光學相干斷層掃描術(shù)在中樞神經(jīng)系統(tǒng)疾病中的應(yīng)用

敖然 于生元

光學相干斷層掃描術(shù)在中樞神經(jīng)系統(tǒng)疾病中的應(yīng)用

敖然 于生元

中樞神經(jīng)系統(tǒng)疾病較為復(fù)雜，常規(guī)檢查方法易受患者主觀因素的影響而缺乏準確性，通過光學相干斷層掃描術(shù)（OCT）可以客觀檢測眼球后結(jié)構(gòu)改變，進而反映神經(jīng)元變性情況。本文旨在探討OCT技術(shù)在中樞神經(jīng)系統(tǒng)疾病中的應(yīng)用，并尋找新型生物學標志物。

體層攝影術(shù)，光學相干； 中樞神經(jīng)系統(tǒng)疾??； 綜述?

視神經(jīng)在胚胎發(fā)育過程中起源于外胚層，屬于中樞神經(jīng)的一部分［1］。視神經(jīng)和眼底結(jié)構(gòu)可以在一定程度上反映中樞神經(jīng)系統(tǒng)疾病。中樞或周圍神經(jīng)系統(tǒng)病理性損害可以導(dǎo)致神經(jīng)元變性［2］，神經(jīng)元變性可發(fā)生于視覺通路［3］。視覺通路由三級神經(jīng)元組成，一級神經(jīng)元為視網(wǎng)膜雙極細胞，其周圍支與視覺感受器視錐細胞和視桿細胞形成突觸，其中樞支與二級神經(jīng)元節(jié)細胞形成突觸，節(jié)細胞軸突形成視神經(jīng)，向后延伸形成視束，止于外側(cè)膝狀體三級神經(jīng)元，其軸突形成視輻射，止于枕葉皮質(zhì)［4］。順行神經(jīng)元變性自視網(wǎng)膜至視輻射或視皮質(zhì)，逆行神經(jīng)元變性則自視皮質(zhì)或視輻射至視網(wǎng)膜［5］。上述病理改變在疾病初期通常呈亞臨床變化，常規(guī)檢測難以發(fā)現(xiàn)，光學相干斷層掃描術(shù)（OCT）可以早期發(fā)現(xiàn)組織結(jié)構(gòu)改變，為及時治療提供時機。

OCT技術(shù)是一種非侵襲性、可重復(fù)性、無創(chuàng)性眼科檢查方法，其技術(shù)原理與超聲類似，根據(jù)眼部各組織結(jié)構(gòu)不同折光率獲得眼底結(jié)構(gòu)的橫斷面成像，從而檢測視網(wǎng)膜、脈絡(luò)膜等結(jié)構(gòu)，分辨率達5～10 μm，接近病理結(jié)構(gòu)水平［6］。OCT 技術(shù)還可以檢測視乳頭旁和黃斑區(qū)視網(wǎng)膜神經(jīng)纖維層（RNFL）厚度。光學相干斷層掃描增強深部成像（EDI?OCT）是新型OCT技術(shù)，與傳統(tǒng)OCT技術(shù)相比，具有較高的信噪比（SNR），分辨率高達2 μm，同時增加視覺追蹤系統(tǒng)，可于數(shù)微秒內(nèi)捕捉到眼球后結(jié)構(gòu)變化，呈現(xiàn)視網(wǎng)膜各層結(jié)構(gòu)和脈絡(luò)膜結(jié)構(gòu)，并形成三維圖像，從而更直觀地觀察中樞神經(jīng)系統(tǒng)疾?。??8］。脈絡(luò)膜是血供最豐富的結(jié)構(gòu)，為視網(wǎng)膜外層和部分視神經(jīng)供血，其結(jié)構(gòu)改變可以在一定程度上反映血供異常［9］。既往主要采用超聲或熒光素眼底血管造影（FFA）對脈絡(luò)膜進行檢測，不能直觀反應(yīng)脈絡(luò)膜結(jié)構(gòu)，EDI?OCT技術(shù)由于更靠近眼球，可以清晰獲得脈絡(luò)膜圖像，實現(xiàn)快捷、無創(chuàng)性檢測脈絡(luò)膜。

