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Article(id=1208862367832731875, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208862365714616539, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2021.09.17, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1626624000000, receivedDateStr=2021-07-19, revisedDate=1628524800000, revisedDateStr=2021-08-10, acceptedDate=null, acceptedDateStr=null, onlineDate=1766144848068, onlineDateStr=2025-12-19, pubDate=1632758400000, pubDateStr=2021-09-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766144848068, onlineIssueDateStr=2025-12-19, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766144848068, creator=13701087609, updateTime=1766144848068, updator=13701087609, issue=Issue{id=1208862365714616539, tenantId=1146029695717560320, journalId=1189873630562394117, year='2021', volume='46', issue='9', pageStart='849', pageEnd='953', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1766144847562, creator=13701087609, updateTime=1766144914151, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208862645055254758, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208862365714616539, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208862645055254759, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208862365714616539, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=946, endPage=953, ext={EN=ArticleExt(id=1208862369288155367, articleId=1208862367832731875, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research progress of stereotactic ablation in treatment of Parkinson’s disease, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Stereotactic ablation or surgery known as the lesioning therapies (LT) is a method to treat nervous system diseases by destroying specific tissue structures in the brain through stereotactic minimally invasive technology, mainly consisting of magnetic resonance guided focused ultrasound surgery (MRgFUS), gamma knife stereotactic radiosurgery (GK) and radiofrequency thermal ablation (RF). For Parkinson's disease (PD) patients with poor drug response, LT can significantly improve the clinical symptoms (such as stiffness, tremor, dyskinesia, etc.), reduce drug dosage and improve the long-term quality of life,and is an important alternative to deep brain stimulation (DBS). Fully understanding the mechanism, characteristics, advantages and disadvantages and applicable population of the different methods of LT is of great guiding significance for formulating an individualized treatment plan. The research progress of MRgFUS, GK and RF in LT in the treatment of PD in recent years were reviewed, and the therapeutic effects and adverse reactions of different methods and targets have been summarized in present paper,so as to provide some reference for the selection of clinical operation scheme in the future.

, correspAuthors=Xue-Mei Li, authorNote=null, correspAuthorsNote=
*E-mail:
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立体定向脑损毁术或称消融术(LT)是指通过立体定向微创技术损毁脑内特定组织结构从而治疗神经系统疾病的手术方法，主要包括磁共振引导超声聚焦消融术(MRgFUS)、伽马刀(GK)及射频消融术(RF)等。对于药物反应欠佳的帕金森病(PD)患者，LT可明显改善临床症状(如僵直、震颤、异动症等)，减少药物用量，提高长期生活质量，同时也是脑深部刺激术(DBS)的重要替代方案。充分认识LT不同手术方法的作用机制、特性、优缺点、适用人群等，对制定个体化治疗方案具有重要指导意义。该文就近年来LT中MRgFUS、GK、RF治疗PD的研究进展进行综述，并针对不同方法、不同靶点的治疗效果及不良反应进行总结，以期为今后临床工作中手术方案的选择提供一定的参考。

, correspAuthors=李雪梅, authorNote=null, correspAuthorsNote=
李雪梅，E-mail：
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尹春宇，硕士研究生，主要从事神经系统变性病及脑血管病方面的研究

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尹春宇，硕士研究生，主要从事神经系统变性病及脑血管病方面的研究

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尹春宇，硕士研究生，主要从事神经系统变性病及脑血管病方面的研究

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Pu. 壳核；Cd.尾状核；GPe. 外侧苍白球；GPi. 内侧苍白球；STN. 丘脑底核；SN. 黑质；Thal. 丘脑

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Imaging localization and application of Vim, GPi, STN and PT targets

, figureFileSmall=null, figureFileBig=null, tableContent=
核团影像学定位适用情况
VimPC前部AC-PC间距的25%，ICL外侧14 mm；或者第三脑室壁外侧11.5 mm，背腹侧与ICL在相同水平治疗各种震颤，包括PD、ET、MS等
GPi中线外侧20 mm，AC-PC中点前3~4 mm，ICL下3 mm缓解PD核心运动症状，减少药物用量，对异动改善明显；合并认知减退、情绪障碍(优先)
STNAC-PC中点外侧12 mm，后3 mm，下4 mm缓解PD核心运动症状，减少药物用量(优先)
PTAC-PC中线，第三脑室壁外侧7.5 mm，背腹侧ICL±1 mm与GPi相似，减少复发
), ArticleFig(id=1209154191893860872, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208862367832731875, language=CN, label=表1, caption=

