关键词：慢性中心性浆液性脉络膜视网膜病变；激光疗法，口服制剂，复发
Abstract: the central serous venous choroid retinal disease (csc) is a common disease that occurs in the retina, and the acute disease has a certain self-limitation, but about five percent of the patients can be changed into chronic diseases, and the current treatment of drugs and laser is beneficial for the treatment of chronic central serous retinal choroid lesions (cCSC)
Keywords: chronic central serous choroid retinopathy; Laser therapy, oral preparation
慢性中心性浆液性脉络膜视网膜病变病程持续时间超3-6个月，主要表现为RPE弥散性失代偿所致的视网膜神经上皮下及色素上皮间液体积存，以及RPE的萎缩。引起患者视物变形，严重危害患者视力，可造成永久性视力损害。目前病因尚不明确，可能受心理压力、睡眠障碍，性格因素，尤其是A型性格，皮质醇激素升高，儿茶酚胺类药物使用等因素影响[[.Yannuzzi LA.?Type A behavior and central serous chorioretinopathy.?Trans Am Ophthalmol Soc. 1986;84:799–845]]，[[ Garg SP, Dada T, Talwar D, Biswas NR.?Endogenous cortisol profile in patients with central serous chorioretinopathy.?Br J Physiol Opt. 1997;81(11):962–964.]]，[[ Haimovici R, Rumelt S, Melby J.?Endocrine abnormalities in patients with central serous chorioretinopathy.?Ophthalmology. 2003;110(4):698–703.]]，[[ Tewari HK, Gadia R, Kumar D, Venkatesh P, Garg SP.?Sympathetic–parasympathetic activity and reactivity in central serous chorioretinopathy: a case–control study.?Invest Ophthalmol Vis Sci. 2006;47(8):3474.?]]，近年来研究还发现补体系统与幽门螺旋杆菌感染等也可能与CSC相关。现常用激光治疗，药物制剂治疗等取得了一定的效果。现对cCSC治疗方法进行综述。
1、激光治疗
1.1光动力疗法：一项ICGA对CSC的研究发现脉络膜血管充血及其无灌注区的局部血管通透性增高是cCSC发生神经上皮下及色素上皮浆液性脱离直接原因[[ Gass JD.?Pathogenesis of disciform detachment of the neuroepithelium. II. Idiopathic central serous choroidopathy.?Am J Ophthalmol?1967;63:587–615.]]?。光动力疗法可通过降低脉络膜通透性来治疗疾病，是目前治疗cCSC的主要方法。常配合使用维替泊芬（商品名Visudyne；瑞士Novartis AG），维替泊芬是一种可以积聚在异常血管的光敏剂，将其注入受损部位，激光通过作用于受损部位表面激活维泊芬产生氧自由基从而触发受损脉络膜血管和RPE的愈合机制。通过利用对脉络膜毛细血管的异常血管造成氧化损伤的机制，PDT可以通过可诱导视网膜下液的吸收和脉络膜血管重塑，以降低脉络膜血管通透性。
Lee等[[ Lee P Y, Kim K S, Lee W K. Severe choroidal ischemia following photodynamic therapy for pigment epithelial detachment and chronic central serous chorioretinopathy[J]. Japanese journal of ophthalmology, 2009, 53(1): 52-56.]]对3例CSC患者进行标准剂量PDT治疗后一例患者视力恢复但光线变暗，一例患者治疗后视力较治疗前视力下降，一例出现了并发性脉络膜新生血管。这说明标准剂量可能存在过度治疗。