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肥厚型脉络膜谱系疾病与脉络膜、涡静脉、巩膜改变的研究进展

Research progress of pachychoroid disease spectrum and changes in the choroid, vortex veins and sclera

来源期刊: 眼科学报 | 2023年10月 第38卷 第10期 693-699 发布时间:2023-10-15 收稿时间:2024/2/18 15:37:25 阅读量:3205
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关键词:
肥厚型脉络膜谱系疾病脉络膜涡静脉巩膜综述
pachychoroid disease spectrum choroid vortex vein sclera review
DOI:
10.12419/2308010001
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肥厚型脉络膜谱系疾病(pachychoroid disease spectrum,PCD)包括肥厚型脉络膜色素上皮病变(pachychoroid pigment epitheliopathy,PPE)、中心性浆液性脉络膜视网膜病变(central serous chorioretinopathy,CSC)、肥厚型脉络膜新生血管病变(pachychoroid neovasculopathy,PNV)、息肉样脉络膜血管病变(polypoidal choroidal vasculopathy,PCV)、局灶性脉络膜凹陷(focal choroidal excavation,FCE)和盘周肥厚型脉络膜综合征(peripapillary pachychoroid syndrome,PPS)。有学者将PCD看作脉络膜功能障碍引发的一系列连续疾病过程,但关于PCD的发病机制、形态改变尚未明确。该文对PCD的脉络膜、涡静脉及巩膜相关改变做一综述。

Pachychoroid disease spectrum include pachychoroid pigment epitheliopathy, central serous chorioretinopathy, pachychoroid neovasculopathy, polypoidal choroidal vasculopathy, focal choroidal excavation, and peripapillary pachychoroid syndrome. Currently, some scholars regard pachychoroid disease spectrum as a series of continuous disease processes caused by choroidal dysfunction, but the pathogenesis and morphological changes of pachychoroid disease spectrum are not yet clear. This paper reviews the changes of choroid, vortex veins and sclera in pachychoroid disease spectrum.

肥厚型脉络膜最初由Warrow等[1]于2013年首次提出,用于描述肥厚型脉络膜色素上皮病变(pachychoroid pigment epitheliopathy,PPE)。后续学者提出“肥厚型脉络膜谱系疾病”(pachychoroid disease spectrum,PCD)的概念,包括PPE、中心性浆液性脉络膜视网膜病变(central serous chorioretinopathy,CSC)、肥厚型脉络膜新生血管病变(pachychoroid neovasculopathy,PNV)、息肉样脉络膜血管病变(polypoidal choroidal vasculopathy,PCV)、局灶性脉络膜凹陷(focal choroidal excavation,FCE)和盘周肥厚型脉络膜综合征(peripapillary pachychoroid syndrome,PPS)[2-3]。PCD的主要特征是脉络膜大血管层(Haller层)扩张导致脉络膜增厚,伴有毛细血管层(Ruysch层)和中血管层(Sattler层)变薄,伴视网膜色素上皮层(retinal pigment epithelium,RPE)改变[1, 4]。目前有学者将PCD看作脉络膜功能障碍引发的一系列连续疾病过程,但关于PCD的发病机制、形态改变尚未明确,现对PCD与脉络膜、涡静脉及巩膜的相关改变做一综述[5]

1 PCD的脉络膜改变

PCD的特征之一是脉络膜病理性增厚,中心凹下脉络膜厚度(subfoveal choroidal thickness,SFCT)>300 μm时为病理性脉络膜增厚[6]。脉络膜厚度增加被认为是Haller层扩张导致。在CSC、PCV、FCE、PPS中均观察到脉络膜血管直径增加[7]。在空间上,脉络膜最厚处的位置与扩张的脉络膜血管和RPE及视网膜内病灶位置相关。近期有研究表明,脉络膜厚度的增加不是定义PCD的最重要标准,脉络膜结构和功能的改变更为重要,如Haller层扩张、脉络膜毛细血管层萎缩、脉络膜血管指数(choroidal vascularity index,CVI)增加、脉络膜高通透性(choroidal vascular hyperpermeability,CVH)[8-10]。脉络膜静脉超负荷引起脉络膜腔内压升高,脉络膜扩张且通透性增高。同时脉络膜静水压升高,导致液体从脉络膜毛细血管或者大脉络膜血管外渗到周围脉络膜,出现脉络膜毛细血管血流障碍。

