吳 曦, 王家莉, 仇一青, 陳劍春, 胡小吾
海軍軍醫(yī)大學(xué)附屬長海醫(yī)院神經(jīng)外科, 上海 200433
刺激參數(shù)優(yōu)化對帕金森病雙側(cè)STN-DBS術(shù)后電刺激誘發(fā)的暫時性非運(yùn)動精神癥狀的改善效果
吳 曦△, 王家莉△, 仇一青, 陳劍春, 胡小吾*
海軍軍醫(yī)大學(xué)附屬長海醫(yī)院神經(jīng)外科, 上海 200433
目的探討帕金森病雙側(cè)丘腦底核腦深部電刺激(STN-DBS)術(shù)后,在出現(xiàn)電刺激誘發(fā)的暫時性非運(yùn)動精神癥狀(stimulation-induced transient nonmotor psychiatric symptoms,SITNPS)時,是否可通過流程圖來確定誘發(fā)癥狀的觸點(diǎn),以及電刺激參數(shù)優(yōu)化在去除精神癥狀的同時維持運(yùn)動癥狀改善的最佳效果。方法回顧性分析了2015年1月1日至12月31日在長海醫(yī)院神經(jīng)調(diào)控門診進(jìn)行程控的帕金森病STN-DBS患者的程控資料。分析使用流程圖確定SITNPS觸點(diǎn)及程控調(diào)整方案的效果,并采用非盲法的統(tǒng)一帕金森病評估量表Ⅲ(unified Parkinson’s disease rating scale-Ⅲ,UPDRS-Ⅲ)評估患者運(yùn)動功能的改變。結(jié)果共有1 287人次程控。11例患者出現(xiàn)了20次SITNPS,包括4次哭泣(2例)、4次莫名的欣快感或傻笑(2例)、2次空間定位感覺異常(1例)、2次幻覺(1例)及8次輕躁狂發(fā)作(5例)。通過優(yōu)化程控參數(shù),10例患者精神癥狀消失,且運(yùn)動改善維持或好于發(fā)生SITNPS時;1例患者在多次程控后由于運(yùn)動癥狀和非運(yùn)動癥狀交替出現(xiàn),在最后設(shè)定的刺激參數(shù)下,UPDRS-Ⅲ評分較前下降了2分。11例患者的UPDRS-Ⅲ評分在程控前后(Med off/IPG on)差異無統(tǒng)計(jì)學(xué)意義[(26.45±10.59)分vs(26.45±10.17)分,P=1.000]。結(jié)論本課題組設(shè)計(jì)的流程圖有助于確定SITNPS誘發(fā)觸點(diǎn);程控參數(shù)優(yōu)化可使患者SITNPS消失,且不影響運(yùn)動功能的改善效果。
帕金森病;丘腦底核;腦深部電刺激;短暫性非運(yùn)動精神癥狀
丘腦底核(subthalamic nucleus,STN)腦深部電刺激(deep brain stimulation, DBS)療法可持續(xù)改善原發(fā)性帕金森病患者震顫、僵直、運(yùn)動遲緩等癥狀以及藥物引起的運(yùn)動并發(fā)癥[1-3]。由于丘腦底核及周邊結(jié)構(gòu)內(nèi)含有與邊緣系統(tǒng)相聯(lián)系的神經(jīng)傳導(dǎo)束[4],因此在刺激STN使運(yùn)動癥狀改善的同時,可能造成患者非運(yùn)動癥狀的改變,甚至出現(xiàn)電刺激誘發(fā)的暫時性非運(yùn)動精神癥狀(stimulation-induced transient nonmotor psychiatric symptoms,SITNPS),如抑郁[5]、焦慮[6]、淡漠[7]、激烈的攻擊性行為[8]、躁狂[9]、莫名的大笑[10]、沖動控制障礙[11]等。由于非運(yùn)動癥狀比運(yùn)動癥狀更影響患者的生活質(zhì)量[12],近年來程控(DBS刺激參數(shù)程序設(shè)置以控制患者癥狀,簡稱程控)醫(yī)師越來越關(guān)注帕金森病的非運(yùn)動癥狀,包括SITNPS。海軍軍醫(yī)大學(xué)附屬長海醫(yī)院帕金森病治療中心自2014年12月制定并啟用了針對帕金森病患者SITNPS的流程圖式的程控方案。本研究主要探討該方案是否可以用于進(jìn)行SITNPS后的可疑觸點(diǎn)定位,以及能否通過程控參數(shù)優(yōu)化,在避免患者出現(xiàn)明顯暫時性非運(yùn)動精神障礙的同時,仍然維持原有的最佳運(yùn)動癥狀的治療效果。
1.1 一般資料 回顧性分析2015年1月1日至12月31日在海軍軍醫(yī)大學(xué)附屬長海醫(yī)院神經(jīng)調(diào)控門診進(jìn)行程控的原發(fā)性帕金森病植入雙側(cè)STN-DBS患者的程控記錄,包括新植入DBS開機(jī)后進(jìn)行滴定程控的患者和達(dá)到最佳刺激參數(shù)后因各種原因來門診程控的患者。原發(fā)性帕金森病的診斷標(biāo)準(zhǔn)采用1997年版英國腦庫標(biāo)準(zhǔn)。本研究在獲得醫(yī)院醫(yī)學(xué)倫理委員會批準(zhǔn),患者知情同意并簽署知情同意書。
