丘脑底核深部脑刺激术对帕金森病非运动症状影响效果的研究进展

刘秀梅 张婷婷 孙 莉



丘脑底核深部脑刺激术对帕金森病非运动症状影响效果的研究进展

刘秀梅 张婷婷 孙 莉

脑深部电刺激术(DBS)被广泛应用于帕金森病(PD)等锥体外系疾病的治疗。长期以来，PD的四大核心运动症状-静止性震颤、肌强直、运动迟缓、姿势步态异常已为人们所熟知，且通过丘脑底核(STN)DBS能明显改善以上症状。而PD的非运动症状(NMS)如自主神经功能障碍、神经精神症状、感觉障碍、睡眠障碍等症状未得到足够重视，而且会随着帕金森病晚期运动症状的进展而加重。虽然NMS不能作为STN DBS靶症状，但是许多研究表明，STN DBS能产生对NMS有益的多种效果，还进一步提高了生活质量，使手术达到更满意的效果[1-3]。与此相反，也有研究报道STN DBS会使一些PD的NMS保持不变或恶化[4-6]。现综述如下。

1 STN DBS对情绪和行为的影响

1.1 抑郁症 临床上的PD晚期患者中有40%～50%显著抑郁症状[7]，此症状构成了影响PD患者生活质量的最重要因素之一。研究表明，抑郁症在PD晚期的病理生理学涉及了含边缘区的大脑区域中的多巴胺能和去甲肾上腺素能的通路功能障碍，而血清素功能障碍的作用相对有限[8]。现关于STN DBS抑郁症状发生变化的报告已经出现了明显的争议，其中包括症状有改善，无变化和恶化。有文献指出抑郁症状通常在行STN DBS后的最初几个月得到改善[9-10]。而长期跟进STN DBS的报告显示，与一般情况相比，术后抑郁症状可得到改善或保持不变[11-12]。国内学者钱浩等在STN DBS术后两年的随访中发现，患者术后两年HAMD及HAMA评分较术前有所减低，即抑郁症状可得到改善[12]。所以STN DBS对抑郁症状的影响有待进一步的随访研究。

1.2 自杀 曾经报道一个行STN DBS的患者术后第1年自杀，这一案例备受关注[13]。然而，随后的随机对照研究发现，与药物治疗后相比，STN DBS后自杀意念或行为的风险没有增加，虽然有人认为这项研究是由于自杀事件的稀有性而可信度不够[14]。Voon V等[13]学者也表明，STN DBS后自杀或自杀意念的比率为0.5%～1.5%，原因是患者对未达到手术结果的不切实际的期望可能有一定的自杀危险[15]。因此，心理医师的介入治疗也是必要的选择手段。

1.3 冷漠 冷漠涉及兴趣的缺乏、正常有目的行为减少、缺乏主动性和对情感反应的淡漠[16]。PD晚期冷漠患病率各不相同，从17%～70%不等，取决于样本人群，诊断标准和评价工具[17]。虽然冷漠的发生通常与认知功能障碍和抑郁症有关，但部分没有抑郁症和老年痴呆症患者也会患上冷漠[5，18]。一些研究报告STN DBS后会促进冷漠，有证据表明，冷漠与边缘系统相关联，多巴胺能神经支配和多巴胺能药物减少似乎是行STN DBS后冷漠的重要原因[19]。事实上，在一项研究中显示，手术后多巴胺能药物突然快速下降后有半数焦虑和抑郁的患者会出现冷漠。但是，从长远来看，冷漠也有可能类似于老年痴呆症，其发展为PD晚期的NMS，是一个自然的过程。

1.4 疯狂和冲动 在术后早期，患者可发展为兴奋、多动和失控。PD晚期的冲动控制相关行为包括多巴胺失调综合征，冲动控制障碍(即性欲亢进、暴饮暴食、病理性赌博、病理性购物)。多巴胺失调综合征患病率和冲动控制障碍率大约分别是3%～4%和6%～14%[20]。可以预期的是，STN DBS术后多巴胺能药物显著削减后下，控制相关行为的症状可得到改善或消失。但是，研究的结果是不一致的，一些报道是改善的结果，一些则没有显著变化，甚至有些报道是行STN DBS后患者会出现新的冲动控制相关行为[21-24]。

