糖尿病患者白内障围手术期管理及术后并发症的研究进展
Advances in Perioperative Management of Cataract and Postoperative Complications in Patients with Diabetes Mellitus
摘要: 糖尿病是世界上发病率和死亡率最高的疾病之一,到2030年,糖尿病总患病率估计为世界人口的4.4%,在欧洲为8.5%。糖尿病可影响所有眼部结构,其中白内障是最常见的眼部并发症。白内障是全世界致盲的主要原因。由于各种机制,糖尿病患者的白内障发生率远高于非糖尿病人群,而白内障手术是解决问题的唯一途径。随着技术的进步,白内障手术已非常成熟及安全,但术后仍存在发生影响视力预后的并发症的风险。本文拟就糖尿病患者白内障手术围手术期管理、术后并发症的类型及治疗的研究进展作一综述。
Abstract: Diabetes is one of the most prevalent diseases in the world in terms of morbidity and mortality, with the overall prevalence of diabetes estimated to be 4.4% of the world’s population by 2030 and 8.5% in Europe. Diabetes can affect all ocular structures, with cataracts being the most common ocular complication. Cataract is the leading cause of blindness worldwide. Due to various mechanisms, the incidence of cataracts is much higher in diabetics than in non-diabetics, and cataract surgery is the only way to solve the problem. With the advancement of technology, cataract surgery has become very sophisticated and safe, but there is still a risk of postoperative complications affecting the prognosis of vision. In this article, we would like to review the research progress on the perioperative management of cataract surgery in diabetic patients, the types of postoperative complications and their treatment.
文章引用:华思茵, 许燕, 全雪. 糖尿病患者白内障围手术期管理及术后并发症的研究进展[J]. 临床医学进展, 2024, 14(12): 474-481. https://doi.org/10.12677/acm.2024.14123106

1. 引言

由于高血糖能使晶状体蛋白糖基化,改变α-晶状体蛋白的伴侣功能,导致晶状体聚集和混浊[1],白内障的发生已被认为是糖尿病患者的并发症。先前的研究表明,糖尿病患者发生白内障的可能性高达常人的5倍,尤其是在早期[2],并且越年轻的糖尿病患者白内障可能越严重。最常见的类型是后囊下型白内障,其进展主要取决于糖尿病的病程以及控制情况[3]。糖尿病患者的白内障治疗相对来说更为复杂,与单纯老年性白内障相比,技术难度更大,治疗效果也更不确切,术前发生威胁视力的并发症的风险也越高,如角膜内皮损伤、虹膜新生血管、后囊膜混浊、眼内炎、糖尿病视网膜病变进展、黄斑水肿等。

2. 术前管理

由于缺乏在术前管理方面良好的证据研究,对于糖尿病眼的白内障手术准备理想方法尚无共识。既往的观点多为保守治疗,如Pollack等[4]不建议糖尿病患者在视力降至20/100~20/200之前进行白内障摘除以避免术后黄斑水肿的发生。Schatz等[5]同样指出,糖尿病合并白内障患者推迟手术更佳,尤其是术前存在视网膜病变的患者。但现在,随着治疗手段的进步、白内障手术技术的更新以及人工晶体的发展等,越来越多的糖尿病患者倾向于早期手术,既能尽早改善视力又能更好地观察眼底病变的进展以及进行治疗。关于糖尿病患者眼部并发症的术前治疗,全视网膜激光光凝推荐用于术前已有增殖性糖尿病视网膜病变的患者。黄斑水肿也应在术前有效治疗,因为已有的黄斑病变可能在术后恶化,并与视力不良密切相关[6]。黄斑水肿的治疗选择有激光光凝、玻璃体内注射抗血管内皮生长因子(vascular endothelial growth factor, VEGF)药物治疗或类固醇[7] [8]

3. 手术类型及术中注意事项

研究表明,糖尿病患者行超声乳化术的效果比囊外或囊内白内障手术更好[9] [10]。在手术过程中糖尿病患者也有一些不同的注意点:1) 由于糖尿病眼前囊易皱缩,撕囊的大小应大于正常,但要小于人工晶状体视径,以防止晶状体前移位和后囊膜混浊[11];2) 减少白内障手术的持续时间和操作的复杂性十分重要,因为这也是视网膜病变进展的主要危险因素[12];3) 糖尿病患者因瞳孔副交感神经供应受损和前列腺素水平升高,存在瞳孔扩张不良的问题,所以,术中应考虑使用虹膜钩等虹膜扩张器[13];4) 在存在虹膜新生血管(neovascularization of the iris, NVI)的病例中,手术中或手术后前房出血也应格外注意[14]

