賈卓鵬 金林 車(chē)紅民

(西安醫(yī)學(xué)院第一附屬醫(yī)院神經(jīng)外科，陜西 西安 710077)

血漿同型半胱氨酸水平與腦靜脈竇血栓形成及預(yù)后的關(guān)系

賈卓鵬*金林 車(chē)紅民

(西安醫(yī)學(xué)院第一附屬醫(yī)院神經(jīng)外科，陜西 西安 710077)

目的探討血漿同型半胱氨酸水平與腦靜脈竇血栓形成及預(yù)后的關(guān)系。方法檢測(cè)31例腦靜脈竇血栓(CVST)患者及30例健康對(duì)照組血同型半胱氨酸(Hcy)水平，將CVST患者分組為高Hcy及正常Hcy組并進(jìn)行神經(jīng)功能缺損評(píng)估，比較不同組之間血Hcy水平的差異及Hcy對(duì)CVST患者預(yù)后的影響。結(jié)果①CVST組中Hcy顯著高于對(duì)照組，而葉酸，維生素B12均顯著低于對(duì)照組(P<0.01)；②CVST患者組中高Hcy組與正常Hcy組預(yù)后比較，好轉(zhuǎn)率高Hcy血癥組低于正常Hcy組(P<0.05)。結(jié)論高同型半胱氨酸血癥是腦靜脈竇血栓形成的危險(xiǎn)因素，伴有高同型半胱氨酸血癥的CVST患者預(yù)后不佳。

同型半胱氨酸; 腦靜脈竇血栓; 危險(xiǎn)因素; 預(yù)后

腦靜脈竇血栓(cerebral venous sinus thrombosis, CVST)為少見(jiàn)的缺血性腦血管病，病因復(fù)雜，臨床表現(xiàn)因靜脈竇閉塞程度、血栓形成速度、受累靜脈的部位、范圍以及側(cè)枝循環(huán)的建立情況等因素不同而常表現(xiàn)為頭痛頭暈、惡心嘔吐、癲癇抽搐、意識(shí)與精神障礙、視乳頭水腫、腦膜刺激征等[1]。癥狀多樣且特異性不強(qiáng)，易誤診，影響預(yù)后。最近的諸多研究發(fā)現(xiàn)同型半胱氨酸(homocysteine, Hcy)在多種血管性疾病中起重要作用,高同型半胱氨酸血癥已被證實(shí)是心腦血管疾病及靜脈栓塞性疾病的危險(xiǎn)因素[2-3]。有學(xué)者從而認(rèn)為不排除高同型半胱氨酸血癥(hyperhomocysteinemia, HHcy)也是腦靜脈竇血栓形成的危險(xiǎn)因素[4-6]。本文通過(guò)分析31例CVST 患者的病因及血漿Hcy水平，探討CVST與Hcy的關(guān)系以及HHcy與CVST預(yù)后的關(guān)系。

對(duì)象與方法

一、一般資料

2010年7月至2016年7月我院收治的CVST患者31例，男11例，女20例；年齡18～65歲，平均(36.1±10.7)歲。診斷標(biāo)準(zhǔn)：依據(jù)2011年美國(guó)心臟協(xié)會(huì)/美國(guó)卒中協(xié)會(huì)制定的CVST診斷和管理指南[7]，所有患者均行CT、MRI及MRV檢查(其中11例同時(shí)行DSA檢查)明確診斷。臨床癥狀：頭暈頭痛2例(6.45%)，惡心嘔吐18例(58.10%)，腦膜刺激征5例(16.10%)，抽搐4例(12.90%)，視乳頭水腫2例(6.45%)，煩躁1例(3.22%)，嗜睡1例(3.22%)肢體活動(dòng)障礙2例(6.45%)。所有患者入院后均予脫水降顱壓及改善循環(huán)治療。確診患者均予皮下注射低分子肝素5000 U，2次/d，7 d后改華法林口服。同時(shí)積極查找病因并給予相應(yīng)治療，經(jīng)治療后僅1例病情加重后自動(dòng)出院，其余患者均好轉(zhuǎn)出院。選取性別、年齡匹配的門(mén)診體檢健康人群30例為對(duì)照組，男11例，女19例，年齡16～62歲，平均(35.3±9.5)歲。嚴(yán)重肝腎功能障礙及檢查前服用葉酸、B族維生素的人群均排除在外。