1.2 運(yùn)動功能評估方法 采用非盲法的統(tǒng)一帕金森病評估量表(unified Parkinson disease rating scale,UPDRS),評估并記錄患者術(shù)前、發(fā)生SITNPS前最后1次調(diào)控后、重新程控至SITNPS消失后的運(yùn)動功能。評估醫(yī)師均有國際帕金森病及其他運(yùn)動障礙疾病協(xié)會的UPDRS評分表培訓(xùn)證書。
1.3 認(rèn)知和精神病學(xué)評估方法 患者術(shù)前和術(shù)后3、6、12個月時,常規(guī)使用UPDRS-Ⅰ、UPDRS-Ⅱ、簡易智能精神狀態(tài)檢查量表(mini-mental state examination, MMSE)和漢密爾頓抑郁評估量表-17項(xiàng)(Hamilton depression scale 17, HAMD-17)進(jìn)行認(rèn)知和抑郁狀態(tài)的評估。SITNPS的診斷:通過患者家屬對患者行為的描述和患者對自身情緒感覺的描述,由神經(jīng)內(nèi)科醫(yī)師用Young躁狂量表(Young mania rating scale, YMRS)[13]評估。新植入DBS開機(jī)的患者僅進(jìn)行術(shù)前評估。
1.4 SITNPS的評估和電刺激參數(shù)記錄 分析程控記錄本中患者的程控主訴、家屬對患者精神癥狀的描述和程控過程中患者的異常精神癥狀。記錄SITNPS發(fā)生時電刺激激活觸點(diǎn)、刺激方式、電壓/電流、脈寬、頻率。記錄程控過程中刺激參數(shù)的改變及最終調(diào)整后的刺激參數(shù)。確定造成SITNPS觸點(diǎn)的方法和程控方案按照既往制定的流程圖完成(圖1、圖2)。程控后隨訪3個月,無相似的精神、心理癥狀復(fù)發(fā),確定SITNPS消失。
圖1 確定引起SITNPS的流程圖
圖2 程控消除SITNPS流程圖
1.5 統(tǒng)計(jì)學(xué)處理 采用SPSS 19.0(IBM, US)軟件進(jìn)行統(tǒng)計(jì)分析。刺激參數(shù)設(shè)置前后UPDRS-Ⅲ的比較采用配對t檢驗(yàn)。檢驗(yàn)水準(zhǔn)(α,雙側(cè))為0.05。
2.1 患者基線資料 共145例原發(fā)性帕金森病患者進(jìn)行雙側(cè)STN-DBS術(shù)并首次開機(jī),進(jìn)行最佳程控參數(shù)的調(diào)整;另有1 142人次進(jìn)行了刺激參數(shù)調(diào)整,包括166例雙側(cè)STN-DBS植入超過1年的患者和231例開機(jī)后未滿1年的患者。其中,11例患者發(fā)生了SITNPS。11例患者中,男性5例,女性6例;手術(shù)時年齡52~74歲,平均年齡為(63.45 ± 8.27)歲;病程7~17年,平均(11.91 ± 3.33)年。11例患者認(rèn)知功能正?;蜉p微減退,6例服用抗抑郁藥物治療,術(shù)后抗抑郁藥物沒有減量和調(diào)整。11例患者術(shù)前左旋多巴等效劑量為(942.5±232.7) mg,術(shù)后減為(284.5±187.8) mg。11例患者基線資料詳見表1,出現(xiàn)SITNPS時的情況見表2,出現(xiàn)SITNPS前最后1次刺激參數(shù)見表3。
表1 患者的基線資料
MMSE:簡易智能精神狀態(tài)檢查量表;HAMD:漢密爾頓抑郁評估量表;LEDD: 左旋多巴等效劑量;UPDRS:非盲法的統(tǒng)一帕金森病評估量表.*抗抑郁治療前(治療后)
表2 患者出現(xiàn)SITNPS時的臨床表現(xiàn)
YMRS:Young躁狂量表
表3 SITNPS出現(xiàn)前最后1次刺激參數(shù)
IPG:脈沖發(fā)生器
2.2 SITNPS發(fā)作時的表現(xiàn) 11例患者出現(xiàn)20次SITNPS發(fā)作,包括4次哭泣(2例)、4次莫名的欣快感或傻笑(2例)、2次空間定位感覺異常(1例)、2次幻覺(1例)、8次輕躁狂發(fā)作(5例)。其中,5例患者SITNPS發(fā)生在首次開機(jī)進(jìn)行最佳程控參數(shù)滴定過程中,2例患者發(fā)生在首次開機(jī)后2 d內(nèi),4例DBS植入超過1年的患者中有3例于程控過程中出現(xiàn)SITNPS。
2.3 程控對SITNPS及運(yùn)動癥狀的影響
