REVIEW ARTICLE
An Update on the Diagnosis and Management of Central Serous Chorioretinopathy David T. Liu, FRCS,* Andrew T. Fok, FRCS,Þ and Dennis S.C. Lam, MD, FRCOphthþ Abstract: Central serous chorioretinopathy (CSC) is a complicated disease with still unclear causes, pathogenesis and management strategy despite active research. CSC has been traditionally considered as a selflimiting disease where spontaneous recovery occurs in 90% of the patients within a few months. This proclaimed ‘‘benign’’ nature of CSC, however, has been queried by increasing scientific evidence that permanent photoreceptors damage and neurosensory-cystoid degeneration of macula occur in the event of chronic CSC. CSC is probably not a benign disease. Treatments for CSC are still evolving. It is very difficult to define the proper timing for active treatment of CSC because it is not easy to define a universally accepted cut-off time point for active intervention. There is a recent suggestion that active CSC treatment should be considered if symptoms last longer than 3 months as atrophy of photoreceptors may occur as early as 4 months after initial presentation. The CSC patients may be stratified into two groups based on the initial presenting visual acuity and duration of symptom: the good visual prognosis group and the dubious visual prognosis group. The management may then be tailor-made based on the visual prognosis group. ‘‘Safety-enhanced’’ photodynamic therapy (PDT) using lower doses and reduced fluence is still the mainstay of treatment. Newer treatment modalities like intravitreal anti-VEGF therapy, micropulsed diode laser treatment, and the use of corticosteroid antagonists do warrant further investigation. Combination therapies involving two or more of the above modalities of treatments may have a role to play in this actively researched area. Key Words: central serous chorioretinopathy, photodynamic therapy, intravitreal anti-VEGF therapy, micropulsed diode laser treatment, corticosteroid antagonists (Asia-Pac J Ophthalmol 2012;1: 296Y302)
C
entral serous chorioretinopathy (CSC) was initially thought to be primarily a retinal inflammatory disorder when it was first coined by Albrecht von Graefe1 in 1866 as ‘‘central recurrent retinitis.’’ Although the pathogenesis of the disease is still not fully understood, advances in investigative technology over the years such as indocyanine green angiography (ICGA) and optical coherence tomography (OCT) have led us to understand that CSC is a chorioretinal disorder. Although most patients with CSC recover spontaneously with good visual outcome, some develop chronic recurrent macular detachments with permanent visual impairment. Multiple treatment methods have been tried over the years with variable success.
From the *Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong; †Hong Kong Eye Hospital; ‡Dennis Lam & Partners Eye Center, Hong Kong; and §Zhongshan Ophthalmic Center, Guangzhou, People’s Republic of China. Received for publication August 1, 2012; accepted August 20, 2012. The authors have no funding or conflicts of interest to declare. Reprints: Dennis S.C. Lam, MD, Dennis Lam & Partners Eye Center, Suite 1515, Central Bldg, 1-3 Pedder St, Central, Hong Kong. E-mail: [email protected]. Copyright * 2012 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0b013e31826fdfd4
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PATHOGENESIS AND RISK FACTORS Central serous chorioretinopathy is believed to be a condition with multietiologic factors that lead to a final pathway of choroidal vascular abnormalities.2 Indocyanine green angiography is able to demonstrate choroidal vascular dilatation and hyperpermeability in patients with CSC.3 The choroidal hydrostatic pressure elevation leads to the breakdown of the retinal pigment epithelial (RPE) tight junctions, allowing fluid to pass from the choroid to the subretinal space.4 Elevated corticosteroid levels are a well-accepted predisposing factor for CSC.5 Common sources of exogenous corticosteroid include systemic steroid intake for conditions such as autoimmune disease and after organ transplantation.6,7 Risk of CSC might also be raised following other routes of corticosteroids administration including topical, intra-articular, and intranasal.8Y10 Causes of elevated endogenous cortisol production include pregnancy and Cushing disease.11Y15 Corticosteroids are believed to increase the risk of CSC through multiple mechanisms including vascular hyperpermeability, reduced nitric oxide levels, and damage to RPE cell tight junctions.16Y18 Yannuzzi19 first suggested an association between CSC and type A personality. It was postulated that elevated catecholamine levels in these patients might cause choroidal vasoconstriction by activating the sympathetic nervous system. Numerous risk factors of CSC including smoking, hypertension, allergic respiratory disease, the use of alcohol, antihistamine, antibiotic, sympathomimetic agents, Raf/MEK/ERK inhibitors, and phosphodiesterase 5 inhibitors have also been suggested in the literature.12,20Y23 Helicobacter pylori infection and obstructive sleep apnea have been reported to be associated with CSC, and their treatment might hasten the resolution of subretinal fluid.24 The association of vascular endothelial growth factor (VEGF) with CSC is unclear. Studies showed that aqueous and plasma VEGF levels are not elevated in patients with CSC.2,25,26 Intravitreal antiVEGF injections also did not yield any promising result.
NATURAL HISTORY Central serous chorioretinopathy is traditionally thought of as a self-limiting disease where spontaneous recovery occurs in 90% of the patients within a few months,27Y29 Visual acuity usually returns to normal after the resolution of subretinal fluid, but the patient might be left with mild residual symptoms such as reduction in contract sensitivity. However, recurrent disease is also problematic as approximately 50% of patients might develop recurrence.30Y33 Half of the recurrences develop within the first year of onset of disease. Study showed that a history of psychiatric illness is associated with a higher rate of recurrence.29 A small percentage of patients may experience progression of chronic diseases with prolonged serous macular detachment. Patients with chronic disease and poor visual acuity on presentation are associated with poor visual outcomes.34 Complications that could lead to severe irreversible visual loss include RPE atrophy, choroidal neovascularization (CNV), and polypoidal choroidal vasculopathy (PCV).35 Therefore, we no longer believe CSC to be a benign disease.