一、中樞神經(jīng)系統(tǒng)脫髓鞘疾病

多發(fā)性硬化（MS）、視神經(jīng)脊髓炎譜系疾病（NMOSD）是中樞神經(jīng)系統(tǒng)脫髓鞘疾病，病變常累及視神經(jīng)，導(dǎo)致視神經(jīng)炎。視神經(jīng)炎包括炎癥反應(yīng)、脫髓鞘改變、軸索損傷等，這一過程可能導(dǎo)致視網(wǎng)膜節(jié)細胞死亡、黃斑體積縮小、視覺功能障礙或永久性失明［10］。疾病早期影像學檢查可能無異常，眼科檢查僅發(fā)現(xiàn)亞臨床改變，如果能夠獲得早期診斷和及時治療，患者預(yù)后良好。

1.多發(fā)性硬化 有25%～50%以急性視神經(jīng)炎首發(fā)的患者最終證實為多發(fā)性硬化［11］。尸檢顯示，49例多發(fā)性硬化患者中35例發(fā)生視網(wǎng)膜神經(jīng)纖維層萎縮［12］。1999 年，Parisi等［13］首次將 OCT 技術(shù)用于多發(fā)性硬化，他們對有視神經(jīng)炎表現(xiàn)且視力恢復(fù)較好的患者進行OCT檢測，發(fā)現(xiàn)仍有6/14例患側(cè)視網(wǎng)膜神經(jīng)纖維層和4/14例健側(cè)視網(wǎng)膜神經(jīng)纖維層較正常對照者變薄。視神經(jīng)炎致視網(wǎng)膜神經(jīng)纖維層厚度改變與視覺誘發(fā)電位（VEP）P100波幅降低相一致，提示軸索變性［14］。視神經(jīng)損害早期視網(wǎng)膜節(jié)細胞內(nèi)叢狀層即變薄，故可準確篩查出早期視神經(jīng)損害［15］。

2.視神經(jīng)脊髓炎譜系疾病 研究顯示，視神經(jīng)脊髓炎譜系疾病患者視乳頭周圍各象限視網(wǎng)膜神經(jīng)纖維層均變薄，特別是上象限和下象限，提示軸索直徑較薄的區(qū)域不易受累。與多發(fā)性硬化患者相比，視神經(jīng)脊髓炎譜系疾病患者黃斑區(qū)視網(wǎng)膜神經(jīng)纖維層顯著變薄［16］，提示后者的視神經(jīng)炎較前者更易導(dǎo)致視網(wǎng)膜神經(jīng)纖維層變薄，且出現(xiàn)時間更早，這可能是由于抗水通道蛋白4（AQP4）抗體聚集使血?腦屏障（BBB）通透性增加［17］。

