鄒志孟,都美玲,李軍,曹慶勇,連慧秀,沈曉君,王濱
(1.濱州醫(yī)學(xué)院煙臺(tái)附屬醫(yī)院,山東煙臺(tái)264100;2.濱州醫(yī)學(xué)院,山東煙臺(tái)264003)
DTI對(duì)急性頸髓損傷ASIA不同殘損等級(jí)的研究
鄒志孟1,都美玲1,李軍1,曹慶勇1,連慧秀1,沈曉君1,王濱2
(1.濱州醫(yī)學(xué)院煙臺(tái)附屬醫(yī)院,山東煙臺(tái)264100;2.濱州醫(yī)學(xué)院,山東煙臺(tái)264003)
目的:研究急性頸髓損傷(Spinal cord injury,SCI)DTI各參數(shù)值在ASIA不同殘損等級(jí)的臨床應(yīng)用價(jià)值。方法:回顧性分析急性SCI常規(guī)MRI T2WI高信號(hào)34例患者,48小時(shí)內(nèi)行MR-DTI檢查,測(cè)量病變區(qū)FA、ADC、λ∥、λ⊥值,臨床采用ASIA等級(jí)標(biāo)準(zhǔn),A級(jí)5例、B級(jí)6例、C級(jí)10例、D級(jí)13例,健康組15例相近年齡段志愿者,測(cè)量C3/4~C5/6相應(yīng)椎間盤(pán)平面。采用單因素方差(ANOVA)分析DTI參數(shù)值在ASIA A~D級(jí)差異,t檢驗(yàn)分析DWI高信號(hào)(DWI高信號(hào)區(qū))與邊緣區(qū)(T2WI高信號(hào)區(qū))DTI參數(shù)差異。結(jié)果:A~D級(jí)與健康組比較FA、ADC、λ∥、λ⊥值均具有統(tǒng)計(jì)學(xué)意義(F=51.90,13.30,24.70,13.01,P<0.001)。A級(jí)與B、C、D級(jí)兩兩比較FA值、ADC值、λ∥值有統(tǒng)計(jì)學(xué)意義(P<0.05),F(xiàn)A值、λ∥值隨著ASIA殘損等級(jí)降低呈下降趨勢(shì),ADC值在A級(jí)降低、B~D級(jí)升高,λ⊥值升高,B級(jí)與A、C、D級(jí)兩兩比較差異有統(tǒng)計(jì)學(xué)意義(P<0.05),A、C、D級(jí)比較差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。DTT顯示A、B級(jí)損傷區(qū)域神經(jīng)纖維束腫脹、中斷,C、D級(jí)損傷區(qū)神經(jīng)纖維束完整。DWI高信號(hào)區(qū)與T2WI高信號(hào)區(qū)ADC、λ∥、λ⊥值具有統(tǒng)計(jì)學(xué)意義(P<0.05),F(xiàn)A值均降低無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)。DTT顯示DWI高信號(hào)區(qū)神經(jīng)纖維束連續(xù)性中斷。結(jié)論:FA值、λ∥值是評(píng)價(jià)急性SCI AISA不同殘損等級(jí)敏感指標(biāo),ADC值越低損傷程度越重,DTT直觀顯示神經(jīng)纖維束損傷部位和損傷程度,為臨床治療提供更多影像學(xué)證據(jù)。
脊髓損傷;磁共振成像,彌散
急性頸髓損傷(Spinal cord injury,SCI)常造成不同程度的神經(jīng)功能障礙,嚴(yán)重者可導(dǎo)致截癱,給患者及家庭和社會(huì)帶來(lái)負(fù)擔(dān)。臨床常采用美國(guó)脊髓損傷協(xié)會(huì)(ASIA)分級(jí)標(biāo)準(zhǔn),作為判斷脊髓損傷的程度。常規(guī)MRI是SCI首選檢查方法,能夠確定損傷區(qū)水腫、出血的范圍,但缺乏損傷程度的量化指標(biāo)。如何早期定量評(píng)估SCI損傷程度,對(duì)臨床采取適宜治療方法、保護(hù)神經(jīng)預(yù)后恢復(fù)十分重要。擴(kuò)散張量成像(Diffusion tensor imaging,DTI)通過(guò)水分子的各向異性擴(kuò)散檢測(cè)中樞神經(jīng)系統(tǒng)(CNS)的組織結(jié)構(gòu),反映定向組織對(duì)水分子運(yùn)動(dòng)的障礙,包括細(xì)胞膜、細(xì)胞骨架和細(xì)胞外基質(zhì)[1]。三維白質(zhì)神經(jīng)纖維束跟蹤技術(shù)(Diffusion tensor teactgrapy,DTT)可非侵入性顯示神經(jīng)纖維束的完整性,如纖維束壓迫和中斷。近年來(lái),越來(lái)越多研究表明[2-7],DTI應(yīng)用于SCI是可行的,可以量化頸髓相關(guān)擴(kuò)散變化,顯示微觀結(jié)構(gòu)損傷較常規(guī)T2WI圖像更敏感。在急性SCI方面,應(yīng)用小鼠模型[1,8-9]研究證實(shí)DTI各參數(shù)的相關(guān)病理學(xué)改變。DTI各參數(shù)在急性SCI與ASIA不同殘損等級(jí)的變化規(guī)律研究較少,尤其是T2WI高信號(hào)區(qū)域中DWI高信號(hào)(稱之DWI高信號(hào)區(qū))與鄰近DWI等信號(hào)區(qū)域(稱之T2WI高信號(hào)區(qū))之間DTI的差異研究方面,是本研究的研究重點(diǎn)。
