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息肉状脉络膜血管病变发生大出血的危险因素和治疗进展

Risk factors and treatment progress in massive hemorrhage secondary to polypoidal choroidal vasculopathy

来源期刊: 眼科学报 | 2024年1月 第39卷 第1期 19-26 发布时间:2024-01-28 收稿时间:2024/4/29 14:59:41 阅读量:441
作者:
关键词:
息肉状脉络膜血管病变视网膜下出血玻璃体积血综述
polypoidal choroidal vasculopathy subretinal hemorrhage vitreous hemorrhage review
DOI:
10.12419/24021801
息肉状脉络膜血管病变(polypoidal choroidal vasculopathy,PCV)是亚洲人群中常见的致盲性眼病,发生大出血并发症后严重危害视力且预后差。PCV大出血包括视网膜下出血(subretinal hemorrhage,SRH)和玻璃体积血(vitreous hemorrhage,VH)。SRH的危险因素包括较长病程、簇型PCV、息肉状病灶不消退、合并视网膜色素上皮脱离;其治疗方式包括抗血管内皮生长因子药物、光动力疗法、激光、玻璃体腔注气、眼内注射组织纤溶酶原激活剂、玻璃体切割术或联合治疗等方式,其中,黄斑中心凹是否受累和出血时间是影响治疗方式选择的主要因素。发病年龄较大、白细胞计数较高、天门氨酸转移酶和丙氨酸转氨酶的比值较高、活化部分凝血活酶时间较长、曾行光动力疗法、有玻璃体腔注药治疗史、SRH面积大、出现视网膜色素上皮脱离的PCV患者发生VH的风险高。浓厚的VH通常需行玻璃体切割术,其手术时机和手术方式的选择是临床关注的焦点。鉴于目前PCV大出血的危险因素尚不完全明确、治疗方面也尚未形成共识,需要开展相关临床研究,提供更多依据。
Polypoidal choroidal vasculopathy (PCV) is a common blinding disease in Asian populations. Massive hemorrhage complications secondary to PCV includes subretinal hemorrhage (SRH) and vitreous hemorrhage (VH). The risk factors for SRH include a long duration, clustered PCV, non-regression of polyp lesions and presented with retinal pigment epithelial detachment. The treatments for SRH including anti-vascular endothelial growth factor drugs, photodynamic therapy, laser, vitreous pneumatic displacement, intravenously injected tissue plasminogen activator, vitrectomy and combination therapy. Whether macular fovea is involved and the time since bleeding onset are the main factors afecting the choice of treatment for SRH. Older age of onset, higher white blood cell count, higher aspartate amino transferase and alanine amino transferase ratio, longer activated partial thromboplastin time retinal pigment epithelium detachment, photodynamic therapy history, intravitreal injection history larger SRH area and presented with retinal pigment epithelial detachment were associated with higher risk of VH. PCV patients with massive VH should be treated with vitrectomy, while the timing and technique of operation should be paid atention to. At present, the risk factors of PCV massive bleeding are not completedly clear, and its treatment methods are diverse, which requires a large number of studies to prove its efectiveness and establish expert diagnosis and treatment consensus.
息肉状脉络膜血管病变( poly poidal choroidal vasculopathy,PCV)以视网膜下橘红色息肉样病变,伴有出血性或浆液性视网膜色素上皮(retinal pigment epithelial,RPE)及神经上皮脱离为特征。吲哚菁绿眼底血管造影(indocyanine green angiography,ICGA)显示有脉络膜异常分支血管网(abnormal branching vascular network, BVN)和血管末端息肉样或动脉瘤样扩张病灶。PCV在亚洲人群中的发病率更高。据报道,在诊断为湿性年龄相关性黄斑变性患者中,基于ICGA结果诊断为PCV的比例在白人中为4%~13.9%,而在亚洲患者中则为22.3%~61.6%[1]。在我国,≥50岁人群的PCV患病率为0.5%[2]
大出血是PCV的严重并发症,严重危害患者视力且预后极差。根据出血部位不同,可分为视网膜下出血(subretinal hemorrhage,SRH)和玻璃体积血(vitreous hemorrhage,VH)。出血后的PCV最终发生脉络膜视网膜萎缩、纤维瘢痕形成,导致中心视力不可逆性丧失。因此,明确PCV患者发生大出血的危险因素、发生出血后的治疗时机和治疗方式,对PCV患者的获益具有非常重要的意义。本文将对PCV发生大出血的危险因素和治疗进展做一综述。