二、神經(jīng)變性病

1.帕金森病 帕金森?。≒D）是臨床常見的神經(jīng)變性病，其病理改變是黑質(zhì)多巴胺能神經(jīng)元變性缺失和路易小體（LB）形成，臨床以運動癥狀為主，表現(xiàn)為運動遲緩、靜止性震顫、肌張力增高、姿勢平衡障礙［18］。視覺障礙在帕金森病患者中較為常見，主要表現(xiàn)為視物模糊、視物成雙、幻視等［19］。視覺相關(guān)檢查常受帕金森病患者認知功能障礙的影響而缺乏準確性，影像學檢查可以較客觀地反映眼部各組織結(jié)構(gòu)異常。有學者提出，多巴胺在視網(wǎng)膜視覺成像過程中發(fā)揮一定作用［20］，而帕金森病患者視網(wǎng)膜多巴胺水平減少可能導(dǎo)致視覺障礙，補充左旋多巴制劑可以改善癥狀［21］。OCT技術(shù)是客觀檢測視網(wǎng)膜形態(tài)學的方法，可以反映出神經(jīng)元功能和突觸傳遞。Bodis?Wollner等［22］對 24 例帕金森病患者和17例性別、年齡相匹配的正常對照者進行OCT檢查，結(jié)果顯示，帕金森病患者視網(wǎng)膜、視網(wǎng)膜神經(jīng)纖維層內(nèi)上和內(nèi)下象限均較正常對照者變薄。Jiménez等［23］認為，帕金森病嚴重程度與視乳頭旁視網(wǎng)膜神經(jīng)纖維層厚度有關(guān)，帕金森病患者視乳頭旁各象限視網(wǎng)膜神經(jīng)纖維層均較正常對照者變薄。Garcia?Martin等［24］探討帕金森病患者生活質(zhì)量與中央凹視網(wǎng)膜神經(jīng)纖維層厚度的相關(guān)性，發(fā)現(xiàn)中央凹視網(wǎng)膜神經(jīng)纖維層厚度減少與帕金森病嚴重程度相關(guān)。α?突觸核蛋白（α?Syn）在帕金森病的發(fā)生與發(fā)展中發(fā)揮重要作用，其聚集與路易小體（LB）形成和多巴胺能神經(jīng)元變性缺失密切相關(guān)。α?Syn參與脂質(zhì)連接、線粒體功能和突觸傳遞［25］。有研究顯示，α?突觸核蛋白基因（SNCA）表達于脊椎動物視網(wǎng)膜外叢狀層［26］。病理學研究顯示，視網(wǎng)膜內(nèi)層細胞間質(zhì)α?Syn 表達上調(diào)［19］。Satue等［27］采用 OCT 技術(shù)檢測帕金森病患者視網(wǎng)膜神經(jīng)纖維層厚度，發(fā)現(xiàn)視網(wǎng)膜外叢狀層視網(wǎng)膜神經(jīng)纖維層較正常對照者變?。灰嘤醒芯匡@示，視網(wǎng)膜其他層視網(wǎng)膜神經(jīng)纖維層也變?。?8?29］。因此，α?Syn 對視網(wǎng)膜結(jié)構(gòu)的影響尚待進一步驗證。

2.阿爾茨海默病 近年關(guān)于阿爾茨海默?。ˋD）患者視覺障礙的研究逐漸增多，眼部癥狀常出現(xiàn)在癡呆前［30］。OCT技術(shù)可以在阿爾茨海默病早期即發(fā)現(xiàn)亞臨床證據(jù)，從而早期診斷阿爾茨海默病。研究顯示，隨著阿爾茨海默病的進展，視網(wǎng)膜神經(jīng)纖維層逐漸變薄，黃斑體積與簡易智能狀態(tài)檢查量表（MMSE）評分顯著相關(guān)［31］。因此，OCT 技術(shù)是評價阿爾茨海默病嚴重程度的便捷方法。