1.5 焦虑 PD晚期焦虑包括广泛性焦虑症，惊恐发作和社交恐惧症。焦虑通常与抑郁症共存，也能与响应多巴胺能药物的一个术前非运动波动的症状共存。有研究表明，STN DBS后能改善焦虑，但从长远来看，与一般情况相比，焦虑似乎未发生改变[10-11]。

2 STN DBS对认知的影响

认知功能障碍是PD晚期的固有障碍。在后期阶段，高达80%的患者患有痴呆，详细的评估显示甚至在疾病的早期阶段也会患上痴呆。已经有人担忧有双边STN DBS后认知恶化的可能。因为永久性刺激电极本身的展示位置和外科手术过程中记录电极的插入会引起双侧皮质和皮质下的损害。此外，仍然不能很好地理解电刺激对认知功能的影响。然而，虽然有关于STN DBS后认知功能减退的一些报道[25-26]，但人们普遍从认知的角度认为双边STN DBS是安全的[6，27-28]。许多研究表明，与治疗后相比，双边STN DBS后全局认知功能无显著变化，痴呆的发病率没有增加，观察到的认知恶化已被归因于该疾病自然过程而不是STN DBS的不利影响[15，29]。为了支持这个猜想，双边STN DBS认知能力下降的危险因素和痴呆的形成与那些药物治疗PD不同。

3 STN DBS对睡眠的影响

在PD晚期睡眠有关的问题包括失眠，白天过度嗜睡，快速眼部运动睡眠行为障碍和不宁腿综合征。在一项研究显示[30]，减少白天嗜睡，增加正常的快速眼部运动睡眠，减少快速眼部运动睡眠，无肌肉麻痹，并减少入睡后的觉醒，提高了总睡眠量表评分，有研究者认为其可能机制是降低多巴胺能药物的作用，减少STN DBS对睡眠的直接影响，并且降低了运动症状的改善[31-33]。尽管报告了STN DBS对PD快速眼部运动睡眠有影响，但以前的报告显示，睡眠行为障碍不受STN DBS影响，即便有报道术后早期涉及睡眠行为障碍的发展[34]。最近关于临床上诊断睡眠行为障碍的研究表明，临床上睡眠行为障碍的患病率在STN DBS后增加，这是因为术前睡眠行为障碍依然存在。关于STN DBS对不宁腿综合征的影响的报告是稀缺的和不确定的。有些报道显示已经改进[35-36]。然而，也有些报道进一步恶化或缺乏显著变化[31，37]。

4 STN DBS对自主神经症状的影响

据报道[38]，64%～87%PD晚期患者有下尿路症状，如尿频、尿急、尿潴留等症状，而27%～39%PD晚期患者有很严重的下尿路症状。有研究表明，STN DBS能改善下尿路症状，尤其是逼尿肌的反射亢进[39]。胃肠动力在PD晚期会明显下降，一项研究报告指出STN DBS可改善胃的排空，然而多巴胺能药物却没有此效果[40]。STN DBS在改善便秘和吞咽方面也有报道[41-42]。然而，这些研究结果的临床意义尚不清楚。STN DBS对出汗的影响效果研究也产生了争议，然而，所有这些研究都受限于受试者的数量少[41，43-45]。

5 STN DBS对疼痛的影响

疼痛是一种常见的症状，但在PD晚期有认识不足和治疗不足的缺陷。研究发现，40%～85%PD晚期患者会出现疼痛，虽然在许多研究中一直报道STN DBS对PD的疼痛可有效改善[46-49]。但通过STN DBS改善PD疼痛的机制没有得到充分的解释[50-51]。值得注意的是，虽然STN DBS改善疼痛，但新疼痛也会随疾病的进展而形成[52-53]。

6 总 结

在PD晚期虽然有些NMS为改变，甚至进一步恶化，但许多NMS在STN DBS治疗后得到改善。这些反应的确切机制是未知的,是STN刺激的直接作用还是降低多巴胺能药物的效果或者是PD晚期本身减缓的过程，其有待于进一步探讨。由于NMS极大影响PD晚期患者的生活质量，因此临床医师在决定是否进行手术应该知道这些NMS，要注意STN DBS这些症状的改变，以确保电刺激参数和药物的最佳调整方案。

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(本文编辑 冯晓倩)

116100 大连市 大连医科大学附属第一医院急诊ICU

刘秀梅：女，本科，主管护师，护士长

孙莉

10.3969/j.issn.1672-9676.2016.19.007

2016-06-16)