1.1 臨床資料
收集濱州醫(yī)學(xué)院煙臺(tái)附屬醫(yī)院2012年8月—2014年12月期間急性SCI常規(guī)MRI T2WI高信號(hào)(排除7例運(yùn)動(dòng)和義齒偽影的病人),共34例患者納入研究,男29例,女5例,年齡16~80歲,平均(48±11)歲,所有患者48小時(shí)內(nèi)行DTI檢查。15例無(wú)外傷史及椎間盤(pán)突出患者作為對(duì)照組,男11例,女4例,年齡21~61歲,平均(38±12)歲,測(cè)量C3~C6節(jié)段DTI數(shù)據(jù),所有患者和志愿者簽署知情同意書(shū)。
臨床專科檢查采用ASIA運(yùn)動(dòng)評(píng)分標(biāo)準(zhǔn):5例A級(jí)(完全性損傷):神經(jīng)平面以下包括骶段無(wú)任何感覺(jué)運(yùn)動(dòng)功能保留;6例B級(jí)(不完全性損傷):在神經(jīng)平面以下包括骶段(S4~S5)存在感覺(jué)功能,但無(wú)運(yùn)動(dòng)功能;10例C級(jí)(不完全性損傷):在神經(jīng)平面以下存在運(yùn)動(dòng)功能,且大部分關(guān)鍵肌的肌力小于3級(jí);13例D級(jí)(不完全性損傷):在神經(jīng)平面以下關(guān)鍵肌的肌力大于或等于3級(jí);本研究無(wú)E級(jí)。
1.2 掃描設(shè)備和方法
應(yīng)用Siemens公司Avanto 1.5T磁共振對(duì)所有患者行常規(guī)矢狀位、軸位和DTI掃描,應(yīng)用8通道頭頸聯(lián)合線圈,患者仰臥,線圈包繞頸部,指導(dǎo)患者不要做吞咽,頸椎前加飽和帶,減少血管搏動(dòng)偽影。常規(guī)TSE序列矢狀位掃描T1WI(TR 550ms,TE 11ms)、T2WI(TR 4 200ms,TE 106ms)、軸位T2WI(TR 4 400ms,TE 114ms)掃描,DTI采用單次激發(fā)平面回波序列(EPI),使用12個(gè)方向梯度場(chǎng),b值采用0和800,TR(3 000 ms,TE 97 ms),F(xiàn)OV 256×256mm2,層厚3mm,無(wú)間隔掃描,層數(shù)15。掃描時(shí)間共計(jì)679 s。
1.3 DTI數(shù)據(jù)處理
DTI成功掃描結(jié)束后,在Siemens公司后處理工作站中,將頸髓DTI原始數(shù)據(jù)自動(dòng)生成FA、ADC、DWI和彩色FA四種圖像,在b0圖像手動(dòng)選擇ROI,大小4~5像素,需避開(kāi)腦脊液和出血灶,連續(xù)多點(diǎn)測(cè)量損傷區(qū)域FA、ADC、λ∥、λ⊥值,測(cè)量T2WI高信號(hào)和DWI高信號(hào)區(qū)。數(shù)據(jù)由兩名高年資中樞神經(jīng)系統(tǒng)醫(yī)師測(cè)量,手動(dòng)測(cè)量?jī)纱?,取其平均值?/p>
將DTI數(shù)據(jù)拖入后處理工作站,點(diǎn)擊Fusion Mode鍵,利用Fused 3D處理軟件,選擇頸髓種子層面手動(dòng)描繪,描繪3~5個(gè)層面頸髓截面,點(diǎn)擊Start Tractograpy鍵獲得DTT圖,本研究設(shè)定的神經(jīng)纖維束FA值下限0.2,角度上限30°。
1.4 統(tǒng)計(jì)學(xué)分析
將所有數(shù)據(jù)錄入Excel表中,應(yīng)用SPSS 17.0統(tǒng)計(jì)分析軟件進(jìn)行分析,數(shù)據(jù)以±s表示。采用單因素方差分析,各組間數(shù)據(jù)方差齊性檢驗(yàn),多重?cái)?shù)據(jù)比較,t檢驗(yàn)分析DWI高信號(hào)(DWI高信號(hào)區(qū))與邊緣區(qū)(T2WI高信號(hào)區(qū))DTI參數(shù)差異。P<0.05具有統(tǒng)計(jì)學(xué)意義。