Vim、GPi、STN、PT影像学定位及适用情况

, figureFileSmall=null, figureFileBig=null, tableContent=
核团影像学定位适用情况
VimPC前部AC-PC间距的25%，ICL外侧14 mm；或者第三脑室壁外侧11.5 mm，背腹侧与ICL在相同水平治疗各种震颤，包括PD、ET、MS等
GPi中线外侧20 mm，AC-PC中点前3~4 mm，ICL下3 mm缓解PD核心运动症状，减少药物用量，对异动改善明显；合并认知减退、情绪障碍(优先)
STNAC-PC中点外侧12 mm，后3 mm，下4 mm缓解PD核心运动症状，减少药物用量(优先)
PTAC-PC中线，第三脑室壁外侧7.5 mm，背腹侧ICL±1 mm与GPi相似，减少复发
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立体定向脑损毁术治疗帕金森病的研究进展
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尹春宇 1 , 宗睿 2 , 潘隆盛 2 , 李雪梅 1, *
解放军医学杂志 | 综述 2021,46(9): 946-953
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解放军医学杂志 | 综述 2021, 46(9): 946-953
立体定向脑损毁术治疗帕金森病的研究进展
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尹春宇1, 宗睿2, 潘隆盛2, 李雪梅1, *
作者信息
  • 1解放军总医院第一医学中心干部诊疗科，北京 100853
  • 2解放军总医院第一医学中心神经外科医学部，北京 100853

    • 尹春宇，硕士研究生，主要从事神经系统变性病及脑血管病方面的研究

通讯作者:

李雪梅，E-mail：
Research progress of stereotactic ablation in treatment of Parkinson’s disease
Chun-Yu Yin1, Rui Zong2, Long-Sheng Pan2, Xue-Mei Li1, *
Affiliations
  • 1Department of Cadre Diagnosis and Treatment, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
  • 2Department of Neurosurgery, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
出版时间: 2021-09-28 doi: 10.11855/j.issn.0577-7402.2021.09.17
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摘要
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立体定向脑损毁术或称消融术(LT)是指通过立体定向微创技术损毁脑内特定组织结构从而治疗神经系统疾病的手术方法，主要包括磁共振引导超声聚焦消融术(MRgFUS)、伽马刀(GK)及射频消融术(RF)等。对于药物反应欠佳的帕金森病(PD)患者，LT可明显改善临床症状(如僵直、震颤、异动症等)，减少药物用量，提高长期生活质量，同时也是脑深部刺激术(DBS)的重要替代方案。充分认识LT不同手术方法的作用机制、特性、优缺点、适用人群等，对制定个体化治疗方案具有重要指导意义。该文就近年来LT中MRgFUS、GK、RF治疗PD的研究进展进行综述，并针对不同方法、不同靶点的治疗效果及不良反应进行总结，以期为今后临床工作中手术方案的选择提供一定的参考。

立体定向脑毁损术  /  磁共振引导超声聚焦消融术  /  射频消融术  /  伽马刀  /  帕金森病

Stereotactic ablation or surgery known as the lesioning therapies (LT) is a method to treat nervous system diseases by destroying specific tissue structures in the brain through stereotactic minimally invasive technology, mainly consisting of magnetic resonance guided focused ultrasound surgery (MRgFUS), gamma knife stereotactic radiosurgery (GK) and radiofrequency thermal ablation (RF). For Parkinson's disease (PD) patients with poor drug response, LT can significantly improve the clinical symptoms (such as stiffness, tremor, dyskinesia, etc.), reduce drug dosage and improve the long-term quality of life,and is an important alternative to deep brain stimulation (DBS). Fully understanding the mechanism, characteristics, advantages and disadvantages and applicable population of the different methods of LT is of great guiding significance for formulating an individualized treatment plan. The research progress of MRgFUS, GK and RF in LT in the treatment of PD in recent years were reviewed, and the therapeutic effects and adverse reactions of different methods and targets have been summarized in present paper,so as to provide some reference for the selection of clinical operation scheme in the future.

