而根据患者实时脑电信号自动调整电刺激参数[58-60]。从理论上讲，感知反馈式DBS在减少电刺激诱发的不良反应、减少症状波动、提高刺激疗效方面较开环式DBS有着明显的优势。但是对于解读触点记录到的LFP的要求也高，我国多个中心的学者在此方面进行了大量的动物和临床研究[61]。该设备的临床疗效较传统DBS效果更佳[62]，并可进一步应用于脑科学研究，进而指导临床工作。该设备可在感知不同LFP信号后，采用多种刺激模式发挥综合、更优的治疗效果。随着对脑电信号解读水平的提高，这类设备将有较大的发展潜力和应用前景。

2.5 刺激参数设置(程控) STN-DBS在高频(≥100 Hz)刺激时，可能引起冻结步态、语言功能下降和吞咽困难等中轴症状的加重，而在60～80 Hz刺激且维持等效刺激强度时，可以一定程度上改善这些症状[63]。但是，低频治疗有效的持续时间可能因人而异，无法持久，且部分患者的核心运动症状可能加重，可通过以下几点预测低频刺激效果[64]：(1)术后1年左旋多巴对轴性症状改善显著；(2)术后高频电刺激使轴性症状加重；(3)高频电刺激导致服药后药效减退。为了兼顾高频对核心运动症状的治疗效果以及低频对中轴症状的治疗效果，清华大学国家神经调控重点实验室研发了变频电刺激技术，初步临床应用显示其达到了预期的治疗效果、减少了不良反应[65-66]，大样本临床研究正在进行。低频刺激或变频刺激改善中轴症状的机制有待进一步研究。

脉宽在刺激参数设置中的调整幅度往往不大，一般最低为60 μs，有研究[67]显示低于60 μs脉宽的电刺激可以减少电刺激引起的不良反应。对于这一参数的设置，可能还需要进行更多的调整和试验。

交叉电脉冲刺激技术是可以在同一根电极上的不同触点，给予两套独立刺激参数的新技术。该技术可以通过分别调节不同激活触点的激活域，在增强治疗效果的同时，避免电刺激引起的不良反应[68-69]。

3 DBS治疗PD的展望

随着PD神经网络研究的进展、对疾病发生的神经电生理机制认识的加深及电极植入准确性的提高，对患者群和靶点的选择、新型DBS设备和方向性电极的使用、多样性刺激参数的设置更加精确。电刺激设备的更新和升级，必然增加程控医师工作量，因此可视化程控[70-71]或者计算机自动化症状评估与程控[72-73]会得到推广，进而进一步提高PD疗效并减少电刺激不良反应。目前国内关于数字化评估患者运动症状的研究已较多且较深入[74]，但是还需要进一步研发智能程控系统，并增强医工协作能力。

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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

国家重点研发计划“数字诊疗装备研发”试点专项课题(2016YFC0105900). Supported by “Digital Equipment of Diagnosis and Treatment” Special Program of National Key Research and Development Plan (2016YFC0105900).

吴 曦, 博士, 讲师、主治医师. 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

[本文编辑] 姬静芳