Advertisement

PentaVision

Retinal Physician

Article

New Insights on Management of Central Serous Chorioretinopathy

Updates to classification, imaging technology, and data on pathophysiology guide treatment.

By: Gideon Nkrumah, MD, Supriya Arora, MD, Jay Chhablani, MD
Retinal Physician May 1, 2021 Vol 18, Issue May 2021 Page(s): 14-18

Related

Central serous chorioretinopathy (CSCR) is characterized by serous detachment of the retina with or without retinal pigment epithelium (RPE) detachment, and it is one of the most common disorders seen in medical retina clinics. An annual incidence of 9.9 in 100,000 in men and 1.7 in 100,000 in women was noted in the Olmstead County, Minnesota population study.1 Although the underlying pathophysiology is not completely understood, it is hypothesized to be due to leakage of fluid from highly permeable choroidal vessels through the dysfunctional RPE to the subretinal layer.2

There have been several advances in the area of imaging, particularly choroidal imaging, which has further enhanced the understanding of CSCR. Advancement in multimodal imaging has been exploited, and a newer classification for CSCR has been proposed by the Central Serous Chorioretinopathy International Group. Concurrently, clinical trials have reported results of oral medication in CSCR, and newer treatment options are being explored. This article seeks to provide a concise and comprehensive commentary on the current status of CSCR management.

NEW CLASSIFICATIONS

There is no universally adopted classification system for CSCR. However, it is important to explore the classification schemes in the literature. The goal of any clinical classification system is to predict the course of disease. Some classification schemes have used disease duration, timing of subretinal fluid (SRF) resolution, grade of activity, spectrum of phenotypes, recurrence, and existence of a causative factor.3

Conventional classification for CSCR as acute or chronic has significant discrepancies in real life. In a multicenter study, Singh et al showed a significantly poor agreement (Fleiss kappa=.218) among 6 retina experts for CSCR classification.4 Thus, there is a need for a new classification system. In pursuit of a more standardized classification system, the Central Serous Chorioretinopathy International Group proposed a diagnostic criteria and classification system for idiopathic CSCR based on consensus among major experts. They described major and minor criteria based on findings of serous retinal detachment (SRD) and RPE alterations detected through multimodal imaging techniques.

According to the classification, a patient must meet both major criteria and 1 minor criterion for the diagnosis of CSCR. The major criteria are (1) presence or evidence of prior SRD documented on optical coherence tomography (OCT) involving the posterior pole unrelated to another disease process and (2) at least 1 area of RPE alteration on fundus autofluorescence (FAF), spectral-domain OCT, or infrared imaging. The minor criteria include mid-phase hyperfluorescent placoid areas on indocyanine angiography (ICGA), one or more focal leaks on fundus fluorescein angiography, or subfoveal choroidal thickness (SFCT) of 400 µm or greater (consider age and axial length).

The Central Serous Chorioretinopathy International Group classified CSCR into 2 major subtypes: simple and complex. Atypical variants types, such as bullous CSCR variant, RPE tear, and CSCR associated with other retinal diseases, were placed into the atypical category. The group used a 2-disc area (DA) diameter of RPE atrophy as the threshold to classify CSCR as simple or complex (≤2 DA=simple, >2 DA=complex). Both groups (simple and complex) were further divided into primary (first known episode of SRF), recurrent (presence of SRF with history or signs of resolved episode) and resolved (absence of SRF on OCT). According to the classification system, when SRF has been present for >6 months, it is described as persistent. Other modifiers include outer retinal atrophy (outer nuclear layer thinning and or external limiting membrane disruption and or ellipsoid zone attenuation), intraretinal fluid with or without macular neovascularization (MNV), and foveal involvement (Table 1).5

Table 1. New Classification for Central Serous Chorioretinopathy
  Simple (≤2 DA of RPE alteration) Complex (>2 DA of RPE alteration or multifocal) Atypical
Primary First episode of SRF First episode of SRF -
Recurrent Presence of SRF with signs of resolved episodes Presence of SRF with signs of resolved episodes -
Resolved Absence of SRF Absence of SRF -
Persistent SRF >6 months SRF >6 months -
Outer retinal atrophy Present or absent ONL thinning and/or ELM disruption and or EZ attenuation Present or absent ONL thinning and/or ELM disruption and or EZ attenuation -
Intraretinal fluid Present or absent Present or absent -
Choroidal neovascularization Present or absent Present or absent -
Bullous variant, RPE tear, other disease association - - Yes
RPE, retinal pigment epithelium; SRF, subretinal fluid; ONL, outer nuclear layer; ELM, external limiting membrane; EZ, ellipsoid zone.

