劉秀梅 張婷婷 孫 莉

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丘腦底核深部腦刺激術(shù)對(duì)帕金森病非運(yùn)動(dòng)癥狀影響效果的研究進(jìn)展

劉秀梅 張婷婷 孫 莉

腦深部電刺激術(shù)(DBS)被廣泛應(yīng)用于帕金森病(PD)等錐體外系疾病的治療。長(zhǎng)期以來(lái)，PD的四大核心運(yùn)動(dòng)癥狀-靜止性震顫、肌強(qiáng)直、運(yùn)動(dòng)遲緩、姿勢(shì)步態(tài)異常已為人們所熟知，且通過(guò)丘腦底核(STN)DBS能明顯改善以上癥狀。而PD的非運(yùn)動(dòng)癥狀(NMS)如自主神經(jīng)功能障礙、神經(jīng)精神癥狀、感覺(jué)障礙、睡眠障礙等癥狀未得到足夠重視，而且會(huì)隨著帕金森病晚期運(yùn)動(dòng)癥狀的進(jìn)展而加重。雖然NMS不能作為STN DBS靶癥狀，但是許多研究表明，STN DBS能產(chǎn)生對(duì)NMS有益的多種效果，還進(jìn)一步提高了生活質(zhì)量，使手術(shù)達(dá)到更滿意的效果[1-3]。與此相反，也有研究報(bào)道STN DBS會(huì)使一些PD的NMS保持不變或惡化[4-6]?，F(xiàn)綜述如下。

1 STN DBS對(duì)情緒和行為的影響

1.1 抑郁癥 臨床上的PD晚期患者中有40%～50%顯著抑郁癥狀[7]，此癥狀構(gòu)成了影響PD患者生活質(zhì)量的最重要因素之一。研究表明，抑郁癥在PD晚期的病理生理學(xué)涉及了含邊緣區(qū)的大腦區(qū)域中的多巴胺能和去甲腎上腺素能的通路功能障礙，而血清素功能障礙的作用相對(duì)有限[8]?，F(xiàn)關(guān)于STN DBS抑郁癥狀發(fā)生變化的報(bào)告已經(jīng)出現(xiàn)了明顯的爭(zhēng)議，其中包括癥狀有改善，無(wú)變化和惡化。有文獻(xiàn)指出抑郁癥狀通常在行STN DBS后的最初幾個(gè)月得到改善[9-10]。而長(zhǎng)期跟進(jìn)STN DBS的報(bào)告顯示，與一般情況相比，術(shù)后抑郁癥狀可得到改善或保持不變[11-12]。國(guó)內(nèi)學(xué)者錢浩等在STN DBS術(shù)后兩年的隨訪中發(fā)現(xiàn)，患者術(shù)后兩年HAMD及HAMA評(píng)分較術(shù)前有所減低，即抑郁癥狀可得到改善[12]。所以STN DBS對(duì)抑郁癥狀的影響有待進(jìn)一步的隨訪研究。

1.2 自殺 曾經(jīng)報(bào)道一個(gè)行STN DBS的患者術(shù)后第1年自殺，這一案例備受關(guān)注[13]。然而，隨后的隨機(jī)對(duì)照研究發(fā)現(xiàn)，與藥物治療后相比，STN DBS后自殺意念或行為的風(fēng)險(xiǎn)沒(méi)有增加，雖然有人認(rèn)為這項(xiàng)研究是由于自殺事件的稀有性而可信度不夠[14]。Voon V等[13]學(xué)者也表明，STN DBS后自殺或自殺意念的比率為0.5%～1.5%，原因是患者對(duì)未達(dá)到手術(shù)結(jié)果的不切實(shí)際的期望可能有一定的自殺危險(xiǎn)[15]。因此，心理醫(yī)師的介入治療也是必要的選擇手段。

