HJOHans Journal of Ophthalmology2167-6542Scientific Research Publishing10.12677/HJO.2022.113029HJO-55341HJO20220300000_23894696.pdf医药卫生 角膜屈光术后干眼发病机制及治疗的研究 Study on the Pathogenesis and Treatment of Dry Eye after Corneal Refractive Surgery 思雨21振国31兰州华厦眼科医院,甘肃中医药大学附属眼科中心,甘肃 兰州甘肃中医药大学第一临床医学院(甘肃省人民医院),甘肃 兰州;兰州华厦眼科医院,甘肃中医药大学附属眼科中心,甘肃 兰州null300820221103207214© Copyright 2014 by authors and Scientific Research Publishing Inc. 2014This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

我国是一个近视大国,许多近视患者想摆脱眼镜的困扰选择了屈光手术,角膜屈光术后干眼通常是暂时的,但会造成不规则散光,诱发高阶像差,造成患者术后视觉质量和手术满意度下降。本文就角膜屈光术后干眼的发病机制、治疗研究进展进行综述,以期屈光医师对有干眼症风险的患者采取预防措施,对角膜屈光术后干眼患者治疗提供依据。 My country is a big country of myopia. Many myopia patients choose refractive surgery to get rid of glasses. Dry eye after corneal refractive surgery is usually temporary, but it can cause irregular astigmatism, induce higher order aberrations, and cause decreased postoperative visual quality and surgical satisfaction in patients. This article reviews the research progress on the pathogenesis and treatment of dry eye after corneal refractive surgery, in order to provide a basis for clinicians to take preventive measures for patients at risk of dry eye after corneal refractive surgery.

屈光外科手术,飞秒激光,准分子激光原位角膜磨镶术,干眼,发病机制,治疗, Refractive Surgery Femtosecond Laser Laser in Situ Keratomileusis Dry Eye Pathogenesis Treatment
摘要 - beplay安卓登录

我国是一个近视大国,许多近视患者想摆脱眼镜的困扰选择了屈光手术,角膜屈光术后干眼通常是暂时的,但会造成不规则散光,诱发高阶像差,造成患者术后视觉质量和手术满意度下降。本文就角膜屈光术后干眼的发病机制、治疗研究进展进行综述,以期屈光医师对有干眼症风险的患者采取预防措施,对角膜屈光术后干眼患者治疗提供依据。

关键词

屈光外科手术,飞秒激光,准分子激光原位角膜磨镶术,干眼,发病机制,治疗

Study on the Pathogenesis and Treatment of Dry Eye after Corneal Refractive Surgery<sup> </sup>

Siyu Zheng1,2, Zhenguo Yan2

1The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, Gansu

2Lanzhou Huaxia Eye Hospital, Affiliated Eye Center of Gansu University of Chinese Medicine, Lanzhou, Gansu

Received: Jul. 25th, 2022; accepted: Aug. 19th, 2022; published: Aug. 30th, 2022

ABSTRACT

My country is a big country of myopia. Many myopia patients choose refractive surgery to get rid of glasses. Dry eye after corneal refractive surgery is usually temporary, but it can cause irregular astigmatism, induce higher order aberrations, and cause decreased postoperative visual quality and surgical satisfaction in patients. This article reviews the research progress on the pathogenesis and treatment of dry eye after corneal refractive surgery, in order to provide a basis for clinicians to take preventive measures for patients at risk of dry eye after corneal refractive surgery.

Keywords:Refractive Surgery, Femtosecond Laser, Laser in Situ Keratomileusis, Dry Eye, Pathogenesis, Treatment