NEW IMAGING TECHNIQUES AND FINDINGS

Multimodal imaging techniques have been the key for the diagnosis and assessment of patients with CSCR. Recently, OCT angiography (OCTA) allows the detection of areas of choroidal nonperfusion.6 In normal eyes, there are consistent OCTA signals at the level of the choriocapillaris. There have been reported abnormal vascular signals at the choriocapillaris in eyes with CSCR. Shinojima et al showed abnormal signals at the level of choriocapillaris in 58 eyes with CSCR and 51 contralateral eyes using OCTA. All patients with CSCR showed abnormal signals at the choriocapillaris, whereas 61% of contralateral eyes showed abnormal signals. They described the abnormal vascular signal patterns at the choriocapillaris level in CSCR eyes on OCTA as type 1, with central high-flow signal surrounded by an inner-low flow signal and an outer high-flow signal (18 eyes); type 2, with central low-flow signal surrounded by a high-flow signal (6 eyes); and type 3, with mosaic flow signal pattern (34 eyes). They defined the “mosaic pattern” as random high-flow and low-flow portions corresponding to neither type 1 nor type 2 on OCTA images. The study noted RPE detachment/irregularities and ellipsoid zone (EZ) irregularities on OCTA in patients with abnormal vascular signals.7 The role of OCTA is already established in identifying choroidal neovascular (CNV) membranes associated with CSCR, and OCTA has a 45.8% to 58.0% greater chance of detecting CNV than conventional dye-based angiography.8,9

Previously, ICGA studies were limited to the posterior pole without peripheral imaging of the vortex veins. Widefield ICGA (WF ICGA) and ultrawidefield ICGA (UWF ICGA) has expanded the ability to extensively image up to 200 degrees with ICGA technique.10,11 A recent hypothesis states that CSCR eyes have reduced peripheral outflow through the vortex veins. Jung et al used UWF ICGA to quantitatively demonstrate asymmetric choroidal outflow in CSCR and pachychoroid pigment epitheliopathy (PPE). The increased brightness levels along the inferior quadrants in mid-phase ICGA showed the venous outflow congestion in CSCR/PPE.11

Adaptive optics scanning laser ophthalmoscopy (AOSLO) has been used to show intraretinal hyperreflective dots (HRDs) in CSCR.12 The exact cellular origins of HRDs are unknown. They are thought to be debris from inflammatory responses incited by CSCR. Hanumunthadu et al showed increased choroidal HRDs on OCT in patients with acute CSCR compared to chronic disease. In patients with acute disease, HRDs were positively correlated with age and SFCT. In chronic disease, HRDs were positively correlated with central macular thickness and neurosensory detachment height. However, in all patient populations, they noted a negative correlation between HRDs, age, and SFCT.13 Adaptive-optics ICGA has recently been employed to visualize choriocapillaris and outer retina at the cellular level.11 This modality may be able to provide additional details of the choriocapillaris layer.

NEWER INSIGHTS ON PATHOPHYSIOLOGY

As stated above, WF-ICGA and UWF-ICGA have expanded visualization and analysis of vortex veins in defining their patterns and coverage from the central retina to the periphery. Choroidal vasculature is divided into 4 quadrants as a result of horizontal and vertical watershed zones. Each quadrant is served by an average of 4 to 5 (range of 3 to 8) vortex veins.14 Recent literature has shown asymmetric dilation of vortex vein and outflow congestion in the pachychoroid spectrum of diseases. The anastomosis of the vortex veins is hypothesized to be caused by the congestive mechanism within the choroid.15 Matsumoto et al, in a retrospective case series, suggested that congestion of the vortex veins might contribute to the development of anastomosis between the superior and inferior vortex veins during the course of disease progression. In their quantitative measure of vortex veins in the posterior pole in eyes with pachychoroid, CSCR eyes had significantly larger mean diameter of vortex veins compared to polypoidal choroidal vasculopathy (P<.05). Anastomosis between superior and inferior vortex veins was observed in more than 90% of eyes with each pachychoroid spectrum disease. Overall, this venous overload theory may explain the pathophysiology for pachychoroid disease spectrum.16

