Physiological characteristics of the choroid and its association with myopia in children and adolescents
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摘要: 脉络膜是位于巩膜和Bruch膜之间的一个多功能动态结构,可能参与了眼球生长调节与近视发展,脉络膜厚度可能是预测儿童青少年近视发展及治疗防控效果的重要生物标志物。研究对脉络膜的生理结构、测量方法进行了综述和总结,探讨了脉络膜的影响因素,包括年龄、生理变化、屈光状态和眼轴长度、药物影响及光学环境等,指出了脉络膜厚度在儿童青少年近视研究中可能的应用。Abstract: The choroid is a multifunctional dynamic structure located between the sclera and the Bruch membrane, which may be involved in the regulation of eye growth and the development of myopia. Choroidal thickness may serve as an important biomarker for predicting the development of myopia and the effectiveness of myopia control treatments in children and adolescents. The study reviews and summarizes the physiological structure and measuring methods of the choroid, and discusses its influencing factors including age, physiological changes, refractive status, axial length, drug effects, optical environment and so on. The review points out the potential applications of choroidal thickness in myopia research among children and adolescents.
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Key words:
- Choroid /
- Physiology /
- Myopia /
- Influencing factor
1) 利益冲突声明 所有作者声明无利益冲突。 -
脉络膜是眼内连接巩膜和视网膜上皮层的关键结构,作为一个高度血管化的多功能组织,其功能不仅仅是向视网膜提供氧气和营养物质,还包括调节眼压和温度、分泌产生多种生长因子参与调节巩膜重塑等[1-2]。自1995年一项研究报道脉络膜可能参与眼球的生长调节以来[3],人们对脉络膜及其在近视中潜在作用的研究突增。越来越多的证据表明,近视患者屈光度数越大,眼轴长度越长,脉络膜厚度越薄,反之亦然[4-6];且脉络膜的变化先于眼轴长度的变化,因此脉络膜可能是预测近视发展和治疗防控效果的生物标志物[7-10]。
由于脉络膜富含血管且血流速度极快,其厚度的变化可能是受外界作用刺激下血流灌注量发生变化而引起的[11]。考虑到血液提供氧气以及营养物质的作用,再结合缺氧与近视之间的关联[12],有研究者提出脉络膜灌注量减少导致巩膜缺血缺氧、结构重塑可能是诱发近视的机制之一[13]。然而,短期刺激引起的脉络膜变化是否会导致眼球发生长期的变化尚不清楚。本研究中,笔者将对脉络膜的生理结构、测量方法、影响因素等进行综述,并探究其与近视的关联以及在近视防治方面可能的应用,以期为后续进一步的研究提供帮助。
1. 脉络膜厚度与测量方法
1.1 生理结构
