Eprints.soton.ac.uk
Discrepancy in current central serous chorioretinopathy (CSCR) classificationTitle of the manuscript: Discrepancy in current central serous chorioretinopathy (CSCR) classificationAuthors: Sumit Randhir Singh1, Alexandre Matet2, Elon HC van Dijk3, Alejandra Daruich4, Sascha Fauser5, Suzanne Yzer6, Enrico Peiretti7,Sobha Sivaprasad8,Andrew J Lotery9,Camiel J Boon3, Francine Behar-Cohen4, K Bailey Freund10, Jay Chhablani1Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad-34, IndiaInstitut Curie, PSL Research University, Ophthalmology Department; and Université Paris Descartes, Sorbonne Paris Cité, F-75005, Paris, FranceDepartment of Ophthalmology, Leiden University Medical Center, Leiden, The NetherlandsINSERM, UMRS 872 Team 17 , Centre de Recherche des Cordeliers , F-75006 Paris , France; and Ophthalmology Department, Cochin University Hospital, APHP, F-75014Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Joseph-Stelzmann-Str. 9, 50931 Cologne, GermanyDepartment of Ophthalmology, Columbia University, New York City, New YorkEye Clinic, University of Cagliari, Cagliari – ItalyNational Institute for Health Research Biomedical Research Centre in Ophthalmology, Moorfields Eye Hospital, London, UKFaculty of Medicine, University of Southampton, Southampton,UKVitreous Retina Macula Consultants of New York, New York, New YorkCorresponding Author: Jay Chhablani, Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Banjara Hills, Hyderabad – 34, India.Contact number +91-40-30612618Email: jay.chhablani@Keywords: Central serous chorioretinopathy, Fundus autofluorescence, Optical coherence tomography, Fluorescein angiography, Indocyanine green angiography. Synopsis: The discordance among the retinal practitioners related to the description of central serous chorioretinopathy (CSCR) subtype is described using multimodal imaging along with the discrepancy in current CSCR classification.Abstract:Aim: To report the discordance in central serous chorioretinopathy (CSCR) classification among practicing retina specialists.Methods: The study conducted was a multicenter survey. Multimodal retinal images along with relevant clinical details of 100 cases diagnosed as CSCR (from six centers) were circulated among six retina specialists across the globe. The image sets included color fundus photographs, fundus autofluorescence images, optical coherence tomography b-scans, fluorescein and indocyanine green angiography of the study and fellow eyes. The graders were asked to classify the disease of study eye, according to their own criteria. The graders were masked to the responses of other graders. The final analysis of the pooled response data was done based on the diagnosis of study eye only. The main outcome measure was degree of agreement between six independent observers using Fleiss Kappa statistics.Results: Grading for 100 eyes of 100 patients (males, 93%) was included in the analysis. 20 patients had a history of steroid use. The graders provided 36 different terms to classify the disease, with poor agreement among graders (Fleiss Kappa=0.134). The consistency in diagnosing acute CSCR was statistically higher than for either chronic (P=0.012) or recurrent CSCR(P<0.0001). When collapsing descriptors into 6 main terms, agreement remained poor (Fleiss Kappa=0.218).Conclusion: The high discordance among experienced retina specialists in describing CSCR clinical subtypes is highlighted.The current work demonstrates the limitations of current empirical CSCR classification methods and the need for a more objective and refined system to bring uniformity in diagnosis and prognostication of the disease. Central serous chorioretinopathy (CSCR) is one of the most common chorioretinal pathologies seen in retina practice. It is classically characterized by one or multiple detachments of the neurosensory retina due to the occurrence of subretinal fluid (SRF),with or without presence of a clinically detectable pigment epithelial detachment (PED). ADDIN EN.CITE <EndNote><Cite><Author>Gass</Author><Year>1967</Year><RecNum>1</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518540982">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gass, JDM</author></authors></contributors><titles><title>Pathogenesis of disciform detachment of the neuroepithelium. II. Idiopathic central serous choroidopathy</title><secondary-title>Am J ophthalmol</secondary-title></titles><periodical><full-title>Am J ophthalmol</full-title></periodical><pages>587-615</pages><volume>63</volume><dates><year>1967</year></dates><urls></urls></record></Cite></EndNote>1 However, multiple additional features can arise within the course of CSCR, including degenerative changes of the retinal pigment epithelium (RPE), identified as atrophy and descending RPE tracts, posterior cystoid retinal degeneration, choroidal neovascularisation(CNV), bullous exudative retinal detachment, and fibrinous subretinal deposits, making sometimes the diagnosis challenging. ADDIN EN.CITE <EndNote><Cite><Author>Yannuzzi</Author><Year>1984</Year><RecNum>2</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518541091">2</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yannuzzi, Lawrence A</author><author>Shakin, Jeffrey L</author><author>Fisher, Yale L</author><author>Altomonte, Mary Ann</author></authors></contributors><titles><title>Peripheral retinal detachments and retinal pigment epithelial atrophic tracts secondary to central serous pigment