1.1 脉络膜增厚

脉络膜厚度增加是PCD的特征改变之一,可通过光学相干断层扫描(optical coherence tomography,OCT)测量Bruch膜内表面到脉络膜-巩膜交界处之间的垂直距离,定量分析脉络膜厚度,但值得注意的是脉络膜厚度易受多种因素的影响,如年龄、眼轴、屈光不正、血压、昼夜节律等,目前PCD的脉络膜厚度参数尚无明确阈值。PCD也可表现为SFCT正常,中央凹外脉络膜厚度增加,即SFCT超过50 μm[6]。与正常对照组相比,急性及慢性CSC的SFCT均显著增加,病程较长的患者可观察到视网膜厚度和体积的减少[11]。Meng等[12]通过超广角扫描源光学相干断层扫描血管造影(wide-field swept-source optical coherence tomography angiography, WF SS-OCTA)关注CSC患眼周围区域脉络膜改变,发现与单眼CSC患者的健眼相比,CSC患眼的中央区及鼻下区的脉络膜厚度显著增高,CSC患眼和健眼各个方向的脉络膜厚度均大于正常对照组。近期有学者发现PCV的SFCT呈现双峰分布,分别在195 μm和285 μm处各有一个峰值,并提出以225 μm为分界点将PCV划分为厚脉络膜型和薄脉络膜型[13]。Lee等[4]的研究表明,薄脉络膜型PCV表现为息肉状病灶处脉络膜增厚,即中央凹外脉络膜增厚,且Haller层扩张,Ruysch层和Sattler层变薄,仍支持薄脉络膜型PCV属于厚脉络膜疾病。Chang等[14]认为,SFCT是PCV患者进行抗血管内皮生长因子(vascular endothelial growth factor, VEGF)治疗效果的唯一影响因素,厚脉络膜型PCV组患者较年轻,湿性年龄相关性黄斑变性(neovascular age-related macular degeneration,nAMD)样特征较少,CSC样特征较多,对抗VEGF治疗反应较差。

1.2 CVI增加

CVI定义为脉络膜管腔面积占脉络膜总面积的比值,CVI升高提示血管成分增加,是显示脉络膜充血的参数,与SFCT相比,CVI表现出较小的变异性,是更为可靠的生物标志物[15-16]。CVI可作为早期诊断的有效指标,CVI降低可评估激光光凝或光动力治疗的有效性,脉络膜高反射灶(hyper reflective foci,HRF)与CVI正相关,亦可预测PCV的复发[17-19]。Shen等[20]研究发现,在初治型PCV中,色素上皮脱离(pigment epithelial detachments,PEDs)体积的减少和治疗前后平均脉络膜厚度的减少与CVI的增加相关。PCV经抗VEGF治疗后CVI下降,而PCV复发时,CVI再次升高至基线水平,治疗控制后再次下降[21]。Kim等[22]发现,相对于急性CSC、无新生血管的慢性CSC,慢性新生血管性CSC组的CVI显著降低,提出CVI降低可能反映CSC形成新生血管。CSC中CVI分布存在区域差异,黄斑区CVI最低,鼻侧及另眼的CVI较高[23]。近期有学者提出三维CVI(three-dimensional CVI,3D CVI)可更好评估脉络膜脉管系统的血管成分,实现脉络膜的三维可视化[24]。CSC中3D-CVI在后极部及沿扩张的涡静脉引流路径显著增高,与SFCT呈正相关,表明涡静脉阻滞可能是CSC的发病机制。

1.3 脉络膜通透性增高

Nishi等[25]从伯努利流体力学原理角度从理论上验证提出CVH是PCD原发病变,认为PCD中脉络膜毛细血管血流速度降低的同时血压升高,产生厚静脉。CVH是提示脉络膜充血的指标,可作为PCD疾病发展的诊断线索和预测指标,如预测复发,与PCD更差的视力预后相关[18, 26]。多模式成像发现,近红外自发荧光(near-infrared autofluorescence,NIRAF)成像显示的低自发荧光区域,尤其在二值化处理后,与CVH位点十分吻合[27]。Yagi等[29]提出CVH是PPE进展为CSC的重要危险因素[28]。然而Ersoz等[10]研究发现,PPE与CSC的CVH比较差异无统计学意义。CVH是CSC患者并发CNV的危险因素。Jeong等[30]通过超广角吲哚菁绿血管造影(ultra-wide field indocyanine green angiography,UWF ICGA)研究发现,相对于正常对照组和单眼CSC患者的健眼,CSC患眼中呈现CVH的面积更大,CVH与涡静脉扩张和SFCT相关。Ramtohul等[31]通过UWF ICGA研究发现,CSC的CVH区域与UWF OCT上脉络膜增厚区域重叠。与无CVH型PCV相比,CVH型PCV者更可能有CSC病史,CVI更大,SFCT更厚,复发间隔时间延长,联合治疗的注射抗VEGF次数更少,视力预后更好[32-33]