NEW TREATMENTS

Acute CSCR presents with decreased vision, metamorphopsias, and central scotomas. Spontaneous resolution of SRF occurs in 80% of patients, especially with discontinuance (and continued avoidance) of topical, inhaled, intranasal, intraarticular, or intravenous steroids.17-19 However, some patients can have recurrence or progression of these acute symptoms to a chronic form usually after 3 months to 6 months. Currently, most retina specialists use photodynamic therapy (PDT) with verteporfin (Visudyne; Bausch + Lomb) (Figure 1; devices listed in Table 2) as well as pharmacologic therapy.

Figure 1. Good response to photodynamic therapy (PDT) in a case of central serous chorioretinopathy. Images of this 46-year-old male patient with blurry vison of 20/25 in the left eye for the prior 4 months show leaks on the juxtafoveal and near-superior arcades on fluorescein angiography (A, arrows) and on indocyanine green angiography (B, arrows). Optical coherence tomography at baseline showing subretinal fluid (SRF) on horizontal (C) and vertical (D) scans. The patient underwent half-fluence PDT and had resolution of symptoms with 20/20 vision at 6 weeks. Optical coherence tomography scans showed no SRF on horizontal (E) and vertical (F) scans.
Figure 1. Good response to photodynamic therapy (PDT) in a case of central serous chorioretinopathy. Images of this 46-year-old male patient with blurry vison of 20/25 in the left eye for the prior 4 months show leaks on the juxtafoveal and near-superior arcades on fluorescein angiography (A, arrows) and on indocyanine green angiography (B, arrows). Optical coherence tomography at baseline showing subretinal fluid (SRF) on horizontal (C) and vertical (D) scans. The patient underwent half-fluence PDT and had resolution of symptoms with 20/20 vision at 6 weeks. Optical coherence tomography scans showed no SRF on horizontal (E) and vertical (F) scans.
Table 2: Retina Lasers and Imaging Devices
TECHNIQUE/MODALITY PRODUCT NAME MANUFACTURER
Photodynamic therapy ML6710i (available for investigational use only in the United States) Modulight; developed with Bausch + Lomb
ML7710 (CE certified; available for investigational use only in the United States) Modulight
Vitra 689 (not available in the United States) Quantel Medical
Laser Zeiss Visulas green Carl Zeiss Meditec
Smart 532, Array Laserlink, Smart Selecta Trio, Vision One Lumenis
IQ 532 Lase, OcuLight, IQ 577 Laser Iridex
Navilas 577s Pro, Navilas 577 Prime OD-OS
Vitra 2 Quantel Medical
Optical coherence tomography 3D OCT, DRI OCT Triton Topcon Healthcare
Spectralis, HRT III Heidelberg Engineering Inc.
RS-3000 Nidek Inc.
Optovue RTVue, iVue Optovue
Silverstone, Monaco Optos
Cirrus 4000, Cirrus 400, Cirrus 500, Cirrus 5000, Stratus OCT III Carl Zeiss Meditec
Optical coherence tomography angiography Spectralis Heidelberg Engineering Inc.
Angioscan Nidek Inc.
Angiovue Optovue
Cirrus 6000, Angioplex, Plex Elite-900 Carl Zeiss Meditec
Scanning laser ophthalmoscope RS-3000 Nidek Inc.
Widefield fundoscopy Optomap Optos
Clarus 500 Carl Zeiss Meditec

In a pivotal nonrandomized multicenter study, complete resorption of SRF occurred in 100% of 82 CSCR patients treated with full-fluence PDT with an average 12-month follow-up; reactivation occurred in only 2% of patients.20 To avoid possible adverse events, half-fluence PDT has shown to be beneficial and was found to be equivalent to full-fluence PDT treatment for CSCR.21 Furthermore, the multicenter PLACE trial showed that half-dose PDT was superior to subthreshold micropulse laser treatment of CSCR.22