epitheliopathy</title><secondary-title>Ophthalmology</secondary-title></titles><periodical><full-title>Ophthalmology</full-title></periodical><pages>1554-1572</pages><volume>91</volume><number>12</number><dates><year>1984</year></dates><isbn>0161-6420</isbn><urls></urls></record></Cite></EndNote>2, ADDIN EN.CITE <EndNote><Cite><Author>Liew</Author><Year>2013</Year><RecNum>3</RecNum><DisplayText><style face="superscript">3,4</style></DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518541426">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Liew, Gerald</author><author>Quin, Godfrey</author><author>Gillies, Mark</author><author>Fraser‐Bell, Samantha</author></authors></contributors><titles><title>Central serous chorioretinopathy: a review of epidemiology and pathophysiology</title><secondary-title>Clinical & experimental ophthalmology</secondary-title></titles><periodical><full-title>Clinical & experimental ophthalmology</full-title></periodical><pages>201-214</pages><volume>41</volume><number>2</number><dates><year>2013</year></dates><isbn>1442-9071</isbn><urls></urls></record></Cite><Cite><Author>Daruich</Author><Year>2015</Year><RecNum>4</RecNum><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518541661">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Daruich, Alejandra</author><author>Matet, Alexandre</author><author>Dirani, Ali</author><author>Bousquet, Elodie</author><author>Zhao, Min</author><author>Farman, Nicolette</author><author>Jaisser, Frédéric</author><author>Behar-Cohen, Francine</author></authors></contributors><titles><title>Central serous chorioretinopathy: recent findings and new physiopathology hypothesis</title><secondary-title>Progress in retinal and eye research</secondary-title></titles><periodical><full-title>Progress in retinal and eye research</full-title></periodical><pages>82-118</pages><volume>48</volume><dates><year>2015</year></dates><isbn>1350-9462</isbn><urls></urls></record></Cite></EndNote>3,4The imaging modalities which primarily aid in diagnosing CSCR are optical coherence tomography (OCT), fundus autofluorescence (FAF), fluorescein angiography (FA), and indocyanine angiography (ICGA).The disease entity of CSCR has been traditionally classified based on duration,in either ‘acute’ or ‘chronic’ forms. 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ADDIN EN.CITE.DATA 4-7 has been used in clinical practice and serves as a period of observation beyond which spontaneous resolution is unlikely. ADDIN EN.CITE <EndNote><Cite><Author>Mehta</Author><Year>2016</Year><RecNum>8</RecNum><DisplayText><style face="superscript">8,9</style></DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518542103">8</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mehta, Pooja H</author><author>Meyerle, Catherine</author><author>Sivaprasad, Shobha</author><author>Boon, Camiel</author><author>Chhablani, Jay</author></authors></contributors><titles><title>Preferred practice pattern in central serous chorioretinopathy</title><secondary-title>British Journal of Ophthalmology</secondary-title></titles><periodical><full-title>British Journal of Ophthalmology</full-title></periodical><pages>bjophthalmol-2016-309247</pages><dates><year>2016</year></dates><isbn>0007-1161</isbn><urls></urls></record></Cite><Cite><Author>Daruich</Author><Year>2017</Year><RecNum>26</RecNum><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1520953017">26</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Daruich, Alejandra</author><author>Matet, Alexandre</author><author>Marchionno, Laetitia</author><author>De Azevedo, Jean-Dominique</author><author>Ambresin, Aude</author><author>Mantel, Irmela</author><author>Behar-Cohen, Francine</author></authors></contributors><titles><title>Acute central serous chorioretinopathy: factors influencing episode duration</title><secondary-title>Retina (Philadelphia, Pa.)</secondary-title></titles><periodical><full-title>Retina (Philadelphia, Pa.)</full-title></periodical><pages>1905</pages><volume>37</volume><number>10</number><dates><year>2017</year></dates><urls></urls></record></Cite></EndNote>8,9 The terminology of ‘chronic’ CSCR is usually assigned to these non-resolving cases, which are believed to warrant treatment because of the risk of irreversible vision loss and reduced quality of life in case of persistent detachment of the macula. ADDIN EN.CITE <EndNote><Cite><Author>Breukink</Author><Year>2017</Year><RecNum>9</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518542273">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Breukink, Myrte B</author><author>Dingemans, Alexander JM</author><author>den Hollander, Anneke I</author><author>Keunen, Jan EE</author><author>MacLaren, Robert E</author><author>Fauser, Sascha</author><author>Querques, Giuseppe</author><author>Hoyng, Carel B</author><author>Downes, Susan M</author><author>Boon, Camiel JF</author></authors></contributors><titles><title>Chronic central serous chorioretinopathy: long-term follow-up and vision-related quality of life</title><secondary-title>Clinical ophthalmology (Auckland, NZ)</secondary-title></titles><periodical><full-title>Clinical ophthalmology (Auckland, NZ)</full-title></periodical><pages>39</pages><volume>11</volume><dates><year>2017</year></dates><urls></urls></record></Cite></EndNote>10There exists another spectrum of CSCR presentations, also termed ‘chronic’ CSCR, which manifests in the form of degenerative RPE changes. The term ‘diffuse retinal pigment epitheliopathy’ was assigned to the cases in the chronic spectrum of the disease that are characterised by larger areas of RPE atrophy, best visible on FAF or