stereotactic ablation  /  magnetic resonance guided focused ultrasound surgery (MRgFUS)  /  radiofrequency thermal ablation  /  gamma knife stereotactic radiosurgery  /  Parkinson's disease
尹春宇, 宗睿, 潘隆盛, 李雪梅. 立体定向脑损毁术治疗帕金森病的研究进展. 解放军医学杂志, 2021 , 46 (9) : 946 -953 . DOI: 10.11855/j.issn.0577-7402.2021.09.17
Chun-Yu Yin, Rui Zong, Long-Sheng Pan, Xue-Mei Li. Research progress of stereotactic ablation in treatment of Parkinson’s disease[J]. Medical Journal of Chinese People’s Liberation Army, 2021 , 46 (9) : 946 -953 . DOI: 10.11855/j.issn.0577-7402.2021.09.17
正文
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帕金森病(Parkinson's disease，PD)的对症治疗始于20世纪30年代后期，最初以各种形式的脑组织切除为主，早期的靶点为中央前回皮质，后来逐渐发展至锥体束(包括脊髓、内囊、大脑脚)，直至1939年，Meyers[1]首次对一例26岁脑炎后左侧帕金森综合征患者进行尾状核前部切除时，发现其肢体震颤随即消失，进而开启了锥体外系作为治疗靶点的可能性。1947年，Spiegel等[2]描述了立体定位仪在人脑外科手术中的应用，标志着无创立体定向脑部手术的开始。1952年，Cooper[3]在一次手术中意外阻断了患者的脉络膜前动脉造成苍白球梗死，同时观察到患者的震颤和运动迟缓症状得到缓解，随后针对PD患者的外科治疗靶点逐渐集中于丘脑和苍白球两个部位。1952—1954年，Spiegel及Wycis[4]结合立体定向仪对苍白球、丘脑、豆状核襻进行射频消融(radiofrequency thermal ablation，RF)以治疗PD相关震颤。Hassler[5]则更加侧重于丘脑腹外侧核，并于1954年首次报道了应用RF进行丘脑腹外侧核消融治疗PD相关性震颤，后该技术因其良好的效果而被广泛应用。同年Fry等[6]首次报道了超声聚焦技术(high-intensity focused ultrasound，HIFU)应用于中枢神经系统组织消融，随后又与Meyers等[7]合作并于1959年首次报道了应用该技术对人脑苍白球纤维进行消融，用于治疗PD、舞蹈病、投掷症等运动相关障碍。1967年Leksell和Larsson建立了第一台钴-60伽马刀设备，Leksell将这项新技术称为“立体定向放射手术”(gamma knife stereotactic radiosurgy，GK)，在后来的12年里该原型机主要应用于功能神经外科，如治疗疼痛、运动障碍、行为障碍等[8]。高频电刺激最初用于损毁术的术中定位，1987年Benabid等[9]报道了丘脑高频电刺激能够可逆性地抑制PD相关性震颤，相对于损毁术而言，该方法是一种可逆、可调节的治疗方法。经过不断探索，脑深部电刺激术(deep brain stimulation，DBS)最终在1997年经FDA批准用于治疗PD相关性震颤和特发性震颤(essential tremor，ET)，并于2002年批准用于治疗PD[10]。近年来，随着磁共振热成像技术和经颅超声技术的发展，经颅磁共振引导超声聚焦消融术(MRI-guided focused ultrasound，MRgFUS)可提供更精准的定位，且并发症更少，分别于2016年、2018年被FDA批准用于治疗ET和PD。鉴于立体定向脑损毁术或称消融术(lesioning therpies，LT)近年来取得了一些新的进展，本文就LT(RF、GK、MRgFUS)治疗PD的研究进展进行综述。
1 基底节环路理论基础