2.3.1 11例患者的程控參數(shù)調(diào)整 通過調(diào)節(jié)程控參數(shù)(表4),10例維持了原來的運(yùn)動能力且精神癥狀消失。程控調(diào)整方案:降低電壓、升高脈寬2例(患者1、11),維持電壓不變、使用正負(fù)雙點(diǎn)(Bipolar)刺激2例(患者2、7),降低電壓、降低頻率、升高脈寬1例(患者9),降低電壓、降低頻率、交叉電脈沖(Interleaving)3例(患者3、4、10),更換背側(cè)激活觸點(diǎn)2例(患者5、8)。11例患者出現(xiàn)SITNPS時UPDRS-Ⅲ評分(Med off/IPG on)與程控后評分(Med off/IPG on)差異無統(tǒng)計(jì)學(xué)意義[(26.45±10.59)分vs(26.45±10.17)分,P=1.000);表5]。
2.3.2 患者的6的程控過程 患者6在多次程控(表6)后,由于運(yùn)動癥狀和非運(yùn)動癥狀交叉出現(xiàn),在最后調(diào)整的刺激參數(shù)下,UPDRS-Ⅲ評分較前下降了2分。患者6以“關(guān)期”的肩部疼痛為主訴來門診進(jìn)行程控,在增加雙負(fù)刺激(Double polar)電壓后癥狀改善,肩膀僵硬緩解、疼痛減輕,但是出現(xiàn)了輕微的頭部“戴帽子樣”束縛感,在服藥(開期)時,出現(xiàn)了SITNPS。患者最終選擇了第8次的程控參數(shù)。通過流程圖,我們確定了誘發(fā)SITNPS的觸點(diǎn),并通過程控使患者的運(yùn)動功能保留,但是患者出現(xiàn)了其他新發(fā)的非運(yùn)動癥狀。與患者充分溝通后,患者選擇在沒有新發(fā)非運(yùn)動癥狀時適當(dāng)改善肩部疼痛,但是犧牲了一部分手和手腕動作的靈活性。
表4 誘發(fā)SITNPS時的刺激參數(shù)和運(yùn)動癥狀評分
*藥物關(guān)期/IPG開
表5 程控后消除SITNPS并維持最佳運(yùn)動癥狀的刺激參數(shù)
STN-DBS應(yīng)用于臨床后,SITNPS隨之出現(xiàn)[10,14]。其被認(rèn)為是DBS治療帶來的不良反應(yīng),表現(xiàn)形式復(fù)雜多樣。DBS對患者帶來的精神心理影響,有時由電刺激直接導(dǎo)致,有時與患者對DBS預(yù)期療效滿足與否引發(fā)的情緒波動有關(guān)[15],需要仔細(xì)鑒別。電刺激引起的輕微情緒波動更適合進(jìn)行STN相關(guān)精神神經(jīng)研究[16],而缺乏臨床意義。因此,本研究中的SITNPS是家屬或患者認(rèn)為需要調(diào)控干預(yù)的臨床癥狀明顯的精神、心理改變。
本研究發(fā)現(xiàn),大多SITNPS患者在程控參數(shù)重新設(shè)置48 h內(nèi)即表現(xiàn)出相關(guān)癥狀,部分患者發(fā)生于服抗帕金森病藥[5]后開期狀態(tài)下或服藥數(shù)小時之后。因此,每次程控后,患者都應(yīng)在服藥開期狀態(tài)下充分評估其精神、心理狀態(tài),然后再讓患者離開醫(yī)院,并提醒患者家屬警惕患者SITNPS的發(fā)生(有些SITNPS患者自己無法察覺)[17]。
表6 患者6的程控過程
*藥物關(guān)期/IPG開
本研究發(fā)現(xiàn),SITNPS往往發(fā)生于程控醫(yī)師根據(jù)患者的主訴增加刺激點(diǎn)電壓或脈寬時。而此時患者的運(yùn)動癥狀改善,或較術(shù)前更好,如何在維持運(yùn)動改善狀態(tài)同時避免SITNPS的發(fā)生,既往文獻(xiàn)報道較少。本課題組在2014年根據(jù)既往文獻(xiàn)報道和本中心的經(jīng)驗(yàn),制定了確定誘發(fā)SITNPS觸點(diǎn)的方案及程控流程,以期快速緩解患者SITNPS同時盡可能改善患者的運(yùn)動癥狀。臨床研究[15,18]顯示,SITNPS與高電壓相關(guān),說明引起邊緣系統(tǒng)神經(jīng)網(wǎng)絡(luò)改變的結(jié)構(gòu)被激活。多種減小或改變激活域范圍以避開上述神經(jīng)網(wǎng)絡(luò)的程控方法也可以改善SITNPS,如降低電壓[18]、更換為bipolar模式[17]、更換背側(cè)激活觸點(diǎn)[9,19-20]。但是,上述程控參數(shù)的調(diào)整使激活域減小的同時[21],也能增強(qiáng)對運(yùn)動癥狀相關(guān)神經(jīng)通路的刺激強(qiáng)度[22]。因此,本研究通過適當(dāng)增加電壓來增強(qiáng)激活域內(nèi)的刺激強(qiáng)度。