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视网膜神经纤维层的定量评估在视网膜疾病中的应用

Application of quantitative assessment of retinal nerve fiber layer in retinal diseases

来源期刊: 眼科学报 | 2023年3月 第38卷 第3期 253-259 发布时间: 收稿时间:2023/3/27 9:25:51 阅读量:7693
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视网膜神经纤维层光学相干断层扫描视网膜疾病视网膜疾病常用治疗方法
retinal nerve fibers layer optical coherence tomography retinal disease common treatments for retinal disease
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10.12419/j.issn.1000-4432.2023.03.09
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视网膜神经纤维层是视网膜的最内层,主要由来自视网膜神经节细胞的无髓鞘轴突组成,此外还有神经胶质细胞与视网膜血管,其厚度与年龄、眼球增长、眼底结构改变等因素相关。光学相干断层扫描可以清晰展示角膜、视网膜、脉络膜、视神经等高分辨率断层图像,可以在活体上显示生物学组织的细微结构,在临床与科研中已获得广泛应用。在青光眼视神经病变中,光学相干断层扫描可以发现视野异常前的视网膜神经纤维层损害,已成为青光眼早期诊断与视神经损伤程度检测的重要手段。除视神经病外,越来越多的研究表明许多视网膜血管疾病、神经元变性疾病等视网膜疾病也有视网膜神经纤维层的损伤。探讨视网膜疾病与神经纤维层的关系,将有利于进一步推进对视网膜疾病发病机制及病理改变的认识。本文就视网膜神经纤维层的定量评估与多种视网膜疾病的关系展开综述,为其在视网膜疾病中的应用提供参考。
The retinal nerve fiber layer, the innermost layer of the retina, consists mainly of unmyelinated axons from retinal ganglion cells, as well as glial cells and retinal blood vessels , the thickness of which is related to factors such as age, ocular growth and fundus structure changes. Optical coherence tomography (OCT) can clearly display the cornea, retina, choroid, optic nerve and other high-resolution tomography images. It can show the fine structure of biological tissues in vivo, which has been widely used in clinical and scientific research. In glaucomatous optic neuropathy, OCT can detect the damage of retinal nerve fiber layer before abnormal visual field, which has become an important means of early diagnosis of glaucoma and detection of the degree of optic ner ve damage. In addition to optic neuropathy, more studies have shown that many retinal diseases such as retinal vascular diseases and neurodegenerative diseases also have retinal nerve fiber layer injury. Exploring the relationship between retinal diseases and nerve fiber layer will be beneficial to further promote the understanding of the pathogenesis and pathological changes of retinal diseases. This paper reviews the relationship between the quantitative evaluation of retinal nerve fiber layer and various retinal diseases, and provides reference for its application in retinal diseases.
视网膜神经纤维层(retinal nerve fibers layer, RNFL)是由视网膜神经节细胞的轴突在视神经结合之前于视网膜内表面形成的丛状结构,许多眼底病有神经节细胞与轴突的病变,如青光眼绝对期、视神经炎、视网膜色素变性等,RNFL厚度可以作为评估轴突丢失和神经元变性的依据[1]。光学相干断层扫描(optical coherence tomography,OCT)具有无创、快速、重复性好、耐受性好的特点,是各种视网膜疾病的诊断、治疗和随访中必不可少的工具,其中RNFL厚度的定量评估和各种视乳头参数的测定在视神经退行性病变的诊断和观察中发挥着核心作用,然而在视网膜疾病中的报道相对较少。

1 视网膜血管性病变

1.1 糖尿病性视网膜病变

糖尿病性视网膜病变(diabetic retinopathy,DR)是糖尿病导致的视网膜微血管损害引起的一系列慢性进行性疾病,是导致成年人失明的常见原因。越来越多的研究表明,DR不仅影响微循环系统,而且会损害神经元细胞和神经胶质细胞,因此视网膜神经退行性变化也是其重要病变改变[2],并且在DR早期甚至眼底血管出现异常改变之前,视网膜神经成分已有损伤,特别是RNFL[3]
Yang等[4]通过频域OCT观察不同时期糖尿病大鼠的RNFL厚度变化,发现28周糖尿病大鼠的RNFL厚度发生了改变,并且随着大鼠糖尿病病程的推进,RNFL厚度逐渐变薄。查汝勤等[5]以5、10、15年的病程为节点将糖尿病患者分为4组,利用OCT测量患者RNFL的厚度,发现随糖尿病患病时间迁移,糖尿病患者的RNFL厚度有变薄的趋势。
Chhablani等[6]发现,与健康人相比,无视网膜血管改变的糖尿病(no diabetic retinopathy,NDR)、非增殖性糖尿病视网膜病变(non-proliferative diabetic retinopathy,NPDR)、增殖性糖尿病视网膜病变(proliferative diabetic retinopathy,PDR)患者RNFL平均厚度与最低厚度均变薄,但糖尿病各组间RNFL厚度比较差异无统计学意义,其最小RNFL厚度低于对照组。Duck等[7]通过比较糖尿病黄斑水肿(diabetic macular edema,DME)和非DME的DR患者的RNFL厚度,发现DME患者的RNFL厚度普遍增加,尤其是颞象限和鼻象限,并且其增厚程度与黄斑水肿程度相关,但其变化机制尚不清楚。此外,他们研究得出玻璃体内注射贝伐珠单抗能够有效改善RNFL的增厚程度。