4. 并发症的具体类型

4.1. 角膜内皮损伤

角膜内皮为排列在角膜后表面的单层细胞,在胚胎发育期间由神经嵴形成,其数值密度出生时高达3000个细胞/mm2,此后缓慢下降。角膜内皮能维持正常的角膜水合、厚度和透明度,内皮细胞的丢失或损伤会导致角膜水肿、角膜失代偿甚至视力丧失[15]。糖尿病能加强氧化应激、使角膜超微结构改变、降低内皮细胞中Na+-K+-ATP酶的活性从而使内皮细胞不能完成正常功能[16]。多项研究表明,超声乳化术对糖尿病患者角膜损伤的影响大于非糖尿病患者,且糖尿病患者术后恢复时间更长[15]-[17]。另外,糖尿病的醛糖还原酶能引起多元醇在细胞内积聚,而多元醇作为一种渗透剂能导致内皮细胞肿胀、角膜水肿,影响白内障术后视力的恢复[15] [17]。因此,在进行白内障手术时,对于糖尿病患者的角膜内皮应做到术前评估、术中保护、术后随访。

4.2. NVI

新生血管性青光眼是一种破坏性的继发性青光眼,其特征是出现NVI以及前房角纤维血管组织增生。新生血管性青光眼病例中,患有糖尿病的比例在30%以上[18],增殖性糖尿病视网膜病变是新生血管性青光眼的主要原因[19]。白内障手术可能加剧新生血管的进展及形成,NVI是糖尿病患者白内障手术后最可怕的前段并发症。因此,若术前存在NVI,需要及时行全视网膜光凝和抗VEGF治疗以控制NVI,一旦NVI消退,应尽早考虑进行超声乳化术,同时或不进行玻璃体切除术,以便治疗后段病变[20]。若术后出现NVI或疾病进展,也需要及时治疗。玻璃体内抗VEGF治疗是短期治疗新生血管性青光眼的关键策略[21]。抗VEGF治疗可直接降低眼内VEGF水平,使视网膜、虹膜角膜角和虹膜新生血管的消退。抗VEGF药物通常在白内障手术前、手术中和手术后都需要使用[22]

4.3. 后囊膜混浊(Posterior Capsular Opacification, PCO)

白内障术中最常见的并发症是后囊膜破裂,而术后最常见的并发症是PCO [2]。白内障手术后前囊残留的晶状体上皮细胞增殖、迁移并通过上皮–间充质转化转变为肌成纤维细胞表型,分泌过多的细胞外基质蛋白,从而通过纤维化导致PCO,对白内障术后视力有着较大影响[23]。PCO的发生率随白内障术后的时间增加而增加,在植入单片人工晶体的患者中,3年时约4.7%~18.6%,5年时约7.1%~22.6% [24]。不断有研究发现糖尿病患者白内障术后发生PCO的风险高于非糖尿病患者,并且这种高风险随着时间推移更为明显[25]。这是一个复杂的过程,有许多机制。近年来,糖尿病房水中的细胞外小囊泡(small extracellular vesicles, sEVs)被认为是一种新的发病机制。高糖促进房水中高表达外泌体miR-1246的sEVs上调,miR-1246能促进人晶状体上皮细胞上皮–间质转化和转移,进一步发生PCO [26]。但研究发现,糖尿病患者白内障术后PCO的程度与前囊收缩程度、糖尿病性视网膜病变(diabetic retinopathy, DR)的分期、糖尿病的全身状态(如病程、糖化血红蛋白稳定性等)等无明显相关性,可能因为这些因素对晶体上皮细胞的刺激作用不足以诱导具有临床意义的PCO [27]。相较而言,患者年龄、人工晶体的性质等更可能是PCO的危险因素,圆边及丙烯酸亲水性人工晶体的PCO发生率高于方边及丙烯酸疏水性IOL [27] [28]

对于糖尿病患者来说,保持整个后囊透明是非常重要的,这不仅是为了视力,也是为了眼底疾病的治疗,Nd:YAG激光后囊切开术仍然是PCO最常用的治疗方法。近年来,药物替代治疗也在蓬勃发展,其常用的方法是在冲洗液的基础上将药物直接注入前房或浸透人工晶状体。丝裂霉素、双氯芬酸钠、皂苷、沙莫苷、米诺地尔、基质金属蛋白酶抑制剂、环氧合酶2抑制剂等细胞毒性和治疗药物,能通过靶向破坏残余晶状体上皮细胞的存活、粘附、增殖、迁移和转分化,从而治疗PCO,但其对周围眼内组织的毒性作用的风险限制了其临床应用[29]。另外,基因疗法也有着一定的前景。Walker等人[30]发现Src家族激酶抑制剂对鸡晶状体囊袋模型中PCO的发展有阻断作用。Malecaze [31] [32]等人提出通过过度表达促凋亡基因诱导治疗性凋亡,从而靶向囊袋中的残余晶状体上皮细胞。但这些新兴治疗方法真正应用于临床还有很长一段路需要走。