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CLINICAL FEATURES Central serous chorioretinopathy typically affects males, and the onset of disease is usually in the most productive age group of 30s to 40s.36 It is more common in Asians than in whites. Central serous chorioretinopathy is uncommon in blacks, but it is more severe when it does happen.37 Initially, usually only 1 eye is affected, but the fellow eye might also be involved in chronic cases and patients with excessive corticosteroids. Patients with CSC commonly present with blurring of vision, relative central scotoma, micropsia, dyschromatopsia, and metamorphopsia. Hyperopic shift might occur because the detached neurosensory retina is displaced anteriorly, shortening the optical system of the eye. The patient might complain of increasing hypermetropia when trying to get new glasses. Binocular indirect ophthalmoscopy is usually adequate in diagnosing CSC. In difficult cases with minimal amount of subretinal fluid, fundus contact lens might be useful. Fundus examination usually reveals an oval area of neurosensory retinal detachment with or without pigment epithelial detachment (PED) in the macular region. The subretinal fluid can either be transparent or cloudy.38 Subretinal or sub-RPE fibrin formation can occur, and spontaneous resolution is the rule, but occasionally fibrosis could occur with subsequent permanent visual loss. Tiny yellow dots are commonly seen underneath the detached retina and are suggested to be related to the phagocytosis process of the shed outer segments of photoreceptors.39 In chronic CSC, RPE change and atrophy might be present. Some patients present with inferior bullous retinal detachments.7,40Y42 If the condition becomes chronic, one might see an atrophic RPE tract connecting the macula to the inferior detachment. Complications of chronic CSC such as cystoid macular edema and secondary CNV might also be seen clinically.
INVESTIGATIONS
Management of Central Serous Chorioretinopathy
Other Investigations Optical coherence tomography, FA, and ICGA are the standard investigations for CSC and are adequate for diagnostic confirmation as well as differentiating it from other differential diagnoses. Other adjunctive investigations might offer information that improves our understanding of the disease. Multifocal electroretinography and microperimetry assess the macular function in objective and subjective manners, respectively. Multifocal electroretinography response amplitudes are reduced in CSC and correlate with visual acuity.48 Microperimetry measures macular sensitivity and is reduced in patients with CSC.49 Macular sensitivity was found to correlate well with OCT macular thickness.49,50 Fundus autofluorescence features in CSC depend on whether the condition is acute or chronic. In acute cases, fundus autofluorescence usually shows hypofluorescence because of blockage by subretinal fluid. However, in chronic cases, hyperfluorescence might be present instead.51
Differential Diagnoses Several disease entities should be considered before labeling a patient with CSC. Age-related macular degeneration and PCV can mimic CSC especially when there is an absence of hemorrhage. Polypoidal choroidal vasculopathy is particularly problematic because it can appear in relatively young patients. Fluorescein angiography and ICGA are useful in differentiating between the conditions. Intraocular tumors, Vogt-Koyanagi-Harada disease, and optic disc pit can all cause serous detachment of the retina. However, they can usually be differentiated from CSC by their typical ocular features. Intraocular tumors such as choroidal metastasis and choroidal hemangioma can be seen as choroidal mass on fundoscopy. Patients with Vogt-Koyanagi-Harada disease might have systemic symptoms, and the condition is often bilateral. Optic disc pit is usually evident on fundoscopy and is usually located on the temporal aspect of the optic disc. Autoimmune disease causing neurosensory retinal detachment usually shows other systemic signs.
Optical Coherence Tomography Optical coherence tomography has become the first-line investigation for CSC in recent years. It allows for high-resolution imaging of the macula and can clearly document the presence of subretinal fluid.43 Other features such as PED and subclinical lesions in the fellow eye can also be detected.44 Optical coherence tomography allows for objective quantification of macular thickness and is perfect for monitoring disease progression and response to treatment. Enhanced depth imagingYOCT scans the deeper structures of the macula and enables the measurement of the degree of choroidal thickness, which is an established feature of CSC. Moreover, studies have used enhanced depth imagingYOCT to demonstrate the reduction in choroidal thickness after treatment with photodynamic therapy (PDT).45
Angiography The classic description of fluorescein angiography (FA) in CSC is the ink-blot and smoke-stack appearance.46 These usually occur in patients with acute CSC. Other features include the pooling of dye in the PED and multifocal leakage in multifocal CSC. In patients with chronic CSC, FA might show RPE window defects and nonspecific leakage patterns. Indocyanine green angiography is very useful in CSC and is a prerequisite for any patients being considered for treatment. In the early phase, there are usually dilated choroidal vessels followed by choroidal hyperpermeability in the later phase.47 The features of hyperdynamic choroidal circulation might be present in the asymptomatic fellow eye as well. * 2012 Asia Pacific Academy of Ophthalmology
TREATMENT OF CENTRAL SEROUS CHORIORETINOPATHY Observation in Most Cases Is CSC a benign disease? This is a difficult question that has haunted ophthalmologists and medical retina specialists worldwide for many years.29 In the past, people believed that CSC was a benign disease, and observation was usually deemed as the first-line management for CSC. Removal of any identifiable endogenous or more commonly exogenous source of corticosteroids through careful history taking is another important yet simple treatment that can be offered to CSC patients. The high successful rate observed (90% resolution of detachment) associated with observation has reinforced the concept that CSC may truly be a benign disease.52 General measures such as psychotherapy and relaxation exercise have been proposed as well.27,53 In 2 recent prevailing reviews on CSC, there have been increasing queries and doubts about the ‘‘benign’’ nature of CSC as pathological studies have shown the presence of photoreceptor damage and neurosensory-cystoid degeneration of macula in the event of chronic CSC.27,53 In the past, it is very difficult to define the proper timing for active treatment of CSC because it is not easy to define a universally accepted cutoff time point for active intervention in the management of CSC. However, there was recent suggestion that active CSC treatment should be considered in case symptoms lasting longer than 3 months as atrophy of photoreceptors may www.apjo.org
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occur as early as 4 months after initial presentation.33,34 The CSC patients may be stratified into 2 groups based on the initial presenting visual acuity and duration of symptom: the good visual prognosis group (good presenting visual acuity and duration of symptom G3 months) and the dubious visual prognosis group (poor presenting visual acuity and duration of symptom 93 months). The management may then be tailor-made based on the visual prognosis group (Fig. 1). The controversy over the best timing for treating CSC, nevertheless, continues, and further research is needed.