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皮质下运动控制系统由基底节和小脑组成，基底节广泛接受整个皮质的传入信号，并通过丘脑将信号投射回皮质，而小脑仅接受皮质运动区和感觉区的传入信号，并将信号投射至脊髓运动中枢(与基底节无直接联系的纤维)。其中，基底节由尾状核(caudate nucleus，Cd)、壳核(putamen，Pu)、苍白球(globus pallidus，GP)、丘脑底核(subthalamic nucleus，STN)、黑质(substantia nigra，SN)5个部分组成。Pu接收来自皮质各区域的输入信号，包括体感皮质、感觉联系皮质和前额叶皮质；Cd主要接受来自前额叶皮质的输入信号。Pu、Cd向内侧苍白球(internal segment of the globus pallidus，GPi)发出纤维，这些纤维连接以γ-氨基丁酸(gamma-aminobutyric acid，GABA)为神经递质，抑制GPi的兴奋性。另外，Pu-外侧苍白球(external segment of the globus pallidus，GPe)-STN之间的纤维也以GABA作为神经递质，STN-GPi之间则以谷氨酸为神经递质。以上两种途径分别称为直接通路(Pu、Cd→GPi)和间接通路(Pu→GPe→STN→苍白球内侧核)。GPi向丘脑腹前核(ventral oral anterior，Voa)、丘脑腹外侧核(ventral oral posterior，Vop)、中脑运动区发出抑制性纤维连接，分别对应运动功能(运动迟缓)、肌肉功能(震颤、僵直)、行走功能(步态异常)。直接通路的兴奋上调丘脑、运动皮质的功能，间接通路的兴奋下调丘脑、运动皮质的功能。SN-Pu、SN-Cd纤维连接以多巴胺作为神经递质，多巴胺可同时兴奋Cd、抑制Pu，通过改变直接通路和间接通路的平衡调节运动功能(易化作用)(图1)。
2 PD治疗靶点
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PD的各种治疗方式本质上均为易化丘脑、皮质运动功能。目前立体定向损毁术靶点主要有丘脑腹外侧核前部(anterior part of the ventrolateral thalamus，VLa)或称丘脑腹中间核(ventrointermedial nucleus of the thalamus，Vim)、GPi、STN、苍白球丘脑束(pallidothalamic tract，PT)。表1总结了Vim、GPi、STN、PT的影像学定位[11]及适用情况，图2—5依次显示了针对Vim、GPi、STN、PT的MRgFUS、GK术后MRI轴位及冠状位的图像。
3 患者选择
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PD的外科治疗需要进行充分的术前评估，以尽可能保证治疗效果及避免并发症的发生。PD外科治疗的适应证包括：明确的PD诊断、合理用药效果不佳、出现药物不良反应影响药物治疗、左旋多巴负荷试验MDS-UPDRS Ⅲ改善≥30%及患者对运动改善有更高要求。禁忌证包括：PD叠加综合征、合并精神心理疾病(如明显的认知功能障碍、严重的焦虑抑郁、精神分裂等疾病)、开期轴性运动评分较低(如步态、平衡等)及其他手术禁忌证。
4 手术技术
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4.1 MRgFUS
Fry等[6]最早提出应用超声聚焦消融治疗运动障碍性疾病，该项技术早期需进行颅骨开窗以减少骨质对超声波的吸收，从而在脑内特定部位达到足够高的声束强度。后来，MRgFUS的成熟得益于两项技术的发展，其中一项是大型独立控制的相控阵换能器，该装置通过相位叠加让透过头皮和颅骨的能量在靶点聚焦，使目标点位达到有效消融温度，还可对颅骨造成的相位偏移进行修正；另一项是MRI与超声聚焦消融技术的结合，超声聚焦消融可在MRI环境下完成操作，MRI可提供准确的实时靶点定位和术中温度监测，使手术的精准度显著提高。术前患者需备皮防止空泡效应，局麻后将标准4针Cosman-Roberts-Wells (CRW)头架和硅胶膜固定于患者头部，然后将头部置于MRI兼容的超声相控阵转换器中，并将1024个单独调节的超声单元聚焦于目标靶点。高强度聚焦超声可输出超过1000 W/cm2的能量强度，随着超声波在组织内传导其波幅衰减并产生热量，这种热效应最终精确聚焦用于组织消融。