1 视网膜下大出血

SRH是PCV的严重并发症,其发病率在确诊PCV的第1年为2.5%,10年内这一比例增加到约30%[3-4]。PCV发生SRH的发病机制包括:1)Bruch膜下的小静脉和小动脉增宽;2)Bruch膜内血管损害和广泛的纤维血管增殖;3)视网膜下小的出血可能是源于动脉瘤样扩张血管的破裂,大的出血则可能是由于小静脉(有时为动脉)的破裂[5]。较长病程、簇型PCV、治疗后polyps持续不消退是PCV、合并色素上皮脱离(pigment epithelial detachment,PED)是PCV患者发生SRH的危险因素。患者在初次就诊后1、3、5和10年内,SRH的发生率分别为2.45%、6.17%、11.09%和29.85%[3]。ICGA检查显示簇状息肉的PCV患者,其发生SRH的风险是非簇状息肉的PCV患者的3.4倍。在3、6和9年内,治疗后polyps持续不消退组的SRH发病率逐渐增加,分别为6.5%、22.6%和38.0%[6]。发生SRH的患者相较于一般PCV患者,其PED发生率更高、荧光造影图像中PED的最大线性直径更大和视网膜下液的发生率更高,潜在机制可能是上述因素产生较大的RPE下静水压,继而引起RPE撕裂,进一步导致视网膜下出血[7]。此外,在全身因素方面,性别、年龄、吸烟、高血压病史、糖尿病史、心血管疾病史和抗凝药物使用均不是PCV患者发生SRH的全身危险因素[8],而SRH初始治疗成功后再出血组与非再出血组相比,前者的高收缩压发生率或高血压病史者比例更高[9]
SRH的出血可积聚在RPE和神经上皮之间,也可以发生于RPE下。发生在黄斑部的SRH,根据出血范围可进行以下分类:小范围是指1~4 PD大小的出血;中等范围的面积至少为4 PD,但不超过颞侧血管弓;大范围指超过颞侧血管弓,但不超过赤道部;巨大范围指至少2个象限的出血范围并超过了赤道部[10]。SRH在早期由于血的遮挡导致视力突然下降,在后期因为对视网膜有毒副作用而导致视力的不可逆损害,因此即使积血自发吸收后视力也无法恢复。在动物实验研究中,SRH在24 h后引起不可逆的视网膜损害,7 d会引起感光细胞的丧失[11]。其损伤机制包括:1)物理性损伤:血块纤维牵拉收缩引起光感受器外节脱离;2)铁离子毒性:氧化损伤导致光感受器细胞凋亡;3)血块阻碍神经网膜与RPE间的物质转运[12]。若不治疗,患者视力预后极差,因此,PCV并发SRH的治疗时机和治疗方式尤为重要。
如果SRH未累积黄斑中心凹,可考虑观察,或者针对息肉病灶及视网膜下积液行眼内注射抗血管内皮生长因子(vascular endothelial growth factor,VEGF)药物、光动力疗法(photodynamic therapy,PDT)、局部激光治疗等。一旦视网膜出血累积黄斑中心凹,多主张积极进行干预,其治疗方式包括抗VEGF药物、玻璃体腔注气、眼内注射组织纤溶酶原激活剂(tissue plasminogen activator,tPA)、玻璃体切割术(pars plana vitrectomy,PPV)和联合治疗等。以下就现有的常用治疗手段进行归纳。

1.1 抗VEGF药物

对于较薄的SRH(<450 μm),可使用抗VEGF单药治疗,以避免气体填充产生的孔源性视网膜脱离或脉络膜出血;在较厚的SRH(>450 μm)中,气体填充与抗VEGF治疗相结合有助于快速改善视力并减少黄斑中央凹厚度[13]。然而在息肉消退率方面,抗VEGF药物的作用是有限的,不能消除息肉病灶和BVN及防止其再生,并且所需重复注射次数较多,个体差异较大,费用也较昂贵。