or extravascular leakage.56Y58 This effect might be prolonged and sustained for years. In site of the proven efficacy, use of PDT in conventional verteporfin dosage, fluence, and spot size might given rise to severe complications such as secondary CNV formation, choriocapillaris ischemia, RPE atrophy, and subtle electrophysiological disturbance recorded on multifocal electroretinography.56,59
Safety-Enhanced Photodynamic Therapy in Selected Cases
Theoretically, standard PDT may be modified by reducing the verteporfin dosage as well as shortening the time between infusion and laser application so as to preserve PDT efficacy in treating CSC while minimizing its adverse effects. For instance, reducing the dosage of verteporfin infusion by half may lower the risk of retinal-choroidal complications without jeopardizing the efficacy of PDT.60 In a number of prospective studies, this half-dose regimen has been shown to be able to achieve similar
Photodynamic Therapy With Verteporfin The efficacy of PDT in treating CSC cases was substantiated by the TAP and VIP studies.54,55 Pathophysiologically, PDT may lead to choroidal vascular remodeling by inducing choriocapillaris narrowing and reducing choroidal exudation
Safety-Enhanced Photodynamic Therapy With Reduced Verteporfin Dosage
FIGURE 1. Suggested management algorithm for CSC. 3/12 = duration of symptoms of 3 months; 6/12 = duration of symptoms of 6 months.
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efficacy as the full-dose PDT without the well-known associated retinochoroidal complications such as choroidal ischemia, CNV formation, and posttreatment visual loss.61Y63 In a study about the use of safety-enhanced PDT with reduced verteporfin dosage in managing chronic CSC, 40 eyes (83.3%) had complete resolution of serous detachment at 3 months after treatment and 43 eyes (89.6%) at 12 months after treatment. The mean visual acuity improvement was 1.6 lines, and 45 eyes (95.8%) had stable or improved vision.63 More than 10 prospective, retrospective, and/or interventional case series, with or without randomization, were published.27,53 Therefore, based on the best available evidence, safety-enhanced PDT with reduced verteporfin dosage was deemed by most ophthalmologists and medical retina specialists as the first-line treatment for those CSC requiring active intervention.
beneficial role of combined PDT and intravitreal anti-VEGF for CSC patients in a small case series.91
Anticorticosteroid Treatment Anticorticosteroid treatment was first suggested by Dr. Lee Jampol from America. This postulation was based on the pathogenetic association between endogenous hypercortisolism and the development of CSC. The use of antiglucocorticoid agents including mifepristone and ketoconazole yielded insignificant results. Rifampin, a semisynthetic antituberculosis antibiotic, is a promising and possibly viable option as a number of rifampin-treated CSC patients showed good results with resolution of the fluid within 1 to 4 weeks.92
Other Potential But Still Exploratory Systemic Therapy Systemic Acetazolamide
Safety-Enhanced Photodynamic Therapy With Reduced Laser Fluence Altering the laser fluence or infusion time may be the alternative to reducing the dose of verteporfin to achieve safetyenhanced PDT. For example, PDT delivered in low fluence was found to be effective and safe in the treatment for chronic CSC despite reports of sinister complications such as RPE rip in a number of cases managed by reduced fluence PDT.64Y69
Historical Thermal (Argon) Laser Photocoagulation and Micropulsed Diode Laser Historically, thermal laser photocoagulation was noted to be able to increase resolution of neurosensory detachment by producing laser photocoagulation over the detectable pigment epithelial leakage on FA.27Y29,70,71 Nevertheless, severe complications associated with thermal laser photocoagulation including enlargement of RPE scar, permanent scotoma, and CNV formation had been reported.72Y75 Therefore, most of the ophthalmic surgeons will reserve thermal laser photocoagulation for a scenario such as a solitary extrafoveal leaking point. There were queries toward the claimed efficacy of thermal laser photocoagulation as the final functional outcomes and the rate of recurrence seemed not to be affected.31 This is due to the fact that the underlying pathophysiological changes such as choriocapillaris hyperpermeability will not be altered by thermal laser photocoagulation. Recently, micropulse diode laser has picked up the momentum to treat CSC.76Y80 The diode laser emitted in micropulsed fashion allows subthreshold therapy without a visible burn end point. Nevertheless, in the event of more than 1 leaking point, the efficacy and safety of micropulse diode laser might be jeopardized.
The use of systemic acetazolamide to treat CSC originated only from several small case series.93 It might speed up the resolution of symptoms but not alter the final visual outcomes and the recurrence rate.94
Antiadrenergic Blockage and A-Blockers Tatham and Macfarlane95 reported the successful management of 2 CSC patients by oral propranolol 40 mg twice a day.
Aspirin, Finasteride, AntiYHelicobacter pylori Treatment The usefulness of low-dose aspirin, finasteride, and standard H. pylori eradication regimen was reported in a couple of single-center studies.96Y98
CONCLUSIONS Central serous chorioretinopathy is not a benign disease as we thought. It is important to note that treatments for CSC are still evolving. ‘‘Safety-enhanced’’ PDT using lower doses and reduced fluence is still the mainstay of treatment. Newer treatment modalities such as intravitreal anti-VEGF therapy, micropulsed diode laser treatment, and the use of corticosteroid antagonists are evolving with reported encouraging results in a limited number of studies, but they do warrant further investigation. Combination therapies involving 2 or more of the above modalities of treatments may be the new horizon in managing this mutifactorial disease and certainly have a role to play in this actively researched area. REFERENCES 1. von Graefe A. Ueber central recidivierende retinitis. Graefes Arch Clin Exp Ophthalmol. 1866;12:211Y215. 2. Spaide RF, Goldbaum M, Wong DWK, et al. Serous detachment of the retina. Retina. 2003;23:820Y846.
Transpupillary Thermotherapy The true efficacy of transpupillary thermotherapy in treating CSC might require further studies to substantiate.81Y84
Intravitreal AntiYVascular Endothelial Growth Factor Therapy With or Without Adjuvant Photodynamic Therapy In the era of intravitreal pharmacotherapy for macular diseases, there have been a couple of studies targeted to use intravitreal anti-VEGF to treat CSC.67,85Y90 These findings suggest that VEGF may be involved in fluid leakage in patients who have had chronic CSC.26 There was evidence suggesting the * 2012 Asia Pacific Academy of Ophthalmology
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73. Gartner J. Long-term follow-up of an ophthalmologist’s central serous retinopathy, photocoagulated by sungazing. Doc Ophthalmol. 1987;66:19Y33.