4.4. 眼内炎

眼内炎是由眼内真菌和细菌感染而引起的炎症,是一种罕见的并发症,只发生在少数白内障手术后[33]。高血糖环境可导致免疫功能障碍,包括中性粒细胞功能受损、抗氧化系统抑制和体液免疫下降。因此,糖尿病患者发生全身性感染的风险增加,特别是肺炎、泌尿系统感染、伤口感染和菌血症[34]。相应地,糖尿病患者白内障术后发生眼内炎的风险也高于常人,并且可能与视力预后不良有关。因此,对于糖尿病患者的白内障手术,术前及术后眼液的规范使用、术中手术时间的控制显得尤为重要。

4.5. DR

关于白内障术后DR是否会进展存在着一定的争议。Squirrell等人的研究[6]和Romero-Aroca等人[3]的研究认为,顺利且无并发症的超声乳化白内障手术可能不会导致DR进展。但这一结论存在一定的片面性,因为这些研究纳入了基线时没有DR的患者,无DR的患者,可能具有健康的血管功能,不易受到手术引起的炎症的影响,而在已有DR的个体中,可能已经存在血管功能异常、动脉血管壁和微血管损伤,因此,已知会诱发炎症和应激的白内障手术,更容易加剧已存在DR的患者的病情进展。而Hong等人的研究[35]和最近更大的队列和数据库研究[36] [37]报道白内障手术后DR的进展加速,白内障手术与DR进展增加之间存在显著关联。并且无论使用何种手术技术,白内障手术与DR进展增加之间存在显著关联,但ECCE等更具侵入性的手术可能会致使DR更快地进展[35]。DR进展加速可能与前房手术操作导致物理性创伤从而引起炎症反应有关[38]。对于这类患者,有研究指出早期视网膜光凝术或抗VEGF等治疗能够在一定程度上阻止术后的进展[38] [39]。综上我们可以认为对于术前存在DR的患者,我们应长期重视其DR在术后的发展情况,严密监测、及时给予干预。

4.6. 黄斑水肿

在接受白内障手术的糖尿病患者中,术后发生黄斑水肿的风险较高,黄斑水肿可能是由于先前存在的糖尿病性黄斑水肿(diabetic macular edema, DME)的恶化或假性晶状体囊样黄斑水肿(pseudolens cystoid macular edema, PCME)的新发病引起的。这两种疾病的特征都是黄斑区视网膜组织中液体的积聚,但这两种疾病应加以区分,DME通常表现为潜在的DR、渗出物和黄斑水肿,而轻度DR和无渗出物更倾向于PCME [20]

4.6.1. DME

高血糖会发生一系列代谢变化从而使视网膜屏障受损,进一步导致视网膜下和视网膜内液体积聚,发生DME [40]。术后炎症及VEGF含量上调都会造成视网膜屏障损害,其中VEGF更为重要,能使视网膜毛细血管阻塞、损伤以及高通透。这些变化导致血液浆液成分渗漏,而黄斑周围视网膜持续水肿会对构成神经血管单位的神经细胞造成损害,从而发生糖尿病性视网膜神经病变和视力下降。如果水肿长期持续存在,则会进一步进展为不可逆的神经病变,对视力造成永久性损害[41]

DME的量化方式多种多样,其中OCT以其极高的视网膜厚度测量精度和在微观水平上监测视网膜变化的高分辨率而优于其他工具[42] [43],是DME诊断和预后监测的金标准[44]。在OCT上DME主要表现为微动脉瘤、硬渗出、中央凹旁外核层与内核层厚度比较高等特征。Im等人通过基于人群的OCT研究发现,糖尿病患者中DME的总患病率为5.47%,中低收入国家为5.81%,高收入国家为5.14% [45]。已存在的DME合并明显的白内障的处理是一个临床难题。若先充分治疗DME而延迟白内障手术,患者不仅会长期处于视力损害的状态,明显的白内障也可能会危及手术安全以及影响眼底病变的监测;若先行白内障术,术后DME的迅速进展以及复发也是一个严峻的问题。

