Choroidal Neovascularization as a Trigger for Central Serous Chorioretinopathy

Choroidal Neovascularization as a Trigger for Central Serous Chorioretinopathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Choroidal Neovascularization as a Trigger for Central Serous Chorioretinopathy Aliénor Vienne-Jumeau, Elodie Bousquet, Jacques Bijon, Sarah Mrejen, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7502868/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Backgrounds: To investigate whether choroidal neovascularization (CNV) can act as a trigger for central serous chorioretinopathy (CSCR) in patients with pachychoroid features, by analyzing cases where fluorescein angiography (FA)-confirmed leakage originated directly within the CNV lesion. Methods: We retrospectively reviewed patients with no prior history or signs of CSCR who presented with a first episode of CSCR and coexisting CNV. Inclusion required at least one FA-confirmed leakage point located within the neovascular complex. Multimodal imaging—including FA, spectral-domain optical coherence tomography (SD-OCT), and OCT angiography (OCTA)—was performed to detect CNV and evaluate its topographical relationship with leakage. Results: Among 202 patients screened, four met inclusion criteria (two males, two females; age range 54–58 years). All presented with a unilateral first episode of CSCR. In each case, FA and OCTA demonstrated precise colocalization of the leakage point within the CNV lesion. CNV was predominantly retrofoveal and appeared mature in morphology. Three patients were diagnosed simultaneously with CSCR and a neovascular membrane, while one developed CSCR during follow-up of a previously identified PNV. Subretinal fluid fluctuations were observed in all cases and often appeared independent of anti-VEGF treatment, suggesting a mechanism not exclusively driven by VEGF-mediated CNV activity. Conclusions: This case series suggests that, within the pachychoroid spectrum, CNV may not only complicate chronic or complex CSCR but may also act as a direct trigger of acute episodes. These findings underscore the importance of multimodal imaging, particularly FA and OCTA, for comprehensive assessment of CSCR. Choroidal Neovascularization Pachychoroid neovascularization Central Serous Chorioretinopathy Leaking point Optical coherence tomography Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Acute central serous chorioretinopathy (CSCR) is defined by the occurrence of serous retinal detachment associated with a leak on fluorescein angiography (FA), showing active dye passage through one or more areas of the retinal pigment epithelium (RPE) barrier break.[ 1 ] , [ 2 ] Other characteristic clinical signs are visual impairment such as contrast loss, color vision impairment, micropsia, and focal blurring, without major loss of visual acuity.[ 3 ] , [ 4 ] Spectral-Domain Optical Coherence Tomography (SD-OCT) examination confirms the diagnosis when characteristic choroidal signs are present, such as thickened choroid compared to fellow eye or age-matched controls and the presence of dilated veins that obscure the choriocapillaris (pachyvessels)[ 5 ] , [ 6 ] and are associated with the serous detachment. On SD-OCT, the leakage site(s) observed on FA often correspond to structural changes such as a pigment epithelial detachment (PED), focal RPE disruption, areas of outer segment ‘erosion’ or elongation[ 3 ] , [ 7 ], and, in some cases, adjacent hyporeflective subretinal lucencies.[ 8 ] In acute forms, FA typically reveals a focal site of RPE leakage. A high intensity of leakage is generally indicative of an episode that will resolve within a few months[ 5 ]. In contrast, diffuse RPE dysfunction without a clearly identified leakage site is more suggestive of chronic episodes and more complex disease forms[ 9 ]. The exact mechanisms of “leakage,” which is transient in acute forms, are not fully understood. Histological analysis of adrenaline-induced CSCR-like disease in monkey showed that spots of fluorescein leakage coincided with focal RPE cell degeneration over area of choriocapillaris endothelial defects with fibrin deposits within the Bruch’s membrane, suggesting that coagulation cascade and macromolecular transports could be involved.[ 10 ] Indocyanine green angiography (ICGA) in patients with acute CSCR confirmed choriocapillaris involvement with area of capillaries hypoperfusion and leakage at the site of RPE leak.[ 11 , 12 ] Several mechanisms have been hypothesized, including bulk fluid flow[ 13 ] and reverse of retinal pigment epithelium pump[ 14 ], which could be promoted by mechanical stresses from the dilated and engorged choroid. The development of choroidal neovascularization (CNV) is a sight threatening complication of CSCR, being responsible for a reduced visual acuity during a long-term follow-up.[ 15 ] Using multimodal imaging, CNV was detected in up to 40% of “chronic” or complex forms of CRSC.[ 16 ] The detection of CNV can indeed be difficult, and it is the presence of a flat irregular PED (FIPED), partially hyperreflective, that should raise suspicion.