54. Chan WM, Lai TY, Tano Y, et al. Photodynamic therapy in macular diseases of Asian populations: when East meets West. Jpn J Ophthalmol. 2006;50:161Y169. 55. Chan WM, Lim TH, Pece A, et al. Verteporfin PDT for non-standard indications Y a review of current literature. Graefes Arch Clin Exp Ophthalmol. 2010;248:613Y626. 56. Chan WM, Lam DS, Lai TY, et al. Choroidal vascular remodelling in central serous chorioretinopathy after indocyanine green guided photodynamic therapy with verteporfin: a novel treatment at the primary disease level. Br J Ophthalmol. 2003;87:1453Y1458. 57. Schlotzer-Schrehardt U, Viestenz A, Naumann GO, et al. Dose-related structural effects of photodynamic therapy on choroidal and retinal structures of human eyes. Graefes Arch Clin Exp Ophthalmol. 2002;240:748Y757. 58. Schmidt-Erfurth U, Laqua H, Schlotzer-Schrehard U, et al. Histopathological changes following photodynamic therapy in human eyes. Arch Ophthalmol. 2002;120:835Y844. 59. Cardillo Piccolino F, Eandi CM, Ventre L, et al. Photodynamic therapy for chronic central serous chorioretinopathy. Retina. 2003;23:752Y763. 60. Maruko I, Iida T, Sugano Y, et al. Subfoveal choroidal thickness after treatment of central serous chorioretinopathy. Ophthalmology. 2010;117:1792Y1799. 61. Fujita K, Yuzawa M, Mori R. Retinal sensitivity after photodynamic therapy with half-dose verteporfin for chronic central serous: short-term results. Retina. 2011;31:772Y778. 62. Lai TY, Chan WM, Li H, et al. Safety enhanced photodynamic therapy with half dose verteporfin for chronic central serous chorioretinopathy: a short term pilot study. Br J Ophthalmol. 2006;90:869Y874. 63. Chan WM, Lai TY, Lai RY, et al. Safety enhanced photodynamic therapy for chronic central serous chorioretinopathy: one-year results of a prospective study. Retina. 2008;28:85Y93. 64. Reibaldi M, Boscia F, Avitabile T, et al. Functional retinal changes measured by microperimetry in standard-fluence vs low-fluence photodynamic therapy in chronic central serous chorioretinopathy. Am J Ophthalmol. 2011;151:953Y960. 65. Reibaldi M, Cardascia N, Longo A, et al. Standard-fluence versus low-fluence photodynamic therapy in chronic central serous chorioretinopathy: a nonrandomized clinical trial. Am J Ophthalmol. 2010;149:307Y315. 66. Shin JY, Woo SJ, Yu HG, et al. Comparison of efficacy and safety between half-fluence and full-fluence photodynamic therapy for chronic central serous chorioretinopathy. Retina. 2011;31:119Y126.
74. Lim JI. Iatrogenic choroidal neovascularization. Surv Ophthalmol. 1999;44:95Y111. 75. Lim JW, Kang SW, Kim YT, et al. Comparative study of patients with central serous chorioretinopathy undergoing focal laser photocoagulation or photodynamic therapy. Br J Ophthalmol. 2011;95:514Y517. 76. Sivaprasad S, Elagonz M, McHugh D, et al. Micropulsed diode laser therapy: evolution and clinical applications. Surv Ophthalmol. 2010;55:516Y530. 77. Gupta B, Elagouz M, McHugh D, et al. Micropulse diode laser photocoagulation for central serous chorioretinopathy. Clin Exp Ophthalmol. 2009;37:801Y805. 78. Chen SN, Hwang JF, Tseng LF, et al. Subthreshold diode micropulse photocoagulation for the treatment of chronic central serous chorioretinopathy with juxtafoveal leakage. Ophthalmology. 2008;115:2229Y2234. 79. Lanzetta P, Furlan F, Morgante L, et al. Nonvisible subthreshold micropulse diode laser (810 nm) treatment of central serous chorioretinopathy. A pilot study. Eur J Ophthalmol. 2008;18:934Y940. 80. Ricci F, Missiroli F, Regine F, et al. Indocyanine green enhanced subthreshold diode-laser micropulse photocoagulation treatment of chronic central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol. 2009;247:597Y607. 81. Hussain N, Khanna R, Hussain A, et al. Transpupillary thermotherapy for chronic central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol. 2006;244:1045Y1051. 82. Shukla D, Kolluru C, Vignesh TP, et al. Transpupillary thermotherapy for subfoveal leaks in central serous chorioretinopathy. Eye. 2008;22:100Y106. 83. Sharma T, Parikh SD. Transpupillary thermotherapy for juxtafoveal leak in central serous chorioretinopathy. Ophthalmic Surg Lasers Imaging. 2010;9:1Y3. 84. Giudice GL, de Belvis V, Tavolato M, et al. Large-spot subthreshold transpupillary thermotherapy for chronic serous macular detachment. Clin Ophthalmol. 2011;5:355Y360. 85. Schaal KB, Hoeh AE, Scheuerle A, et al. Intravitreal bevacizumab for treatment of chronic central serous chorioretinopathy. Eur J Ophthalmol. 2009;19:613Y617. 86. Lim SJ, Roh MI, Kwon OW. Intravitreal bevacizumab injection for central serous chorioretinopathy. Retina. 2010;30:100Y106.
67. Bae SH, Heo JW, Kim C, et al. Randomized pilot study of low-fluence photodynamic therapy versus intravitreal ranibizumab for chronic central serous chorioretinopathy. Am J Ophthalmol. 2011;152:784Y792.
87. Artunay O, Yuzbasioglu E, Rasier R, et al. Intravitreal bevacizumab in treatment of idiopathic persistent central serous chorioretinopathy: a prospective, controlled clinical study. Curr Eye Res. 2010;35:91Y98.