ASIA-A級(jí)5例、共累及17個(gè)節(jié)段,B級(jí)6例、累及14個(gè)節(jié)段,C級(jí)10例、累及13個(gè)節(jié)段,D級(jí)13例、累及13個(gè)節(jié)段,共計(jì)57個(gè)節(jié)段,損傷平面以C3/4~C5/6多見(jiàn)。A~D級(jí)與健康組15例(45個(gè)節(jié)段)FA、ADC、λ∥、λ⊥值對(duì)照研究。數(shù)據(jù)齊性方差檢驗(yàn),符合正態(tài)分布,采用LSD法多重比較。A~D級(jí)與健康組比較,F(xiàn)A、ADC、λ∥、λ⊥值差異有統(tǒng)計(jì)學(xué)意義(P<0.001)見(jiàn)表1。組間比較,A級(jí)與B、C、D級(jí)兩兩比較FA值、ADC值、λ∥值有統(tǒng)計(jì)學(xué)意義(P<0.05),ADC值在A級(jí)降低與B~D級(jí)升高有統(tǒng)計(jì)學(xué)意義,λ⊥值B級(jí)升高與A、C、D級(jí)兩兩比較差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。DTT顯示A、B級(jí)顯示損傷區(qū)域神經(jīng)纖維束腫脹、扭曲和中斷(圖1~5);C、D級(jí)顯示神經(jīng)纖維束走行連續(xù)(圖7~9)。
表1 健康組與脊髓損傷ASIA分級(jí)FA、ADC、λ∥、λ⊥值的比較
DWI高信號(hào)區(qū)9例(A級(jí)5/5例、B級(jí)4/6例),共16個(gè)節(jié)段,與T2WI高信號(hào)區(qū)比較(圖6),ADC、λ∥、λ⊥值具有統(tǒng)計(jì)學(xué)意義(P<0.05),F(xiàn)A值DWI高信號(hào)較T2WI高信號(hào)區(qū)均降低,但二者無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05),見(jiàn)表2,DTT顯示DWI高信號(hào)區(qū)神經(jīng)纖維束連續(xù)性中斷。
FA值、λ∥值隨ASIA殘損等級(jí)降低呈下降趨勢(shì),數(shù)值越低,損傷程度越嚴(yán)重。ADC值在A級(jí)降低,B級(jí)中變化較復(fù)雜,本研究發(fā)現(xiàn)在椎間盤(pán)慢性壓迫節(jié)段ADC值升高,無(wú)慢性壓迫節(jié)段ADC值降低,在同一病人多節(jié)段損傷也出現(xiàn)相同結(jié)果,C~D級(jí)ADC值升高。λ⊥值A(chǔ)~D級(jí)升高。表明FA值、λ∥值是預(yù)測(cè)損傷損傷程度重要指標(biāo),ADC值越降低,多提示損傷越嚴(yán)重,代表?yè)p傷中心區(qū)域。
表2 匹配區(qū)與不匹配區(qū)FA、ADC、λ∥、λ⊥值的比較
圖1~6 同一患者,男,16歲,高空墜落5小時(shí),ASIA-A級(jí)。T2WI(圖1)C7粉碎性骨折壓迫頸髓,C5/6~T1平面頸髓損傷呈T2WI高信號(hào)。DWI(圖2)C6~T1頸髓高信號(hào)。ADC(圖3)C6~T1頸髓低信號(hào)。DTT(圖4,5)C7損傷平面矢狀位、冠狀位頸髓神經(jīng)纖維紊亂變細(xì),連續(xù)性中斷。DWI、T2WI高信號(hào)測(cè)量(圖6),紅色為T(mén)2WI高信號(hào)區(qū)域,綠和紫色為DWI高信號(hào)區(qū)域。圖7~9同一患者,男,67歲,車(chē)禍12小時(shí),ASIA-C級(jí)。T2WI(圖7)C3/4平面頸髓損傷呈T2WI高信號(hào)。DWI(圖8)為等信號(hào)。DTT(圖9)冠狀位頸髓神經(jīng)纖維束連續(xù)。Figure 1~6.The same patient,male,16 years old.Five hours after falling-down injures.ASIA-grade A.T2WI(Figure 1)showed comminuted fracture in C7,by compressing the cervical spinal cord.Cervical spinal injury in C5/6~T1plane was proved by T2WI hyperintensity.DWI(Figure 2)showed hyperintensity in C6~T1.ADC map(Figure 3)showed hypointensity in C6~T1.DTT(Figure 4,5)revealed the thinning and interruption of nerve fiber at C7plane in sagittal and coronal positions.Measurement