FA. ADDIN EN.CITE <EndNote><Cite><Author>Yannuzzi</Author><Year>1992</Year><RecNum>10</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518573792">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yannuzzi, LA</author><author>Slakter, JS</author><author>Kaufman, SR</author><author>Gupta, K</author></authors></contributors><titles><title>Laser treatment of diffuse retinal pigment epitheliopathy</title><secondary-title>European journal of ophthalmology</secondary-title></titles><periodical><full-title>European journal of ophthalmology</full-title></periodical><pages>103-114</pages><volume>2</volume><number>3</number><dates><year>1992</year></dates><isbn>1120-6721</isbn><urls></urls></record></Cite></EndNote>11 Multifocal posterior pigment epitheliopathy was the term proposed for chronic CSCR with subretinal exudation, but is not widely used nowadays. ADDIN EN.CITE <EndNote><Cite><Author>Uyama</Author><Year>1999</Year><RecNum>11</RecNum><DisplayText><style face="superscript">12</style></DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518573865">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Uyama, Masanobu</author><author>Matsunaga, Hiroshi</author><author>Matsubara, Takashi</author><author>Fukushima, Ichiro</author><author>Takahashi, Kanji</author><author>Nishimura, Tetsuya</author></authors></contributors><titles><title>Indocyanine green angiography and pathophysiology of multifocal posterior pigment epitheliopathy</title><secondary-title>Retina (Philadelphia, Pa.)</secondary-title></titles><periodical><full-title>Retina (Philadelphia, Pa.)</full-title></periodical><pages>12-21</pages><volume>19</volume><number>1</number><dates><year>1999</year></dates><isbn>0275-004X</isbn><urls></urls></record></Cite></EndNote>12 Other controversies persist in the terminology of CSCR subtypes. The healed, resolved or inactive CSCR represent a subset of cases with presence of RPE defects, PED with or witout CNV but without presence of SRF. ADDIN EN.CITE <EndNote><Cite><Author>Bujarborua</Author><Year>2005</Year><RecNum>12</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>12</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518573948">12</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bujarborua, Dhiren</author><author>Chatterjee, Samrat</author><author>Choudhury, Amit</author><author>Bori, Geetanjali</author><author>Sarma, Ajit K</author></authors></contributors><titles><title>Fluorescein angiographic features of asymptomatic eyes in central serous chorioretinopathy</title><secondary-title>Retina</secondary-title></titles><periodical><full-title>Retina</full-title></periodical><pages>422-429</pages><volume>25</volume><number>4</number><dates><year>2005</year></dates><isbn>0275-004X</isbn><urls></urls></record></Cite></EndNote>13Thus, the classification and terminology in CSCR is variable and subject to controversy. Whether the acute or chronic forms of CSCR are a continuum or if they represent a different spectrum of the disease with different pathophysiology still remains obscure. Furthermore, patients with extrafoveal neurosensory detachments at disease onset may not have any visual symptoms until later in the disease course when the fovea becomes involved, and may be erroneously classified to be part of the acute form of CSCR, based on duration of symptoms. The spectrum of clinical manifestations of CSCR and the array of different terminologies pose a unique challenge to clinicians in terms of non-uniformity in reporting and prognostication of the disease. Recently, Daruich et al ADDIN EN.CITE <EndNote><Cite><Author>Daruich</Author><Year>2015</Year><RecNum>4</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518541661">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Daruich, Alejandra</author><author>Matet, Alexandre</author><author>Dirani, Ali</author><author>Bousquet, Elodie</author><author>Zhao, Min</author><author>Farman, Nicolette</author><author>Jaisser, Frédéric</author><author>Behar-Cohen, Francine</author></authors></contributors><titles><title>Central serous chorioretinopathy: recent findings and new physiopathology hypothesis</title><secondary-title>Progress in retinal and eye research</secondary-title></titles><periodical><full-title>Progress in retinal and eye research</full-title></periodical><pages>82-118</pages><volume>48</volume><dates><year>2015</year></dates><isbn>1350-9462</isbn><urls></urls></record></Cite></EndNote>4 have raised these issues and proposed a nomenclature which needs certain modifications and a wider agreement to be implemented in daily practice and clinical studies.To explore the discrepancy in classifying CSCR among the retina specialists, we performed a survey on current classification using multimodal imaging by experts across the globe. This study addresses the extent and the possible causes of discrepancy that occur during classifying CSCR.MethodsClinical study dataThis study was observational and involved compilation of clinical and imaging data of patients with a presumptive diagnosis of CSCR. This study was considered exempt from ethical approval after consultation from ethics committee and Institutional Review Board (IRB) due to its purely observational nature.A pooled anonymized data set was created which included clinical details of 100 patients with presumed CSCR in at least one eye. The diagnosis of CSCR was made on the basis of duration of symptoms, presence of SRF with or without PED in the absence of intraocular inflammation, RPE changes in FAF and leakage or window defects seen in FA or