1.4 脉络膜毛细血管改变

与正常眼相比,PPE患眼脉络膜毛细血管密度(vascular density of the choriocapillaris,VDcc)降低,脉络膜毛细血管信号缺失灶面积增加,脉络膜毛细血管信号缺失灶与厚血管区域重叠,即PCD早期便表现出脉络膜毛细血管血流障碍,下层的厚血管影响脉络膜毛细血管的灌注[34]。Matet等[35]通过OCTA发现,CSC患眼中的脉络膜毛细血管流空灶与脉络膜毛细血管变薄和Haller层扩张区域一致,且流空灶面积与年龄、CSC持续时间、严重程度呈正比。Meng等[12]发现,单眼CSC患眼的双眼中央区域VDcc较正常对照组增加,且单眼CSC健眼的中央区域VDcc最大。

1.5 脉络膜超负荷

Spaide等[36]提出眼静脉流出控制涉及Starling效应,而CSC患眼中涡静脉壶腹部的Starling效应异常,壶腹部的静脉流出阻力增加从而影响静脉流出,导致局部脉络膜血管充盈缺损,提出脉络膜静脉超负荷的概念,认为脉络膜静脉超负荷引起脉络膜腔内压升高,脉络膜毛细血管通透性增高,导致RPE层血-视网膜外屏障受损,随后液体通过RPE缺损处流向视网膜下间隙。Brinks等[37]提出脉络膜动静脉吻合是引起脉络膜超负荷的潜在机制。脉络膜动静脉吻合绕过毛细血管床,缺少毛细血管对血压的缓冲作用,脉络膜动脉血流直接充盈静脉,涡静脉充血肥厚,导致脉络膜超负荷。

1.6 PCD的脉络膜改变差异

脉络膜增厚、CVI增加、脉络膜通透性增高、脉络膜毛细血管改变及脉络膜超负荷是PCD脉络膜改变的常见特征。在PCD各疾病中脉络膜改变亦存在差异。研究发现,CSC患眼的SFCT值最高、其次是PNV和PCV患眼[38]。在厚脉络膜型PCV中厚静脉表现为局限性,在CSC和厚脉络膜型PCV患者中厚静脉呈现弥漫性[39]。CSC的CVI最高,其次为PPE,PCV的CVI最低,表明各疾病具有不同的血管结构特征[40]。VDcc升高和Sattler层血管密度降低是PCV的独立危险因素,Haller层血管密度升高是CSC的独立危险因素[41]

2 PCD的涡静脉改变

正常人眼中涡静脉壶腹位于赤道部,呈相对对称的四个象限分布,涡静脉向后极部走形逐渐变细,形成功能独立的分水岭,而PCD中涡静脉充血,涡间静脉吻合广泛存在,上涡静脉和下涡静脉吻合跨越分水岭,将血液从超负荷的涡静脉象限分流到相邻的涡静脉象限,形成新的引流途径缓解脉络膜充血。涡静脉瘀滞导致脉络膜毛细血管充盈延迟,出现脉络膜增厚,脉络膜毛细血管闭塞,继发脉络膜新生血管(choroidal neovascularization,CNV)形成。Matsumoto等[42]研究发现,PCD的SFCT与涡静脉面积、涡静脉平均直径相关,PCD的涡静脉吻合率高于对照组,提出在PCD的疾病进展中通过建立涡静脉吻合引流途径补偿脉络膜充血,涡静脉面积、平均直径及SFCT可作为评估脉络膜充血程度的指标。