[ 17 ] , [ 18 ] , [ 19 ] Detection of choroidal neovascularization (CNV) is notably easier with OCT-Angiography (OCT-A), which enables visualization in approximately 35% of cases, compared to 25% with ICGA. This is because, unlike in age-related macular degeneration (AMD), type 1 CNV in these conditions does not frequently form hyperfluorescent plaques in the late phase of ICGA.[ 20 ] Although FIFED have been identified in around 40% of acute CSCR, the exact occurrence of CNV in these cases has been poorly documented. Within the pachychoroid spectrum, another entity has been recognized: pachychoroid neovasculopathy (PNV). These are patients who have no history of CSCR but present mature neovascularization secondary to pachychoroid and area of ICGA hyperpermeability, with or without associated epitheliopathy and no exudative detachment.[ 21 ] Differential diagnosis with AMD can be difficult, and it is the thickness of the choroid and the absence of drusen that will guide this diagnosis, the boundary with AMD currently being debated.[ 22 ] In this ever-expanding spectrum of pachychoroid disease, the definition of different forms of CSCR is an ongoing process.[ 23 ] , [ 24 ] We report here the cases of patients presenting with a first episode of acute CRSC and an active FA leakage site located on the edge of a neovascular membrane. Based on these cases, we discuss the mechanisms, diagnostic methods, and implications for management. Methods Ethics Statement. The study was approved by the Ethics Committee of the French Society of Ophthalmology (00008855). It adhered to the tenets of the Declaration of Helsinki (1964). Oral informed consent was obtained from all patients prior to inclusion. Study Design. This retrospective observational study was conducted at the Department of Ophthalmology, Cochin Hospital (Paris), and the Department of Ophthalmology, Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts (Paris). All patients aged ≥ 18 years who presented with either a new diagnosis or follow-up of central serous chorioretinopathy (CSCR) associated with choroidal neovascularization (CNV) between December 2024 and April 2025 were retrospectively reviewed for inclusion. Patients. Patients were eligible if diagnosed with acute CSCR associated with concurrent CNV. Inclusion criteria were: no prior history of CSCR, absence of clinical or imaging signs of complex CSCR, and presence of at least one leakage point located within the neovascular network. Multimodal imaging—including fluorescein angiography (FA), indocyanine green angiography (ICGA), spectral-domain optical coherence tomography (SD-OCT; Spectralis®, Heidelberg), and optical coherence tomography angiography (OCTA)—had to be performed within one month of CSCR diagnosis. Data Collection : For each patient, the following data were collected: age at diagnosis, gender, CNV maturity, contralateral eye choroidal characteristics, and refractive error (spherical equivalent). CNV maturity was defined on OCTA as vascular morphology graded into immature (tangled or rosette-like cluster of indistinct capillary vessels) or mature (presence of a prominent, dilated core vessel within a more organized vascular network).[ 25 ] The leaking point was defined as a focal area of hyperfluorescence with an increased in size over time on FA as previously described.[ 26 ] CNV was defined on OCTA as abnormal flow within the outer retinal slab.[ 27 ] When necessary, the outer retina and choriocapillaris slabs were manually adjusted to refine segmentation. CNV lesions were classified based on en face OCTA projections (ORCC slab) according to established vascular morphology criteria. Following identification of the leaking point and CNV, the OCTA was accurately realigned with the angiographic images by referencing the retinal vessels at the level of the superficial microvasculature, in order to precisely localize the site of leakage. Results Patients Among 202 eligible patients with CSCR and CNV seen between December 2024 and April 2025, four patients met the inclusion criteria (Supplementary Fig. 1). The cohort comprised two men and two women (Table 1 ). The age at CSCR onset ranged from 54 to 58 years. In all cases, only one eye was affected. The left eye was involved in two patients and the right eye in two. All patients were either emmetropic or mildly hyperopic, with absolute refractive errors < 3 diopters. Table 1 – Description of included patients Gender Eye Diagnosis fellow eye Age at CSCR diagnosis vessel type at diagnosis Vessel location Number of leaking point(s) Mid-phase hyperfluorescent plaque (ICGA) Late-phase hyperfluorescent plaque (ICGA) Time to CSCR Patient 1 Male OS PNV 54 mature “dead-tree” Retrofoveal (temporal) 1 Yes Yes At diagnosis Patient 2 Female OD FCE 54 intermediate Retrofoveal (infero-temporal) 1 Yes Yes 12 months Patient 3 Male OD Uncomplicated pachychoroid 58 immature “corallike" Temporal 1 Yes Yes At diagnosis Patient 4 Female OS PPE 54 mature “dead-tree” Retrofoveal (temporal) 1 Yes Yes At diagnosis SE : Spheric equivalent; PPE : Pachychoroid pigment epitheliopathy; PNV : Pachychoroid neovascularization; CSCR: Central serous chorioretinopathy. CSCR diagnosis and diagnosis in the Fellow Eye All cases presented with a first