illustrations on hyperintensity areas on DWI and T2WI(Figure 6).Hyperintensity on T2WI was shown in red,and hyperintensity on DWI was shown in green and purple.Figure 7~9.The same patient,male,67 years old.Twelve hours after car accident.ASIA-grade C(Figure 7)cervical spinal injury at C3/4plane,was proved by T2WI hyperintensity.DWI(Figure 8)showed isointensity.Coronal positon of DTT(Figure 9)showed continuous bundles of cervical spinal nerve fibers.
ASIA殘損等級(jí)是臨床常用標(biāo)準(zhǔn),常規(guī)MRI對(duì)急性SCI常用的檢查方法,兩者不能提供損傷量化指標(biāo)。DTI是在DWI基礎(chǔ)發(fā)展起來(lái),是目前唯一無(wú)創(chuàng)性顯示活體研究神經(jīng)纖維結(jié)構(gòu)的方法。DTT是通過(guò)連接每個(gè)體素內(nèi)近似本征向量(擴(kuò)散張量主方向)對(duì)全部軸突路徑進(jìn)行重建[10],以主方向擴(kuò)散范圍內(nèi)的體素為基礎(chǔ),提供三維神經(jīng)纖維跟蹤,可顯示虛擬頸髓纖維束損傷和連接狀況。
FA和ADC值是DTI兩個(gè)最常用的量化指標(biāo)。λ∥值表示與脊髓纖維擴(kuò)散方向相平行,代表主方向,λ⊥值表示與脊髓纖維擴(kuò)散方向相垂直的前后和左右方向平均值,代表垂直方向。Eric等[11]和Joong等[1]研究表明,λ∥值對(duì)軸突損傷敏感,λ⊥值對(duì)髓鞘破壞敏感。本征值變化反映了組織結(jié)構(gòu)的方向性與完整性程度[12]。
本研究中DTI各參數(shù)值在不同ASIA殘損等級(jí)中變化規(guī)律:隨著損傷程度的加重,ASIA殘損分級(jí)越低,F(xiàn)A值降低越明顯,與以前研究[3,13]相一致。在損傷區(qū)域細(xì)胞外水腫存在,導(dǎo)致水分子擴(kuò)散方向受損,提示損傷后神經(jīng)結(jié)構(gòu)不完整性,F(xiàn)A值是反映損傷重要指標(biāo)。ADC值變化是可能與損傷相關(guān)的軸突結(jié)構(gòu)變化有關(guān),軸突間距和細(xì)胞外體積分?jǐn)?shù)下降可能會(huì)降低ADC值[2]。Zhang等[14]在急性SCI中CTA研究發(fā)現(xiàn),輕度損傷顯示脊髓前動(dòng)脈完整,嚴(yán)重?fù)p傷導(dǎo)致脊髓前動(dòng)脈痙攣缺血。我們研究發(fā)現(xiàn)在ADC圖A級(jí)表現(xiàn)為明顯低信號(hào),ADC值明顯降低,B級(jí)表現(xiàn)為高低混雜信號(hào),B級(jí)中損傷節(jié)段無(wú)椎間盤(pán)慢性壓迫ADC值是降低的,合并慢性頸髓壓迫ADC值輕度升高,發(fā)現(xiàn)在同一患者中多節(jié)段損傷,測(cè)量也出現(xiàn)類(lèi)似結(jié)果,以往脊髓型頸椎病研究,長(zhǎng)期慢性頸髓壓迫,ADC值升高,因此我們推測(cè),B級(jí)中ADC值輕度升高,并不能真實(shí)代表?yè)p傷程度,可能存在數(shù)值“抵消”存在假象。C級(jí)和D級(jí)ADC值升高。ADC值降低只見(jiàn)于A級(jí)和部分B級(jí),ADC值降低提示嚴(yán)重?fù)p傷。λ∥值降低是軸突損傷的標(biāo)志,隨著損傷程度加重,ASIA殘損評(píng)級(jí)越低,λ∥值下降越明顯,與Cheran等[13]研究相同。λ⊥值升高提示髓鞘損傷程度,本研究中A~D級(jí)λ⊥值均升高,提示急性SCI易導(dǎo)致髓鞘損傷。組間比較與損傷程度無(wú)統(tǒng)計(jì)學(xué)意義,但以B級(jí)升高明顯,這需要更多樣本進(jìn)一步總結(jié)。DTT顯示A、B級(jí)患損傷區(qū)域神經(jīng)纖維束腫脹、神經(jīng)纖維毛糙紊亂、不同程度中斷,C和D級(jí)神經(jīng)纖維束完整、走行連續(xù)。DTT可直觀顯示神經(jīng)纖維束損傷嚴(yán)重程度。