1.2 玻璃体腔注气术

适用于出血量不是特别大的患者,于SRH发生后48 h进行。多数患者需术中行前房穿刺,然后于角膜缘后4 mm处注入0.3~0.4 mL的过滤空气或膨胀气体(C3F8或SF6),然后保持俯卧位24 h至2周。当SRH的病程超过72 h,由于出血凝固机化,玻璃体腔注气将无意义。该治疗方式具有操作简便、早期治疗效果理想的优点,但操作时间窗较短,还存在一定的并发症,包括SRH复发(13.6%)、VH(11.4%)、眼压升高(4.5%)、白内障(4.5%)和眼内炎(0.75%)[10, 14-15]

1.3 眼内注射tPA

tPA主要由血管内皮细胞合成、分泌,对纤维蛋白有高度的亲和力,促进酪氨酸纤溶酶原形成纤溶酶,降解纤维蛋白和部分凝血因子,是纤溶系统的关键物质。tPA可溶解血凝块并促进积血转移和吸收,适用于SRH发生后7~10 d、SRH最大高度>500 μm的患者[16-17]。选择合适的干预时间,是tPA治疗SRH的关键,如果手术过早进行,由t-PA引起术后再出血的风险增高;若手术过晚进行,SRH不能完全被溶解导致清除不彻底。由于tPA具有毒性,其安全剂量为25 ~ 50μg tPA/0.1 mL生理盐水。如果tPA的注射浓度过低,就可能无法完全溶解视网膜下较大的血块;若浓度过高则引起视网膜毒性,导致严重的RPE坏死和光感受器丢失。
眼内使用tPA的方式常采用玻璃体注射或视网膜下注射,前者使tPA更易扩散,而后者会使tPA作用更充分。不少学者比较了两种tPA的注射方式,结果发现两组患者在治疗后均得到显著的视力改善和中央视网膜厚度降低,视网膜下(指神经上皮和RPE之间)出血厚度、视力预后、治愈率在两组间比较差异无统计学意义[18-19]。视网膜下注射tPA过程中,药物对RPE和脉络膜可能造成机械性损伤,因此控制注射压力在低水平是很重要的。研究表明,内界膜(internal limiting membrane,ILM)是视网膜下注射阻力的最大来源,因此,在注射部位去除ILM可能更有利于降低注射tPA时产生的压力[20]。SRH发生后清除积血可减少外层视网膜损伤,有利于恢复视力,但存在VH的风险,而且仅注射tPA而不排出积血并不能防止视网膜退化,因此常需要联合玻璃体腔注气或PPV[21]。视网膜下出血液化后,可通过玻璃体腔注气将其驱离黄斑区,也可以通过PPV行局部视网膜切开放液或巩膜外切开放液。局部视网膜切开放液的优点是可以更快地排出视网膜下出血,减少积血纤维机化物的产生和黄斑区瘢痕化,减少色素上皮层和感光细胞的损伤,进而使患者更快获得视力收益[22]。其缺点是增加了医源性损伤、术中活动性出血、术后前房泥沙样积血、高眼压等风险等。另外,有文献报道PCV并发SRH> 2个象限者,采用玻璃体切割术及重水辅助联合经巩膜外穿刺引流视网膜下积血的方法具有良好的临床效果[23-24]