术中首先使用低强度超声校正焦点位置，并通过MRI确定最高可达温度及扩散范围(热图)，此阶段温度控制在41~46 ℃；接着，将温度逐渐提高至46~50 ℃产生暂时性消融效应，通过对坐标、临床症状(画圆、写字、握水杯等)、并发症等的评估，调整消融靶点；最后，将温度提高至不超过60 ℃对靶点进行消融，正常或非正常组织于57 ℃持续1 s(或等效热剂量)即可造成蛋白质变性，通常单次消融时间曲线约20 s，有效消融温度52~60 ℃持续2~3 s，整个过程可能需要重复多次，以确保覆盖预定治疗区域，也有研究显示多次消融比单次消融具有更好的远期预后[14]。
影响MRgFUS的因素包括：消融靶点位置及患者颅骨密度比(skull density ratio，SDR)，消融靶点(如GPi)解剖位置偏心可造成MRgFUS焦点难以触及，颅骨密度比过低(SDR<0.3)可造成MRgFUS焦点无法达到有效消融温度。另外，MRI环境相关幽闭恐惧症、难以耐受卧位、过度肥胖、体内有金属植入物等也会限制患者选择MRgFUS[15]。MRgFUS治疗的不良反应以感觉障碍、步态和平衡障碍为主，其他还包括运动、感觉、语言障碍(Vim)，认知障碍，视野障碍(GPi)，偏侧投掷症(STN)等，以上不良反应大部分呈一过性(与局部水肿改变有关)，在术后3个月内可逐渐消失，少部分可能因损伤邻近白质纤维、视束等结构而长期存在[10,16]。多项研究显示，MRgFUS治疗PD的效果与DBS相近，如Martínez-Fernández等[17]的一项队列研究纳入了10例有严重单侧肢体症状且药物控制不佳的PD患者，接受MRgFUS单侧STN消融术后6个月，统一帕金森病评定量表(unified Parkinson's disease rating scale，UPDRS)评分与基线相比，关期下降53%[术前(16.6±2.9)分 vs. 术后(7.5±3.9)分]，开期下降47%[术前(11.9±3.1)分 vs. 术后(5.8±3.5)分]。近年来，MRgFUS治疗PD的进展还包括对其他靶点及双侧消融的探索，如Gallay等[18]的一项前瞻性队列研究纳入了51例PD患者，应用MRgFUS行苍白球丘脑束消融(pallidothalamic tractotomy，PTT)，术后3个月UPDRS Ⅲ评分下降37%(开期)、47%(关期)；术后1年MDS-UPDRS Ⅲ评分下降46%(开期)、54%(关期)，其中震颤、僵直、运动迟缓分别下降84%、70%、73%，左旋多巴每日等效剂量(levodopa equivalent daily dose，LEDD)下降55%，而轴性症状、认知功能无明显变化；随后Gallay等[19]又报道了10例接受双侧MRgFUS PTT治疗的PD患者术后1年的随访结果，MDS-UPDRS总分平均降低52%，其中震颤、强直、运动迟缓分别降低91%、67%、54%，LEDD从(690±250) mg降至(110±190) mg，步态、平衡功能无明显改变，言语困难增加了58%(P=0.06)。MRgFUS临床进展的另一个方向是通过联合静脉注射微气泡打开血脑屏障(blood brain barrier，BBB)辅助药物治疗神经系统退行性疾病，如Gasca-Salas等[20]应用MRgFUS对帕金森病痴呆(Parkinson's disease dementia，PDD)患者以右侧额-顶-枕叶皮质为治疗靶点的Ⅰ期临床试验结果显示，术后患者认知功能轻度改善[蒙特利尔认知评估量表(Montreal cognitive assessment，MoCA量表)、韦氏记忆量表第四版(WMS-Ⅳ)等]，淀粉样蛋白和氟脱氧葡萄糖正电子发射计算机断层扫描(positron emission tomography，PET)-CT无明显改变，治疗过程中未见明显不良反应，初步表明MRgFUS是一种安全、有效、可逆、可重复进行的PDD治疗方法。
4.2 GK