三、原發(fā)性頭痛

1.偏頭痛 偏頭痛是發(fā)作性神經(jīng)系統(tǒng)疾病，我國患病率約為9%［32］。皮質(zhì)擴散性抑制（CSD）是公認的有先兆偏頭痛的病理生理學機制［33］，是神經(jīng)元去極化后出現(xiàn)的興奮性抑制，通過釋放大量炎性因子和神經(jīng)遞質(zhì)以激活三叉神經(jīng)血管系統(tǒng)，最終導(dǎo)致偏頭痛［34］。三叉神經(jīng)血管系統(tǒng)包括三叉神經(jīng)、顱內(nèi)外腦膜血管，以及腦干、顱外軟組織、眼部等［35］。亦有學者開始關(guān)注偏頭痛患者眼球后結(jié)構(gòu)變化。研究顯示，偏頭痛發(fā)作期脈絡(luò)膜厚度顯著增加［36］，偏頭痛非發(fā)作期脈絡(luò)膜厚度較正常對照者減少，可能是由于偏頭痛反復(fù)發(fā)作致腦血流量減少，使脈絡(luò)膜變??；其中，有先兆偏頭痛組脈絡(luò)膜厚度減少得更明顯［37］，此與有先兆偏頭痛易引起顱內(nèi)血管事件相一致［38］。Martinez等［39］發(fā)現(xiàn)，偏頭痛組患者視網(wǎng)膜神經(jīng)纖維層厚度較對照組減少，視網(wǎng)膜神經(jīng)纖維層厚度與偏頭痛殘疾程度評價問卷（MIDAS）、偏頭痛發(fā)作頻率和病程相關(guān)。視網(wǎng)膜神經(jīng)纖維層變薄可能是逆行性神經(jīng)元變性所致，皮質(zhì)擴散性抑制源于枕葉皮質(zhì)，視覺先兆發(fā)生時枕葉血流量減少［40］，偏頭痛反復(fù)發(fā)作可以引起視覺皮質(zhì)神經(jīng)元逆行性變性，從而導(dǎo)致視網(wǎng)膜神經(jīng)纖維層變薄。

2.叢集性頭痛 叢集性頭痛是臨床最為常見的三叉神經(jīng)自主神經(jīng)性頭痛，表現(xiàn)為偏側(cè)頭痛、程度劇烈，嚴重影響生活質(zhì)量［41］。多項研究顯示，叢集性頭痛發(fā)作時眼部血管發(fā)生血流動力學改變，從而導(dǎo) 致 視 覺 障 礙［42］。Ewering 等［43］采 用 OCT 技 術(shù) 對107例叢集性頭痛患者視網(wǎng)膜神經(jīng)纖維層厚度進行檢測，發(fā)現(xiàn)雙眼顳側(cè)象限視網(wǎng)膜神經(jīng)纖維層厚度均較正常對照者減少，其中，慢性叢集性頭痛患者黃斑區(qū)視網(wǎng)膜神經(jīng)纖維層厚度較偶有頭痛發(fā)作者和正常對照者均減少，提示視網(wǎng)膜神經(jīng)纖維層厚度改變可能是長期血供異常所致。

綜上所述，OCT技術(shù)是非侵襲性、可重復(fù)性、無創(chuàng)性檢測方法，不受患者主觀影響，可以客觀、精確地捕捉眼球后結(jié)構(gòu)變化，廣泛應(yīng)用于中樞神經(jīng)系統(tǒng)疾病的早期診斷，尤其對存在眼部癥狀的中樞神經(jīng)系統(tǒng)疾病、神經(jīng)變性病和發(fā)作性疾病具有重要臨床意義。視網(wǎng)膜神經(jīng)纖維層厚度有望成為新型生物學標志物，可以早期發(fā)現(xiàn)亞臨床改變，為疾病早期診斷提供依據(jù)。

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The application of optical coherence tomography in central nervous system diseases

AO Ran,YU Sheng?yuan

Department of Neurology,Chinese PLA General Hospital,Beijing 100853,China

YU Sheng?yuan(Email:yusy1963@126.com)

Central nervous system diseases are complicated,and general examinations are lack of accuracy because they are easily influenced by subjective factors of patients.Objective results from optical coherence tomography(OCT)can detect the changes of ocular posterior structures,and then further reflect the neuronal degeneration.The aim of this review is to discuss the application of OCT in central nervous system diseases and look for new biomarkers.

Tomography,optical coherence; Central nervous system diseases; Review

This study was supported by the National Natural Science Foundation of China(No.81471147).

10.3969/j.issn.1672?6731.2017.05.013

國家自然科學基金資助項目（項目編號：81471147）

100853 北京，解放軍總醫(yī)院神經(jīng)內(nèi)科

于生元（Email：yusy1963@126.com）

2017?04?06）