脉络膜位于巩膜与Bruch膜之间,其内层借助Bruch膜与视网膜色素上皮层相连,最外层则为由疏松结缔组织构成的脉络膜上腔与巩膜相连[14-15]。脉络膜作为一种高度血管化的组织,由外向内大致分为血管直径最大的Haller层、血管直径中等的Sattler层和毛细血管层[15]。脉络膜的动脉血管起源于眼动脉的分支睫状后长动脉和睫状后短动脉,是人体内血流速度最快的组织之一,这也反映了脉络膜作为视网膜外层营养来源的重要作用[16]。
脉络膜厚度一般定义为从视网膜上皮层到巩膜与脉络膜交界处之间的厚度[17]。以黄斑中心凹为原点,一般分鼻侧、颞侧、上方和下方4个方位进行观察,其中以黄斑中心凹下脉络膜厚度(subfoveal choroidal thickness, SFCT)的研究最多。一项对中国8~11岁非高度近视儿童脉络膜厚度的研究显示,鼻侧脉络膜较薄,其他3个方位距中心凹2~3 mm处较厚,颞侧最厚[18]。人类青壮年脉络膜的平均厚度为250~350 μm[11],但不同个体之间差异较大,实际脉络膜厚度与眼轴长度(axial length, AL)、屈光度等多种因素有关。
1.2 测量方法
测量脉络膜厚度的技术主要有光学生物测量仪和光学相干断层扫描技术(optical coherence tomography, OCT)。部分研究通过光学眼球生物测量仪如Lenstar测量AL, 将AL作为脉络膜厚度变化的替代指标,主要是基于AL对脉络膜厚度的变化很敏感,与脉络膜厚度呈负相关的假设[19-20]。然而,这种方法的缺陷在于AL还可能受到其他因素变化的影响而发生变化,测量结果的可靠性相对较差。
相较而言,近些年OCT应用较为广泛。随着增强深部成像等新技术的发展,OCT已经可以捕获高分辨率的人类脉络膜图像,从而对脉络膜厚度进行精准测量。然而,目前大多数商用仪器不提供自动分割巩膜与脉络膜界面的工具,需要专业人员对OCT图像进行手动分析。由此近几年已发展了数种自动分割脉络膜并从OCT图像中提取厚度数据的方法。其中,深度学习算法具有分析速度快、准确性高的特点,其应用极大提高了分割脉络膜的效率及准确率[21-23]。然而值得注意的是,由于脉络膜与巩膜边界的对比度通常相对较低,在受到短期刺激后脉络膜变化的幅度通常也较小,大约只有5~30 μm,因此对于自动分割的结果仍然建议进行人工检查校正[24-25]。
对脉络膜血流和灌注量进行测量评估的方法早期有吲哚菁绿血管造影术(indocyanine green angiography, ICGA),其原理是通过吲哚菁绿(ICG)染料与血清蛋白结合,利用近红外波长进行成像[26];但由于这种方法是侵入性的,具有需要静脉注射染料、成像时间较长等缺点[27]。其他包括激光多普勒测速法、激光干涉测量法等二维成像的方法[28],在检测到脉络膜血流信号的同时可能也检测到视网膜的血流,因此用这些方法测量脉络膜血流只能集中于无血管的中央凹部分[29],在临床上应用有限。相比之下,光学相干断层扫描血管造影(optical coherence tomography angiography, OCTA)则是一种无创、快速、高分辨率的成像技术。其利用移动红细胞引起的OCT信号的变化捕获视网膜和脉络膜血管的精细结构细节,可以在不使用染料的情况下对视网膜和脉络膜微血管进行三维体积评估[30]。因此,目前关于脉络膜血流灌注量的绝大多数研究都采用OCTA进行检测。
2. 影响脉络膜厚度的因素
2.1 年龄
大量研究已发现,不考虑屈光不正的影响,脉络膜厚度随着年龄的增加也会发生一定的变化[31-33]。一项前瞻性队列研究发现,在6~9岁儿童中观察到脉络膜厚度变薄[(-9±25)μm],且发生近视的儿童变薄的幅度更大[(-12±25)μm]。而在10~13岁的青少年时期,未发生近视的儿童脉络膜厚度又会大幅度增加[(9±23)μm][32]。脉络膜厚度在青少年时期达到最高峰,而成人时期随着年龄的增长逐渐变薄,有研究发现脉络膜厚度与年龄呈负相关[33]。
2.2 生理变化
研究发现,人类脉络膜的厚度呈现昼夜节律性变化。Brown等[34]报道成人与儿童的脉络膜厚度在24 h内均表现出强劲的昼夜变化,振幅约为25 μm,脉络膜厚度在傍晚增厚,午夜前后达到峰值,而在早晨变薄,中午前后达到最低值[35-36]。
