丘腦底核深部腦刺激術(shù)對帕金森病非運動癥狀影響效果的研究進展

劉秀梅 張婷婷 孫 莉

?

丘腦底核深部腦刺激術(shù)對帕金森病非運動癥狀影響效果的研究進展

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。長期以來，PD的四大核心運動癥狀-靜止性震顫、肌強直、運動遲緩、姿勢步態(tài)異常已為人們所熟知，且通過丘腦底核(STN)DBS能明顯改善以上癥狀。而PD的非運動癥狀(NMS)如自主神經(jīng)功能障礙、神經(jīng)精神癥狀、感覺障礙、睡眠障礙等癥狀未得到足夠重視，而且會隨著帕金森病晚期運動癥狀的進展而加重。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NMS有益的多種效果，還進一步提高了生活質(zhì)量，使手術(shù)達到更滿意的效果[1-3]。與此相反，也有研究報道STN DBS會使一些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有限[8]?，F(xiàn)關(guān)于STN DBS抑郁癥狀發(fā)生變化的報告已經(jīng)出現(xiàn)了明顯的爭議，其中包括癥狀有改善，無變化和惡化。有文獻指出抑郁癥狀通常在行STN DBS后的最初幾個月得到改善[9-10]。而長期跟進STN DBS的報告顯示，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]。國內(nèi)學者錢浩等在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對抑郁癥狀的影響有待進一步的隨訪研究。

1.2 自殺 曾經(jīng)報道一個行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，隨后的隨機對照研究發(fā)現(xiàn)，與藥物治療后相比，STN DBS后自殺意念或行為的風險沒有增加，雖然有人認為這項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%，原因是患者對未達到手術(shù)結(jié)果的不切實際的期望可能有一定的自殺危險[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、缺乏主動性和對情感反應(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，診斷標準和評價工具[17]。雖然冷漠的發(fā)生通常與認知功能障礙和抑郁癥有關(guān)，但部分沒有抑郁癥和老年癡呆癥患者也會患上冷漠[5，18]。一些研究報告STN DBS后會促進冷漠，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]。事實上，在一項研究中顯示，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出現(xiàn)冷漠。但是，從長遠來看，冷漠也有可能類似于老年癡呆癥，其發(fā)展為PD晚期的NMS，是一個自然的過程。

1.4 瘋狂和沖動 在術(shù)后早期，患者可發(fā)展為興奮、多動和失控。PD晚期的沖動控制相關(guān)行為包括多巴胺失調(diào)綜合征，沖動控制障礙(即性欲亢進、暴飲暴食、病理性賭博、病理性購物)。多巴胺失調(diào)綜合征患病率和沖動控制障礙率大約分別是3%～4%和6%～14%[20]。可以預期的是，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，一些報道是改善的結(jié)果，一些則沒有顯著變化，甚至有些報道是行STN DBS后患者會出現(xiàn)新的沖動控制相關(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術(shù)前非運動波動的癥狀共存。有研究表明，STN DBS后能改善焦慮，但從長遠來看，與一般情況相比，焦慮似乎未發(fā)生改變[10-11]。

2 STN DBS對認知的影響

認知功能障礙是PD晚期的固有障礙。在后期階段，高達80%的患者患有癡呆，詳細的評估顯示甚至在疾病的早期階段也會患上癡呆。已經(jīng)有人擔憂有雙邊STN DBS后認知惡化的可能。因為永久性刺激電極本身的展示位置和外科手術(shù)過程中記錄電極的插入會引起雙側(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認知功能的影響。然而，雖然有關(guān)于STN DBS后認知功能減退的一些報道[25-26]，但人們普遍從認知的角度認為雙邊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后全局認知功能無顯著變化，癡呆的發(fā)病率沒有增加，觀察到的認知惡化已被歸因于該疾病自然過程而不是STN DBS的不利影響[15，29]。為了支持這個猜想，雙邊STN DBS認知能力下降的危險因素和癡呆的形成與那些藥物治療PD不同。

3 STN DBS對睡眠的影響

在PD晚期睡眠有關(guān)的問題包括失眠，白天過度嗜睡，快速眼部運動睡眠行為障礙和不寧腿綜合征。在一項研究顯示[30]，減少白天嗜睡，增加正常的快速眼部運動睡眠，減少快速眼部運動睡眠，無肌肉麻痹，并減少入睡后的覺醒，提高了總睡眠量表評分，有研究者認為其可能機制是降低多巴胺能藥物的作用，減少STN DBS對睡眠的直接影響，并且降低了運動癥狀的改善[31-33]。盡管報告了STN DBS對PD快速眼部運動睡眠有影響，但以前的報告顯示，睡眠行為障礙不受STN DBS影響，即便有報道術(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，這是因為術(shù)前睡眠行為障礙依然存在。關(guān)于STN DBS對不寧腿綜合征的影響的報告是稀缺的和不確定的。有些報道顯示已經(jīng)改進[35-36]。然而，也有些報道進一步惡化或缺乏顯著變化[31，37]。