且在此前Yaman等[[ Yaman A, Arikan G, Saatci A O, et al. Choroidal neovascularization following photodynamic therapy in a patient with chronic central serous chorioretinopathy[J]. Bulletin de la Societe belge d'ophtalmologie, 2007, 303: 69-74. Shin J]]观察2例子接受标准剂量PDT治疗的患者均出现了脉络膜新生血管(CNV)。Shin等[ Shin J Y, Woo S J, Yu H G, et al. Comparison of efficacy and safety between half-fluence and full-fluence photodynamic therapy for chronic central serous chorioretinopathy[J]. Retina, 2011, 31(1): 119-126.]发现半剂量PDT治疗患者与全剂量PDT治疗患者预后视力无明显差异，但全剂量组复发率100%明显高于剂量组复发率94.1％(P?= 0.493）。董道权等[[ 董道权,董应丽,王志立, 等.60％剂量维替泊芬光动力疗法治疗慢性中心性浆液性脉络膜视网膜病变的远期效果及安全性[J].中华实验眼科杂志,2015,33(10):945-948.]]发现 60％剂量维替泊芬光动力疗法治疗发现其远期疗效及安全性均优于全剂量PDT，但治疗后 3个月，4眼仍有轻度遮挡感，视网膜轻度受损变薄。
为了减少并发症，现常用的是低剂量光动力疗法，选用半剂量、半通量或更低剂量维替泊芬光动力疗法。陈有信等[[ 陆慧琴,王尔茜,陈有信.半剂量维替泊芬光动力疗法治疗慢性中心性浆液性脉络膜视网膜病变疗效观察[J].中华眼底病杂志,2015,31(3):226-229.]]对35例35眼cCSC患者使用半剂量维替泊芬光动力疗法(PDT)治疗，发现治疗一月视网膜下积液吸收率（SRF）完全吸收率占82．9％；未完全吸收占17．1％。治疗后3个月，所有患眼SRF完全吸收率100．0％。治疗6月后复发3眼，经再次治疗后治愈，且治疗前后BCVA、CMT差异具有统计学意义（P<0.05）。刘洋等[[ 刘洋,黎蕾,徐格致, 等.半剂量光动力疗法治疗慢性中心性浆液性脉络膜视网膜病变二年的疗效评估[J].中华眼科杂志,2016,52(5):328-334.]]观察32例(35只眼)cCSC患者2年发现视力平均提高3.5行，均未较治疗前下降，治疗期间仅一只眼复发再次接受治疗。马为梅等[[ 马为梅,雷晓琴,田芳, 等.半剂量维替泊芬与半能量光动力疗法治疗慢性中心性浆液性脉络膜视网膜病变[J].眼科新进展,2017,37(4):341-343.]]比较半剂量维替泊芬（半剂量维替泊芬(3 mg·m-2。)和标准能量PDT(83 s，50 J·cm 2)治疗）与半能量光动力疗法组（全剂量维替泊芬(6 mg· m-2)和半能量PDT(42 s，25 J·cm-2)治疗）观察半年发现两组间视力、SFR等指标差异无统计学意义（P>0.05），安全性及有效性一致。吴敏等[[ 吴敏,胡竹林,薛黎萍, 等.半剂量维替泊芬和半能量PDT治疗慢性中心性浆液性脉络膜视网膜病变[J].眼科新进展,2015,35(7):646-648.]]采用相同的实验设计也发现两者安全性及有效性一致，但此外存在反复持续发作病例SRF虽然最终吸收，但视力的恢复差。无论是半剂量半能量PDT治疗安全性及有效性都是肯定的。而Nicolo等[ Nicolo M, Eandi CM, Alovisi C, Grignolo FM, Traverso CE, Musetti D, et al. Half-fluence versus half-dose photodynamic therapy in chronic central serous chorioretinopathy. Am J Ophthalmol. 2014;157:1033–7.]认为半剂量的PDT起效更快，效果更持久。
邹玉凌等[[ 邹玉凌,游志鹏.1/3剂量维替泊芬光动力疗法治疗慢性CSC的远期疗效观察[J].中国实用眼科杂志,2013,31(4):460-463.]]对43例cCSC患者45只眼采用1／3剂量维替泊芬光动力疗法治疗发现sh术后半年有效率100%，视力提高率达93%。徐建锋等[[ 徐建锋,莫荔,叶瑞珍, 等.1/3剂量与半剂量光动力疗法治疗慢性中心性浆液性脉络膜视网膜病变对比研究[J].中国实用眼科杂志,2017,35(3):273-276.]]比较低剂量1/3剂量PDT与半剂量PDT治疗发现两者安全性及有效性一致，但半剂量疗法复发率及效果可能优于1/3剂量组，最终治愈率1/3剂量组70．8％，而半剂量组96．2％，差异具有统计学意义（P=0．021)。虽然对不同PDT治疗进行尝试，但目前认为半剂量PDT疗法仍是首选。