ICGA. The clinical images were obtained from six centers across the globe. Six retina specialists from these centers (SF, EP, SS, CJB, FB, JC) who are considered to be experts in CSCR with five years of clinical practice and research focused on CSCR, with atleast one peer-reviewed publication related to CSCR,either as first or corresponding author in the last two years were provided with the anonymized clinical data of these 100 patients (25 each from Italy, Netherlands, France, India).These included demography (age, gender,ethnicity), duration of symptoms, history of previous similar episodes, prior steroid use, medical history and medication use. Clinical evaluation included best-corrected visual acuity (BCVA) in LogMAR units and multimodal imaging including OCT, FAF, FA, and ICGA were provided for each patient at the presenting visit.The anonimized clinical details and images of both eyes were shared with the six observers to facilitate better clinical correlation.OCT (Carl Zeiss Meditec Cirrus HD-OCT, Dublin, CA; or Heidelberg Spectralis HRA +OCT; Heidelberg Engineering, Inc, Vista, CA) included 6-mm horizontal line scanspassing through the fovea. FAF, fundus photographs, FA,and ICGA (Zeiss Visupac? FF4 and FF450-plus, Carl Zeiss, Dublin, CA; orHeidelberg Spectralis HRA +OCT; Heidelberg Engineering, Inc, Vista, CA) were obtained, including both early and late phase images of FA and ICGA. However, the images readers were provided with additional images on their request in cases with diagnostic dilemma. Grading procedure and statiscal analysisThe observers were asked to provide a diagnosis as per their own criteria and clinical experience for the involved eye of each case using the available details. The graders were masked and were unaware of other graders’ details and their responses. The final analysis from the pooled data of the responses was done based on the diagnosis of the study eye. The study eye was decided based on the severity of the disease and the discretion of the practicing physician. The study eye was preallocated to the readers by principal investigator (JC). To assess the degree of agreement between independent observers, the Fleiss Kappa statistic, an adaptation of Cohen’s Kappa for threeor more raters, was used. Calculations were performed on the ‘irr’package on R (Version 3.3.0, R Foundation for Statistical Computing, R Core Team, 2016, Vienna, Austria;; ).The level of agreement was determined by the Kappa coefficientas excellent (>0.90), substantial (0.75-0.90), moderate (0.50-0.75), or poor (<0.50).Descriptive and comparative statistics were computed on GraphPad Prism (version 5.0f, GraphPad Software, La Jolla, CA). Quantitative continuous values were reported as mean ± standard deviation. The Mann-Whitney test was used to compare means.ResultsThe data of 100 patients with presumptive diagnosis of CSCR was pooled from six different centers across the globe. A total of 63, 32, and 5 patients had involvement (either presence of subretinal fluid on OCT or changes in FAF, FA and ICGA) of right eye, left eye, and both eyes respectively. The more severely involved eye (worse vision) was exclusively used for analysis in cases with bilateral involvement at presentation. The gender distribution was skewed towards the male gender with 93 patients out of all patients being males (93%).A total of 20 patients (20%) declared a history of prior steroid usage in various forms: oral (n=6), topical dermal (n=6), intranasal (n=5),intra-articular (n=2) and topical ocular(n=1).Thirty-six different terms, reported in Figure 1, were employed by the six independent observers to describe the clinical presentations of the 100 CSCR cases, totalizing 600 descriptors.There was a poor agreement between the six observers (Fleiss Kappa = 0.134), as visible on the detailed distribution of descriptors among observers (Table 1).The most frequently employed terms were ‘chronic’ (n=230/600, 38.3%), ‘acute’ (n=144/600, 24.0%), ‘recurrent’ (n=46/600, 7.7%), ‘chronic persistent’ (n=31/600, 5.2%), ‘acute recurrent’ (n=23/600, 3.8%) and ‘acute on chronic’ (n=21/600, 3.5%). The degree of agreement varied between terms. In order to assess the robustness of these observations, the number of terms employed by observers to describe CSCR subtypes was collapsed, resulting in six major terms approximating each description (acute, chronic, recurrent, resolved, atypical and subclinical).Agreement between the six observers remained poor with this more homogeneous distributiuon of terms (Fleiss Kappa= 0.218). To simplify it further, we considering only the three most frequent descriptors. We found that a significantly higher number of consistent observations were made for the term ‘acute’, as compared to both ‘chronic’ and‘recurrent’ (P=0.012 and P<0.0001, respectively), and for the term ‘chronic’ as compared to ‘recurrent’ (P<0.0001) (Table 2).To illustrate this discrepancy, Figure 2 and 3 display the multimodal imaging of two representative cases, and the responses from different observers. DiscussionCSCR is an intriguing chorioretinal disease, and in particular its correct diagnosis and the appropriate treatment and timing still remains a challenge. The variety of clinical manifestations and terminologies used in clinical practice shed some light on the ambiguity in diagnosis and the management of this condition.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW5udXp6aTwvQXV0aG9yPjxZZWFyPjE5ODQ8L1llYXI+