4 STN DBS對自主神經(jīng)癥狀的影響

據(jù)報道[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[39]。胃腸動力在PD晚期會明顯下降，一項研究報告指出STN DBS可改善胃的排空，然而多巴胺能藥物卻沒有此效果[40]。STN DBS在改善便秘和吞咽方面也有報道[41-42]。然而，這些研究結(jié)果的臨床意義尚不清楚。STN DBS對出汗的影響效果研究也產(chǎn)生了爭議，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對疼痛的影響

疼痛是一種常見的癥狀，但在PD晚期有認識不足和治療不足的缺陷。研究發(fā)現(xiàn)，40%～85%PD晚期患者會出現(xiàn)疼痛，雖然在許多研究中一直報道STN DBS對PD的疼痛可有效改善[46-49]。但通過STN DBS改善PD疼痛的機制沒有得到充分的解釋[50-51]。值得注意的是，雖然STN DBS改善疼痛，但新疼痛也會隨疾病的進展而形成[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晚期本身減緩的過程，其有待于進一步探討。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。

[1] Floden D,Cooper SE,Griffith SD,et al.Predicting quality of life outcomes after subthalamic nucleus deep brain stimulation[J].Neurology,2014,83(18):1627-1633.

[2] Cury RG,Galhardoni R,Fonoff ET,et al.Effects of deep brain stimulation on pain and other nonmotor symptoms in Parkinson disease[J].Neurology,2014,83(16):1403-1409.

[3] Nazzaro JM,Pahwa R,Lyons KE.The impact of bilateral subthalamic stimulation on non-motor symptoms of Parkinson’s disease[J].Parkinsonism Relat Disord,2011,17(8):606-609.

[4] Le Jeune F,Drapier D,Bourguignon A,et al.Subthalamic nucleus stimulation in Parkinson disease induces apathy: a PET study[J].Neurology,2009,73(21):1746-1751.

[5] Thobois S,Ardouin C,Lhommée E,et al.Non-motor dopamine withdrawal syndrome after surgery for Parkinson’s disease: predictors and underlying mesolimbic denervation[J].Brain,2010,133(4):1111-1127.

[6] Witt K,Daniels C,Reiff J,et al.Neuropsychological and psychiatric changes after deep brain stimulation for Parkinson’s disease:a randomised, multicentre study[J].Lancet Neurol,2008,7(7):605-614.

[7] Reijnders JS,Ehrt U,Weber WE,et al.A systematic review of prevalence studies of depression in Parkinson's disease[J].Mov Disord,2008,23(2):183-189.

[8] Vriend C, Raijmakers P,Veltman DJ,et al.Depressive symptoms in Parkinson’s disease are related to reduced [123I]FP-CIT binding in the caudate nucleus[J].J Neurol Neurosurg Psychiatry,2014,85(2):159-164.

[9] Witt K, Daniels C, Reiff J, et al. Neuropsychological and psychiatric changes after deep brain stimulation for Parkinson’s disease: a randomised, multicentre study[J].Lancet Neurology，2008, 7(7): 605-614.

[10]Couto MI,Monteiro A,Oliveira A,et al.Depression and anxiety following deep brain stimulation in Parkinson’s disease: systematic review and meta-analysis[J].Acta Med Port,2014,27(3):372-382.

[11]Aviles-Olmos I,Kefalopoulou Z,Tripoliti E,et al.Long-term outcome of subthalamic nucleus deep brain stimulation for Parkinson’s disease using an MRI-guided and MRI-verified approach[J].J Neurol Neurosurg Psychiatry,2014,85(12):1419-1425.

[12]錢 浩,劉金龍,符小麗，等.雙側(cè)丘腦底核腦深部電刺激治療中晚期帕金森病療效(術(shù)后2年隨訪)[J].中國神經(jīng)精神疾病雜志,2013，39(5):284-290.

[13]Voon V,Krack P,Lang AE,et al.A multicentre study on suicide outcomes following subthalamic stimulation for Parkinson’s disease[J].Brain,2008,131(10):2720-2728.