高頻刺激可以使激活域內(nèi)的不同神經(jīng)細(xì)胞表現(xiàn)不同的應(yīng)答[23],激活域內(nèi)的神經(jīng)細(xì)胞對不同頻率的刺激也可能表現(xiàn)不同的應(yīng)答,從而出現(xiàn)不同的臨床表現(xiàn)[24]。降低刺激頻率也可以降低激活域內(nèi)的刺激強(qiáng)度,因此本研究嘗試降低刺激頻率以減輕SITNPS的發(fā)作。交叉電脈沖的使用要求刺激頻率降低到125 Hz及以下,還可以讓不同觸點(diǎn)有獨(dú)立的激活域,因此在降低刺激誘發(fā)不良反應(yīng)的同時可提高刺激效果[25]。位于STN前內(nèi)下部的觸點(diǎn)更容易引發(fā)SITNPS[16],如果上述程控方案仍然無法消除SITNPS,同時不能最大程度改善運(yùn)動癥狀時,改為更背側(cè)的觸點(diǎn),以獲得更大的刺激參數(shù)調(diào)整范圍。
經(jīng)過1年篩查,11位患者被確定存在需要調(diào)控干預(yù)的SITNPS,并使用流程圖成功定位了誘發(fā)SITNPS的觸點(diǎn),經(jīng)過刺激參數(shù)程控后,患者SITNPS癥狀消失。其中,8例患者的運(yùn)動功能較發(fā)生SITNPS前沒有下降,甚至改善;2例患者SITNPS在第1次開機(jī)調(diào)試時出現(xiàn),其運(yùn)動癥狀改善率約70%。患者6因?yàn)檎{(diào)控過程中出現(xiàn)其他的非運(yùn)動癥狀,因此沒能獲得與發(fā)生SITNPS時相同的運(yùn)動改善[6]。因此,SITNPS并不限制患者的運(yùn)動癥狀改善。
綜上所述, 通過本課題組設(shè)計(jì)的流程圖可以確定SITNPS誘發(fā)觸點(diǎn),并可通過適當(dāng)?shù)某炭厥够颊逽ITNPS消失的同時獲得最佳的運(yùn)動癥狀改善。本研究的局限性在于患者數(shù)量較少、SITNPS的種類較少,且采用的流程圖主要針對Medtronic Activa PC和RC,應(yīng)用于其他型號的IPG時需要進(jìn)行調(diào)整。
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Improvement effect for stimulus parameter programming on stimulation-induced transient nonmotor psychiatric symptoms after bilateral subthalamic nucleus deep brain stimulation for Parkinson disease
WU Xi△, WANG Jia-li△, QIU Yi-qing, CHEN Jian-chun, HU Xiao-wu*
Department of Neurosurgery, Changhai Hospital, Navy Military Medical University, Shanghai 200433, China
Objective: Stimulation-induced transient non-motor psychiatric symptom (SITNPS) was one of the side effects following bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease (PD) patients. The electrode contact inducing these psychiatric symptoms and the protocol to eliminate SITNPS with maintaining the optimal motor function were designed in this study, and the effectiveness of these algorithms was analyzed.MethodsAll the PD patients who underwent programming sessions after STN-DBS implantations from January 1, 2015, to December 31, 2015, at the DBS programming clinic of Changhai Hospital were retrospectively analyzed. Only patients who were diagnosed with SITNPS