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ADDIN EN.CITE.DATA 4,14,15 Furthermore, certain patients may present pathological features suggestive of CSCR but without SRF at the time of examination. Few of the observers have used a “subclinical” term when there was no intra- or subretinal fluidon OCT,but only hypoautofluorescence on FAF suggestive of either a resolved CSCR episode or a subclinical manifestation of the disease. The clinical and imaging findings in the recently introduced term pachychoroid pigment epitheliopathy show overlap with cases labelled as “subclinical” CSCR. ADDIN EN.CITE <EndNote><Cite><Author>Warrow</Author><Year>2013</Year><RecNum>15</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>15</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518620296">15</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Warrow, David J</author><author>Hoang, Quan V</author><author>Freund, K Bailey</author></authors></contributors><titles><title>Pachychoroid pigment epitheliopathy</title><secondary-title>Retina</secondary-title></titles><periodical><full-title>Retina</full-title></periodical><pages>1659-1672</pages><volume>33</volume><number>8</number><dates><year>2013</year></dates><isbn>0275-004X</isbn><urls></urls></record></Cite></EndNote>16 Activity of the disease is only based on the presence of subretinal fluid but the exact reasons for vision alteration are not fully identified and RPE degeneration can be observed in absence of SRF as described in the pigment epitheliopathy spectrum. The graders have used different terminologies, with chronic and acute being the most frequently used terms to describe the disease status in CSCR patients, as illustrated in Figure 1. Noticeably, the expert graders have proposed these terms based on their empirical experience and clinical sense, in the absence of objective criteria defining them.However, ambiguity arises with usage of even more equivocal terms like chronic persistent, acute recurrent, chronic recurrent, acute on chronic, and subclinical disease, pointing to the difficulties of a synthetic terminology qualifying both disease course and findings on multimodal imaging. The agreement between observers was very poor, as shown by low Fleiss Kappa value (0.134), that remained low if reducing the terms to the 6 more frequent (Fleiss Kappa=0.218). The graders were more consistent with the diagnosis of acute CSCR, as compared to the other terms that were most often used (chronic and recurrent), which was statistically significant, as shown in Table 2. This highlights the fact that the diagnosis of acute CSCRmay be more straightforward.The classification of CSCR based on the duration of disease has certain inherent flaws. Extrafoveal leaks with no ocular symptoms on many occasions may go unnoticed which with time may either worsen or regress. Spontaneous resolution leads to presence of extrafoveal RPE defects which can be seen in fellow eyes of patients with CSCR. Conversely, worsening may result in foveal involvement with drop in vision. In both scenarios, an accurate duration of disease may not be discernible based on the duration of symptoms.Expert graders in this study have employed the terms non-resolving and chronic CSCR interchangeably, as often occurs in the literature and in the clinical setting. The differentiation between non-resolving and chronic CSCR needs further deliberation. ADDIN EN.CITE <EndNote><Cite><Author>Daruich</Author><Year>2015</Year><RecNum>4</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518541661">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Daruich, Alejandra</author><author>Matet, Alexandre</author><author>Dirani, Ali</author><author>Bousquet, Elodie</author><author>Zhao, Min</author><author>Farman, Nicolette</author><author>Jaisser, Frédéric</author><author>Behar-Cohen, Francine</author></authors></contributors><titles><title>Central serous chorioretinopathy: recent findings and new physiopathology hypothesis</title><secondary-title>Progress in retinal and eye research</secondary-title></titles><periodical><full-title>Progress in retinal and eye research</full-title></periodical><pages>82-118</pages><volume>48</volume><dates><year>2015</year></dates><isbn>1350-9462</isbn><urls></urls></record></Cite></EndNote>4 Non-resolution can result from multifactorial processes, including prolonged leakage or insufficient SRF drainage by a non-functioning RPE. In chronic CSCR, RPE damage due to previous episodes could be present, and further reduce the pumping capacity of RPE cells over the affected area. Among less typical cases, those with SRF, intraretinal fluid,or PED with no leakage lead to diagnostic dilemma with few graders terming them as chronic, and others naming them recurrent.Diffuse retinal pigment epitheliopathy (DRPE), a term previously used for these cases with diffuse RPE changes, is not in common usage. It represents a severe form of the disease and invariably has moderate to severe vision loss. It therefore becomes prudent to not interchange DRPE and chronic CSCR, two different entities. ADDIN EN.CITE <EndNote><Cite><Author>Yannuzzi</Author><Year>1992</Year><RecNum>10</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>10</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518573792">10</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yannuzzi, LA</author><author>Slakter, JS</author><author>Kaufman, SR</author><author>Gupta, K</author></authors></contributors><titles><title>Laser treatment of diffuse retinal pigment epitheliopathy</title><secondary-title>European journal of ophthalmology</secondary-title></titles><periodical><full-title>European