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青光眼睫状体炎综合征病因及治疗的研究进展

Research progress in etiology and treatment of Posner-Schlossman syndrome

来源期刊: 眼科学报 | 2021年12月 第36卷 第12期 998-1005 发布时间:2021-12 收稿时间:2023/5/9 17:01:45 阅读量:5741
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青光眼睫状体炎综合征病因治疗方法巨细胞病毒
Posner-Schlossman syndrome etiology treatment cytomegalovirus
DOI:
10.3978/j.issn.1000-4432.2021.08.13
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青光眼睫状体炎综合征(Posner-Schlossman syndrome,PSS)表现为单眼反复发作性非肉芽肿性前葡萄膜炎,伴有眼压升高,可发展为慢性继发性青光眼,最终导致视神经损伤。尽管PSS总体预后良好,但仍有部分患者因反复眼压骤升造成视神经损伤持续进展,甚至导致失明。目前,PSS的确切病因尚不明确,治疗方式以控制炎症及眼压为主。本文将从病因及治疗两方面阐述PSS的研究现状,以期为PSS相关基础研究及临床诊治提供思路及参考。
Posner-Schlossman syndrome (PSS), also called glaucomatocyclitic crisis, is characterized by recurrent non-granulomatous anterior uveitis, accompanied by elevated intraocular pressure. It is able to develop into chronic secondary glaucoma and eventually lead to optic nerve injury. Although the overall prognosis of PSS is favourable, there are still some patients whose optic nerve injury continues to progress and even lead to blindness due to recurrent attacks of ocular hypertension. At present, the exact cause of PSS is not clear, and the treatment is mainly to control inflammation and intraocular pressure. This article will elaborate the research status of PSS from two aspects of etiology and treatment to provide ideas and reference for the basic research clinical diagnosis and treatment of PSS.
1948年,Posner和Schlossman首次报道了9个青光眼睫状体炎综合征病例,后称青睫综合征(Posner-Schlossman syndrome,PSS),是一种继发性青光眼[1]。其典型临床特征包括:1 )单眼反复发作性的显著眼压升高;2 )无明显疼痛,仅轻度不适或视物模糊;3 )通常无虹膜后粘连或者周边虹膜前粘连;4 )轻度前房反应或少量白色角膜后沉着物(keratic precipitates,KP);5)发作时间持续数小时至数月不等;6 )发作间歇期眼压正常,无葡萄膜炎的体征;7 )虹膜异色症和患侧眼瞳孔散大[2-4]。尽管PSS预后良好,但其反复发作会导致视盘的杯盘比增大、视网膜神经纤维层变薄和视野缩小[5-8]。由于PSS的确切病因及发病机制尚不明确,目前为止临床治疗主要以控制炎症及降低眼压为目标,无法针对病因进行有效干预从而减少复发率。本文将着重从病因及治疗2个方面阐述PSS的研究现状,以期为PSS相关基础研究及临床诊治提供思路及参考。