1.2 亚阈值微脉冲激光治疗（SML）：微脉冲是一种短促高频的重复脉冲激光，现常用577nm、532nm、810nm波长激光于黄斑疾病中， Sousa等[[ Sousa Keissy,Calv?o-Santos Gil,Jo?o Marina et al. 532-nm Subthreshold Micropulse Laser for the Treatment of Chronic Central Serous Retinopathy.[J] .Clin Ophthalmol, 2020, 14: 525-531.]]运用532nmSML治疗发现仅42.3％（n = 11）的患者BCVA有提升，视网膜下液完全吸收患者超过50%，且无并发症出现。而577 nm SML具有中央凹附近的治疗相对安全的优点，可能是由于被叶黄素（一种位于黄斑内层和外层丛状层中的色素）吸收最少的原因[[ Mainster MA. Wavelength selection in macular photocoagulation. Tissue optics, thermal effects, and laser systems. Ophthalmology. 1986;93:952–8.]]。廖丹等[[ 廖丹,许立帅,戴乐, 等.577nm阈下微脉冲激光治疗黄斑中心凹渗漏的慢性中心性浆液性脉络膜视网膜病变[J].眼科新进展,2018,38(2):139-142.]]运用577 nm阈下微脉冲激光治疗cCSC发现患者在治疗后1个月、3 个月、6个月与治疗前比较视力提高，CMT及SRF降低，差异具有统计学意义。Scholz等[[ Scholz, P., Altay, L. & Fauser, S. Comparison of subthreshold micropulse laser (577?nm) treatment and half-dose photodynamic therapy in patients with chronic central serous chorioretinopathy.?Eye30,?1371–1377 (2016).?]]回顾性分析接受SML治疗的42例患者与接受半剂量PDT治疗的58例患者，患病小一年的患者SML组无反应者1例，半剂量PDT组无反应13例，差异具有统计学意义（P?= 0.246），而在病程大于一年患者治疗无反应者无明显差异。治疗期间1例患者对维替泊芬出现过敏反应，一例接受PDT治疗的患者疗程结束后出现了CNV。在病程小于一年的患者对SML的治疗反应明显大于PDT，SML的尽早治疗能更大获益。SML与PDT相比，由于SML对降低脉络膜厚度的作用有限，SML的疗效也会受到限制[[ Cheung CMG, Lee WK, Koizumi H, Dansingani K, Lai TYY, Freund KB. Pachychoroid disease. Eye (Lond). 2019;33:18–33.]]。
1.3 热激光疗法：Russo等[[ Russo A, Turano R, Morescalchi F, et al. Comparison of half-dose photodynamic therapy and 689 nm laser treatment in eyes with chronic central serous chorioretinopathy[J]. Graefe's Archive for Clinical and Experimental Ophthalmology, 2017, 255(6): 1141-1148.]]发现689nm激光疗法与半剂量PDT疗法均能有效治疗慢性CSC，能提高患者的BCVA，且能降低视网膜中央厚度及脉络膜厚度，并且在接受治疗的20只眼中有7只眼感光细胞完全恢复，其原理可能与亚致命热效应相关，刺激HSPs表达的热效应可解释非性效应致命连续波689-LT。
2、药物治疗：
2.1 抗VEGF药物：据报道慢性CSC视网膜下液的存在可能是由潜在的CNV所致。Shangli等[[ Ji, S., Wei, Y., Chen, J.?et al.?Clinical efficacy of anti-VEGF medications for central serous chorioretinopathy: a meta-analysis.?Int J Clin Pharm?39,?514–521 (2017).]]发现慢性CSC患者接受抗VEGF药物治疗后BCVA及CMT显著改善，是治疗慢性CSC的有效选择。Yumusak等[[ Yumusak Erhan,Gokcinar Nesrin Buyuktortop,Ornek Kemal,Choroidal thickness changes in non-treated acute and ranibizumab-treated chronic central serous chorioretinopathy.[J] .Medicine (Baltimore), 2018, 97: e12885.]]运用雷珠单抗治疗得到了同样的研究结论。