Copyright © 2022 by author(s) and beplay安卓登录

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

近视是我国面临的一个严重的公共卫生问题,越来越多近视患者选择屈光手术来进行视力矫正,从传统的放射状角膜切开术(Radial Keratotomy, RK)、准分子激光角膜切削术(Photorefractive Keratectomy, PRK)、准分子激光原位角膜磨镶术(Laser in Situ Keratomileusis, LASIK),到最新技术的飞秒激光辅助下准分子激光原位角膜磨镶术(femtosecond Laser-Assisted Laser in Situ Keratomileusis, FS-LASIK)、飞秒激光小切口基质透镜取出术(Small Incision Lenticule Extraction, SMILE),设计越微创,对角膜和泪膜稳定影响越小,从而术后干眼发病率越小 [1]。干眼是屈光性角膜手术后的早期并发症之一,据报道显示手术相关性干眼大多出现在术后1月,LASIK术后第1天、1周和1月分别有94.8%、85.4%和59.4%的患者出现干眼症状,通常在术后6至9个月内消失 [2]。飞秒激光的应用彻底进一步提高了安全性和视觉效果。FS-LASIK是将飞秒激光应用于LASIK,利用飞秒制瓣,可减少皮瓣相关并发症和干眼症状 [3]。SMILE的无瓣技术使术后反应和干眼症状更轻 [4]。角膜屈光术后干眼机制复杂,与手术中角膜神经损伤、角膜知觉和敏感度改变、角膜形态学改变、结膜杯状细胞受损、角膜修复的炎症反应、术后用药等有关 [1] [5] [6]。目前,治疗术后干眼症主要方法为术后应用人工泪液、抗生素、糖皮质激素、神经营养因子(Nerve Growth Factor, NGF) [7]、自体血清、免疫抑制剂等 [6] [8],还有热敷 [9]、泪点栓塞、强脉冲光(Intense Pulsed Light, IPL)治疗 [10] 等。干眼作为角膜屈光术后早期常见的并发症之一,有必要就其发病机制和治疗研究进行讨论。

2. 角膜屈光术后干眼的发病机制 2.1. 术前泪膜不稳定

虽然几乎所有患者在手术后都会出现短暂的泪膜稳定性下降,但已有干眼的患者发生更严重或长期眼表疾病的风险显著增加。术前患有慢性干眼症的患者基础泪液分泌量的减少、眼表生理平衡本遭到破坏,加之手术损伤,术后上皮细胞修复、泪膜稳定性及眼表动态平衡恢复速度较术前无干眼症的患者更慢 [11]。因此,对患者眼表进行仔细术前评估对于确保手术成功至关重要。

2.2. 角膜神经受损、敏感度下降

LASIK、FS-LASIK会切断角膜神经,造成泪液分泌功能失调、角膜敏感性降低,后者会导致患者瞬目减少,睑板腺分泌减少,眼表干燥增加,从而导致泪液高渗,上述机制共同作用使术后干眼患病率增加。Eydelman M [12] 研究发现有28%的患者在接受LASIK和FS-LASIK术后3个月出现干眼症状。SMLIE无需制瓣,而且大约2 mm的微切口对角膜神经受累少,而更少的神经截断不仅保留了更多的神经,还保留了更多的施万细胞。施万细胞可以使轴突功能得到维持,使轴突再生得到保证,为神经再生提供了更有利的微环境 [13] [14] [15]。SMILE对角膜基质影响也小,角膜神经释放神经介质以维持角膜细胞的健康和完整性,而角膜细胞反过来释放生长因子和细胞因子以维持角膜神经的健康和再生 [16]。Demirok等 [17] 比较了LASIK和SMILE术后的中央角膜感觉发现SMILE和LASIK术后1周、1个月和3个月的平均中央角膜感觉较术前降低,然而,SMILE组在所有时间点的中央角膜感觉显著高于LASIK组。即使在术后4.1年,LASIK眼的角膜神经纤维分支密度、长度仍显著低于SMILE眼,两组差异在高度近视治疗中更为显著 [18]。

2.3. 角膜屈光术后炎症反应增加

角膜伤口愈合通过前列腺素和细胞因子介导的途径进行,这一过程也促进角膜细胞凋亡和炎症细胞的募集。包括基质金属蛋白酶(Matrix Metalloproteinase, MMP)-9被释放,MMP-9可破坏泪膜的稳定性,破坏角膜的屏障功能。角膜的感觉神经释放神经肽、P物质和降钙素基因相关肽(Calcitonin Gene-Related Peptide, CGRP)进一步增强了这种炎症反应,对角膜缘血管系统的促炎作用也破坏泪膜的稳定性 [11]。白细胞介素-6 (Interleukin-6, IL-6)是一种由角膜内皮细胞合成的促炎症细胞因子,在角膜屈光术后干眼患者泪液中可检测到IL-6浓度上调。在术后第1周和1月检测SMILE组的IL-6水平低于FS-LASIK组,且SMILE组术后IL-6水平恢复到术前的速度更快 [19]。与SMILE相比,LASIK术后1周时白细胞迁移和伤口愈合、体液免疫反应和细胞凋亡显著上升,泪液黏蛋白样和P物质水平存在显著差异 [20]。与角膜快速神经恢复还有NGF的参与,肿瘤坏死因子-α (Tumor Necrosis Factor α, TNF-α)和细胞间粘附分子-1在内的其他炎症因子也能在角膜屈光术后干眼患者泪液中检测到 [21] [22]。炎症在角膜屈光术后干眼中的作用仍需更多的证据来支持。