Lasak等[8]最早尝试采用X线、交叉质子束结合直线加速器和导向装置作用于人体特定部位来治疗疾病，如以半月神经节为靶点治疗面部疼痛等。随后，由于交叉质子束设备比较笨重，且直线加速器不稳定，Lunsford[21]最终于1967年选取了钴-60作为理想放射源，钴-60经β衰变成为稳定的镍-60放射性核素，同时释放1个电子(315 kev)和2个伽马粒子(1.17 MeV、1.33 MeV)，其中伽马射线的生物学效应可用于特定组织的消融。首台原型机将179个钴-60源置于半球形的阵列中，全部射线汇聚于一个焦点，通过调节射线直径生成不同形状的等剂量分布区域。当代伽马刀设备仍沿用最初的工作原理，仅因内部设计不同而主要分为4种型号，即U型、B型、C型(均有201个钴源)及Perfexion型(192个钴源)，其中Perfexion型因采用了多直径准直系统(4 cm、8 cm、16 cm)、可移动放射源、自动射线屏蔽、固定导向装置等技术，具有更灵活、更舒适、治疗范围更大等优点。术前患者局麻下将Leksell G立体定向坐标框架固定于头部，使框架中心尽量靠近病变部位，随后完成头颅高分辨MRI检查及目标靶点(Vim、GPi、STN)定位，由于存在个体差异，应注意靶点X轴上的位置要在MRI影像直视下进行校正，而非依靠经验参数决定[22]。适应形状的剂量方案以往需要经验丰富的外科医师建立，目前可由GammaPlan软件辅助手动或半自动勾划靶区边缘，从而量化测定靶点体积及制定治疗计划。GK治疗PD通常采用低剂量策略(120~180 Gy)，中心剂量低于110 Gy无法有效消融，高于200 Gy则易引起广泛水肿，很多学者认为130~150 Gy的治疗效果最佳[23-24]。虽然靶区周围的接收剂量会快速下降而免于有害影响，但邻近的重要结构如锥体束(Vim、GPi、STN)、视束(GPi)对射线较为敏感，其安全剂量分别为20 Gy、10 Gy，需要应用射线屏蔽技术进行保护，目前伽马刀4C型、Perfexion型可由系统自动完成此过程。GK术后至出现临床改善平均间隔2~3个月，之后的一段时间改善率还可进一步提高，影像学改变平均3个月内出现、6个月内达峰。Ohye等[25]描述了GK(Vim)术后的3种影像学表现，即A型(环形强化，内囊无条纹)、B型(环形强化，内囊有条纹)、C型(明显扩大的不规则高信号累及内囊等结构)，其中A型、B型直径<5 mm，C型直径可达9~10 mm。GK的不良反应一般于术后6~8个月甚至更久才出现，多表现为暂时性且可逆的轻瘫、麻木、构音障碍等，较严重的神经功能障碍如偏瘫、偏盲、步态障碍等通常与患者的高敏反应有关，影像学可见内囊、视束、下丘脑后部、桥脑、皮质下白质等结构不同程度受累。在标准化放射剂量条件下，这类高敏反应仍可见于2%的人群，目前具体机制仍不清楚，亦无相关检查可以术前预判，Drummond等[26]认为该现象可能与共济失调-毛细血管扩张症基因、糖尿病脑血管病变有关，但也有很多个案并无明确的危险因素，应用糖皮质激素、内皮生长因子抑制剂可缓解这类高敏反应症状。
GK治疗PD的效果与RF相似，许多文献报道其对震颤的疗效确切，如Young等[27]纳入了102例PD患者，以单侧Vim为靶点，其中90例患者对侧肢体震颤可明显缓解甚至消失；GK以GPi为靶点的研究也显示出PD患者震颤、异动、僵直、运动迟缓持久缓解，不良反应率仅为4%[12]；GK以STN为靶点的研究相对有限且结论仍存在争议，如Witjas等[28]采用110 Gy剂量对12例PD患者进行单侧/双侧STN消融，术后1年仅异动明显缓解(66.0%)，而UPDRS评分、运动波动仅缓解17.6%、18.0%，LEDD无明显下降，故认为以STN为靶点时，GK并不适合作为DBS的替代方案。然而Drummond等[26]的一项前瞻性队列研究发现，PD患者单侧STN消融1年后，对侧肢体UPDRS Ⅲ与震颤、僵直、异动相关项目评分明显降低，简易智力状态检查(mini-mental state examination，MMSE)、帕金森患者的生活质量问卷(Parkinson's disease questionnaire，PDQ-39)、Beck抑郁自评量表(Beck depression rating scale，BDI)评分无明显变化，但该队列研究因患者的不良反应较多而中止。整体而言，GK对PD的疗效略逊于DBS，但仍具有3个方面的优势：一是GK对于存在DBS、RF禁忌，或SDR<0.3不适合MRgFUS的患者仍然适用；二是GK在脑动静脉畸形(brain arteriovenous malformation，AVM)领域的广泛应用，使其成为AVM继发性PD患者的较好方案；三是与热消融机制不同，GK对神经组织的效应更为复杂，由于靶区周围组织仍可接收低于细胞致死剂量的射线，其最终效应类似于靶点中心组织破坏+周围组织生理学改变，因此GK的疗效相对稳定而持久。但GK本身的局限性也较为明显，如射线范围无法直接观测、术中无法与患者建立反馈、高敏反应人群无法预测等。针对以上问题，Yamada等[29]提出应用弥散张量成像(diffusion tensor imaging，DTI)技术，通过显示纤维束连接进一步辅助靶点定位；而对于GK高敏反应人群的评估，尤其是STN靶点高反应出现率高于Vim靶点的现象，Higuchi等[30]认为针对靶点特异性、患者用药情况等还需进一步研究。