另外,考虑到血流速度与灌注量的影响,有研究发现眼灌注压(ocular perfusion pressure, OPP)与黄斑中心凹下脉络膜厚度呈负相关[37-38]。可能是由于相对较厚的脉络膜需要较低的OPP维持眼血流量。另外,收缩压也与脉络膜厚度呈负相关[38],其具体机制还需要进一步研究。
2.3 屈光状态与轴长
大量研究结果显示,无论对成人或是儿童,近视程度越高,脉络膜厚度越薄[39-41]。在Read等[42]的研究中,非近视成人的中央凹下脉络膜厚度[(271~439)μm]大于高度近视成人的报告值[(96~245)μm],儿童亦然。这一观点在动物实验中也得到了一定的验证,研究者对3种近视豚鼠模型(自发性近视、形觉剥夺性近视和晶状体诱导性近视)进行研究发现,与非近视对照组相比,自发性近视豚鼠的脉络膜厚度和灌注量均减少,形觉剥夺性近视和负性晶状体诱导性近视也有类似发现[43]。AL则与脉络膜厚度呈负相关[44-46],Tan等[47]报道轴长每增加1 mm,脉络膜就会变薄20~60 μm。
2.4 药物影响
阿托品近年来被尝试应用于控制近视的发展,一项对受试儿童施用0.01%质量体积浓度阿托品滴眼液的研究发现,在使用8周后儿童的脉络膜增厚,不同方位脉络膜厚度变化的幅度不同,中心凹下脉络膜厚度增幅最大[48]。然而,Ye等[49]的研究却发现在使用0.01%质量体积浓度阿托品6个月后观察到脉络膜变薄;与之相反,使用1%质量体积浓度的阿托品则可以使脉络膜厚度增加。由此看来,阿托品的浓度以及施用时间似乎影响着最终效应的方向,关于阿托品影响脉络膜厚度以及控制近视的机制仍需要进一步研究。
2.5 光学环境
Ogawa等[50]的研究发现,儿童在加强户外活动1周后观察到其脉络膜厚度增加,与以往增强户外活动、增加暴露于户外光线的时间有益于儿童青少年近视防控[51-52]的研究结果相一致。而人为增加光照暴露似乎也能起到同样的效果,有研究显示,在使用低强度激光治疗后可以观察到脉络膜厚度显著增加[53]。此外,通过使用角膜塑形镜也可以达到使脉络膜增厚的效果[53]。值得注意的是,光照的强度、时间、波长都可能会影响最终脉络膜厚度的变化效果[54-55]。
3. 脉络膜厚度在近视研究中的应用
由于近视屈光度与脉络膜厚度的负相关关系,已有报道提出或许可以通过观察脉络膜厚度的变化判断某种刺激是导致近视还是预防近视,然而这一推论仍有待证实[11]。另外,有研究在使用角膜塑形镜进行治疗时,发现戴镜1个月后脉络膜厚度的变化与12个月后观察到的轴伸长程度相关[56],表明脉络膜的变化先于AL变化,结合脉络膜厚度与屈光状态的关系,脉络膜厚度可能是预测未来近视发展、眼轴伸长重要的生物标志物,同时也能够反映某种临床治疗近视方案的效果。已有报道显示,在近些年的近视临床试验中越来越多地采用了后节段的OCT成像[57],并将脉络膜厚度作为一项结果测量指标,可能将在未来成为近视患者的治疗标准之一。针对脉络膜变化的影响因素,还可以加以探索更多近视防控有效的干预措施,比如环境控制(增加户外活动的时间和适当条件的光暴露[52])以及药物手段进行干预(如阿托品[49])。
4. 存在的问题和未来展望
尽管已有大量研究支持脉络膜厚度这一指标对儿童青少年近视防控有着重要的作用,但仍有一些问题有待解决:首先,在上述研究中观察到的近视屈光度以及AL与脉络膜厚度之间的负向关联是否存在因果关系,还需要大量前瞻性的人群研究加以证实。其次,脉络膜在眼球生长调节中发生作用的具体机制也尚不清楚。再者,针对短期刺激下脉络膜厚度极微小的变化,其测量仍然具有一定的挑战性。由于目前尚无标准化的成像方案,且在测量过程中脉络膜的厚度还可能会受到多种因素的影响,导致不同研究间难以比较,数据的分析解释具有难度。因此,在未来需要研究者设计出科学合理的研究方案,并做到达成统一、公开透明,注意控制混杂因素的影响。
综上所述,脉络膜作为连接巩膜和视网膜的关键部位,其厚度很可能是预测儿童青少年近视发展以及治疗效果的重要生物标志物。由于脉络膜受到生理因素、药物干预、光学环境等多方面的影响,未来有必要采用更科学标准的研究设计及更精确的测量方法对脉络膜在人类、尤其是处于发育中的儿童少年近视发展与治疗防控过程中可能扮演的角色进行进一步的深入研究。
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