1 病因

1.1 感染前房内感染被认为是PSS发病的诱因之一,能够引起前节感染的病原体如巨细胞病毒等均有可能引起PSS。PSS患者房水病原体DNA的检出及抗病毒治疗的有效性为前房感染诱发PSS提供了部分证据。
1.1.1 人巨细胞病毒
人巨细胞病毒(human cytomegalovirus,CMV)隶属于人类疱疹病毒家族,是引起前房感染的主要病原体[9-10]。CMV感染率在全球范围内均处于较高水平,在不发达地区甚至可达100%[11]。我国一项献血志愿者流行病学[12]统计发现CMV-IgG和IgM血清流行率约为37.3%和8.9%。前节CMV感染主要表现为角膜内皮炎或伴高眼压的虹膜睫状体炎,有时上述两种炎症反应同时存在。最初这被认为是免疫功能不全患者全葡萄膜炎的部分表现,后来研究者[13-14]发现在免疫功能正常患者也可单独发作前葡萄膜炎,其最典型的表现就是PSS。
早在30多年前便有研究[15]提出:CMV或水痘带状疱疹病毒(varicella-zoster virus,VZV)感染可能与PSS发病有关。近年来,越来越多研究[16-18]证实:部分PSS患者房水内存在CMV的DNA片段,其阳性率在37.5%~62%。CMV在PSS发作患者房水中的高检出率提示,其可能是该病发生发展的原因之一。因此,房水CMV相关分析是临床诊治中评估病情的重要指标。为提高房水中CMV检测的特异度和敏感度,Wang等[19]利用房水和血清中的白蛋白含量,分别对CMV-IgG测定值进行校正,以提高房水CMV-IgG抗体检测的特异性,同时联合应用PCR提高检测敏感性;并以此方法检测了26例PSS患者,发现57.7%的患者CMV检测阳性,CMV阳性组的平均眼压显著高于CMV阴性组。另有研究[8]发现:CMV相关前葡萄膜炎患者房水中病毒高拷贝数是眼压升高的危险因素(OR=2.5,95%CI:1.1~5.4)。
不同研究报道的CMV阳性与阴性PSS患者临床表现差异并不完全一致。Murata等[18]对21例PSS患者进行回顾性分析发现,CMV阳性组的年龄、性别分布及眼压、视锐度、角膜内皮计数、复发率与CMV阴性组均无显著性差异;而CMV阳性组手术率远高于阴性组(84.6% vs 37.5%),这意味着CMV阳性患者更容易出现药物不可控性高眼压状态。黎燕英等[8,20]比较CMV阳性和CMV阴性PSS患者的临床特征,发现CMV阳性组平均眼压、发作眼与对侧眼的角膜内皮细胞数差升高,角膜内皮细胞数减少,而两组患者年龄、性别、眼别、发作时间、视力、杯盘比等无差异。Chee等[16]则认为CMV阳性与阴性PSS患者的临床表现如年龄、性别分布,眼压、角膜内皮损伤等均无明显差异。除眼科常规检查外,房水炎症因子水平在CMV阳性和阴性PSS患者也有所不同。CMV阳性PSS患者炎症因子前列腺素2(PGE2)、白介素-4(IL-4)、抗体IgA、IgG、IgM、补体C3、C4、C1q等水平显著高于阴性组,Th1/Th2平衡漂移[21]。而Li等[22]研究了CMV与房水细胞因子包括IL-8、趋化因子2(CCL2)、CCL4、集落细胞刺激因子(granulocyte colony-stimulating factor,GCSF)、转化生长因子-β(TGF-β)等的相关性,发现两组之间并无差异。可见CMV感染与PSS临床表现的关系较为复杂,不可一概而论。
CMV感染表现出广泛的遗传多样性。包膜糖蛋白在宿主免疫应答和病毒复制中起重要作用,编码这些蛋白的基因的变异可能是该菌株的毒力的原因。其中CMV糖蛋白B(gB)是由UL55基因编码的CMV主要包膜糖蛋白。最新研究[23]发现:gB基因型1是CMV感染PSS患者房水中最常见的基因型,而gb3基因型患者以双侧发病为主。CMV-gB基因可能与PSS患者CMV毒株的致病性有关。CMV感染引发的小梁网急性炎症、水肿及房水细胞因子水平改变可能是高眼压症状产生的关键[2]。CMV感染可以上调前房自分泌移动因子(ATX)和TGF-β,其中ATX的表达量和眼压值相关[24]。这些结果提示,CMV感染与PSS患者遗传异质性相关,并对发病眼压具有一定影响。
在PSS发病过程中,CMV在眼部的靶细胞尚未完全确定,角膜内皮、小梁网组织及虹膜睫状体可能均为潜在受累组织。目前针对CMV存在与否的检测手段仅局限于房水PCR及相关抗体含量测定,缺乏原位组织学证据(如原位杂交、病毒包涵体等),对PSS眼前节病理改变的认知也有待进一步提高。
1.1.2 单纯疱疹病毒
相对于CMV,PSS患者房水单纯疱疹病毒(herpes simplex virus,HSV)阳性率较低。Yamamoto等[15]检测了3例急性发作的PSS患者房水病毒DNA含量,发现HSV为阳性,为眼内HSV感染提供了证据。Hong等[25]用在体激光共聚焦显微镜观察了PSS、单纯疱疹病毒性角膜炎(herpes simplex keratitis,HSK)、HLA-B27阳性前葡萄膜炎(B27AU)和急性发作期开角型青光眼(aPAC),发现PSS患者角膜中央郎格罕氏细胞分级和角膜基质细胞激活等级较B27AU和aPAC患者显著性升高,和HSK患者角膜特征相似,从组织结构角度提示PSS发作可能和HSV相关。
1.1.3 其他
幽门螺杆菌(Helicobacter pylori,Hp)是一种与胃炎、胃溃疡、胃癌等疾病关系密切的革兰氏阴性菌,也被认为可能与PSS发病有关。1988年Knox等[26]通过回顾性分析PSS患者病史,提出PSS和消化性溃疡之间具有一定相关性。Choi等[27]检测了PSS患者血清Hp-IgG抗体,发现PSS组与对照组抗体阳性率分别为80.0%和56.2%,具有显著性差异;多因素线性回归分析显示血清抗Hp-IgG抗体阳性是PSS的发病的高危因素之一。另有研究[28]报道PSS患者血清HP-IgG、HP-IgM抗体阳性率分别为22.0%和17.1%,均显著高于对照组10.0%和2.0%。然而,Hp如何影响PSS发病,还需更多研究进一步探索。此外,链球菌溶血素O在PSS患者血清中阳性率为17.1%,显著高于对照组的7.0%,提示溶血性链球菌在PSS的发生和发展中可能起到一定作用[28]