白内障手术后DME的新发及进展在术前与DR的分级、糖化血红蛋白水平、糖尿病病史、术后炎症等有关[46]。术前管理中,血糖的长期稳定至关重要,大量前瞻性临床研究已经证明高血糖引发的氧化应激、炎症和血管功能障碍是导致术后DME发病的主要危险因素[47]。术后DME的主要预防措施包括外用非甾体抗炎药、外用/眶周/玻璃体内类固醇或玻璃体内抗VEGF注射[48]。对于没有DME病史的糖尿病患者,术前局部应用1周非甾体抗炎药可降低术后早期DME新发的风险。局部类固醇的使用对降低术后DME的发生没有显著作用,但能抑制其他形式的眼内炎症[48]。另外,研究表明,抗VEGF联合白内障手术可显著改善糖尿病合并DME患者的最佳矫正视力[49]。但不仅VEGF,白内障手术后DME患者的几种细胞因子,包括白细胞介素-6 (IL-6)、IL-8、IL-10、IL-1β、干扰素诱导蛋白-10 (IP-10)、单核细胞趋化蛋白-1 (MCP-1)都显著升高。VEGF以外的细胞因子也在白内障手术后DME的发病和进展中发生了作用因此,单独的抗VEGF药物未能维持白内障手术后视网膜中央厚度的减少。综合以上观点,与单独使用类固醇或抗VEGF相比,DME患者进行白内障手术时联合两者治疗能更好地维持视网膜中央厚度的减少[41]

最新研究还发现,0.7 mg地塞米松玻璃体内植入物(DEX)联合白内障手术似乎可以避免糖尿病患者术后视网膜厚度增加,为DME患者提供更好的解剖学结果[50]。但值得注意的是,如果后囊膜不完整,玻璃体内地塞米松植入物有迁移到前房的风险[48]。对于DME患者,白内障手术联合DEX的方法是否与白内障手术联合抗VEGF药物的方法具有可比性,目前还没有研究。需要进一步的随机试验将直接比较这两种不同的联合方法,以证实这些结果[46]

4.6.2. PCME

Zhang等人通过对81,984只接受白内障手术的眼睛进行分析发现,无DR的糖尿病患者中有2.15%发生PCME。合并轻度、中度、重度非增殖性DR和增殖性DR时,PCME的发生率分别为9.43%、9.75%、7.69%和12.07%,并且与非糖尿病患者相比,发生PCME的糖尿病患者在手术后3个月视力恢复有限[49]。糖尿病的病程、严重的DR、类型、糖化血红蛋白和晶状体硬度是糖尿病患者白内障术后发生PCME的危险因素[51]。Yang等人认为中心凹厚度增加40%和黄斑敏感性降低20%为PCME的可靠诊断标准[51]。PCME大多采用局部治疗。白内障手术期间,人工晶状体植入术诱导晶状体上皮细胞产生促炎细胞因子,包括前列腺素前列腺素破坏血眼屏障的完整性。因此,非甾体抗炎药(前列腺素合成抑制剂)在非糖尿病和糖尿病人群中预防PCME的作用已被充分证明[52]。Boscia等人建议,所有接受白内障手术的糖尿病患者均应使用局部非甾体抗炎药来预防PCME [48]。皮质类固醇常规用于白内障术后,但先前的研究发现,与单药使用皮质类固醇相比,局部使用皮质类固醇和非甾体抗炎药可降低白内障手术后发生PCME的风险[51]。另外,最新研究发现与单独使用非类固醇或局部类固醇药物相比,围手术期接受额外抗VEGF治疗干预是唯一一种在预防PCME和改善术后最佳矫正视力方面优于单独使用局部类固醇药物的[50]。总之,与单独使用局部类固醇滴眼液相比,额外使用非甾体抗炎药和抗VEGF均能有效预防接受白内障手术的糖尿病患者的PCME。对于视力结果,额外的抗VEGF干预与更好的术后最佳矫正视力相关。

5. 小结

总的来说,糖尿病患者的白内障手术是一个非常成功的手术,提高了大多数患者的视力。手术的成功离不开围手术期预防管理,其中最重要的包括术前血糖的良好控制、术中平稳的手术操作、充分的眼部检查以确定术前眼部的基本情况,从而便于判断术后疾病是否进展。在对糖尿病患者进行白内障手术时,有许多特殊的术后并发症也必须注意,包括角膜内皮损伤、PCO、眼内炎、NVI、DR进展、黄斑水肿等。以上并发症都可能对接受白内障手术治疗的糖尿病患者的视力预后产生不利影响,需要我们术后定期跟踪随访以及时识别干预,特别是患有中度至重度非增殖性DR和DME的患者。对于术前存在眼底病的患者,通常建议术前可根据具体情况使用非甾体类抗炎药、玻璃体内VEGF抑制剂及类固醇类激素、眼底激光等治疗以控制和治疗DME和DR。在过去的几十年里,手术技术的进步极大地改善了预后,减少了相关的手术创伤,并缩短了糖尿病患者和非糖尿病患者的恢复时间。尽管总体结果良好,我们仍需认识到糖尿病患者发生并发症的风险较高,并应充分告知这一风险,让患者对白内障手术后视力恢复建立合理的期望。

NOTES

*通讯作者。

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