4.3 RF
Spiegel及Wycis[4]最早设计出针对脑部手术的立体定位仪，并于1954年最先尝试与RF相结合消融Vim靶点治疗PD相关性震颤，术中患者肢体震颤立即消失，且无明显不良反应，术后患者日常生活能力明显改善，治疗效果可长期维持。之后的近50年里，RF不但成为外科治疗PD的重要手段，也为其后更加先进的手术方式奠定了理论基础。目前，随着DBS技术的不断发展成熟，RF逐渐被DBS取代，然而DBS对医疗条件、术后程控要求较高，在无法实施DBS的医疗单位，RF作为最简单、最直接的消融方式，设备及成本要求相对较低，仍是重要的替代手术方案。术前患者局麻下将立体定位框架固定于头部，使其尽量与联合间线平面平行；接着完成头颅CT/MRI检查、建立3D影像、确定靶点坐标。术中首先在患者头部钻一个宽孔，并将导管插入皮质仔细观察反应；然后将微电极经由导管插向靶点，通过记录靶点周围电活动或用微电流刺激观察症状缓解率，进一步确定靶点边界；最后选取直径为1.1 mm，暴露尖端2 mm或4 mm的消融电极置于靶点不同深度，40~60 ℃持续10 s进行预热，70~85 ℃持续60~70 s进行消融，整个过程需重复数次，并结合患者的实时反馈调整至最佳治疗效果。由于RF热效应从电极中心向周围扩散，最终消融范围主要受电极直径、电极尖端暴露长度、消融时间、消融峰温度等因素影响[31]。大量研究证实，RF治疗PD的效果肯定，其中对Vim靶点的消融结果显示，以震颤为主的PD患者术后震颤可立即缓解60%~100%，长期仍可维持57%~90%的疗效[32-33]；对GPi靶点的消融结果显示，PD患者震颤、僵直、运动迟缓、步态、异动、平衡功能均不同程度改善，UPDRS Ⅲ总分平均降低30%[34-37]；对STN靶点的治疗结果显示，PD患者术后12、24、36个月的关期UPDRS Ⅲ评分分别下降50%、30%、18%，而LEDD分别下降45%、36%、28%；双侧RF的研究显示，Vim、GPi、STN双侧治疗均较单侧治疗获益更多[38]。RF的不良反应除了外科常见的侵入性操作带来的出血、感染等风险之外，还包含一系列靶点相关并发症，如共济失调、构音障碍、运动或感觉异常(Vim)，视野缺损、轻瘫、神经心理障碍(GPi)，偏侧投掷症、构音障碍、癫癎(STN)。以上不良反应绝大部分呈一过性，主要与靶区周围术后水肿有关，其中STN消融若出现较严重的偏侧投掷症，可进一步行GPi消融缓解症状。在最新的研究中，de Hemptinne等[39]应用皮质脑电图(intraoperative subdural electrocorticography，ECoG)与体感诱发电位(somatosensory evoked potential，SSEP)初步揭示了RF消融GPi的电生理改变。PD患者GPi消融后初级运动皮层(M1)立即出现频率70~80 Hz的震荡峰，并伴随出现僵直、运动迟缓、震颤的明显缓解。这种窄带γ震荡峰可能是GPi消融的特殊表现，因其仅在70 ℃消融GPi后出现，而术前微电流刺激或其他靶点消融(如Vim)均不出现。γ震荡峰可解释GPi消融过程中出现的异动，最终可通过其平衡促动力性和抗动力性皮质节律，使PD患者运动功能得到改善。该研究为核团损毁术提供了一种客观的电生理指标，同时也为进一步揭示脑功能网络连接提供了可靠方法。
4.4 手术技术选择
目前，PD的外科治疗主要有DBS、MRgFUS、GK、RF四种手术方法，相同的是疾病治疗机制上均为易化丘脑-皮质功能，平衡促动力性和抗动力性皮质节律；不同的是DBS采用高频电刺激，而后三者则采用不同方式进行核团损毁。对于药物控制不佳的PD患者选择何种手术方式，目前的主流观点认为，DBS作为一种可后期调节的手术方案应作为首选，因各种原因无法选择DBS时，LT可作为替代方案。LT中MRgFUS因既能术中实时监测，又能与患者即时交互，使其在手术精度方面具有更多优势；GK存在无法直接监测射线、效果延迟出现、无法预测高敏反应等缺点，使其较少应用于PD的治疗，但多数研究显示GK整体不良反应率低、术后效果稳定而持久，这种优点源于γ射线对神经系统具有的独特作用，随着技术和设备的进步，GK将会成为推荐级别更高的手术方案；RF作为最直接的热消融方式，出现时间最早，研究证据最为充分，但RF与DBS相比不能进行术后调节，且创伤较MRgFUS、GK更大，因此，其优势更多体现在经济效应和对脑功能网络机制的探究中。