journal of ophthalmology</full-title></periodical><pages>103-114</pages><volume>2</volume><number>3</number><dates><year>1992</year></dates><isbn>1120-6721</isbn><urls></urls></record></Cite></EndNote>11 Similarly, sick RPE syndrome has been described as either chronic CSCR or a subdivision of chronic CSCR. ADDIN EN.CITE <EndNote><Cite><Author>Gemenetzi</Author><Year>2010</Year><RecNum>23</RecNum><DisplayText><style face="superscript">17</style></DisplayText><record><rec-number>23</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518622922">23</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gemenetzi, M</author><author>De Salvo, G</author><author>Lotery, AJ</author></authors></contributors><titles><title>Central serous chorioretinopathy: an update on pathogenesis and treatment</title><secondary-title>Eye</secondary-title></titles><periodical><full-title>Eye</full-title></periodical><pages>1743</pages><volume>24</volume><number>12</number><dates><year>2010</year></dates><isbn>1476-5454</isbn><urls></urls></record></Cite></EndNote>17One important goal of any clinical classification is its ability to predict the course of the disease. Ideally, RPE atrophic changes need to be elaborated in further detail. As is seen clinically and with multimodal imaging, RPE changes can be either focal or multifocal, or diffuse, which is important for its clinical course and visual outcome. Moreover, RPE alterations in the fellow eye of CSCR comprise a wide spectrum of manifestations, ranging from minor extrafoveal RPE changes to extensive atrophic RPE changes like previously described DRPE. Without any recorded previous SRF leakage, this indicates the presence of pachychoroid pigment epitheliopathy. It is currently unclear if such ‘forme fruste’ CSCR-like RPE changes as described in pachychoroid pigment epitheliopathy can also be present without a thickened choroid and/or leaking underlying choriocapillaris.Due to the frequent bilateral and asymmetrical presentation of pachychoroid-spectrum disorders, we had provided the observers with complete fellow eye imaging. 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ADDIN EN.CITE.DATA 18-20 This complication should be part of upcoming CSCR classification systems as it might have an impact on the therapeutic decision. Similarly, whether bullous exudative retinal detachments, another rare clinical finding in CSCR,are related to chronicity or severity of disease, needs to be clarified and should be included in future nomenclatures. ADDIN EN.CITE <EndNote><Cite><Author>Balaratnasingam</Author><Year>2016</Year><RecNum>27</RecNum><DisplayText><style face="superscript">21</style></DisplayText><record><rec-number>27</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1520954692">27</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Balaratnasingam, Chandrakumar</author><author>Freund, K Bailey</author><author>Tan, Anna M</author><author>Mrejen, Sarah</author><author>Hunyor, Alex P</author><author>Keegan, David J</author><author>Dansingani, Kunal K</author><author>Dayani, Pouya N</author><author>Barbazetto, Irene A</author><author>Sarraf, David</author></authors></contributors><titles><title>Bullous variant of central serous chorioretinopathy: expansion of phenotypic features using multimethod imaging</title><secondary-title>Ophthalmology</secondary-title></titles><periodical><full-title>Ophthalmology</full-title></periodical><pages>1541-1552</pages><volume>123</volume><number>7</number><dates><year>2016</year></dates><isbn>0161-6420</isbn><urls></urls></record></Cite></EndNote>21The present study has certain strengths and weaknesses. Categorization into CSCR subtypes were based solely on multimodal imaging and succinct clinical data, whereas in real-life free anamnesis and interaction with the patients are critical to refine challenging diagnoses. Regarding multimodal imaging data provided to observers, images had a limited field of view, as currently obtained with conventional (non-widefield) imaging devices. ADDIN EN.CITE <EndNote><Cite><Author>Hirahara</Author><Year>2016</Year><RecNum>21</RecNum><DisplayText><style face="superscript">22,23</style></DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518621873">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hirahara, Shuichiro</author><author>Yasukawa, Tsutomu</author><author>Kominami, Aoi</author><author>Nozaki, Miho</author><author>Ogura, Yuichiro</author></authors></contributors><titles><title>Densitometry of choroidal vessels in eyes with and without central serous chorioretinopathy by wide-field indocyanine green angiography</title><secondary-title>American journal of ophthalmology</secondary-title></titles><periodical><full-title>American journal of ophthalmology</full-title></periodical><pages>103-111</pages><volume>166</volume><dates><year>2016</year></dates><isbn>0002-9394</isbn><urls></urls></record></Cite><Cite><Author>Pang</Author><Year>2014</Year><RecNum>22</RecNum><record><rec-number>22</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518621922">22</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pang, Claudine E</author><author>Shah, Vinnie P</author><author>Sarraf, David</author><author>Freund, K Bailey</author></authors></contributors><titles><title>Ultra-widefield imaging with autofluorescence and indocyanine green angiography in central serous chorioretinopathy</title><secondary-title>American journal of ophthalmology</secondary-title></titles><periodical><full-title>American journal of