68. Kim SW, Oh J, Oh IK, et al. Retinal pigment epithelial tear after half fluence PDT for serous pigment epithelial detachment in central serous chorioretinopathy. Ophthalmic Surg Lasers Imaging. 2009;40:300Y303.
88. Inoue M, Kadonosono K, Watanabe Y, et al. Results of one-year follow-up examinations after intravitreal bevacizumab administration for chronic central serous chorioretinopathy. Ophthalmologica. 2011;225:37Y40.
69. Smretschnig E, Ansari-Shahrezaei S, Moussa S, et al. Half-fluence photodynamic therapy in acute central serous chorioretinopathy. Retina. 2012;10:1Y6.
89. Lim JW, Kim MU. The efficacy of intravitreal bevacizumab for idiopathic central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol. 2011;249:969Y974.
70. Ascaso FJ, Rojo M, Minguez E, et al. Diagnostic and therapeutic challenges. Retina. 2011;31:616Y622.
90. Symeonidis C, Kaprinis K, Manthos K, et al. Central serous chorioretinopathy with subretinal deposition of fibrin-like material
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and its prompt response to ranibizumab injections. Case Report Ophthalmol. 2011;2:59Y64. 91. Arevalo JF, Espinoza JV. Single-session combined photodynamic therapy with verteporfin and intravitreal antiYvascular endothelial growth factor therapy for chronic central serous chorioretinopathy: a pilot study at 12-month follow-up. Graefes Arch Clin Exp Ophthalmol. 2011;249:1159Y1166. 92. Khorram D. The retina blog: rifampin for central serous chorioretinopathy. August 2010. Available at: http://theretinablog.com/ 2010/08/30/rifampin-for-central-serous-chorioretinopathy. Accessed July 29, 2011. 93. Gonzalez C. Serous retinal detachment. Value of acetazolamide [in French]. J Fr Ophtalmol. 1992;15:529Y536.
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94. Pikkel J, Beiran I, Ophir A, et al. Acetazolamide for central serous retinopathy. Ophthalmology. 2002;109:1723Y1725. 95. Tatham A, Macfarlane A. The use of propranolol to treat central serous chorioretinopathy: an evaluation by serial OCT. J Ocul Pharmacol Ther. 2006;22:145Y149. 96. Rahbani-Nobar MB, Javadzadeh A, Ghojazadeh L, et al. The effect of Helicobacter pylori treatment on remission of idiopathic central serous chorioretinopathy. Mol Vis. 2011;17:99Y103. 97. Caccavale A, Romanazzi F, Imparato M, et al. Low-dose aspirin as treatment for central serous chorioretinopathy. Clin Ophthalmol. 2010;4:899Y903. 98. Forooghian F, Meleth AD, Cukras C, et al. Finasteride for chronic central serous chorioretinopathy. Retina. 2011;31:766Y771.
‘‘If I have seen farther than others, it is because I was standing on the shoulders of giants.’’ - Issac Newton
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An Update on the Diagnosis and Management of Central Serous Chorioretinopathy David T. Liu, FRCS,* Andrew T. Fok, FRCS,Þ and Dennis S.C. Lam, MD, FRCOphthþ Abstract: Central serous chorioretinopathy (CSC) is a complicated disease with still unclear causes, pathogenesis and management strategy despite active research. CSC has been traditionally considered as a selflimiting disease where spontaneous recovery occurs in 90% of the patients within a few months. This proclaimed ‘‘benign’’ nature of CSC, however, has been queried by increasing scientific evidence that permanent photoreceptors damage and neurosensory-cystoid degeneration of macula occur in the event of chronic CSC. CSC is probably not a benign disease. Treatments for CSC are still evolving. It is very difficult to define the proper timing for active treatment of CSC because it is not easy to define a universally accepted cut-off time point for active intervention. There is a recent suggestion that active CSC treatment should be considered if symptoms last longer than 3 months as atrophy of photoreceptors may occur as early as 4 months after initial presentation. The CSC patients may be stratified into two groups based on the initial presenting visual acuity and duration of symptom: the good visual prognosis group and the dubious visual prognosis group. The management may then be tailor-made based on the visual prognosis group. ‘‘Safety-enhanced’’ photodynamic therapy (PDT) using lower doses and reduced fluence is still the mainstay of treatment. Newer treatment modalities like intravitreal anti-VEGF therapy, micropulsed diode laser treatment, and the use of corticosteroid antagonists do warrant further investigation. Combination therapies involving two or more of the above modalities of treatments may have a role to play in this actively researched area. Key Words: central serous chorioretinopathy, photodynamic therapy, intravitreal anti-VEGF therapy, micropulsed diode laser treatment, corticosteroid antagonists (Asia-Pac J Ophthalmol 2012;1: 296Y302)
C
entral serous chorioretinopathy (CSC) was initially thought to be primarily a retinal inflammatory disorder when it was first coined by Albrecht von Graefe1 in 1866 as ‘‘central recurrent retinitis.’’ Although the pathogenesis of the disease is still not fully understood, advances in investigative technology over the years such as indocyanine green angiography (ICGA) and optical coherence tomography (OCT) have led us to understand that CSC is a chorioretinal disorder. Although most patients with CSC recover spontaneously with good visual outcome, some develop chronic recurrent macular detachments with permanent visual impairment. Multiple treatment methods have been tried over the years with variable success.