1.2 免疫遗传因素

PSS患者前房房水中的炎症因子水平较非PSS对照患者显著升高,如TNF-α、IL-8、IL-10等[29]。越来越多研究关注到PSS患者前房的免疫炎症反应和免疫遗传因素,探讨潜在病因或发病因素。
人白细胞抗原(human leucocyte antigen,HLA)作为一类细胞膜表面抗原,在多种生理、免疫防御、自身免疫反应过程中发挥重要作用[30]。前葡萄膜炎、多发性硬化相关中间葡萄膜炎及交感性眼炎等与HLAI类分子相关联[31-34]。对PSS患者的HLA测序分型结果[31-34]显示:等位基因HLA-Bw54、HLA-C*1402、HLA-E*01:03频率及单倍型HLA-Bw54-Cw1频率显著高于对照组,另外基因型HLA-E*01:01/01:03、HLA-E*01:03/01:03频率亦高于对照组。Zhao等[35-37]还在1例中国PSS患者中发现了新的HLA-G等位基因——HLA-G*01:01:01:07,提示HLA可能参与PSS的发生发展。
Toll样受体(Toll-like receptors,TLRs)定位于细胞膜表面,是一类与固有免疫及适应性免疫相关联的模式识别受体。已有研究[38]报道:PSS患者基因型TLR2/rs3804100 TT频率及T等位基因频率高于正常人群,而基因型TLR2/rs5743705 TT频率则低于正常人群。由于上述显著性差异未通过Bonferroni校正,TLR基因多态性及此类模式识别受体与PSS的关联尚需更多研究来验证。
细胞毒性T淋巴细胞相关蛋白4(CTLA-4)和程序性细胞死亡1(PD-1)是关键的免疫检查点。一项研究[39]对中国南方人群进行基因分型,发现PSS患者CTLA-4的rs733618 T等位基因频率和rs733618 A等位基因频率显著高于健康对照组;且PSS患者血浆sCTLA-4和sPD-1水平明显高于对照组。提示CTLA-4和PD-1基因多态性与中国南方人群PSS易感性有关,血浆sCTLA-4和sPD-1蛋白水平的上调可能是PSS活动期免疫检查点功能紊乱的原因之一。
此外,有研究[40]对6个补体途径基因的27个变异体的单核苷酸多态性基因分型法进行检测,分析发现补体因子H变异与PSS及其临床参数的遗传联系,提示补体替代途径可能在PSS的发病机制中起重要作用。

1.3 血管内皮功能异常

血管内皮参与调节眼部血管血供,其功能异常会导致眼部供血不足,局部组织缺血-再灌注损伤可造成青光眼视神经病变[41]。肱动脉血流介导的血管扩张(flow-mediated vasodilation,FMD)是评价血管内皮功能的主要指标,临床研究[42-43]发现青光眼患者肱动脉FMD与正常对照组相比显著变小,推测青光眼患者可能存在血管内皮功能受损。PSS患者肱动脉FMD显著小于对照组,提示PSS患者存在血管内皮功能异常[44]