2.1 涡静脉扩张充血

Kishi等[43]研究发现,在急性CSC中脉络膜毛细血管充盈部位与涡静脉扩张区明显重叠,表明涡静脉充血扩张和脉络膜毛细血管血液流动延迟导致脉络膜增厚。Ishikura等[44]通过UWF SS-OCT观察CSC患眼周边脉络膜形态及厚度,发现CSC导致的脉络膜增厚不仅表现在中心凹,周边脉络膜也明显增厚,且沿扩张的涡静脉走行分布,为涡静脉血流瘀滞或脉络膜超负荷参与CSC发病机制提供依据。Chung等[45]通过ICGA研究发现PCV较正常对照组中更易出现涡静脉充血,且脉络膜增厚与脉络膜血管通透性相关,Jeong等[46]通过UWF ICGA也得出相同结论,表明涡静脉充血参与PCV的发病机制。通过ICGA研究发现,PNV的新生血管形成区域与脉络膜毛细血管充盈延迟区域重叠,表明继发于涡静脉充血的慢性脉络膜毛细血管缺血参与PNV的发生、发展[47]

2.2 优势涡静脉

若扩张的涡静脉从壶腹部延伸至中心凹水平线之外,并累及整个黄斑或后极,则判断上下涡静脉不对称,扩张的涡静脉壶腹所在一侧称优势侧,对侧为非优势侧[44]。Hirooka等[48]研究发现,PCD中不对称扩张的涡静脉血流速度明显慢于另一侧的涡静脉,提示不对称扩张的涡静脉充血。有学者发现CSC和PPE患眼均存在不对称的优势涡静脉,提出不对称优势涡静脉是PCD的诱发因素,优势涡静脉充血导致黄斑区脉络膜毛细血管通透性增高[49]

2.3 涡静脉吻合

Matsumoto等[38]比较PCD各疾病中上下涡静脉吻合率,研究发现在PCD中发现超过90%存在涡静脉吻合,吻合血管显示扩张和高通透性,PCV的涡静脉吻合率高于CSC,认为PCV患者年龄较大,长期的涡静脉充血是PCV患眼吻合率高的原因,同时发现CSC的SFCT最大,PNV次之,最后是PCV,表明涡静脉吻合可重塑新的脉络膜引流途径补偿脉络膜充血。存在涡静脉吻合的CSC患眼CVI高于无涡静脉吻合的CSC患眼[50]

2.4 涡静脉搏动

Matsumoto等[51]研究PCD患者的ICGA视频发现,25.8%患眼中可见涡静脉搏动,且搏动的涡静脉与涡静脉吻合处相连。研究者认为出现在原先水平分水岭的涡静脉吻合口是涡静脉充血状态下扩张的血管,当脉络膜静脉血流流入涡静脉时,若涡静脉充血,流入壶腹部的血流通过吻合处逆行流入相邻象限,涡静脉搏动是原引流途径的血压和来自充血涡静脉血流逆行压力共同作用的结果。搏动性PCV的特征为患者就诊时年龄较小、存在出血倾向(尤其是广泛出血),搏动的加强和延长可能与PCV患者视网膜下出血增加相关[52-53]

2.5 涡静脉血流动力学改变

李青楠等[54]通过彩色多普勒超声研究PCV患眼的血流动力学改变,发现患眼的涡静脉血流速度、视网膜中央动脉及睫状后短动脉收缩期峰值流速(peak systolic velocity,PSV)低于正常对照组,视网膜中央动脉阻力指数(resistance index,RI)高于正常对照组,睫状后短动脉的PSV和涡静脉血流速度与SFCT、CVI呈负相关,与VDcc呈正相关,睫状后短动脉的舒张末期血流速度(end-diastolic velocity,EDV)与SFCT呈负相关,表明PCV患眼的脉络膜增厚、脉络膜大血管层扩张、脉络膜毛细血管萎缩缺血与脉络膜血液回流障碍、血流速度降低、循环阻力增加等血流动力学改变相关。Kilic等[55]研究发现CSC患眼的眼动脉(ophthalmic artery,OA)的PSV和EDV较低,而OA的RI无明显改变,并且睫状后短动脉的PSV和EDV与SFCT呈负相关,提示CSC患者的眼循环功能障碍。

2.6 PCD的涡静脉改变差异

涡静脉扩张充血、优势涡静脉、涡静脉吻合、涡静脉搏动及涡静脉血流动力学改变是PCD涡静脉改变的常见特征。长期涡静脉充血扩张可能导致PCD的发展,脉络膜充血可通过涡静脉吻合形成新的引流途径来补偿。在PCD各疾病中涡静脉改变亦存在差异。研究发现,PCV患者的涡静脉吻合率高于CSC患者[38]。PPS的涡静脉吻合位于视盘周围, CSC和PNV的涡静脉吻合位于黄斑区[36, 56]