[14]Weintraub D,Duda JE,Carlson K,et al.Suicide ideation and behaviours after STN and GPi DBS surgery for Parkinson’s disease: results from a randomised, controlled trial[J].J Neurol Neurosurg Psychiatry,2013,84(10):1113-1118.

[15]Castrioto A,Lhommée E,Moro E,et al.Mood and behavioural effects of subthalamic stimulation in Parkinson’s disease[J].Lancet Neurol,2014,13(3):287-305.

[16]孟慶進,柴曉斌,胡國華.帕金森病后抑郁的最新研究進展[J].中國老年學雜志, 2013，33(2):477-480.

[17]Starkstein SE, Merello M, Jorge R,et al.The syndromal validity and nosological position of apathy in Parkinson’s disease[J].Mov Disord, 2009, 24(8):1211-1216.

[18]Funkiewiez A,Ardouin C,Caputo E,et al.Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood, and behaviour in Parkinson’s disease[J].J Neurol Neurosurg Psychiatry,2004, 75(6):834-839.

[19]Tremblay L,Worbe Y,Thobois S,et al.Selective dysfunction of basal ganglia subterritories: from movement to behavioral disorders[J].Mov Disord,2015,30(9):1155-1170.

[20]Zhang G,Zhang Z,Liu L,et al.Impulsive and compulsive behaviors in Parkinson’s disease[J].Front Aging Neurosci,2014(6):318.

[21]Amami P,Dekker I,Piacentini S,et al.Impulse control behaviours in patients with Parkinson’s disease after subthalamic deep brain stimulation: de novo cases and 3-year follow-up[J].J Neurol Neurosurg Psychiatry,2015,86(5):562-564.

[22]Castrioto A,Funkiewiez A,DebB,et al.Iowa gambling task impairment in Parkinson’s disease can be normalised by reduction of dopaminergic medication after subthalamic stimulation[J].J Neurol Neurosurg Psychiatry,2015,86(2):186-190.

[23]Kim YE,Kim HJ,Kim HJ,et al.Impulse control and related behaviors after bilateral subthalamic stimulation in patients with Parkinson’s disease[J].J of Clin Neurosci,2013,20(7):964-969.

[24]Lhommée E,Klinger H,Thobois S,et al.Subthalamic stimulation in Parkinson’s disease: restoring the balance of motivated behaviours[J].Brain,2012,135(5):1463-1477.

[25]Aybek S,Gronchi-Perrin A,Berney A,et al.Long-term cognitive profile and incidence of dementia after STN-DBS in Parkinson’s disease[J].Mov Disord, 2007, 22(7):974-981.

[26]Kim HJ,Jeon BS,Paek SH,et al.Long-term cognitive outcome of bilateral subthalamic deep brain stimulation in Parkinson’s disease[J].J Neurol,2014,261(6):1090-1096.

[27]Fasano A,Romito LM, Daniele A,et al.Motor and cognitive outcome in patients with Parkinson’s disease 8 years after subthalamic implants[J].Brain, 2010, 133(9):2664-2676.

[28]Zangaglia R, Pasotti C, Mancini F,et al.Deep brain stimulation and cognition in Parkinson’s disease: an eight-year follow-up study[J].Mov Disord, 2012, 27(9):1192-1194.

[29]Massano J,Garrett C.Deep brain stimulation and cognitive decline in Parkinson’s disease: a clinical review[J].Front Neurol,2012(3):66.

[30]Nishida N,Murakami T,Kadoh K,et al.Subthalamic nucleus deep brain stimulation restores normal rapid eye movement sleep in Parkinson’s disease[J].Mov Disord,2011,26(13):2418-2422.

[31]Arnulf I,Bejjani BP,Garma L,et al.Improvement of sleep architecture in PD with subthalamic nucleus stimulation[J].Neurology, 2000, 55(11):1732-1734.

[32]Cicolin A,Lopiano L,Zibetti M,et al.Effects of deep brain stimulation of the subthalamic nucleus on sleep architecture in parkinsonian patients[J].Sleep Med,2004,5(2):207-210.

[33]Amara AW,Watts RL,Walker HC.The effects of deep brain stimulation on sleep in Parkinson’s disease[J].Ther Adv Neurol Disord,2011,4(1):15-24.

[34]Piette T,Mescola P,Uytdenhoef P,et al.A unique episode of REM sleep behavior disorder triggered during surgery for Parkinson's disease[J].J Neurol Sci,2007,253(1-2):73-76.