1.2 视网膜静脉阻塞

视网膜静脉阻塞(retinal vein occlusion,RVO)是常见的视网膜血管疾病,根据阻塞静脉的位置分为视网膜分支静脉阻塞(branch retinal vein occlusion,BRVO)和视网膜中央静脉阻塞(central retinal vein occlusion,CRVO)。视网膜的缺血可导致RNFL萎缩,而视网膜水肿消退后易被误诊为青光眼引起的RNFL萎缩[8]
Kim等[9]利用OCT分析BRVO患者RNFL厚度的纵向变化,发现其厚度显著降低。Ahn等[10]发现,与基线相比,24个月时BRVO和CRVO患眼与对侧眼的视乳头周围视网膜神经纤维层(peripapillary RNFL,pRNFL)厚度均减少,并且与正常对照组相比,对侧眼的pRNFL厚度也减少。Kim等[11]研究发现,单侧RVO患者的对侧眼RNFL厚度降低,常发生在颞下区和颞上区,这些区域正是青光眼结构变化最常见的区域,且与正常对照组间视野测试结果的差异也很明显,但是眼压与对照组相同,他们认为RVO与青光眼可能有相似的发病机制,都是血管异常的表现,并不具有因果关系。Shin等[12]也发现单侧RVO患者的对侧眼RNFL和神经节细胞内丛状层(ganglion cell-inner plexiform layer,GC-IPL)平均厚度均较正常对照组薄,同时其视盘周围血管密度(vascular density,VD)和灌注密度(perfusion density,PD)也明显低于对照组,并且RNFL和GC-IPL厚度与乳头周围VD和PD呈正相关,或许表明单侧RVO患者的对侧眼出现RVO的可能性要超过健康人。RNFL对RVO的进展及预后评价作用还需要更多深入的研究。

1.3 视网膜动脉阻塞

视网膜动脉阻塞(retinal artery occlusion,RAO)是一种具有对视功能有破坏性的眼科急症,预后不良与长时间的视网膜缺血有关,会导致不可逆转的视网膜损伤。根据阻塞部位或范围可分为视网膜中央动脉阻塞(central retinal artery occlusion, CRAO)、视网膜分支动脉阻塞(branch retinal artery occlusion,BRAO)或睫状视网膜动脉阻塞。研究发现,RAO导致急性期内层与外层视网膜增厚,随后出现萎缩,频域OCT可能成为一种RAO诊断、判断分期和预后有用的无创成像工具[13-14],但RNFL厚度的研究相对较少。
Kim等[15]研究发现,3、6和12个月时,BRAO眼闭塞区GC-IPL、RNFL平均厚度比对侧眼显著减少,而且在6、12个月时,对侧眼的pRNFL厚度也明显低于健眼。Leung等[16]随访至少一年后发现,RAO患者的黄斑及pRNFL厚度均明显降低,且与阻塞的部位相对应,CRAO和BRAO分别表现为弥漫性和节段性变薄。此外,视野缺损也与黄斑和RNFL变薄的位置相对应,且与结构损害程度密切相关,提示黄斑和RNFL越广泛变薄,功能预后越差。