1.4 其他

PSS病因还包括过敏反应及自主神经功能紊乱。1985年Demailly等[45]报道了13例具有过敏体征的PSS患者,在特定的脱敏治疗下,发作频率降低,甚至最终消失。1998年Puri等[46]报道了一位双眼同时发作的PSS患者,其患有以双侧强直性瞳孔和深腱反射缺失为特征的霍姆斯-阿迪综合征,Puri等[46]认为霍姆斯-阿迪综合征导致的自主神经失衡可能是PSS潜在致病因素。
此外,最新的研究报道首次使用代谢组学方法检测到患者房水样品中14种受干扰的代谢物,确定11条碳水化合物、氨基酸代谢和能量代谢途径为PSS的主要干扰途径;异常的赖氨酸降解代谢、缬氨酸-亮氨酸-异亮氨酸生物合成和柠檬酸循环被认为是PSS发生的最重要因素[47],可能会为PSS疾病提供新的潜在的代谢生物标志物。

2 治疗进展

PSS患者的治疗主要包括药物治疗和手术治疗,其中主要以药物治疗(抗炎、抗病毒、抗感染等)为主,对于出现视神经损伤、药物治疗不敏感的PSS患者,再行手术治疗以达到降低眼压、保护视神经的目的。

2.1 药物治疗

2.1.1 抗炎药物
由于PSS是一组以前葡萄膜炎为中心的综合征,抗炎药物是治疗的首要选择之一。抗炎药物主要包括糖皮质激素如醋酸泼尼松龙等,及非甾体类抗炎药如双氯酚酸钠等。在PSS炎症发作急性期,局部应用糖皮质激素能够有效控制炎症,但应用激素类滴眼液可能会诱发眼压升高,使PSS患者病情更为复杂。对于这类患者,非甾体类抗炎药可替代激素类药物发挥作用[3]。单用激素与激素联合醋氮酰胺治疗效果无显著差异,可见抗炎治疗在PSS病情控制中的首要地位[48]。另外,口服消炎痛在治疗PSS方面可达到与激素联合醋氮酰胺相同的效果[49]
2.1.2 抗青光眼药物
反复眼压升高会导致视盘的杯盘比增大、视网膜神经纤维层变薄和视野缩小,严重者甚至出现失明。因此,控制眼压是PSS治疗目标之一。常用方案为局部应用β肾上腺素受体抑制剂或口服碳酸酐酶抑制剂[3]。前列腺素在PSS病情进展中发挥重要作用,发作眼PGE2水平显著升高,因此与原发性青光眼治疗方案不同,PSS治疗过程禁用前列腺素类降眼压药物[50]。然而,抗青光眼药物并不改善PSS的复发率,因此不用于复发间期的巩固治疗。
2.1.3 抗病毒药物
局部应用皮质类固醇及抗青光眼药物是首要选择。除此之外,越来越多研究证实清除前房内CMV有助于控制PSS发作及进展并显著改善其预后。Accorinti等对接受抗病毒治疗的CMV相关前葡萄膜炎患者进行了回顾性分析,结果显示抗病毒治疗能够减少前葡萄膜炎的发作次数[14]。一项前瞻性研究[51]收集了126例PSS患眼,其中CMV阳性的68例眼使用2%更昔洛韦滴眼液3个月后(诱导剂量:2~3 h/次;维持剂量:4 h/次),房水CMV转阴;长期使用可有效控制眼压、保留角膜内皮细胞数目。与上述结果一致,翟如仪等给予PSS患者2%更昔洛韦滴眼液(4次/d)治疗约5周后,患者的临床表现均有好转[52]。长期使用更昔洛韦眼凝胶或更昔洛韦口服药,可有效维持眼压稳定,减少发作次数,保留较好的中央视力和角膜内皮细胞数[53-57]。Hwang等[58]给予CMV阳性前葡萄膜炎患者单次玻璃体腔注射更昔洛韦(2 mg/0.05 mL),后续口服更昔洛韦(900 mg bid)1~3个月或不口服,发现在12~22个月后,其炎症及眼压均控制良好。
Wong等[53]对口服更昔洛韦(负荷剂量900 mg bid 2周,维持剂量450 mg bid≥6周)的治疗效果进行了评估,发现CMV阳性前葡萄膜炎患眼视觉灵敏度由0.58提高到0.37;平均眼压由18.3 mmHg降至11.7 mmHg(1 mmHg=0.133 kPa),但在停药后,有38.5%患眼出现复发,在PSS组复发率为60%。新加坡一项研究[59]对72例CMV阳性前葡萄膜炎患眼进行了回顾性分析,结果显示全身或玻璃体内应用更昔洛韦相对于更昔洛韦凝胶对症状的改善作用更为明显,但同时也有很高的复发率;更昔洛韦凝胶虽疗效中等,但复发率相对较低。Sobolewska等[57]则观察了长期口服更昔洛韦(负荷剂量900 mg bid持续6周,维持剂量450 mg bid持续4~6个月)对11例PSS患者的治疗效果,其中63.6%患者的炎症及眼压得到有效控制,54.5%患者能在约14个月时停药,在停药患者中复发率为33.3%。值得注意的是,尽管低浓度(≤0.5 mg/mL)则对细胞活力无明显影响,高浓度更昔洛韦(≥5 mg/mL)对角膜内皮细胞毒性作用显著[60]。因此在选择应用更昔洛韦药物时,应谨慎权衡其浓度与剂量。
尽管不同国家的多个研究均已证实了抗病毒治疗的有效性,仍有部分患者在随访结束时存在慢性小梁网炎症或眼压升高,这些患者往往需要持续抗青光眼治疗或接受滤过手术;也有部分患者在停药后出现复发。由此可见对症治疗(皮质类固醇及降眼压药物)联合抗病毒治疗的局限性,针对PSS确切机制及药物靶点的进一步研究迫在眉睫。