1.4 PPV手术

有学者主张PPV作为玻璃体腔注气术和tPA失败后的二次干预手段[25]。光学相干断层扫描(optical coherence tomography,OCT)图像上的对比度噪声比值可作为治疗方案选择的依据[26]。该比值是利用中心凹下一小块的出血区域和整个玻璃体腔的背景区域,通过软件测量其平均灰度值及标准差值计算得到。对比度噪声比值较低意味着黄斑下出血较软,进行单纯玻璃体腔注气术即能够有效实现出血的早期移位。如果注射气体后出血移位欠佳,可再考虑PPV联合tPA注射作为二次治疗。另有学者提出黄斑部出血的治疗新策略:对于累及黄斑中心凹的大面积SRH,建议先行玻璃体腔注气术+tPA,操作后第一天和第三天复查患者情况,必要时使用乙酰唑胺和其他经典的青光眼用药。若成功将SRH移出中心凹,没有或只剩下少量血液,则无需进一步干预;否则,需尽快行PPV+视网膜下注射tPA +气体填充术或硅油填充术,术后第一天、一周、一个月复查患者眼部情况[27]。但也有学者认为当出血面积超过后极部血管弓>1 DD时,应首选PPV,并在SRH发病1个月内进行[28]。对于视网膜下出血量大,且出血时间小于1个月的患者,有学者主张先行tPA玻璃体腔或视网膜下注射,待血凝块液化后,再通过联合PPV手术将视网膜下液化的血液清除。对于陈旧的视网膜下出血,tPA注射后通常难以将其液化,有学者尝试大范围视网膜切开后清除,可部分改善患者视力[22]。但也有学者认为,该手术复杂,操作难度大,手术时间长,对RPE损害严重,同时还可能出现术中大出血、术后视网膜脱离、增生性玻璃体视网膜病变等严重并发症,难以改善视力[29]。还有学者对比了多种手术方式,认为PPV+视网膜下注射tPA +气体填充术应作为SRH的主流手术方式,因为该术式比视网膜切开术和机械清除等术式更安全、有效[17, 30]。然而,就目前现有研究来看,陈旧的SRH是否应行PPV治疗,国内外专家还没有达成共识。
综上所述,PCV并发大面积的SRH未累积黄斑中心凹时,主要针对息肉病灶及其并发的视网膜下积液进行治疗,常用方式包括眼内注射抗VEGF药物、PDT、激光治疗等。当SRH累及黄斑中心凹时,可以单纯抗VEGF治疗,但出血吸收时间长,可导致视网膜感光细胞、RPE萎缩,引起不可逆视功能损害。积极的处理措施包括玻璃体腔注气、tPA眼内注药、PPV手术及联合治疗等,可尽早清除黄斑部视网膜下出血,有利于视力恢复,但存在手术操作相对复杂及并发症风险。至于陈旧性视网膜下血凝块是否行视网膜切开取出,目前尚无定论,需要进一步研究证实其疗效和安全性。