1.3 冷漠 冷漠涉及興趣的缺乏、正常有目的行為減少、缺乏主動(dòng)性和對(duì)情感反應(yīng)的淡漠[16]。PD晚期冷漠患病率各不相同，從17%～70%不等，取決于樣本人群，診斷標(biāo)準(zhǔn)和評(píng)價(jià)工具[17]。雖然冷漠的發(fā)生通常與認(rèn)知功能障礙和抑郁癥有關(guān)，但部分沒(méi)有抑郁癥和老年癡呆癥患者也會(huì)患上冷漠[5，18]。一些研究報(bào)告STN DBS后會(huì)促進(jìn)冷漠，有證據(jù)表明，冷漠與邊緣系統(tǒng)相關(guān)聯(lián)，多巴胺能神經(jīng)支配和多巴胺能藥物減少似乎是行STN DBS后冷漠的重要原因[19]。事實(shí)上，在一項(xiàng)研究中顯示，手術(shù)后多巴胺能藥物突然快速下降后有半數(shù)焦慮和抑郁的患者會(huì)出現(xiàn)冷漠。但是，從長(zhǎng)遠(yuǎn)來(lái)看，冷漠也有可能類似于老年癡呆癥，其發(fā)展為PD晚期的NMS，是一個(gè)自然的過(guò)程。

1.4 瘋狂和沖動(dòng) 在術(shù)后早期，患者可發(fā)展為興奮、多動(dòng)和失控。PD晚期的沖動(dòng)控制相關(guān)行為包括多巴胺失調(diào)綜合征，沖動(dòng)控制障礙(即性欲亢進(jìn)、暴飲暴食、病理性賭博、病理性購(gòu)物)。多巴胺失調(diào)綜合征患病率和沖動(dòng)控制障礙率大約分別是3%～4%和6%～14%[20]?？梢灶A(yù)期的是，STN DBS術(shù)后多巴胺能藥物顯著削減后下，控制相關(guān)行為的癥狀可得到改善或消失。但是，研究的結(jié)果是不一致的，一些報(bào)道是改善的結(jié)果，一些則沒(méi)有顯著變化，甚至有些報(bào)道是行STN DBS后患者會(huì)出現(xiàn)新的沖動(dòng)控制相關(guān)行為[21-24]。

1.5 焦慮 PD晚期焦慮包括廣泛性焦慮癥，驚恐發(fā)作和社交恐懼癥。焦慮通常與抑郁癥共存，也能與響應(yīng)多巴胺能藥物的一個(gè)術(shù)前非運(yùn)動(dòng)波動(dòng)的癥狀共存。有研究表明，STN DBS后能改善焦慮，但從長(zhǎng)遠(yuǎn)來(lái)看，與一般情況相比，焦慮似乎未發(fā)生改變[10-11]。

2 STN DBS對(duì)認(rèn)知的影響

認(rèn)知功能障礙是PD晚期的固有障礙。在后期階段，高達(dá)80%的患者患有癡呆，詳細(xì)的評(píng)估顯示甚至在疾病的早期階段也會(huì)患上癡呆。已經(jīng)有人擔(dān)憂有雙邊STN DBS后認(rèn)知惡化的可能。因?yàn)橛谰眯源碳る姌O本身的展示位置和外科手術(shù)過(guò)程中記錄電極的插入會(huì)引起雙側(cè)皮質(zhì)和皮質(zhì)下的損害。此外，仍然不能很好地理解電刺激對(duì)認(rèn)知功能的影響。然而，雖然有關(guān)于STN DBS后認(rèn)知功能減退的一些報(bào)道[25-26]，但人們普遍從認(rèn)知的角度認(rèn)為雙邊STN DBS是安全的[6，27-28]。許多研究表明，與治療后相比，雙邊STN DBS后全局認(rèn)知功能無(wú)顯著變化，癡呆的發(fā)病率沒(méi)有增加，觀察到的認(rèn)知惡化已被歸因于該疾病自然過(guò)程而不是STN DBS的不利影響[15，29]。為了支持這個(gè)猜想，雙邊STN DBS認(rèn)知能力下降的危險(xiǎn)因素和癡呆的形成與那些藥物治療PD不同。