二、方法

1.藥品與試劑：患者及健康對(duì)照組均在清晨空腹采靜脈血檢測(cè)Hcy、葉酸、維生素B12指標(biāo)。Hcy于空腹抽血分離血漿后立即檢測(cè)，應(yīng)用日立7170S生化分析儀，檢測(cè)方法為循環(huán)酶法，所用試劑由德賽診斷系統(tǒng)上海有限公司提供，正常值<15 μmol/L。其他指標(biāo)均由自動(dòng)生化分析儀檢測(cè)完成。

2.神經(jīng)功能缺損評(píng)估：將31例CVST患者依血Hcy檢查結(jié)果，分為高Hcy組(Hcy>15 μmol/L) 19例及正常Hcy組12例，根據(jù)美國(guó)國(guó)立衛(wèi)生院神經(jīng)功能缺損評(píng)分(National Institute of Health Stroke Scale, NIHSS)評(píng)分標(biāo)準(zhǔn)，分別評(píng)定不同分組患者入院和住院2 w時(shí)的神經(jīng)功能缺損，比較兩組患者的病情和預(yù)后﹝預(yù)后指標(biāo)：好轉(zhuǎn)率=(入院時(shí)神經(jīng)功能缺損評(píng)分-住院2 w時(shí)神經(jīng)功能缺損評(píng)分)/入院神經(jīng)功能缺損評(píng)分﹞。

結(jié) 果

一、CVST 組和對(duì)照組Hcy、葉酸、維生素B12指標(biāo)的比較

CVST組中Hcy顯著高于對(duì)照組，而葉酸，維生素B12均顯著低于對(duì)照組(P<0.05，表1)。

二、CVST患者組中高Hcy組與正常Hcy組預(yù)后比較

兩組入院時(shí)神經(jīng)功能缺損NIHSS評(píng)分比較無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)，好轉(zhuǎn)率高Hcy血癥組顯著低于正常Hcy組(P<0.05，表2、3)。

GroupAge(years)Male(%)Hcy(μmol/L)Folicacid(ng/mL)VitaminB12(pg/mL) Blankcontrolgroup35.3±9.511(36.7)12.65±5.607.12±2.14383.10±168.62 CVSTgroup36.1±10.711(35.5)20.70±9.50a4.51±3.26a296.51±134.72a

aP<0.05,vsblank control group.

表2 高Hcy組病例NIHSS評(píng)分

Tab 2 The NIHSS score of the high Hcy group

InstructionsScaledefinition1d2w 1a.LOC(levelofconsciousness)0=alertandresponsive;1=arousabletominorstimulation;2=arousableonlytopainfulstimula-tion;3=reflexreponsesorunarousable1.3±0.90.9±0.8 1b.LOCquestions0=answerstwoquestionscorrectly;1=answersonequestioncorrectly;2=answersneitherquestioncorrect-ly0.5±0.90.4±0.9 1c.LOCcommands0=performsbothtaskscorrectly;1=performsonetaskcorrectly;2=performsneithertaskcor-rectly0.8±0.90.5±0.7 2Bestgaze0=norma;1=partialgazepalsy;2=forcedeyedeviationortotalparesiswhichcannotbeovercomebyDoll's0.1±0.30.1±0.4 3.Visual0=novisualloss;1=partialhemianopia;2=completehemianopia;3=bilateralhemianopiaorblindness0.1±0.40.1±0.4 4.Facialpalsy0=normal;1=minorparalysis;2=partialparaly-sis;3=completeparalysisofoneorbothsides0.1±0.50.1±0.3 5.Motorarm(5a:leftarm;5b:rightarm)0=nodrift,limbholds90degreesforfull10seconds;1=drift,limbholds90degrees,butdriftsdownbeforefull10seconds;doesnothitbedorothersupport;2=someeffortagainstgrav-ity,limbcannotgettoormaintain90degrees,driftsdowntobed,buthassomeeffortagainstgravity;3=noeffortagainstgravity,limbfalls;4=nomovement;9=amputation,jointfu-sion0.4±0.60.3±0.7 6.Motorleg(6a:leftleg;6b:rightleg)0=nodrift,legholds30degreespositionforfull5seconds;1=drift,legfallsbytheendofthe5secondperiodbutdoesnothitbed;2=someeffortagainstgravity;legfallstobedby5seconds,buthassomeeffortagainstgravity;3=noefforta-gainstgravity,legfallstobedimmediately;4=nomovement;9=amputation,jointfusion0.4±0.70.3±0.6 7.Limbataxia0=absent;1=presentinonelimb;2=presentintwolimbs0.1±0.50.1±0.5 8.Sensory0=normal;1=mildtomoderatesensoryloss;2=severetototalsensoryloss0.3±0.70.3±0.4 9.Bestlanguage0=noaphasia;1=mildtomoderateaphasia;2=severeaphasia;3=mute,globalaphasia0.2±0.40.2±0.7 10.Dysarthria0=normal;1=mildtomoderate;2=severe;9=intubatedorotherphysicalbarrier0.2±0.50.1±0.6 11.Ignore0=normal;1=visual,touching,listening,spaceorpersonalignore;2=seriouspartialbodyignore0.2±0.60.2±0.4 Totalscores4.74±2.703.58±3.10