[35]Kim YE,Jeon BS,Paek SH,et al.Rapid eye movement sleep behavior disorder after bilateral subthalamic stimulation in Parkinson’s disease[J].J Clin Neurosci,2015,22(2):315-319.

[36]Driver-Dunckley E,Evidente VG,Adler CH,et al.Restless legs syndrome in Parkinson’s disease patients may improve with subthalamic stimulation[J].Mov Disord,2006,21(8):1287-1289.

[37]Kedia S,Moro E,Tagliati M,et al.Emergence of restless legs syndrome during subthalamic stimulation for Parkinson disease[J].Neurology,2004,63(12):2410-2412.

[38]Sakakibara R,Tateno F,Kishi M,et al.Pathophysiology of bladder dysfunction in Parkinson’s disease[J].Neurobiol Dis,2012,46(3):565-571.

[39]Winge K,Nielsen KK,Stimpel H,et al.Lower urinary tract symptoms and bladder control in advanced Parkinson’s disease: effects of deep brain stimulation in the subthalamic nucleus[J].Mov Disord,2007,22(2):220-225.

[40]Arai E,Arai M,Uchiyama T,et al.Subthalamic deep brain stimulation can improve gastric emptying in Parkinson’s disease[J].Brain,2007,135(5):1478-1485.

[41]Zibetti M,Torre E,Cinquepalmi A,et al.Motor and nonmotor symptom follow- up in parkinsonian patients after deep brain stimulation of the subthalamic nucleus[J].Eur Neurol,2007,58(4):218-223.

[42]Chou KL,Taylor JL,Patil PG.The MDS-UPDRS tracks motor and non-motor improvement due to subthalamic nucleus deep brain stimulation in Parkinson disease[J].Parkinsonism Relat Disord,2013,19(11):966-969.

[43]Wolz M,Hauschild J,Koy J,et al.Immediate effects of deep brain stimulation of the subthalamic nucleus on nonmotor symptoms in Parkinson’s disease[J].Parkinsonism Relat Disord,2012(18):994-997.

[44]Chou KL,Taylor JL,Patil PG.The MDS-UPDRS tracks motor and non-motor improvement due to subthalamic nucleus deep brain stimulation in Parkinson disease[J].Pavkinsonism Relat Disovd,2013,19(11):966-969.

[45]Trachani E,Constantoyannis C,Sirrou V,et al.Effects of subthalamic nucleus deep brain stimulation on sweating function in Parkinson’s disease[J].Clin Neurol Neurosurg,2010,112(3):213-217.

[46]Beiske AG,Loge JH,R?nningen A,et al.Pain in Parkinson’s disease: prevalence and characteristics[J].Pain,2009,141(1-2):173-177.

[47]Defazio G,Berardelli A,Fabbrini G,et al.Pain as a nonmotor symptom of Parkinson disease: evidence from a case-control study[J].Arch Neurol,2008,65(9):1191-1194.

[48]Lee MA,Walker RW,Hildreth TJ,et al.A survey of pain in idiopathic Parkinson’s disease[J].J Pain Symptom Manage,2006,32(5):462-469.

[49]Nègre-Pagès L,Regragui W,Bouhassira D,et al.Chronic pain in Parkinson’s disease: the cross-sectional French DoPaMiP survey[J].Mov Disord,2008,23(10):1361-1369.

[50]Kim HJ,Paek SH,Kim JY,et al.Chronic subthalamic deep brain stimulation improves pain in Parkinson disease[J].J Neurol,2008,255(12):1889-1894.

[51]Sürücü O,Baumann-Vogel H,Uhl M,et al.Subthalamic deep brain stimulation versus best medical therapy for L-dopa responsive pain in Parkinson’s disease[J].Pain,2013,154(8):1477-1479.

[52]Jung YJ,Kim HJ,Jeon BS,et al.An 8-Year Follow-up on the Effect of Subthalamic Nucleus Deep Brain Stimulation on Pain in Parkinson Disease[J].JAMA Neurol, 2015, 72(5):504-510.

[53]Kim HJ,Jeon BS,Lee JY,et al.The benefit of subthalamic deep brain stimulation for pain in Parkinson disease: a 2-year follow-up study[J].Neurosurgery,2012,70(1):18-23.

(本文編輯 馮曉倩)

116100 大連市 大連醫(yī)科大學附屬第一醫(yī)院急診ICU

劉秀梅：女，本科，主管護師，護士長

孫莉

10.3969/j.issn.1672-9676.2016.19.007

2016-06-16)