2 变性类疾病

2.1 年龄相关性黄斑变性

    年龄相关性黄斑变性(age-related macular degeneration,AMD)是发达国家老年人致盲的主要原因,存在视网膜神经元变性的发病机制,这与青光眼相似,但它们累及不同的视网膜层。青光眼主要累及视网膜内层,而AMD主要导致视网膜外层的改变。过去对于AMD的研究多集中于视网膜外层和脉络膜结构的异常,对于视网膜内层的研究很少。现一些学者假设AMD也可能影响视网膜最内层的3层,内丛状层(inner plexiform layer,IPL)、神经节细胞层(ganglion cell layer,GCL)和RNFL——统称为神经节细胞复合体(ganglion cell complex,GCC)。
Zucchiatti等[17]通过分析不同类型AMD的GCC和RNFL层的形态学变化发现,与健康对照组比较,GCC在干性AMD(dry age-related macular degeneration,dAMD)和湿性AMD(neovascular age-related macular degeneration,nAMD)中显著降低,pRNFL在nAMD中显著降低,在26例晚期dAMD(地图状萎缩)中无明显变化。他们认为脉络膜新生血管的快速发展可能导致神经元连接的不可逆损失和RNFL变薄。然而Lee等[18]研究发现76例dAMD患者的平均pRNFL厚度低于对照组,尤其是上、下和颞侧明显小于健康对照眼。这与黄斑区视网膜节细胞的轴突主要位于视盘的颞区有关,因此视神经乳头黄斑纤维束优先变薄。Ozcaliskan等[19]发现,与健康对照组相比,58例中期dAMD(玻璃膜疣直径> 125 μm,或有与AMD相关的色素异常)患者副中央凹(距离黄斑中心凹1~3 mm的圆环)的RNFL、GCL、IPL明显变薄,且浅表毛细血管丛(superficial capillary plexus,SCP)血管密度明显降低,而深部毛细血管丛(deep capillary plexus,DCP)血管密度无降低。GCC与SCP血管密度测量值有关,这表明内层视网膜厚度同时受结构和微血管的影响,并为探讨AMD的发病机制提供了一种新的思路。
研究结果的不一致有可能与样本量及纳入标准的差异相关。RNFL厚度变薄是正常的衰老过程。Fortune等[20]发现,RNFL厚度与血管直径均随着年龄的增长而减小,并且RNFL厚度测量中总是包括血管,所以可能高估了年龄相关的轴突损失的程度,还有很大一部分原因是血管的老化。但大部分学者认为AMD虽然主要累及视网膜外层,但视网膜内层神经元也可能对光感受器变性做出反应,使视网膜内层也受到损害,pRNFL厚度变薄。

2.2 原发性视网膜色素变性

原发性视网膜色素变性(retinitis pigmentosa, RP)是一种进行性、遗传性、营养不良性退行性病变,主要表现为视杆、视锥细胞进行性丧失并引发相应的视野缺损,以及夜盲和色素性视网膜病变等,最终可导致视力下降。近年来,有报道RP患者也存在视神经轴突变性和脱髓鞘的病理变化[21],表现为RNFL厚度的异常。
Oishi等[22]通过对RP患者RNFL厚度变化速率的纵向研究发现,与正常人相比,RP患者年龄依赖性RNFL变薄的速度更快,这支持了RP病理改变同时涉及内层和外层视网膜的观点。Yoon等[23]发现不同程度的RP患者的RNFL厚度均比正常组厚,且RNFL厚度与患者的视力和视野范围呈弱负相关,并且研究通过比较不同分期RP患者的纵向变化发现,随访过程中均出现脉络膜厚度变薄,仅晚期患者RNFL变薄[24]。Birtel等[25]在RPGR相关RP(一种X染色体连锁的RP)中也发现RNFL厚度显著增加。

2.3 病理性近视

病理性近视(pathologic myopia,PM)是一种视网膜变性疾病,随着眼轴增加,形成后巩膜葡萄肿,视盘与后极部视网膜受力改变,出现视盘及RNFL的改变,同时视网膜色素上皮和脉络膜变薄,可伴有视网膜色素上皮萎缩、脉络膜新生血管和视网膜下出血,严重影响视力。
Lim等[26]比较10岁以下儿童高度近视眼与低度近视眼的pRNFL厚度研究发现,高度近视眼的下象限和整体pRNFL明显更薄。Lee等[27]发现,高度近视眼在2年内的pRNFL下降幅度明显大于正常眼,此外,高度近视老年患者的pRNFL厚度减少率更高。Guo等[28]与Wang等[29]的研究均发现,高度近视眼与对照组相比,其中央凹旁RNFL、pRNFL和中央凹下脉络膜的厚度降低,且浅表毛细血管旁微血管密度较低,与pRNFL厚度呈正相关。Wang等[29]认为,视网膜和脉络膜血管的变化可能与近视进展中的轴向伸长有关,OCTA可以有效监测近视眼的进展。