GroupnFirstNIHSSscoreImprovementrate NormalHcygroup124.30±2.980.47±0.31 HighHcygroup194.74±2.700.24±0.42a

aP<0.05,vsnormal Hcy group.

討 論

CVST是缺血性腦血管病的一種少見(jiàn)類(lèi)型，占全部腦卒中0.5%～3.0%[8]，文獻(xiàn)報(bào)道每年腦靜脈竇血栓形成的發(fā)病率為3/100萬(wàn)～4/100萬(wàn)[9]。其死亡率較高，病因復(fù)雜，早期確診，及時(shí)治療能夠顯著改善預(yù)后。

引起腦靜脈竇血栓疾病可分為非感染性與感染性?xún)纱箢?lèi)，前者多為顱腦外傷、嚴(yán)重貧血、消耗性疾病、妊娠、高凝狀態(tài)、嚴(yán)重脫水等原因。后者多繼發(fā)于頭面部感染及化膿性腦膜炎、腦膿腫、敗血癥等。有研究發(fā)現(xiàn)CVST患者常伴有繼發(fā)性或遺傳性易栓癥,各種原因的易栓癥是導(dǎo)致CVST的重要原因[10]，如因子V Leiden基因、凝血酶原G20210A基因的突變,抗磷脂抗體綜合征及高同型半胱氨酸血癥等。一項(xiàng)Meta分析表明HHcy可導(dǎo)致靜脈血栓發(fā)生率的增加[5]，Martinelli等[4]的研究說(shuō)明高同型半胱氨酸血癥可導(dǎo)致腦靜脈血栓形成的風(fēng)險(xiǎn)增加大約4倍。

Hcy是蛋氨酸代謝的中間產(chǎn)物，對(duì)人體內(nèi)同型半胱氨酸水平的影響因素有遺傳因素、飲食營(yíng)養(yǎng)缺乏、年齡與性別、腎功能損傷及藥物等。血Hcy水平與飲食有著密切關(guān)系，飲食中攝入葉酸、維生素B12和維生素B6越少，其Hcy的濃度就越高。

本研究通過(guò)對(duì)腦靜脈竇血栓患者的病例-對(duì)照研究，觀(guān)察對(duì)象入院Hcy等指標(biāo)，以及NIHSS評(píng)分等預(yù)后評(píng)估指標(biāo)。通過(guò)結(jié)果我們發(fā)現(xiàn)，CVST組與對(duì)照組之間年齡、性別均無(wú)顯著性差異，但CVST組血Hcy水平較對(duì)照組顯著升高，提示高同型半胱氨酸血癥與腦靜脈竇血栓的發(fā)病之間有著密切的聯(lián)系，可能是腦靜脈竇血栓形成的重要危險(xiǎn)因素。

高Hcy通過(guò)破壞血管內(nèi)皮、促進(jìn)血小板聚集、凝血因子V活性增加、凝血酶原激活及抑制組織纖溶酶原激活物與內(nèi)皮細(xì)胞的結(jié)合等途徑導(dǎo)致靜脈血栓的形成[11]。CVST患者中高Hcy組與正常Hcy組相比較，兩組入院時(shí)神經(jīng)功能缺損NIHSS評(píng)分無(wú)顯著差異，治療方法相同，但好轉(zhuǎn)率高Hcy血癥組顯著低于正常Hcy組，提示高同型半胱氨酸血癥與腦靜脈竇血栓的預(yù)后不佳有關(guān)。這可能與高Hcy可致患者腦內(nèi)小動(dòng)脈廣泛受損，側(cè)支循環(huán)不佳，不利于神經(jīng)功能恢復(fù)。