2.4. 角膜屈光术后角膜形态学改变

角膜屈光手术会使角膜形态变薄、变形,角膜曲率和平滑度的变化可能会改变角膜和眼睑之间的作用力,增加相互间的摩擦,导致泪膜不稳定 [23]。与SMILE相比,LASIK在矫正高度近视中对角膜基质层和角膜神经的影响更大,对角膜形态的影响也更大,因此在角膜表面规则性指数的评估上SMILE更具优势 [24],更能保持角膜生物学的稳定 [25]。

2.5. 其他机制

术中负压环吸引会导致结膜杯状细胞受损,使其黏蛋白分泌减少,这也会导致角膜屈光术后干眼的发生。术后干眼的发生也与术后用药有关,其机制是大部分滴眼液有防腐剂(苯扎氯铵和三叔氯丁醇),防腐剂会诱导的毒性角膜上皮病,苯扎氯铵可溶解脂质层,从而增加泪液蒸发并造成泪膜不稳定 [11]。此外,它还导致结膜杯状细胞和微绒毛破坏,破坏上皮紧密连接,增加细胞的通透性,使上皮细胞受损,进一步促进术后干眼的发生。

3. 角膜屈光术后干眼的治疗 3.1. 一般注意事项

对术后干眼的高危人群的眼表进行合理的评估和管理,术前对患者进行睑缘清洁、热敷和睑板腺按摩,选择合适的手术方式,对慢性干眼症的患者不做或缓做手术,给予适当的治疗,若不能控制可选择对角膜影响最小的晶体植入手术,同时避免高危因素 [11]。术中操作轻柔,避免过多干扰眼表。在结膜囊冲洗时和负压吸引前各点1次盐酸奥布卡因进行表面麻醉,达到麻醉效果即可,避免频繁使用表面麻醉药。控制负压吸引的时间,术者需避免角膜表面过多水分以尽快而准确中心定位,同时嘱咐患者消除紧张情绪保持良好固视,这也可以减少术中负压环失吸的风险 [26]。角膜屈光术后干眼某种定义来说可称为“神经性干眼”,一部分患者也与全身的疾病有关,对这些患者进行共病的管理和全身系统治疗很重要 [27]。

3.2. 泪液补充剂

人工泪液是干眼治疗的常规药物,尤其适用于水液缺乏型干眼,慢性干眼的患者长期用药时使用不含防腐剂的眼药更佳。玻璃酸钠是常用的人工泪液之一,玻璃酸钠具有良好的保水和润滑作用,能促进上皮恢复,还可以与纤维蛋白结合,在角膜形成一层保护膜,加速上皮细胞的黏附和延展,促进角膜修复,稳定泪膜 [28] [29]。这与权菊玲 [30] 等研究提出的观点一致。且浓度越高,效果越好,郑晓红等研究发现0.3%玻璃酸钠较0.1%的更能显著改善FS-LASIK术后轻度干眼患者眼表疾病指数(Ocular Surface Disease Index, OSDI)、角膜染色情况 [28]。聂惠玲 [31] 等研究提出术前应用人工泪液也可有助于减少近视激光术后干眼症的症状,使患者角膜表面更加平滑,提高干眼症患者的视觉成像质量。

地夸磷索钠(P2Y2受体激动剂)和瑞巴派特是另外两种泪液补充剂 [32],两者都可上调角膜和结膜粘蛋白的生成和分泌,增加结膜杯状细胞,并在体内改善角膜和结膜的损伤,也有助于干眼患者浅层点状角膜病变,同时也可以降低炎性细胞因子的浓度 [32] [33]。地夸磷索钠和玻璃酸钠联合治疗更能改善LASIK术后的视觉质量、缓解术后干眼症状 [34]。

3.3. 局部抗炎药物

炎症反应参与角膜屈光术后干眼的发生,因此应用局部抗炎症药物是重要的治疗方法之一,抗炎症药物可抑制细胞因子介导的眼表炎症反应,改善泪膜质量,促进眼表修复,使杯状细胞密度增加,加速角膜知觉的恢复。糖皮质激素滴眼液虽可有效缓解角膜屈光术后干眼的症状,但需注意的是不要长期频繁使用,会导致眼压升高、诱发白内障等,因此需要严格控制用药频率、监测有无并发症的发生 [35]。

局部使用环孢素A在屈光手术后干眼治疗中具有重要作用,可以通过阻止T细胞活化和炎性细胞因子的产生发挥作用,也可调节黏蛋白的合成与分泌,达到抑制结膜杯状细胞和泪腺细胞的凋亡 [36]。尤其适用于慢性、难治性干眼症患者,角膜屈光术后应用环孢素A可使患者干眼症状得到有效控制,也使患者获得更好的屈光效果。