2.2 口服药物：研究显示患者性别为男性发生持续性复发性CSC的独立危险因素[[ I. Chatziralli, S. A. Kabanarou, E. Parikakis, A. Chatzirallis, T. Xirou, and P. Mitropoulos, “Risk factors for central serous chorioretinopathy: multivariate approach in a case-control study,”?Current Eye Research, vol. 42, no. 7, pp. 1069–1073, 2017.]]，可能与患者血清睾丸激素水平升高相关，该激素的升高能扩张血管，可能引起脉络膜血管扩张导致血管通透性升高。Forooghian等[[ Forooghian F, Meleth AD, Cukras C, Chew EY, Wong WT, Meyerle CB.?Finasteride for chronic central serous chorioretinopathy.?Retina. 2011;31(4):766–771. doi:10.1097/IAE.0b013e3181f04a35]]使用5-α还原酶抑制剂非那雄胺治疗疗效肯定，但存在停药后复发风险。同时盐皮质激素螺内酯和依普利酮也具有抗雄激素作用[[ P. M. Seferovic, F. Pelliccia, I. Zivkovic et al., “Mineralocorticoid receptor antagonists, a class beyond spironolactone—focus on the special pharmacologic properties of eplerenone,”?International Journal of Cardiology, vol. 200, pp. 3–7, 2015.]]，但原理并不清楚。盐皮质激素受体拮抗剂依普利酮可调节局部通透性，可有效减少SRF，SRF的光学密度可预测依普利酮治疗有效性[[ Joshi N P, Adam M K, Samara W A, et al. Optical density of subretinal fluid as a predictive biomarker for eyes with chronic central serous retinopathy treated with eplerenone[J]. Journal of VitreoRetinal Diseases, 2018, 2(1): 6-11.]]。研究显示抗糖皮质激素治疗如利福平等取得良好的疗效，利福平具有抗新生血管生成、抗氧化以及抗糖皮质激素作用[[ Shichiri M, Fukai N, Kono Y, Tanaka Y. Rifampicin as an oral angiogenesis inhibitor targeting hepatic cancers. Cancer Res. 2009;69:4760–8.]]，[[ Guengerich FP. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol. 1999;39:1–17.]]。Mattingly等[[ Mattingly J J, Amram A L, El-Annan J. Low-dose rifampin as maintenance therapy in chronic central serous chorioretinopathy[J]. Canadian Journal of Ophthalmology, 2018, 53(5): e182-e183.]]建议持续低剂量的利福平可作为维持治疗，同时降低不良事件的发生风险，Shulman等[[ Shulman Shiri,Goldenberg Dafna,Schwartz Roy et al. Oral Rifampin treatment for longstanding chronic central serous chorioretinopathy.[J] .Graefes Arch. Clin. Exp. Ophthalmol., 2016, 254: 15-22.]]对12名患者的14眼慢性CSC患者连续3个月每天口服300 mg一天两次在，患者BCVA第3个月时从治疗前20/60提高至平均20/50（P> 0.05）。3个月内视网膜厚度分别减少了25.3％，21.2％和21％（P <0.05）。平均脉络膜厚度为从476μ（SD 188μ）降至4??27μ（SD 125μ）（P> 0.05）。治疗3个月后的SRF减少了9眼（64％），其中6眼完全消退，这6眼中有4眼在第6个月仍没有积液。此外针对睡眠障碍的褪黑素及幽门螺旋杆菌感染抗HP治疗药物的运用也对疾病的治疗取得了良好的效果。