盡管，由于CVST發(fā)病率較低，對(duì)于Hcy與CVST之間的關(guān)系仍有待大樣本研究及長(zhǎng)期隨訪(fǎng),但臨床醫(yī)生對(duì)于高Hcy患者，應(yīng)考慮有CVST可能。在CVST治療中對(duì)于伴有高Hcy者，均應(yīng)通過(guò)補(bǔ)充維生素(如葉酸、維生素B12和維生素B6)減低血Hcy水平，利于改善預(yù)后?？傊?，高同型半胱氨酸血癥是腦靜脈竇血栓形成的危險(xiǎn)因素，伴有高同型半胱氨酸血癥的CVST患者預(yù)后不佳，因此對(duì)所有的CVST患者均應(yīng)常規(guī)檢測(cè)血Hcy水平，積極干預(yù)Hcy具有重要的臨床意義。

1LINN J, BRUCKMANN H. Cerebral venous and dural sinus thrombosis: state of the artimaging [J]. Clin Neuroradiol, 2010, 20(1): 25-37.

2OGER E, LACUT K, LE GAL G, et al. Hyperhomocysteinemia and low B vitamin levels are in-dependently associated with venous thromboembolism: results from the EDITH study: a hospital-based case-control study [J]. J Thromb Haemost, 2006, 4(4): 793-799.

3SUN Y, CHIEN K L, HSU H C, et al. Use of serum homocysteine to predict stroke, coronary heart disease and death in ethnic Chinese-12-year prospective cohort study [J]. Circ J, 2009, 73(8): 1423-1430.

4MARTINELLI I, BATTAGLIOLI T, PEDOTTI P, et al. Hyperhomocysteinemia in cerebral vein thrombosis [J]. Blood, 2003, 102(4): 1363-1366.

5DENTALI F, CROWTHER M, AGENO W. Thrombophilic abnormalities,oral contraceptives, and risk of cerebral vein thrombosis: a Meta-analysis [J]. Blood, 2006, 107(7): 2766-2773.

6VENTURA P, COBELLI M, MARIETTA M, et al. Hyperhomocysteinemia and other newly recognized inherited coagulation disorders (factor V Leiden and prothrombin gene mutation) in patients with idiopathic cerebral vein thrombosis [J]. Cerebrovasc Dis, 2004, 17(2-3): 153-159.

7SAPOSNIK G, BARINAGARREMENTERIA F, BROWN R D, Jr, et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association [J]. Stroke, 2011, 42(4): 1158-1192.

8BOUSSER M G, FERRO J M. Cerebral venous thrombosis: an update [J]. Lancet Neurol, 2007, 6(2): 162-170.

9STAM J. Thrombosis of the cerebral veins and sinuses [J]. N Engl J Med, 2005, 352(17): 1791-1798.

10IORIO A, BARNES C, VEDOVATI M C, et al. Thrombophilia and cerebral vein thrombosis [J]. Front Neurol Neurosci, 2008, 23: 55-76.

11KAROLCZAK K, OLAS B. Mechanism of action of homocysteine and its thiolactone in hemostasis system [J]. Physiol Res, 2009, 58(5): 623-633.

Therelationshipbetweentheplasmahomocysteinelevelsandtheprognosisofcerebralvenoussinusthrombosis

JIAZhuopeng,JINLin,CHEHongmin

DepartmentofNeurosurgery,FirstAffiliatedHospitalofXi'anMedicalUniversity,Xi'an710077, China

ObjectiveThe relationship between the plasma homocysteine levels and the prognosis of cerebral venous sinus thrombosis were discussed.MethodsThe blood homocysteine (Hcy) data of 31 patients with cerebral venous sinus thrombosis (CVST) and 30 cases of healthy controls were collected. These CVST patients were divided into high Hcy and normal Hcy group and the neural function defects were evaluated. The blood Hcy levels of different groups were compared, and the effect of Hcy on the prognosis of patients with CVST was analyzed.ResultsHcy level in CVST group was significantly higher than that of the control group, and while the levels of folic acid and vitamin B12were significantly lower than those of control group (P<0.01); compared with normal Hcy group, the prognosis of high Hcy group was poorer than that of the normal Hcy group (P<0.05).ConclusionHigh homocysteine level is a risk factor for the cerebral venous sinus thrombosis. The patients with CVST complicated by high homocysteine levels have the poor prognosis.

Homocysteine; Cerebral venous sinus thrombosis; Risk factors; Prognosis

1671-2897(2017)16-225-04

賈卓鵬，碩士研究生，主治醫(yī)師，E-mail: kenny19781004@163.com

*通訊作者： 賈卓鵬，碩士研究生，主治醫(yī)師，E-mail: kenny19781004@163.com

R 651

A

2016-09-16；

2016-11-10)