There is a current shift toward the preference of pharmacologic treatment for the management of CSCR. The recent VICI trial was a randomized, double-blind, placebo-controlled trial of 114 patients at 22 hospitals in United Kingdom that concluded that eplerenone was not superior to placebo for improving best corrected visual acuity (BCVA) in patients with chronic CSCR after 12 months of treatment (placebo BCVA 79.5±4.5, eplerenone 80.4±4.6, adjusted mean difference of 1.73 letters; 95% CI 1.12-4.47; P=.24). The study concluded that ophthalmologists who currently prescribe eplerenone for CSCR should discontinue the practice.23

Since the VICI trial, several articles have been published that support the use of eplerenone for the management of CSCR, contradicting the recommendations of the VICI trial. In a letter to the authors, both Sacconi et al24 and Stanescu-Segall et al25 stated the recommendation against eplerenone was too strong due to the presence of several reports of increased efficacy of eplerenone in treating CSCR. Fraenkel et al, in a retrospective study, assessed the morphologic and functional outcome of 30 patients with chronic CSCR treated with oral eplerenone. All patients had improved BCVA from 0.2±0.2 to 0.09±0.15 at 3 months (P=.01).26 Another retrospective study by Petkovsek et al confirmed the anatomic improvement of patients with chronic CSCR within the first year of eplerenone study. Although these studies showed improvement in BCVA and anatomic markers, these studies had a small sample size and were nonrandomized in nature.27

Apart from eplerenone, there has been contradicting evidence of the efficacy of numerous medical therapies in the management of CSCR. Among them are nonsteroidal anti-inflammatory drugs (NSAIDs), oral propranolol, and topical carbonic anhydrase inhibitors like dorzolamide. In a recent retrospective study by Bahadorani et al, patients diagnosed with new-onset CSCR on NSAIDs showed a faster rate of SRF reduction compared to control patients who were observed without any treatment. In the 14 eyes treated with topical bromfenac or nepafenac, there was a significant reduction in central macular thickness (-192 µm in treated eyes and -43.5 µm in control eyes; P<.006).28 In a randomized prospective study of 120 patients with CSCR, Chen et al showed the efficacy (95% success rate) of oral propranolol over placebo in treating patients with CSCR over a 4-month period. Patients on oral propranolol showed complete remission in 1.9 months, whereas those receiving placebo achieved remission in 3.5 months. The recurrence rate was 5.3% in the propranolol group and 25.5% in the placebo group.29 In another prospective nonrandomized study, 18 patients with chronic CSCR treated with the topical carbonic anhydrase inhibitor dorzolamide showed significant improvement in central macular thickness compared to 15 observed control patients (-145.6 µm, 95% CI -170.5 to -120.7 in the treatment group; -45.1 µm, 95% CI -65.3 to -25.1 in the control group) within the 3-month study period. At 3 months, 77.8% patients in the treatment group and 40.0% in the control group achieved complete resolution of SRF (P=.04).30

CONCLUSION

There have been numerous recent advances in the classification, diagnosis, and management of CSCR. The Central Serous Chorioretinopathy International Group classification system was created to standardize the descriptors used by ophthalmologists across the globe and helps to establish standard treatment guidelines. The advent of newer venous congestion theory using WF imaging has added further to the understanding of this disease spectrum. However, controversy remains around medical management of CSCR. Photodynamic therapy continues to be the mainstay treatment, although ophthalmologists have found success with numerous therapies, such as eplerenone, topical dorzolamide, NSAIDs, and oral propranolol. RP

Gideon Nkrumah is a medical student with the department of ophthalmology at the University of Pittsburgh Medical Center Eye and Ear Institute in Pittsburgh, Pennsylvania. Supriya Arora, MD, is a vitreoretinal surgeon and medical retina specialist with the Eye Care Center of Princess Margaret Hospital in Nassau, Bahamas. Jay Chhablani, MD, is a vitreoretinal specialist with the department of ophthalmology at the University of Pittsburgh Medical Center Eye and Ear Institute. Drs. Nkrumah and Arora report no disclosures. Dr. Chhablani reports consultancy to Allergan, Salutaris, and Biogen. Reach him at jay.chhablani@gmail.com.