2.3 复方樟柳碱：研究显示复方樟柳碱能改善局部微循环对慢性CSC有效[[ 罗彤，陈丽华．复方樟柳碱治疗中心性浆液性脉络膜视网膜病 变的疗效观察[J]．中国药房，2008，19(26)：2044-2046．]]、[[ 李桂芹,管英朝,李克芳.复方樟柳碱在中心性浆液性脉络膜视网膜病变临床治疗中的应用价值分析[J].临床医药文献电子杂志,2017,4(28):5505+5508.]]。苏雯琪等[[ 苏雯琪,胡立影,李筱荣, 等.复方樟柳碱注射液治疗慢性中心性浆液性脉络膜视网膜病变的临床研究[J].眼科新进展,2018,38(12):1137-1140.]]对比17例18眼复方樟柳碱注射液颞浅动脉旁注射联合常规药物（甲钴胺、迈之灵）治疗组及10例(11眼)单纯常规药物(甲钴胺、迈之灵)对照组，发现治疗3月后两组视力均有提升，但治疗6月后治疗组视力仍提升，但对照组较治疗3月时有所降低，且6个月内治疗组SRF持续降低。
3、总结讨论：
激光及药物的运用被证明对慢性CSC是有效的，睡眠障碍、男性、高龄、酒精等也被认为是CSC反复发作的独立危险因素[[ R. Haimovici, S. Koh, D. R. Gagnon, T. Lehrfeld, and S. Wellik, “Risk factors for central serous chorioretinopathy,”?Ophthalmology, vol. 111, no. 2, pp. 244–249, 2004.]]，[32]，但Jia等[36]并没有发现酒精与CSC的相关性，可能与原始数据精确性相关。仍存在部分反复复发的病例该部分病例可能存在导致疾病危险因素如睡眠障碍等持续存在，睡眠障碍是除外性别、年龄外唯一可以治疗或控制的CSC危险因素[[ Yu J, Xu G, Chang Q, et al. Risk Factors for Persistent or Recurrent Central Serous Chorioretinopathy[J]. Journal of ophthalmology, 2019, 2019.]]。褪黑素具有调节昼夜节律、降低VEGF水平、抗氧化因子、和抑制糖皮质激素等作用[[ Pandi-Perumal SR, Trakht I, Spence DW, Srinivasan V, Dagan Y, Cardinali DP. The roles of melatonin and light in the pathophysiology and treatment of circadian rhythm sleep disorders. Nat Clin Pract Neurol. 2008;4:436–47.]]，[[ Lissoni P, Rovelli F, Malugani F, Bucovec R, Conti A, Maestroni GJ. Anti-angiogenic activity of melatonin in advanced cancer patients. Neuro Endocrinol Lett. 2001;22:45–7.]]，[[ Siu AW, Maldonado M, Sanchez-Hidalgo M, Tan DX, Reiter RJ. Protective effects of melatonin in experimental free radical-related ocular diseases. J Pineal Res. 2006;40:101–9.]]，[[ Esposito E, Cuzzocrea S. Antiinflammatory activity of melatonin in central nervous system. Curr Neuropharmacol. 2010;8:228–42.]]，可以考虑将其运用于慢性CSC的替代疗法。Inoue 等[[ ?Inoue R, Sawa M, Tsujikawa M, Gomi F.?Association between the efficacy of photodynamic therapy and indocyanine green angiography findings for central serous chorioretinopathy.?Am J Ophthalmol. 2010;149(3):441–6.e1-2.]]发现部分cCSC患者ICGA脉络膜无强烈高荧光的患者PDT治疗复发率高，这和患者脉络膜血管静水压相关，静水压低的情况下对PDT治疗浆液性视网膜脱离反应欠佳。
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Haga等[[Haga F, Maruko R, Sato C, et al. Long-term prognostic factors of chronic central serous chorioretinopathy after half-dose photodynamic therapy: a 3-year follow-up study[J]. PloS one, 2017, 12(7).]]研究表明术前BCVA视力水平对术后视力恢复也有一定影响，但Tseng[[ Tseng CC, Chen SN.?Long-term efficacy of half-dose photodynamic therapy on chronic central serous chorioretinopathy.?Br J Ophthalmol. 