在DTI自動(dòng)形成DWI圖像(b=800),高信號(hào)僅見(jiàn)A級(jí)(5/5,100%)、B級(jí)(4/6,66%),A級(jí)常累及兩個(gè)以上脊髓節(jié)段,超過(guò)B級(jí)。Pouw等[15]研究表明,高信號(hào)檢出率在T2WI和DWI分別為94%、72%,本研究結(jié)果基本相同。本研究發(fā)現(xiàn)矢狀位常規(guī)T2WI高信號(hào)范圍超過(guò)DWI高信號(hào),兩者存在不匹配區(qū)域。T2WI高信號(hào)區(qū)域中DWI高信號(hào)(稱之DWI高信號(hào)區(qū))與鄰近DWI等信號(hào)區(qū)域(稱之T2WI高信號(hào)區(qū)),DWI高信號(hào)區(qū)較T2WI高信號(hào)ADC值和λ∥值降低、λ⊥值升高,F(xiàn)A值均降低。DTT顯示DWI高信號(hào)區(qū)神經(jīng)纖維束扭曲、連續(xù)性中斷,提示損傷中心區(qū)域。
綜上所述,F(xiàn)A值、ADC值和λ∥值降低,見(jiàn)于ASIA A級(jí),提示完全性損傷;在不完全性損傷B~D級(jí)中,隨著ASIA殘損等級(jí)降低,F(xiàn)A值和λ∥值呈下降趨勢(shì)、ADC值升高。由此說(shuō)明,F(xiàn)A值、λ∥值、ADC值可量化評(píng)價(jià)急性SCI損傷嚴(yán)重程度的重要指標(biāo),數(shù)值下降明顯,表明損傷程度越嚴(yán)重,與ASIA殘損分級(jí)密切相關(guān),反映了損傷后神經(jīng)纖維髓鞘不完整,同時(shí)累及軸突損傷等微細(xì)結(jié)構(gòu)病理改變,與Cheran等[13]研究基本一致。其中本研究對(duì)11例不同程度損傷患者1月后隨訪,測(cè)量損傷區(qū)域DTI各參數(shù)值在治療前后動(dòng)態(tài)變化,尤其是損傷中心區(qū)域變化,與患者臨床神經(jīng)功能轉(zhuǎn)歸,兩者存在相關(guān)性,將作為下一步的研究重點(diǎn)。
本研究存在不足之處,DTT檢查存在一定的限度,當(dāng)神經(jīng)纖維FA低于0.2、角度超過(guò)30°,神經(jīng)纖維束出現(xiàn)連續(xù)性中斷等假象,需謹(jǐn)慎對(duì)待。A和B級(jí)損傷樣本量較少,數(shù)據(jù)難免存在誤差。檢查時(shí)間較長(zhǎng),患者不合作影響圖像質(zhì)量等。研究結(jié)果顯示DTI參數(shù)值可提供急性SCI臨床ASIA不同殘損等級(jí)的量化指標(biāo),為治療后隨訪提供了依據(jù),本研究將繼續(xù)關(guān)注急性SCI神經(jīng)功能轉(zhuǎn)歸的DTI參數(shù)值動(dòng)態(tài)變化,為預(yù)后評(píng)估和康復(fù)治療提供更為準(zhǔn)確的信息。
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The study of DTI in acute cervical spinal injury w ith different ASIA grades
ZOU Zhi-meng1,DU Mei-ling1,LI Jun1,CAO Qing-yong1,LIAN Hui-xiu1,SHEN Xiao-jun1,WANG Bin2
(1.Yantai Affiliated Hospital of Binzhou Medical University,Yantai Shandong 264100,China;2.Binzhou Medical University,Yantai Shandong 264003,China)
Objective:To study the clinical value of DTI in acute spinal cord injury(SCI)with different ASIA grades.Methods:A retrospective analysis of 34 acute SCI patients with conventional MRI T2WI hyperintensity was made.All patients underwent MR-DTI examination in 48 hours.According to ASIA grades,we measured the values of FA,ADC,λ∥,λ⊥in the injury area.We recruited 15 healthy volunteers of matched ages,and measured the same parameters in the corresponding level of