From the *Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong; †Hong Kong Eye Hospital; ‡Dennis Lam & Partners Eye Center, Hong Kong; and §Zhongshan Ophthalmic Center, Guangzhou, People’s Republic of China. Received for publication August 1, 2012; accepted August 20, 2012. The authors have no funding or conflicts of interest to declare. Reprints: Dennis S.C. Lam, MD, Dennis Lam & Partners Eye Center, Suite 1515, Central Bldg, 1-3 Pedder St, Central, Hong Kong. E-mail: [email protected]. Copyright * 2012 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0b013e31826fdfd4
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PATHOGENESIS AND RISK FACTORS Central serous chorioretinopathy is believed to be a condition with multietiologic factors that lead to a final pathway of choroidal vascular abnormalities.2 Indocyanine green angiography is able to demonstrate choroidal vascular dilatation and hyperpermeability in patients with CSC.3 The choroidal hydrostatic pressure elevation leads to the breakdown of the retinal pigment epithelial (RPE) tight junctions, allowing fluid to pass from the choroid to the subretinal space.4 Elevated corticosteroid levels are a well-accepted predisposing factor for CSC.5 Common sources of exogenous corticosteroid include systemic steroid intake for conditions such as autoimmune disease and after organ transplantation.6,7 Risk of CSC might also be raised following other routes of corticosteroids administration including topical, intra-articular, and intranasal.8Y10 Causes of elevated endogenous cortisol production include pregnancy and Cushing disease.11Y15 Corticosteroids are believed to increase the risk of CSC through multiple mechanisms including vascular hyperpermeability, reduced nitric oxide levels, and damage to RPE cell tight junctions.16Y18 Yannuzzi19 first suggested an association between CSC and type A personality. It was postulated that elevated catecholamine levels in these patients might cause choroidal vasoconstriction by activating the sympathetic nervous system. Numerous risk factors of CSC including smoking, hypertension, allergic respiratory disease, the use of alcohol, antihistamine, antibiotic, sympathomimetic agents, Raf/MEK/ERK inhibitors, and phosphodiesterase 5 inhibitors have also been suggested in the literature.12,20Y23 Helicobacter pylori infection and obstructive sleep apnea have been reported to be associated with CSC, and their treatment might hasten the resolution of subretinal fluid.24 The association of vascular endothelial growth factor (VEGF) with CSC is unclear. Studies showed that aqueous and plasma VEGF levels are not elevated in patients with CSC.2,25,26 Intravitreal antiVEGF injections also did not yield any promising result.
NATURAL HISTORY Central serous chorioretinopathy is traditionally thought of as a self-limiting disease where spontaneous recovery occurs in 90% of the patients within a few months,27Y29 Visual acuity usually returns to normal after the resolution of subretinal fluid, but the patient might be left with mild residual symptoms such as reduction in contract sensitivity. However, recurrent disease is also problematic as approximately 50% of patients might develop recurrence.30Y33 Half of the recurrences develop within the first year of onset of disease. Study showed that a history of psychiatric illness is associated with a higher rate of recurrence.29 A small percentage of patients may experience progression of chronic diseases with prolonged serous macular detachment. Patients with chronic disease and poor visual acuity on presentation are associated with poor visual outcomes.34 Complications that could lead to severe irreversible visual loss include RPE atrophy, choroidal neovascularization (CNV), and polypoidal choroidal vasculopathy (PCV).35 Therefore, we no longer believe CSC to be a benign disease.
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CLINICAL FEATURES Central serous chorioretinopathy typically affects males, and the onset of disease is usually in the most productive age group of 30s to 40s.36 It is more common in Asians than in whites. Central serous chorioretinopathy is uncommon in blacks, but it is more severe when it does happen.37 Initially, usually only 1 eye is affected, but the fellow eye might also be involved in chronic cases and patients with excessive corticosteroids. Patients with CSC commonly present with blurring of vision, relative central scotoma, micropsia, dyschromatopsia, and metamorphopsia. Hyperopic shift might occur because the detached neurosensory retina is displaced anteriorly, shortening the optical system of the eye. The patient might complain of increasing hypermetropia when trying to get new glasses. Binocular indirect ophthalmoscopy is usually adequate in diagnosing CSC. In difficult cases with minimal amount of subretinal fluid, fundus contact lens might be useful. Fundus examination usually reveals an oval area of neurosensory retinal detachment with or without pigment epithelial detachment (PED) in the macular region. The subretinal fluid can either be transparent or cloudy.38 Subretinal or sub-RPE fibrin formation can occur, and spontaneous resolution is the rule, but occasionally fibrosis could occur with subsequent permanent visual loss. Tiny yellow dots are commonly seen underneath the detached retina and are suggested to be related to the phagocytosis process of the shed outer segments of photoreceptors.39 In chronic CSC, RPE change and atrophy might be present. Some patients present with inferior bullous retinal detachments.7,40Y42 If the condition becomes chronic, one might see an atrophic RPE tract connecting the macula to the inferior detachment. Complications of chronic CSC such as cystoid macular edema and secondary CNV might also be seen clinically.
INVESTIGATIONS
Management of Central Serous Chorioretinopathy
Other Investigations Optical coherence tomography, FA, and ICGA are the standard investigations for CSC and are adequate for diagnostic confirmation as well as differentiating it from other differential diagnoses. Other adjunctive investigations might offer information that improves our understanding of the disease. Multifocal electroretinography and microperimetry assess the macular function in objective and subjective manners, respectively. Multifocal electroretinography response amplitudes are reduced in CSC and correlate with visual acuity.48 Microperimetry measures macular sensitivity and is reduced in patients with CSC.49 Macular sensitivity was found to correlate well with OCT macular thickness.49,50 Fundus autofluorescence features in CSC depend on whether the condition is acute or chronic. In acute cases, fundus autofluorescence usually shows hypofluorescence because of blockage by subretinal fluid. However, in chronic cases, hyperfluorescence might be present instead.51
Differential Diagnoses Several disease entities should be considered before labeling a patient with CSC. Age-related macular degeneration and PCV can mimic CSC especially when there is an absence of hemorrhage. Polypoidal choroidal vasculopathy is particularly problematic because it can appear in relatively young patients. Fluorescein angiography and ICGA are useful in differentiating between the conditions. Intraocular tumors, Vogt-Koyanagi-Harada disease, and optic disc pit can all cause serous detachment of the retina. However, they can usually be differentiated from CSC by their typical ocular features. Intraocular tumors such as choroidal metastasis and choroidal hemangioma can be seen as choroidal mass on fundoscopy. Patients with Vogt-Koyanagi-Harada disease might have systemic symptoms, and the condition is often bilateral. Optic disc pit is usually evident on fundoscopy and is usually located on the temporal aspect of the optic disc. Autoimmune disease causing neurosensory retinal detachment usually shows other systemic signs.