were enrolled in this study. In these patients, the electrode contact inducing SITNPS was found and the programming protocol algorithms were used. The unified Parkinson disease rating scale part Ⅲ (UPDRS-Ⅲ) score was assessed with non-blinded method to analyze the motor functions before and after programming.ResultsThere were 1 287 patients-time enrolled in this study, and 11 patients were diagnosed with SITNPS of totally 20 times. Among these patients, 2 cases had 4 episodes of crying, 2 cases had 4 episodes of mirthful laughter, 1 case had 2 episodes of abnormal sense of spatial orientation, 1 case had 2 episodes of hallucination and 5 cases had 8 episodes of hypomania. After programming sessions, the mental symptoms in 10 patients were disappeared and the motor functions were maintained or better compared with SITNPS. In 1 patient, the motor and non-motor symptoms occurred alternately, at last, the UPDRS-Ⅲ score was decreased by 2 scores after stimulus parameter setting. There was no statistical difference of UPDRS-Ⅲ score before and after final stimulation parameter setting (without SITNPS) in 11 cases ([26.45±10.59]vs[26.45±10.17],P=1.000).ConclusionsThe flow diagram in this study is helpful for determining electrode contact inducing SITNPS in PD patients, and the modified programming protocol employed in treatment of these symptoms is effective to make SITNPS disappear, without influencing the curative effect on motor function.
Parkinson disease; subthalamic nucleus; deep brain stimulation; transient nonmotor psychiatric symptoms
2016-12-19接受日期2017-09-12
國家重點(diǎn)研發(fā)計(jì)劃“數(shù)字診療裝備研發(fā)”試點(diǎn)專項(xiàng)課題(2016YFC0105900). Supported by “Digital Equipment of Diagnosis and Treatment” Special Program of National Key Research and Development Plan (2016YFC0105900).
吳 曦, 博士,講師、主治醫(yī)師. E-mail:wuxi_smmu@sina.com 王家莉, 技師. E-mail:1664108205@qq.com
△共同第一作者(Co-first authors)
*通信作者(Corresponding author). Tel: 021-31161787,E-mail:huxiaowu_smmu@sina.com
10.12025/j.issn.1008-6358.2017.20161169
R 742.5
A
[本文編輯] 姬靜芳