C3/4~C5/6intervertebral disc plane.Single factor analysis of variance(ANOVA)was applied to analyze the difference in DTI parameters in ASIA grade A to D.Independent sample t test was used to analyze DTI parameters in DWI image matching area(hyperintense on both DWI and T2WI)and mismatch area(isointense on DWI but hyperintense on T2WI)in the same patients.Results:The number of patients is 7 in grade A,5 in grade B,19 in grade C,and 13 in grade D.Compared with the healthy group,the A~D groups showed significant differences in FA,ADC,λ∥andλ⊥(F=51.90,13.30,24.70,13.01,P<0.001).Compared with grade B,C and D,the values of FA,ADC andλ∥in grade A were significantly reduced by pairwise comparison(P<0.05).FA andλ∥showed a downward trend as ASIA grade was reduced.ADC values increased in grade A,however decreased in grade B to D.As forλ⊥elevation,by pairwise comparison,grade B showed significant difference from grade A,C and D(P<0.05).There was no significant difference between grade A,C or D inλ⊥by pairwise comparison(P>0.05).DTT showed in injured area nerve fiber bundle swelling,distortion and interruption in grade A.The nerve fiber bundles were swelling,coarse and partially interrupted in grade B.Integrated nerve fiber bundles could be found in grade C and D.Comparing DWI match area with mismatch area,ADC,λ∥decreased andλ⊥increased significantly(P<0.05),whereas the changes of FA value had no difference(P>0.05).DTT demonstrated that the nerve fiber bundle in DWImatch area was interrupted.Conclusion:FA value andλ∥value are sensitive indexes among different AISA grades in acute SCI.The lower the ADC value is,the more serious the injury is.DTT can display the position and injury extent of nerve fiber bundles,and provide more imaging evidence for clinical treatment.
Spinal cord injuries;Diffusion magnetic resonance imaging
R651.2;R445.2
A
1008-1062(2017)01-0008-04
2016-03-24;
2016-04-12
鄒志孟(1971-),男,山東煙臺(tái)人,主治醫(yī)師。E-mail:zzmmprm@163.com
王濱,濱州醫(yī)學(xué)院,264003。E-mail:binwang001@yahoo.com
山東省自然科學(xué)基金(ZR2015HM081);山東省煙臺(tái)市科技計(jì)劃項(xiàng)目(2014WS049)。