2015. Epub 2015/02/15.]] 的一项观察cCSC远期疗效的研究表明术前BCVA与术后BCVA水平并无相关性。Nicholson等[[ Nicholson B，Noble J，Forooghian F，et a1．Central serous ehorioretinopathy：update on pathophysiology and treatment[J]．Surv Ophthalmol，2013，58(2)：103—126．doi：10．1016／j．survophthal． 2012．07．004．]]发现患者的病程对疾病视力预后会产生影响，特别是病程大于一年的患者，长期病程会导致局部视细胞丢失，视网膜进行性萎缩变薄。此外Haga[43]还发现尽早的使用PDT治疗，可以提高患者预后，这也说明疾病的病程对患者视力预后的影响。但Chung等[[ C. Y. Chung, Y. Y. Chan, and K. K. W. Li, “Angiographic and tomographic prognostic factors of chronic central serous chorioretinopathy treated with half-dose photodynamic therapy,”?Ophthalmologica, vol. 240, no. 1, pp. 37–44, 2018. ]]和Iacono等[[ P. Iacono, M. Tedeschi, B. Boccassini, A. C. Valloti, M. Varano, and M. C. Parravano, “Chronic central serous chorioretinopathy: early and late morphological and functional changes after verteporfin photodynamic therapy,”?Retina, vol. 39, no. 5, pp. 980–987, 2018.]]发现症状的持续时间与视网膜下液的无关 Sousa等[[ Sousa K, Viana A R, Pires J, et al. Outer Nuclear Layer as the Main Predictor to Anatomic Response to Half Dose Photodynamic Therapy in Chronic Central Serous Retinopathy[J]. Journal of ophthalmology, 2019, 2019.]]等发现该疾病的视网膜功能障碍可能与发生的外部视网膜变化有关，但和患病时间无相关性，且发现外核心层厚度是SRF吸收的唯一预测因子??。现在还缺乏大规模多中心的试验去研究术前术后BCVA的有无关联，出现这种结果差异还可能与选择病例的个体差异性相关，尤其是所选患者视网膜受损情况相关。
对无反应或慢性复发性CSC，常运用激光与药物结合方式治疗，PDT联合口服制剂：陈威等[ 陈威,高晶,朱晖, 等.螺内酯联合30％剂量维替泊芬光动力疗法治疗慢性中心性浆液性脉络膜视网膜病变[J].医药导报,2018,37(10):1220-1223.]运用螺内酯联合30％剂量维替泊芬（治疗组）对比半剂量PDT（对照组）发现两者均安全有效，但治疗组中央黄斑区视网膜厚度(CMT)及黄斑中心凹下脉络膜厚度(SFCT)明显降低，差异有统计学意义，且治疗组在两个月治疗后视力恢复更为迅速。PDT联合抗VEGF药物：Asahi 等[ Asahi Masumi G,Chon Andrew T,Gallemore Esmeralda et al. Photodynamic therapy combined with antivascular endothelial growth factor treatment for recalcitrant chronic central serous chorioretinopathy.[J] .Clin Ophthalmol, 2017, 11: 2051-2056.
]对8例顽固性慢性CSC患者PDT联合抗VEGF药物治疗其中7例接受贝珠伐单抗，1例接受阿柏西普治疗，经治疗所有患者视网膜下液均消失，对其观察随访13个月，只发现一例患者在接受治疗8个月后复发，但在再次接受联合治疗后好转。
综上所述针目前PDT治疗仍是主要治疗方式，其中半剂量PDT疗法是常用治疗方法，但除此之外亚阈值微脉冲激光治疗、经瞳孔温热疗法、药物治疗等也是可选治疗方式。慢性CSC治疗的难点在于其复发性及低反应性，但可考虑交叉治疗或联合治疗等方式。
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论文作者: 雷羽1,，郑燕林▲
论文发表刊物:《医师在线》2020年6期
论文发表时间:2020/4/21
标签：剂量论文; 视网膜论文; 脉络论文; 浆液论文; 患者论文; 心性论文; 疗法论文; 《医师在线》2020年6期论文;