REFERENCES

  1. Kitzmann AS, Pulido JS, Diehl NN, Hodge DO, Burke JP. The incidence of central serous chorioretinopathy in Olmsted County, Minnesota, 1980-2002. Ophthalmology. 2008;115(1):169-173. doi:10.1016/j.ophtha.2007.02.032
  2. Matet A, Daruich A, Zola M, Behar-Cohen F. Risk factors for recurrences of central serous chorioretinopathy. Retina. 2018;38(7):1403-1414. doi:10.1097/IAE.0000000000001729
  3. Vilela M, Mengue C. Central Serous Chorioretinopathy Classification. Pharmaceuticals (Basel). 2020;14(1):26. Published 2020 Dec 30. doi:10.3390/ph14010026
  4. Singh SR, Matet A, van Dijk EHC, et al. Discrepancy in current central serous chorioretinopathy classification. Br J Ophthalmol. 2019;103(6):737-742. doi:10.1136/bjophthalmol-2018-312435
  5. Chhablani J, Cohen FB, Central Serous Chorioretinopathy International G. Multimodal imaging-based central serous chorioretinopathy classification. Ophthalmol Retina. 2020;4(11):1043-1046. doi:10.1016/j.oret.2020.07.026
  6. Cakir B, Reich M, Lang S, et al. OCT angiography of the choriocapillaris in central serous chorioretinopathy: a quantitative subgroup analysis. Ophthalmol Ther. 2019;8(1):75-86. doi:10.1007/s40123-018-0159-1
  7. Shinojima A, Kawamura A, Mori R, Fujita K, Yuzawa M. Findings of optical coherence tomographic angiography at the choriocapillaris level in central serous chorioretinopathy. Ophthalmologica. 2016;236(2):108-113. doi:10.1159/000448436
  8. Wu JS, Chen SN. Optical coherence tomography angiography for diagnosis of choroidal neovascularization in chronic central serous chorioretinopathy after photodynamic therapy. Sci Rep. 2019;9(1):9040. doi:10.1038/s41598-019-45080-8
  9. Quaranta-El Maftouhi M, El Maftouhi A, Eandi CM. Chronic central serous chorioretinopathy imaged by optical coherence tomographic angiography. Am J Ophthalmol. 2015;160(3):581-587 e1. doi:10.1016/j.ajo.2015.06.016
  10. Hirahara S, Yasukawa T, Kominami A, Nozaki M, Ogura Y. Densitometry of choroidal vessels in eyes with and without central serous chorioretinopathy by wide-field indocyanine green angiography. Am J Ophthalmol. 2016;166:103-111. doi:10.1016/j.ajo.2016.03.040
  11. Jung JJ, Yu DJG, Ito K, Rofagha S, Lee SS, Hoang QV. Quantitative assessment of asymmetric choroidal outflow in pachychoroid eyes on ultra-widefield indocyanine green angiography. Invest Ophthalmol Vis Sci. 2020;61(8):50. doi:10.1167/iovs.61.8.50
  12. Vogel RN, Langlo CS, Scoles D, Carroll J, Weinberg DV, Kim JE. High-resolution imaging of intraretinal structures in active and resolved central serous chorioretinopathy. Invest Ophthalmol Vis Sci. 2017;58(1):42-49. doi:10.1167/iovs.16-20351
  13. Hanumunthadu D, Matet A, Rasheed MA, Goud A, Vuppurabina KK, Chhablani J. Evaluation of choroidal hyperreflective dots in acute and chronic central serous chorioretinopathy. Indian J Ophthalmol. 2019;67(11):1850-1854. doi:10.4103/ijo.IJO_2030_18
  14. Sharma A, Parachuri N, Kumar N, et al. Vortex vein anastomosis and pachychoroid-an evolving understanding. Eye (Lond). 2021;doi:10.1038/s41433-021-01423-2
  15. Spaide RF, Ledesma-Gil G, Gemmy Cheung CM. Intervortex venous anastomosis in pachychoroid-related disorders. Retina. Oct 26 2020;doi:10.1097/IAE.0000000000003004