3 STN DBS對(duì)睡眠的影響

在PD晚期睡眠有關(guān)的問(wèn)題包括失眠，白天過(guò)度嗜睡，快速眼部運(yùn)動(dòng)睡眠行為障礙和不寧腿綜合征。在一項(xiàng)研究顯示[30]，減少白天嗜睡，增加正常的快速眼部運(yùn)動(dòng)睡眠，減少快速眼部運(yùn)動(dòng)睡眠，無(wú)肌肉麻痹，并減少入睡后的覺(jué)醒，提高了總睡眠量表評(píng)分，有研究者認(rèn)為其可能機(jī)制是降低多巴胺能藥物的作用，減少STN DBS對(duì)睡眠的直接影響，并且降低了運(yùn)動(dòng)癥狀的改善[31-33]。盡管報(bào)告了STN DBS對(duì)PD快速眼部運(yùn)動(dòng)睡眠有影響，但以前的報(bào)告顯示，睡眠行為障礙不受STN DBS影響，即便有報(bào)道術(shù)后早期涉及睡眠行為障礙的發(fā)展[34]。最近關(guān)于臨床上診斷睡眠行為障礙的研究表明，臨床上睡眠行為障礙的患病率在STN DBS后增加，這是因?yàn)樾g(shù)前睡眠行為障礙依然存在。關(guān)于STN DBS對(duì)不寧腿綜合征的影響的報(bào)告是稀缺的和不確定的。有些報(bào)道顯示已經(jīng)改進(jìn)[35-36]。然而，也有些報(bào)道進(jìn)一步惡化或缺乏顯著變化[31，37]。

4 STN DBS對(duì)自主神經(jīng)癥狀的影響

據(jù)報(bào)道[38]，64%～87%PD晚期患者有下尿路癥狀，如尿頻、尿急、尿潴留等癥狀，而27%～39%PD晚期患者有很嚴(yán)重的下尿路癥狀。有研究表明，STN DBS能改善下尿路癥狀，尤其是逼尿肌的反射亢進(jìn)[39]。胃腸動(dòng)力在PD晚期會(huì)明顯下降，一項(xiàng)研究報(bào)告指出STN DBS可改善胃的排空，然而多巴胺能藥物卻沒(méi)有此效果[40]。STN DBS在改善便秘和吞咽方面也有報(bào)道[41-42]。然而，這些研究結(jié)果的臨床意義尚不清楚。STN DBS對(duì)出汗的影響效果研究也產(chǎn)生了爭(zhēng)議，然而，所有這些研究都受限于受試者的數(shù)量少[41，43-45]。

5 STN DBS對(duì)疼痛的影響

疼痛是一種常見(jiàn)的癥狀，但在PD晚期有認(rèn)識(shí)不足和治療不足的缺陷。研究發(fā)現(xiàn)，40%～85%PD晚期患者會(huì)出現(xiàn)疼痛，雖然在許多研究中一直報(bào)道STN DBS對(duì)PD的疼痛可有效改善[46-49]。但通過(guò)STN DBS改善PD疼痛的機(jī)制沒(méi)有得到充分的解釋[50-51]。值得注意的是，雖然STN DBS改善疼痛，但新疼痛也會(huì)隨疾病的進(jìn)展而形成[52-53]。

6 總 結(jié)

在PD晚期雖然有些NMS為改變，甚至進(jìn)一步惡化，但許多NMS在STN DBS治療后得到改善。這些反應(yīng)的確切機(jī)制是未知的,是STN刺激的直接作用還是降低多巴胺能藥物的效果或者是PD晚期本身減緩的過(guò)程，其有待于進(jìn)一步探討。由于NMS極大影響PD晚期患者的生活質(zhì)量，因此臨床醫(yī)師在決定是否進(jìn)行手術(shù)應(yīng)該知道這些NMS，要注意STN DBS這些癥狀的改變，以確保電刺激參數(shù)和藥物的最佳調(diào)整方案。

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(本文編輯 馮曉倩)

116100 大連市 大連醫(yī)科大學(xué)附屬第一醫(yī)院急診ICU

劉秀梅：女，本科，主管護(hù)師，護(hù)士長(zhǎng)

孫莉

10.3969/j.issn.1672-9676.2016.19.007

2016-06-16)