3.4. 神经生长因子

NGF在神经的发育、分化和再生中起着至关重要的作用 [5],NGF由各种角膜细胞合成和分泌,包括上皮细胞、内皮细胞等,并可被感觉神经末梢吸收,促进神经再生 [37]。局部重组NGF治疗可促进机械性角膜神经损伤后的角膜再神经支配。神经生长因子包括纳曲酮、纤维连接蛋白、P物质衍生肽、FGLM酰胺和IGF-1等,但这些NGF需要进一步的研究和开发才能用于临床实践。一项研究提出与传统疗法相比,富含生长因子血浆(PRGF)滴眼液对LASIK手术患者的干眼症状的改善更有效,PRGF可作为角膜屈光术后干眼患者的一种替代方法 [7],研究证实PRGF应用于蒸发性干眼症、持续性上皮缺损或难治性眼表疾病 [38] [39]。重组牛碱性成纤维细胞生长细胞因子(Recombinant Bovine Basic Fibroblasts Growth Factor, rb-bFGF)是一种源自于中胚层和外胚层细胞的细胞生长因子,具有促进组织修复和再生的功能,联合羟糖苷能够上调转化生长因子-β1 (TGF-β1)表达,降低IL-16表达,抑制眼表炎症反应,缓解眼部干涩症状 [40]。NGF虽可以加速LASIK手术后角膜敏感性的恢复,尽管在临床试验中取得了令人鼓舞的结果,但不具有成本效益,因此其在临床上使用受到限制 [41]。

3.5. 维生素D3、脂肪酸等口服药物

林颖 [42] 等研究得出维生素D3可以改善LASIK术后干眼的症状,降低OSDI评分。研究表明维生素D3可调节包括角膜上皮细胞在内的各种细胞中各种炎性细胞因子的表达,在免疫系统中起着重要的免疫调节作用 [43],能降低细胞炎症因子如IL-17、IL-21水平,最终达到稳定泪膜的作用。有研究表明口服Omega-3脂肪酸,如二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)以及植物源5-氨基乙酰丙酸(ALA)可改善干眼症状 [44]。

3.6. 自体血清

含有生长因子和抗炎介质的自体血清也有益于角膜屈光术后干眼的患者 [45]。自体血清中的血小板提供的生长因子有利于眼表组织再生。包括自体血清在内的血液衍生物由于其加速组织愈合的潜力使再生医学引起许多研究者的兴趣 [46]。

3.7. 物理治疗

术前、术后对有干眼症状的患者都可进行热敷和睑板腺按摩治疗。热敷可暂时增加角膜屈光手术后干眼患者的泪膜厚度和稳定性,减少不完全眨眼,增强睑板腺功能 [9]。对于睑板腺功能障碍(Meibomian Gland Dysfunction, MGD)的干眼患者,热敷辅以外用抗生素覆盖是一种有效的治疗方法 [47]。对于难治性或慢性的MGD患者,可使用较新的方法IPL [48],IPL通过光热作用封闭睑缘扩张的毛细血管,使炎症介质分泌减少,同时熔解睑板腺脂质,疏通睑板腺管道,还可以杀死螨虫。IPL联合睑板腺按摩、睑板腺探通术治疗在临床上可应用 [49]。泪点栓塞除了改善眼表外,还可以通过影响泪膜的曲率、表面张力、体积和动力学来提高视力和视觉质量,减少低阶和高阶像差。有研究得出LASIK术后泪点栓塞可以最大限度地减少人工泪液的使用,提高患者满意度 [50]。有研究证明对干眼的患者针灸可以刺激自主神经和免疫系统,刺激泪腺功能从而增加泪液分泌,也可增加免疫蛋白的合成,针灸治疗干眼综合征的有效性、安全性得到证实 [51]。

4. 总结

干眼是角膜屈光术后早期常见的并发症之一,其发病机制复杂,包括术前眼表环境失衡、术后角膜神经受损、角膜敏感度下降、炎症反应增加、角膜形态学变化,其他发病机制仍需进一步证实。角膜屈光术后干眼的治疗除常规眼表管理和治疗外,新的药物和物理治疗方法不断在临床上推广应用,对干眼患者的评估和治疗需得到每一位屈光医师的重视。

文章引用

郑思雨,燕振国. 角膜屈光术后干眼发病机制及治疗的研究Study on the Pathogenesis and Treatment of Dry Eye after Corneal Refractive Surgery[J]. 眼科学, 2022, 11(03): 207-214. https://doi.org/10.12677/HJO.2022.113029

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