3 PCD的巩膜改变

脉络膜静脉循环主要经涡静脉引流,涡静脉以一斜角经巩膜流出,长度可达4 mm,经眼上静脉、眼下静脉回流至海绵窦。巩膜由致密交错的胶原纤维组成,巩膜的厚度改变可能会影响涡静脉的血流动力学,巩膜增厚可机械性阻塞涡静脉血流流出,增加血流阻力,表现出涡静脉血流瘀滞、脉络膜扩张充血。研究发现,在高度近视伴巩膜变薄的情况下较少发生CSC,眼轴较短的CSC中更易出现不对称扩张的涡静脉,而在巩膜较厚的真性小眼球中可发生葡萄膜渗漏,有学者提出巩膜增厚可能是PCD的发病机制之一,与葡萄膜渗漏综合征的发病机制重叠[57-59]
目前OCT对巩膜后界的检出有较为严苛的条件限制,如屈光度应偏向负值、眼轴需较长、脉络膜厚度需较薄,多用于研究高度近视患者的后极部巩膜厚度改变,故无法通过OCT直接测量PCD的后极部巩膜厚度,只能由前段巩膜厚度推测后极部巩膜的改变情况[60]。多项研究利用眼前段光学相干断层扫描(anterior segment OCT,AS-OCT)等检查手段聚焦PCD中前段巩膜厚度的改变[58]。近期研究者发现,CSC和PNV患眼的前段巩膜厚度大于正常对照组,提出厚巩膜可能是PCD发病机制之一,认为厚巩膜可导致脉络膜管腔成分改变[61-62]
Lee等[63]通过增强深度扫描OCT(enhanced-depth imaging OCT,EDI-OCT)和AS-OCT定量测量SFCT和前段巩膜厚度,发现CSC患眼SFCT和巩膜厚度大于正常对照组,且SFCT与巩膜厚度呈正相关,进一步证实巩膜可能通过影响脉络膜静脉的流出阻力而参与CSC的发病机制。Spaide等[64]通过20 MHz同心相控阵超声装置和EDI-OCT测量了CSC患者的后极部和赤道部的巩膜厚度发现, CSC患者的后极部和赤道部巩膜厚度均较对照组增厚,且SFCT和赤道部及后极部巩膜厚度是CSC独立的预测因素,赤道部巩膜厚度(而非后极部巩膜厚度)是SFCT的重要预测因素。赤道部及后极部巩膜厚度是两个独立的预测因子,赤道部巩膜厚度与SFCT相关,而后极部巩膜厚度与SFCT无关,提示两个位置的巩膜可能通过不同的机制影响CSC的病理生理,证实了巩膜厚度参与静脉超负荷理论导致PCD形成。Venkatesh等[65]对一例慢性CSC患者用丝裂霉素C切除部分巩膜,患者渗出性视网膜脱离消退,视力提高,从另一方面证明巩膜厚度增加可能参与CSC的发病机制。
巩膜厚度增加可能导致涡静脉血流流出阻力增加,导致涡静脉扩张充血,进而继发脉络膜静脉超负荷出现脉络膜增厚,导致PCD的发生、发展。此外巩膜厚度增加可能影响巩膜导水管排出障碍,液体不仅积聚在脉络膜,同时也积聚在脉络膜上腔,进一步增加脉络膜血管压力导致脉络膜通透性增高。目前PCD巩膜相关改变的研究仅限于CSC和PNV,其他PCD疾病的巩膜改变仍需进一步探索。

4 结语

本文对PCD中脉络膜、涡静脉和巩膜的改变进行综述,阐释了其参与PCD发病机制,但完善的发病机制尚待进一步揭示。脉络膜厚度增加不一定是定义PCD的最重要标准,PCD中巩膜厚度增加、涡静脉血流瘀滞和脉络膜扩张充血间的动态关联需要进一步的研究探索,是否能通过改变巩膜厚度从而改善PCD病情发展,可作为未来的一个研究方向。

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1、白求恩?朗沐中青年眼科科研基金(BJ-LM2021014J);广州市科技计划项目 (SL2022A03J00452)。
This work was supported by the Bethune·Lumitin Research Funding for the young and middle-aged Ophthalmologists, China (BJ-LM2021014J) and the Science and Technology Program of Guangzhou, China (SL2022A03J00452).()
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