5 总结与展望
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PD外科治疗的选择除有明确的禁忌证外，很大程度上取决于患者对其症状和运动能力改善的期望度。此外，治疗时机也应充分考虑患者的依从性、期望度、风险耐受、术后支持治疗等方面的综合情况。对于患者而言，对PD外科治疗准确、客观的认识，能够避免患者对手术方案产生过度恐惧或过度积极的反应，因此，医患之间对手术方案的详尽讨论十分必要。值得强调的是，PD外科治疗方案应尽量在患者尚可获得运动功能改善的阶段(即“时间窗”)进行，而非作为PD晚期患者的最后治疗手段。
关于治疗靶点的选择目前仍缺乏头-头研究证据，目前普遍认为Vim用于治疗震颤为主的PD患者，而GPi、STN、PT对缓解PD患者核心运动症状、减少药物用量更为有效。无论采用何种治疗方式或靶点，PD患者短期内均可获得显著的症状缓解，多数研究随访1~3年，这种治疗效果仍可部分保持，但更长随访时间的研究显示，大部分患者症状复发甚至加重，意味着外科治疗也许仅能缓解症状，并不能阻止疾病进展。虽然有研究提出DBS(STN)存在疾病修饰作用[40]，但对于该观点仍存在争议，其焦点主要在于一些研究招募的晚期PD患者中未见到疾病修饰作用。MDS协会认为，由于PD确诊4年内壳核多巴胺能神经支配已基本消失，因此任何神经保护治疗均应在PD确诊后立即进行，另外对疾病修饰作用的研究，应更侧重于DBS增加脑源性神经生长因子酪氨酸激酶受体B(TrkB)信号传导释放的潜在机制[41]。未来PD的外科治疗仍将主要探索更加精准、效果更稳定、不良反应更少的方案。与此同时，多种手术方案的综合应用，运动皮质、脊髓等新靶点的探索，术后脑电网络和代谢功能改变的机制探究等，也是值得深入研究的重要课题。
基金
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  • 军委后勤保障部保健专项研究项目(17BJ39)
文献
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参考文献 引证文献
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2021年第46卷第9期
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doi: 10.11855/j.issn.0577-7402.2021.09.17
  • 接收时间：2021-07-19
  • 首发时间：2025-12-19
  • 出版时间：2021-09-28
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  • 收稿日期：2021-07-19
  • 修回日期：2021-08-10
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Research Project on Health Care of the Logistics Support Department of the Central Military Commission(17BJ39)
军委后勤保障部保健专项研究项目(17BJ39)
作者信息
    1解放军总医院第一医学中心干部诊疗科，北京 100853
    2解放军总医院第一医学中心神经外科医学部，北京 100853

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李雪梅，E-mail：
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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