2 玻璃体积血

PCV患者发生VH时严重威胁患者视力,国外报道PCV患者发生VH的发病率为1%,而国内报道为19.9%[31-33]。突破性玻璃体积血的发生与大面积SRH有关,但视网膜下出血如何进入玻璃体腔的机制一直未被阐明。有动物研究认为VH是视网膜下的红细胞碎片而非红细胞穿过完整的内界膜迁移至玻璃体内而形成,其发生时间为出现SRH后的2~6周[34-35]。另有学者认为,PCV患者视网膜下出血量特别剧烈时,瞬时升高的视网膜下压力导致锯齿缘或视盘旁的视网膜开口出现撕裂,积血由此进入玻璃体腔[36]。PCV患者发生VH时,常伴有不同程度的出血性视网膜脱离,会导致PCV患者出现严重的视功能障碍,因此应予以高度重视。
既往文献表明,PCV患者发生VH的眼部危险因素包括PDT治疗史、玻璃体腔注药治疗史、出现PED、大面积的SRH等[37-38];而全身危险因素则包括发病年龄较大、部分血液指标。在眼部危险因素中,PDT可损伤血管内皮细胞,导致血管脆性增加,继而引起VH,其中较大激光斑(直径>3 500μm)是VH风险增加的因素[39]。关于玻璃体腔注药术触发VH的机制,可能是由于脉络膜血流的改变引起SRH,也可能是由于抗VEGF效应引起的脉络膜血管收缩所致,在RPE附着于Bruch膜的部位产生剪切力,继而引起RPE撕裂[8]。国内学者比较了并发和不并发VH的PCV患者临床特征,发现前者出现PED、出血型PCV、更大的SRH面积、出血性视网膜脱离或合并出血性脉络膜脱离[38]。在全身危险因素中,白细胞计数升高、天门氨酸转移酶和丙谷转氨酶的比值升高、活化部分凝血活酶时间延长是PCV继发VH的独立危险因素,其比值比(odds ratios,OR)值分别为1.247、2.339和1.196,表明体内炎症水平较高、肝功能异常和凝血功能受损的PCV患者,发生VH的风险较高[40]。而性别、吸烟史、高血压病史、糖尿病史、心血管疾病史和抗凝药物使用史均不是PCV患者发生VH的全身危险因素[37-38]
PCV患者并发的VH通常比较浓厚,通常需要进行PPV手术治疗。关于PPV的手术时机,不少学者认为应在VH发生后2.5~4.0个月,原因是过早手术会因玻璃体前后皮质处理困难、产生医源性裂孔而增加手术难度。有文献表明,PCV合并VH行PPV时最常见的手术并发症是医源性视网膜裂孔,发生率可高达17.8%,裂孔主要发生在玻璃体后脱离的诱导过程中[41]。因此,待VH发生自发性玻璃体后脱离后再进行PPV可降低上述风险。当然也有学者主张早期手术,认为早期手术可避免长时间积血导致的视网膜损害[42]
关于PPV的手术方式,专家们多主张行单纯玻璃体积血切除,如果黄斑中心凹下无明显受累,通常视力可显著提高。如术中发现黄斑下大出血时,根据血液是否凝固而选择不同的处理方式:1)当出血新鲜没有凝固时,可以考虑电凝切开引流;或者不切开视网膜而选择注入气体,从而将血液驱离黄斑区[43]。2)当出血已凝固但未机化时,可考虑术前使用tPA,或手术结束时注射tPA,待出血液化后再清除或驱离黄斑区[44]。3)当出血已明显机化时,有学者尝试大范围视网膜切开后清除机化的血凝块,但视力改善不明显,该手术方式尚存争议。如果术中发生医源性视网膜裂孔,通常需要大范围切开视网膜,彻底清除视网膜下出血,否则术后很容易导致前房积血,进而发生继发性青光眼和角膜血染[32]
在PPV的围术期合理使用抗VEGF药物可增加患者获益。PPV术前使用抗VEGF药物可降低手术难度,减少术后并发症。有研究者发现,术前使用抗VEGF药物可缩短手术时间、减少视网膜切开,并能减少重水、膨胀气体和硅油的使用;术后可减少早期前房积血、再次VH、二次手术、术后PDT治疗等,但术后远期视力及黄斑中心凹厚度与术后抗VEGF比较差异无统计学意义[45]。对于PPV术后使用抗VEGF药物辅助治疗的适应证,包括以下几种:1)最佳矫正视力下降超过两行(0.2 LogMAR);2)示SRH或视网膜内液体;3)OCT示中央黄斑厚度增加超过100μm;4)荧光素眼底血管造影、ICGA及OCT检测息肉渗漏和(或)BVN[38]
PCV并发VH时,患者的视力预后较差,与视网膜下长期出血导致RPE和视网膜外层变性有关。Lin等[35]的一项队列研究报道,未并发VH时的患者视力为(0.95±0.60)LogMAR,发生VH后行PPV术前,视力为(2.63±0.57)LogMAR,PPV术后3个月的视力改善至(1.62±0.67)LogMAR,而最终视力为(1.43±0.82)LogMAR,仍较发生VH之前的视力差。PCV并发VH行PPV后的恢复情况主要取决于黄斑受累情况,此外,患者年龄较大、合并糖尿病或高血压等全身病史、polyps在黄斑区内、术前SRH较厚,随访过程中黄斑区瘢痕形成,往往提示患者术后视力预后差[31, 35, 46-47]

3 总结与展望

PCV患者发生大出血的危险因素,目前已有初步探索,但现有已关注的危险因素和大出血之间的因果关系和具体致病机制还需进一步探索。当PCV患者发生大出血后,治疗的根本原则是尽可能驱离或清除黄斑中心凹下出血,最大程度缩短病程提高视力。PCV大出血的处理,除了本文所述的方法外,仍有许多问题尚待解决,如:陈旧性SRH出血该如何治疗、联合治疗如何优化、如何提高PCV患者的视力获益等。PCV大出血的治疗尚未达成共识,有赖于研究者们进一步开展相关临床研究,为临床治疗选择提供更充分的依据。

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1、国家自然科学基金(82070972,82271093)
2、广州市科技重点研发项目((202103000045)
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    主办:中山大学
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  • Eye Science

    主管:中华人民共和国教育部
    主办:中山大学
    承办:中山大学中山眼科中心
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