ophthalmology</full-title></periodical><pages>362-371. e2</pages><volume>158</volume><number>2</number><dates><year>2014</year></dates><isbn>0002-9394</isbn><urls></urls></record></Cite></EndNote>22,23 Moreover, observers were provided with a maximum of two images of both FFA and ICGA, which in certain cases may be insufficient to reach an accurate diagnosis. A small proportion of ICGA images were obtained with a fundus camera, which had a lower resolution compared to confocal scanning laser ophthalmoscopes. Still, a discordance between the expert praticing physicians in classifying CSCR was highlighted. Although the present results were based on subjective assessments by these experts, the high number of cases (n=100), muliplicated by the relatively high number of participating experts (n=6), reduced the probability that the observed discordance was due to chance only. As CSCR is known to vary in different geographic locations, with Asians prone for a more severe disease, ADDIN EN.CITE <EndNote><Cite><Author>How</Author><Year>2006</Year><RecNum>20</RecNum><DisplayText><style face="superscript">24</style></DisplayText><record><rec-number>20</rec-number><foreign-keys><key app="EN" db-id="t5txexdzkv9trhezt0kxpx5t9xt5zpeza2x2" timestamp="1518621766">20</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>How, ACSW</author><author>Koh, Adrian HC</author></authors></contributors><titles><title>Angiographic characteristics of acute central serous chorioretinopathy in an Asian population</title><secondary-title>ANNALS-ACADEMY OF MEDICINE SINGAPORE</secondary-title></titles><periodical><full-title>ANNALS-ACADEMY OF MEDICINE SINGAPORE</full-title></periodical><pages>77</pages><volume>35</volume><number>2</number><dates><year>2006</year></dates><isbn>0304-4602</isbn><urls></urls></record></Cite></EndNote>24 the varied geographical distribution of cases provided a worldwide collection covering all the different forms of the disease, and reduced any potential inclusion bias.Moreover, the six observers from different locations across the globe also provided different outlooks, and different practice patterns in diagnosing CSCR, which, reduced potential interpretation bias.To conclude, CSCR is a complex disease entity that presents as multiple clinical subtypes depending on the extent of SRF, RPE alterations, fluorescein leakage, past and present disease course, and fellow eye involvement. To date these diverse manifestations of CSCR are not easily recapitulated in a synthetic and consensual terminology. The outcome of this study points to conduct observational studies across different centers and countries using algorithm based on various parameters such as choroidal thickness, autofluorescence, and to better characterize and reclassify CSCR and its subtypes. Acknowledgements/Disclosure:Funding/Support:NoneFinancial Disclosure: No financial disclosures.Other Acknowledgments?:NoneCompeting interests: None declared.Contributors: SRS, AM, JC were involved in the designing of the study. AM, EVD, AD, EP, CJB, JC were involved in the collection of data. SF, EP, SS, CJB, FB, JC were responsible for interpretation of the data (clinical images). AM, EVD, AD did the analysis. SRS, AM, EVD, AD were involved in manuscript writing. SF, SY, SS, AJ, CJB, FB, KBF, JC reviewed the article. All the authors conducted the study and equally contributed in the preparation, review and approval of the manuscript.References: ADDIN EN.REFLIST 1.Gass J. Pathogenesis of disciform detachment of the neuroepithelium. II. Idiopathic central serous choroidopathy. Am J Ophthalmol 1967;63:587-615.2.Yannuzzi LA, Shakin JL, Fisher YL, Altomonte MA. Peripheral retinal detachments and retinal pigment epithelial atrophic tracts secondary to central serous pigment epitheliopathy. Ophthalmology 1984;91(12):1554-1572.3.Liew G, Quin G, Gillies M, Fraser‐Bell S. Central serous chorioretinopathy: a review of epidemiology and pathophysiology. Clin Exp Ophthalmol 2013;41:201-214.4.Daruich A, Matet A, Dirani A, et al. Central serous chorioretinopathy: recent findings and new physiopathology hypothesis. Prog Retin Eye Res 2015;48:82-118.5.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(2):307-315.e2.6.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;31:119-126.7.Yannuzzi LA. Central serous chorioretinopathy: a personal perspective. Am J Ophthalmol 2010;149:361-363. 8.Mehta PH, Meyerle C, Sivaprasad S, Boon C, Chhablani J. Preferred practice pattern in central serous chorioretinopathy. Br J Ophthalmol 2017;101:587-590.9.Daruich A, Matet A, Marchionno L, et al. Acute central serous chorioretinopathy: factors influencing episode duration. Retina 2017;37:1905-15.10.Breukink MB, Dingemans AJ, den Hollander AI, et al. Chronic central serous chorioretinopathy: long-term follow-up and vision-related quality of life. Clin Ophthalmol 2017;11:39-46.11.Yannuzzi L, Slakter J, Kaufman S, Gupta K. Laser treatment of diffuse retinal pigment epitheliopathy. Eur J Ophthalmol 1992;2:103-114.12.Uyama M, Matsunaga H, Matsubara T, et al. Indocyanine green angiography and pathophysiology of multifocal posterior pigment epitheliopathy. Retina 1999;19:12-21.13.Bujarborua D, Chatterjee S, Choudhury A, Bori G, Sarma AK. Fluorescein angiographic features of asymptomatic eyes in central serous chorioretinopathy. Retina 2005;25:422-429.14.Nicholson B, Noble J, Forooghian F, Meyerle C. Central serous chorioretinopathy: update on pathophysiology and treatment. Surv Ophthalmol 2013;58:103-126.15.Bujarborua D. Long‐term follow‐up of idiopathic central serous chorioretinopathy without laser. Acta Ophthalmol 2001;79:417-421.16.Warrow DJ, Hoang QV, Freund KB. Pachychoroid pigment epitheliopathy. Retina 2013;33:1659-72.17.Gemenetzi M, De Salvo G, Lotery A. Central serous chorioretinopathy: an update on pathogenesis and treatment. Eye 2010;24:1743-56.18.Chan W-M, Lai TY, Liu DT, Lam DS. Intravitreal bevacizumab (avastin) for choroidal neovascularization secondary to central serous chorioretinopathy, secondary to punctate inner choroidopathy, or of idiopathic origin. Am J Ophthalmol 2007;143:977-983. 