Optical Coherence Tomography Optical coherence tomography has become the first-line investigation for CSC in recent years. It allows for high-resolution imaging of the macula and can clearly document the presence of subretinal fluid.43 Other features such as PED and subclinical lesions in the fellow eye can also be detected.44 Optical coherence tomography allows for objective quantification of macular thickness and is perfect for monitoring disease progression and response to treatment. Enhanced depth imagingYOCT scans the deeper structures of the macula and enables the measurement of the degree of choroidal thickness, which is an established feature of CSC. Moreover, studies have used enhanced depth imagingYOCT to demonstrate the reduction in choroidal thickness after treatment with photodynamic therapy (PDT).45
Angiography The classic description of fluorescein angiography (FA) in CSC is the ink-blot and smoke-stack appearance.46 These usually occur in patients with acute CSC. Other features include the pooling of dye in the PED and multifocal leakage in multifocal CSC. In patients with chronic CSC, FA might show RPE window defects and nonspecific leakage patterns. Indocyanine green angiography is very useful in CSC and is a prerequisite for any patients being considered for treatment. In the early phase, there are usually dilated choroidal vessels followed by choroidal hyperpermeability in the later phase.47 The features of hyperdynamic choroidal circulation might be present in the asymptomatic fellow eye as well. * 2012 Asia Pacific Academy of Ophthalmology
TREATMENT OF CENTRAL SEROUS CHORIORETINOPATHY Observation in Most Cases Is CSC a benign disease? This is a difficult question that has haunted ophthalmologists and medical retina specialists worldwide for many years.29 In the past, people believed that CSC was a benign disease, and observation was usually deemed as the first-line management for CSC. Removal of any identifiable endogenous or more commonly exogenous source of corticosteroids through careful history taking is another important yet simple treatment that can be offered to CSC patients. The high successful rate observed (90% resolution of detachment) associated with observation has reinforced the concept that CSC may truly be a benign disease.52 General measures such as psychotherapy and relaxation exercise have been proposed as well.27,53 In 2 recent prevailing reviews on CSC, there have been increasing queries and doubts about the ‘‘benign’’ nature of CSC as pathological studies have shown the presence of photoreceptor damage and neurosensory-cystoid degeneration of macula in the event of chronic CSC.27,53 In the past, it is very difficult to define the proper timing for active treatment of CSC because it is not easy to define a universally accepted cutoff time point for active intervention in the management of CSC. However, there was recent suggestion that active CSC treatment should be considered in case symptoms lasting longer than 3 months as atrophy of photoreceptors may www.apjo.org
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occur as early as 4 months after initial presentation.33,34 The CSC patients may be stratified into 2 groups based on the initial presenting visual acuity and duration of symptom: the good visual prognosis group (good presenting visual acuity and duration of symptom G3 months) and the dubious visual prognosis group (poor presenting visual acuity and duration of symptom 93 months). The management may then be tailor-made based on the visual prognosis group (Fig. 1). The controversy over the best timing for treating CSC, nevertheless, continues, and further research is needed.
or extravascular leakage.56Y58 This effect might be prolonged and sustained for years. In site of the proven efficacy, use of PDT in conventional verteporfin dosage, fluence, and spot size might given rise to severe complications such as secondary CNV formation, choriocapillaris ischemia, RPE atrophy, and subtle electrophysiological disturbance recorded on multifocal electroretinography.56,59
Safety-Enhanced Photodynamic Therapy in Selected Cases
Theoretically, standard PDT may be modified by reducing the verteporfin dosage as well as shortening the time between infusion and laser application so as to preserve PDT efficacy in treating CSC while minimizing its adverse effects. For instance, reducing the dosage of verteporfin infusion by half may lower the risk of retinal-choroidal complications without jeopardizing the efficacy of PDT.60 In a number of prospective studies, this half-dose regimen has been shown to be able to achieve similar
Photodynamic Therapy With Verteporfin The efficacy of PDT in treating CSC cases was substantiated by the TAP and VIP studies.54,55 Pathophysiologically, PDT may lead to choroidal vascular remodeling by inducing choriocapillaris narrowing and reducing choroidal exudation
Safety-Enhanced Photodynamic Therapy With Reduced Verteporfin Dosage
FIGURE 1. Suggested management algorithm for CSC. 3/12 = duration of symptoms of 3 months; 6/12 = duration of symptoms of 6 months.
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efficacy as the full-dose PDT without the well-known associated retinochoroidal complications such as choroidal ischemia, CNV formation, and posttreatment visual loss.61Y63 In a study about the use of safety-enhanced PDT with reduced verteporfin dosage in managing chronic CSC, 40 eyes (83.3%) had complete resolution of serous detachment at 3 months after treatment and 43 eyes (89.6%) at 12 months after treatment. The mean visual acuity improvement was 1.6 lines, and 45 eyes (95.8%) had stable or improved vision.63 More than 10 prospective, retrospective, and/or interventional case series, with or without randomization, were published.27,53 Therefore, based on the best available evidence, safety-enhanced PDT with reduced verteporfin dosage was deemed by most ophthalmologists and medical retina specialists as the first-line treatment for those CSC requiring active intervention.