2.2 手术

对出现视神经损伤,且抗炎及抗青光眼药物治疗不敏感的PSS患者,需进行手术治疗以达到降低眼压,减缓神经纤维层及视野损伤的目的。尽管相对于非葡萄膜炎患者,葡萄膜炎患者滤过性手术成功率较低,其仍是PSS的治疗手段之一。造成葡萄膜炎患者滤过性手术失败的原因可能是其结膜内含有更多的成纤维细胞、淋巴细胞、巨噬细胞等,更易导致滤过泡粘连;而联合应用抗代谢药物如丝裂霉素C、5-氟尿嘧啶等则有助于防止粘连,维持滤过泡的正常功能[2]
Jap等[61]对53例PSS患眼的治疗过程进行了回顾性分析,其中17%接受小梁切除术联合丝裂霉素C治疗,80%患眼术后眼压控制良好。Iwao等[62]则对101例接受小梁切除术的葡萄膜炎性青光眼(uveitic glaucoma,UG)患眼进行了超过30个月的观察,并以103例POAG患眼为对照,发现UG组手术成功率仅稍低于POAG组(71.3% vs 89.7%),且两组并发症发生率无显著差异。Artini等[63]在此基础上应用可调整缝线,对5位经抗青光眼及抗炎治疗效果不佳,PSS反复发作且视神经损伤持续进展的患者进行治疗。其中4位患者在观察期内未出现复发,1位患者虽症状复发,但眼压未超过22 mmHg,所有患者滤过泡功能良好,视神经损伤进展停止。由此可见,小梁切除术有助于预防眼压急剧升高所导致的神经损伤,是一种安全有效的术式。
除此之外,小梁消融术,深层巩膜切除术等也被应用于PSS患者。Pahlitzsch等[64]对7例CMV阳性PSS患眼施行小梁消融术,术后其平均眼压由40 mmHg降至13 mmHg,在12个月观察期内,所有患者均未出现复发。对于处在炎症状态下的患眼,非穿透性手术——深层巩膜切除术被认为拥有更低的术后并发症发生率[65]。Dupas等[65]对1例接受深层巩膜切除术的患者进行了长达7年的观察,发现其眼压控制良好,未出现并发症及明显视神经损伤。相对于小梁消融术及小梁切开术,小梁切除术控制眼压成功率更高。深层巩膜切除术成功率则与小梁切除术相当,但深层巩膜切除术要求患者有较高的依从性且需要更多的术后调整操作。
综上所述,PSS是以前节炎症(青光眼睫状体炎或角膜内皮炎)为主要表现的复发性疾病,具体病因尚不明确,感染、免疫遗传因素及血管内皮功能障碍等均可能与其相关。尽管PSS总体预后良好,现有治疗手段如抗炎、抗青光眼等均以对症为主要目标,并不能有效控制复发率;而反复眼压骤升易造成青光眼视神经病变。PSS进程中,局部病原体感染与炎症的关系、复发的病理生理机制以及免疫因素在其中发挥的作用,亟需更多的研究提供证据支持。对PSS病因及发病机制的进一步了解将有助于探索药物新靶点,从而达到有效控制炎症发生发展、降低复发率及保护视神经的目的。

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