19.Fung AT, Yannuzzi LA, Freund KB. Type 1 (sub-retinal pigment epithelial) neovascularization in central serous chorioretinopathy masquerading as neovascular age-related macular degeneration. Retina 2012;32:1829-1837.20.Hage R, Mrejen S, Krivosic V, et al. Flat irregular retinal pigment epithelium detachments in chronic central serous chorioretinopathy and choroidal neovascularization. Am J Ophthalmol 2015;159:890-903.21.Balaratnasingam C, Freund KB, Tan AM, et al. Bullous variant of central serous chorioretinopathy: expansion of phenotypic features using multimethod imaging. Ophthalmology 2016;123:1541-1552.22.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;166:103-111.23.Pang CE, Shah VP, Sarraf D, Freund KB. Ultra-widefield imaging with autofluorescence and indocyanine green angiography in central serous chorioretinopathy. Am J Ophthalmol 2014;158:362-371. 24.How A, Koh AH. Angiographic characteristics of acute central serous chorioretinopathy in an Asian population. Ann Acad Med?Singapore 2006;35:77-9.Figure legendsFigure 1: Terms used by six independent observers, ordered by number of occurence, to characterize a set of 100 cases with central serous chorioretinopathy. (CNV-Choroidal neovascularization; PCV – Polypoidal choroidal vasculopathy; PED – Pigment epithelial detachment)Figure 2: Representative case. The patient was a 56 year old male who presented with metamorphopsia with best corrected visual acuity of 0.9 LogMAR with 12 months duration of symptoms . Fundus autofluorescence (A) showed presence of mixed patches of stippled hyper- and hypoautofluorescence. Fluorescein angiography (late phase) (B) showed presence of staining with no definite leakage. Indocyanine green angiography (C) revealed large choroidal vessels with no hot spots or obvious leakage. Optical coherence tomography (D) showed presence of neurosensory detachment with thickened inner segment – outer segment (IS-OS) junction with presence of hyperereflectivity in subretinal space suggestive of fibrin. Autofluorescence of fellow eye (E) showed presence of hypoautofluorescent patches suggestive of retinal pigment epithelium (RPE) atrophy. Among six observers, four made a diagnosis of chronic central serous chorioretinopathy (CSCR), one recurrent and one observer diagnosed the patient as a case of acute CSCR in the right eye. Figure 3: Representative case. Multimodal images of a 60 years old male with best corrected visual acuity of 0.83 LogMAR in his right eye. He had received triamcinolone acetonide injection in tendon on two separate occasions 6 months prior to the onset of the disease. Fluorescein angiography early phase (A) and late phase (B) showed presence of window defects with no leakage. Indocyanine angiography (ICGA) (C) showed focal hyperfluorescence with no leak. Optical coherence tomography (OCT) (D) revealed presence of subfoveal neurosensory detachment with subretinal fluid. Fundus autofluorescence (E) of the fellow eye had presence of very few areas of hypoautofluorescence suggestive of RPE atrophy. Among the six observers, three, two and one observer made a diagnosis of chronic, acute and acute recurrent CSCR respectively for his right eye.Table 1. Distribution of terms among 6 independent observers to describe clinical presentations of 100 cases with central serous chorioretinopathy (CSCR).ObserversTerm#1#2#3#4#5#6Chronic792439223531Acute113029252227Recurrent00017263Chronic persistent0270004Acute recurrent0202100Acute on chronic0021000Chronic recurrent090024Subclinical550010Severe0001100Chronic with diffuse retinal pigment epitheliopathy000063Chronic with CNV311003Persistent000007Chronic multifocal000060PCV102000Resolved001110Acute on chronic recurrent003000Chronic persistent with diffuse retinal pigment epitheliopathy000003Acute persistent000003Masquerade010110Chronic resolved100001Multifocal acute on chronic002000Acute with multifocal PED000002Chronic persistent multifocal010000Occult CNV001000Multifocal with PED001000Hyperpermeable choroid000100Atypical multifocal000001Acute atypical with schisis-like intraretinal edema000001Atypical with CNV000001Persistent with CNV000001Chronic persistent with CNV type 1000001Chronic persistent with CNV type 2000001Pachychoroid pigment epitheliopathy000001Acute bullous000001Chronic with CNV type 1000001Hyperpermeable choroid000100CNV= choroidal neovascularization; PCV= polypoidal choroidal vasculopathy; PED= pigment epithelial detachmentTable 2. Descriptive and comparative statistics for the three most frequent terms (‘chronic’, ‘acute’ and ‘recurrent’) used by 6 independent observers to describe 100 cases with central serous chorioretinopathy (CSCR).TermAgreement betweenP value*6 raters5 raters4 raters2-3 ratersConsistent raters, N.(mean± SD)vs Acutevs RecurrentChronic, N. (%)0 (0%)8 (17%)15 (31%)25 (52%)3.50 ± 0.950.012<0.0001Acute, N. (%)3 (11%)7 (26%)7 (26%)10 (37%)4.21 ± 1.10-<0.0001Recurrent, N. (%)0 (0%)0 (0%)0 (0%)15 (100%)2.25 ± 0.50--* Mann-Whitney test ................
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