beneficial role of combined PDT and intravitreal anti-VEGF for CSC patients in a small case series.91
Anticorticosteroid Treatment Anticorticosteroid treatment was first suggested by Dr. Lee Jampol from America. This postulation was based on the pathogenetic association between endogenous hypercortisolism and the development of CSC. The use of antiglucocorticoid agents including mifepristone and ketoconazole yielded insignificant results. Rifampin, a semisynthetic antituberculosis antibiotic, is a promising and possibly viable option as a number of rifampin-treated CSC patients showed good results with resolution of the fluid within 1 to 4 weeks.92
Other Potential But Still Exploratory Systemic Therapy Systemic Acetazolamide
Safety-Enhanced Photodynamic Therapy With Reduced Laser Fluence Altering the laser fluence or infusion time may be the alternative to reducing the dose of verteporfin to achieve safetyenhanced PDT. For example, PDT delivered in low fluence was found to be effective and safe in the treatment for chronic CSC despite reports of sinister complications such as RPE rip in a number of cases managed by reduced fluence PDT.64Y69
Historical Thermal (Argon) Laser Photocoagulation and Micropulsed Diode Laser Historically, thermal laser photocoagulation was noted to be able to increase resolution of neurosensory detachment by producing laser photocoagulation over the detectable pigment epithelial leakage on FA.27Y29,70,71 Nevertheless, severe complications associated with thermal laser photocoagulation including enlargement of RPE scar, permanent scotoma, and CNV formation had been reported.72Y75 Therefore, most of the ophthalmic surgeons will reserve thermal laser photocoagulation for a scenario such as a solitary extrafoveal leaking point. There were queries toward the claimed efficacy of thermal laser photocoagulation as the final functional outcomes and the rate of recurrence seemed not to be affected.31 This is due to the fact that the underlying pathophysiological changes such as choriocapillaris hyperpermeability will not be altered by thermal laser photocoagulation. Recently, micropulse diode laser has picked up the momentum to treat CSC.76Y80 The diode laser emitted in micropulsed fashion allows subthreshold therapy without a visible burn end point. Nevertheless, in the event of more than 1 leaking point, the efficacy and safety of micropulse diode laser might be jeopardized.
The use of systemic acetazolamide to treat CSC originated only from several small case series.93 It might speed up the resolution of symptoms but not alter the final visual outcomes and the recurrence rate.94
Antiadrenergic Blockage and A-Blockers Tatham and Macfarlane95 reported the successful management of 2 CSC patients by oral propranolol 40 mg twice a day.
Aspirin, Finasteride, AntiYHelicobacter pylori Treatment The usefulness of low-dose aspirin, finasteride, and standard H. pylori eradication regimen was reported in a couple of single-center studies.96Y98
CONCLUSIONS Central serous chorioretinopathy is not a benign disease as we thought. It is important to note that treatments for CSC are still evolving. ‘‘Safety-enhanced’’ PDT using lower doses and reduced fluence is still the mainstay of treatment. Newer treatment modalities such as intravitreal anti-VEGF therapy, micropulsed diode laser treatment, and the use of corticosteroid antagonists are evolving with reported encouraging results in a limited number of studies, but they do warrant further investigation. Combination therapies involving 2 or more of the above modalities of treatments may be the new horizon in managing this mutifactorial disease and certainly have a role to play in this actively researched area. REFERENCES 1. von Graefe A. Ueber central recidivierende retinitis. Graefes Arch Clin Exp Ophthalmol. 1866;12:211Y215. 2. Spaide RF, Goldbaum M, Wong DWK, et al. Serous detachment of the retina. Retina. 2003;23:820Y846.
Transpupillary Thermotherapy The true efficacy of transpupillary thermotherapy in treating CSC might require further studies to substantiate.81Y84
Intravitreal AntiYVascular Endothelial Growth Factor Therapy With or Without Adjuvant Photodynamic Therapy In the era of intravitreal pharmacotherapy for macular diseases, there have been a couple of studies targeted to use intravitreal anti-VEGF to treat CSC.67,85Y90 These findings suggest that VEGF may be involved in fluid leakage in patients who have had chronic CSC.26 There was evidence suggesting the * 2012 Asia Pacific Academy of Ophthalmology
3. Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyanine green videoangiography of central serous chorioretinopathy. Arch Ophthalmol. 1994;112:1057Y1062. 4. Pryds A, Sander B, Larsen M. Characterization of subretinal fluid leakage in central serous chorioretinopathy. Invest Ophthalmol Vis Sci. 2010;51:5853Y5857. 5. Zakir SM, Shukla M, Simi ZU, et al. Serum cortisol and testosterone levels in idiopathic central serous chorioretinopathy. Indian J Ophthalmol. 2009;57:419Y422. 6. Eller AW. Serous retinal detachment resembling central serous chorioretinopathy following organ transplantation. Graefes Arch Clin Exp Ophthalmol. 1990;228:305Y309.
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7. Gass JD, Little H. Bilateral bullous exudative retinal detachment complicating idiopathic central serous chorioretinopathy during systemic corticosteroid therapy. Ophthalmology. 1995;102:737Y747. 8. Hurvitz AP, Hodapp KL, Jadgchew J, et al. Central serous chorioretinopathy resulting in altered vision and color perception after glenohumeral corticosteroid injection. Orthopedics. 2009;32:600. 9. Haimovici R, Gragoudas ES, Duker JS, et al. Central serous chorioretinopathy associated with inhaled or intranasal corticosteroids. Ophthalmology. 1997;104:1653Y1660. 10. Fernandez C, Mendoza AJ, Arevalo JF. Central serous chorioretinopathy associated with topical dermal corticosteroids. Retina. 2004;24:471Y474. 11. Garg SP, Dada T, Talwar D, et al. Endogenous cortisol profile in patients with central serous chorioretinopathy. Br J Ophthalmol. 1997;81:962Y964. 12. Haimovici R, Koh S, Gagnon DR, et al. Risk factors for central serous chorioretinopathy: a case-control study. Ophthalmology. 2004;111:244Y249.
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30. Gass JD. Pathogenesis of disciform detachment of the neuroepithelium. Am J Ophthalmol. 1967;63(suppl):1Y139. 31. Ficker L, Vafidis G, While A, et al. Long-term follow-up of a prospective trial of argon laser photocoagulation in the treatment of central serous retinopathy. Br J Ophthalmol. 1988;72:829Y834. 32. Yap EY, Robertson DM. The long-term outcome of central serous chorioretinopathy. Arch Ophthalmol. 1996;114:689Y692. 33. Fok AC, Chan PP, Lam DS, et al. Risk factors for recurrence of serous macular detachment in untreated patients with central serous chorioretinopathy. Ophthalmic Res. 2011;46:160Y163. 34. Aggio FB, Roisman L, Melo GB, et al. Clinical factors related to visual outcome in central serous chorioretinopathy. Retina. 2010;30:1128Y1134. 35. Fung AT, Yannuzzi LA, Freund KB. Type 1 (sub-retinal pigment epithelial) neovascularization in central serous chorioretinopathy masquerading as neovascular age-related macular degeneration [published online ahead of print August 7, 2012]. Retina. 2012.
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