3 常见视网膜病变治疗方法对RNFL的影响

3.1 玻璃体腔注射抗血管内皮生长因子药物

抗血管内皮生长因子(vascular endothelial growth factor,VEGF)对视网膜新生血管的消退和黄斑水肿的改善有积极的作用,但VEGF作为一种神经营养因子,反复抗VEGF治疗抑制VEGF的神经保护作用可能会导致RNFL损伤[30]
Jayoung等[31]评估玻璃体内注射雷珠单抗或阿柏西普对nAMD患者pRNFL厚度的影响,发现在基线、3个月、6个月、12个月时,两组眼与正常对照眼的所有区域pRNFL厚度均未见明显差异。与基线相比,两组眼在12个月后平均RNFL厚度减少,但在6个检查部位(颞、颞上、鼻上、鼻、鼻下和颞下)中并没有观察到明显的差异。Shin等[32]通过至少12个月的随访发现,RNFL厚度在nAMD组无明显变化,但DR组、RVO组和未注射组的RNFL厚度均有所下降,且三组的下降程度并无明显差异,研究还发现,DR和RVO患者RNFL厚度降低与视网膜缺血严重程度相关,提示视网膜内缺血本身可能是RNFL丢失的原因,而非抗VEGF的作用。然而,Wang等[33]研究发现,在接受大量注射的患者中,RNFL变薄与注射次数之间存在剂量反应关系,他们认为更大的样本量,更长时间的随访,抗VEGF也许对RNFL厚度有一定的影响,当然不能排除疾病进展的影响。

3.2 全视网膜激光光凝术

全视网膜激光光凝术(panretinal photocoagulation,PRP)是临床上常见的DR及RVO治疗方法,通过激光的光热效应,造成相应的脉络膜视网膜瘢痕,减少细胞耗氧,改善视网膜的缺血、缺氧状态,抑制病变进展。有研究者提出,激光光凝术可能会造成内层视网膜损伤,PRP后的视觉障碍可能与GCL和RNFL损伤相关[34]
Kim等[35]通过回顾性分析重症DR患者,发现RNFL的平均厚度在PRP后的前3个月略有增加,之后逐渐下降,在PRP后的2年显示出RNFL厚度的下降有统计学意义,尤其是上、下象限,颞象限RNFL的厚度无显著下降。荟萃分析显示PRP对RNFL厚度无显著影响,但是糖尿病本身引起的神经元细胞凋亡、糖基化终末产物对RNFL的影响、高强度激光对整个视网膜层的损伤以及PRP使血管通透性增高,加重视网膜炎症和水肿,导致视网膜细胞的丢失及RNFL变性,这些异质因素的相互作用可能导致PRP对RNFL的最终影响不同[36]
在缺血性RVO的治疗中,Bitirgen等[37]研究发现,PRP治疗眼的pRNFL平均厚度、平均神经纤维密度(nerve fiber density,NFD)、神经分支密度和神经纤维长度(nerve fiber length,NFL)显著低于对侧眼,pRNFL平均厚度与NFD和NFL呈显著的正相关。Li等[38]总结发现,在接受PRP治疗缺血性CRVO的患眼中,平均pRNFL厚度明显降低,且PRP能够增加缺血性CRVO患眼的视网膜血流量。

4 小结

OCT是视网膜疾病诊断、治疗和随访中不可或缺的工具,并且利用OCT定量评估RNFL已经应用于青光眼等视神经病变的诊断及预测病情发展等临床工作中。而关于各视网膜疾病与RNFL厚度间关系的研究结果尚存在一定的争论,这与纳入标准、样本量大小、随访时间等密切相关,他们之间的关系还需要进行更深入、更大规模的研究来确定。但现大多学者认为RNFL的定量评估对常见视网膜疾病的早期筛查、进展预测及病理生理学研究也有一定的意义,可能将有助于指导临床治疗策略。

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1、张帅,蒋爱民.屈光参差性弱视儿童视网膜神经纤维层和黄斑区视网膜厚度的相关性分析[J].国际眼科杂志,2023,23(11):1925-1929.
2、高丽煜,李梦馨,贾帅等.新发缺血性脑卒中患者的视网膜黄斑区OCT特征[J].眼科学报,2023,38(05):414-421.GAO Liyu, LI Mengxin, JIA Shuai, et al. OCT characteristics of retinal macular region in patients with new-onset ischemic stroke[J]. Eye Sci, 2023, 38(5): 414-421.
1、山东第一医科大学(山东省医学科学院)青年科学基金培育资助计划项目(202201-118)。
This work was supported by Shandong First Medical University (Shandong Academy of Medical Sciences) Youth Science Foundation Incubation Grant Program(202201-118)()
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