  16. Matsumoto H, Hoshino J, Arai Y, et al. Quantitative measures of vortex veins in the posterior pole in eyes with pachychoroid spectrum diseases. Sci Rep. 2020;10(1):19505. doi:10.1038/s41598-020-75789-w
  17. Gilbert CM, Owens SL, Smith PD, Fine SL. Long-term follow-up of central serous chorioretinopathy. Br J Ophthalmol. 1984;68(11):815-820. doi:10.1136/bjo.68.11.815
  18. Bujarborua D. Long-term follow-up of idiopathic central serous chorioretinopathy without laser. Acta Ophthalmol Scand. 2001;79(4):417-421. doi:10.1034/j.1600-0420.2001.079004417.x
  19. Nicolo M, Desideri LF, Vagge A, Traverso CE. Current pharmacological treatment options for central serous chorioretinopathy: a review. Pharmaceuticals (Basel). 2020;13(10):264. doi:10.3390/ph13100264
  20. Ruiz-Moreno JM, Lugo FL, Armada F, et al. Photodynamic therapy for chronic central serous chorioretinopathy. Acta Ophthalmol. 2010;88(3):371-376. doi:10.1111/j.1755-3768.2008.01408.x
  21. Shin JY, Woo SJ, Yu HG, Park KH. Comparison of efficacy and safety between half-fluence and full-fluence photodynamic therapy for chronic central serous chorioretinopathy. Retina. 2011;31(1):119-26. doi:10.1097/IAE.0b013e3181e378f2
  22. van Dijk EHC, Fauser S, Breukink MB, et al. Half-dose photodynamic therapy versus high-density subthreshold micropulse laser treatment in patients with chronic central serous chorioretinopathy: the PLACE trial. Ophthalmology. 2018;125(10):1547-1555. doi:10.1016/j.ophtha.2018.04.021
  23. Lotery A, Sivaprasad S, O’Connell A, et al. Eplerenone for chronic central serous chorioretinopathy in patients with active, previously untreated disease for more than 4 months (VICI): a randomised, double-blind, placebo-controlled trial. Lancet. 2020;395(10220):294-303. doi:10.1016/S0140-6736(19)32981-2
  24. Sacconi R, Borrelli E, Querques G. Eplerenone for chronic central serous chorioretinopathy. Lancet. 2020;396(10262):1556. doi:10.1016/S0140-6736(20)31610-X
  25. Stanescu-Segall D, Touhami S, Bodaghi B, LeHoang P. Eplerenone for chronic central serous chorioretinopathy. Lancet. 2020;396(10262):1556-1557. doi:10.1016/S0140-6736(20)32327-8
  26. Fraenkel D, Suffo S, Langenbucher A, Seitz B, Abdin AD. Eplerenone for treatment of chronic central serous chorioretinopathy. Eur J Ophthalmol. 2020:1120672120952648. doi:10.1177/1120672120952648
  27. Petkovsek DS, Cherfan DG, Conti FF, et al. Eplerenone for the treatment of chronic central serous chorioretinopathy: 3-year clinical experience. Br J Ophthalmol. 2020;104(2):182-187. doi:10.1136/bjophthalmol-2019-314047
  28. Bahadorani S, Maclean K, Wannamaker K, et al. Treatment of central serous chorioretinopathy with topical NSAIDs. Clin Ophthalmol. 2019;13:1543-1548. doi:10.2147/OPTH.S202047
  29. Chen LC, Ma JW, Shieh PC, Horng CT. Oral treatment of central serous chorioretinopathy patients using propranolol tablets. Pharmaceuticals (Basel). 2020;13(11)doi:10.3390/ph13110336
  30. Liew G, Ho IV, Ong S, Gopinath B, Mitchell P. Efficacy of topical carbonic anhydrase inhibitors in reducing duration of chronic central serous chorioretinopathy. Transl Vis Sci Technol. 2020;9(13):6. doi:10.1167/tvst.9.13.6

What to Read Next