episode of CSCR, which by definition manifests as serous detachment associated with an angiographic leaking point in the context of pachychoroid. No signs of chronicity or complexity were observed, such as outer retinal atrophy or widespread and/or multifocal RPE atrophy (≥ 2 disc diameters) (Figs. 1 A-F, 2 A-D, 3 A-D, 4 A-D). The fellow eye of each patient showed distinct pachychoroid spectrum features. One patient had PNV, another had focal choroidal excavation (FCE), while the remaining two exhibited either pachychoroid pigment epitheliopathy (PPE) or uncomplicated pachychoroid. The patient with contralateral PNV manifest as a subtle flat irregular PED overlying a large and mature CNV and no sign or symptoms of an episode of subretinal fluid (Supplementary Fig. 2). CNV and Leaking Points In all cases, the CNV lesions were located close to the fovea, with three classified as retrofoveal (cases 1, 2, 4) and one as temporal (case 3). The morphology of the vessels varied: two patients had mature, “dead-tree” type vessels (Figs. 1 G, 4 E) and two had immature “coral-like” or intermediate pattern (Figs. 2 E, 3 E). Each patient exhibited a single fluorescein angiography-confirmed leakage point. In all cases, the leakage site colocalized precisely with the neovascular lesion identified on OCTA. Multimodal imaging for each case, including FA and OCTA overlay, demonstrated the clear spatial association between the area of FA-confirmed leakage and the corresponding CNV lesion. Other signs of leakage were observed on SD-OCT such as lucency in cases 1 and 3, outer segment erosion above RPE in case 3 and RPE break in cases 1 and 4 (Figs. 1 I, 3 , 4 L). Timing of CSCR Onset and Serous Fluid Fluctuations In three patients, CSCR was diagnosed at the same time as the CNV. In the remaining case, CSCR developed 12 months after the initial identification of CNV in a patient with FCE. Fluctuations in subretinal fluid were observed in all four cases, occurring independently of anti-VEGF IVT injections. These changes were not temporally associated with injections, suggesting a mechanism not solely driven by VEGF-dependent CNV exudative activity. In one case (Case 4), the subretinal fluid persisted despite monthly anti-VEGF injections (Fig. 4 F–K). Discussion This series of rare cases highlights a potential pathogenic link between CNV and the onset of acute CSCR in the context of pachychoroid. In these patients, FA revealed that the leaking point associated with and possibly responsible for subretinal fluid was located at the site of an RPE elevation above a CNV lesion. This spatial colocalization and the chronology of the events suggest that CNV may not merely be a late complication of chronic CSCR, but may instead act as a direct trigger for acute CSCR CNV has been typically recognized as a complication of complex/ chronic CSCR[ 28 ] in about 36% of cases and presenting as elevated RPE with double sign layer[ 29 ]. In a prospective longitudinal study, CNV complicated about 13% of CRSC, with higher risks for chronic cases, long-lasting fluid during the first year, older age and foveal involvement[ 30 ]. In the time course of chronic CSCR complicated by CNV, episodes of leakage can occur, often located in area of mid-phase ICG hyperpermeability, near or far from the neovessels and despite ongoing anti-VEGF treatment. It is therefore important to accurately locate the areas of leakage that could be treated by laser or focal PDT.[ 31 ] The multifactorial origin of the subretinal fluid in these cases could explain an incomplete response to anti-VEGF[ 32 ]. On the other hand, Pang and Freund described ten years ago, the PNV phenotype as the presence of type 1 CNV underlying a shallow RPE elevation in eyes with thick choroid and no evidence of exudative detachment or autofluorescence changes suggestive of previous or actual CSCR.[ 21 ] The angiographic characteristics of PNV are a late fluorescein leakage with undetermined origin, and a typical late staining plaque on ICGA.[ 21 ] The clinical presentation of our cases does not correspond to any of these descriptions and appears rather as a simple and acute form of CRSC whose leakage point overlooks a neovessel. Although not formally described, this clinical form was suggested, as neovessels could be added signs in simple or complex forms of CRSC when we proposed reclassifying the disease.[ 33 ] The recognition of CNV-induced acute CSCR is important, as it may carry therapeutic implications and raise intriguing pathogenic hypotheses. From a diagnostic perspective, while SD-OCT is widely used in routine cases of acute or simple CSCR, it does not allow precise localization of leakage sites (as seen on FA) or direct visualization of CNV, which is better detected with OCT-A. However, the interpretation of OCT-A can be limited by signal attenuation in areas of subretinal fluid, making repeat imaging after fluid resolution often necessary. The best therapeutic option in this clinical presentation is uncertain and whether an initial combination of anti-VEGF and PDT would lead to more favourable outcome would need to be evaluated. PNV can be managed with either anti-VEGF or photodynamic therapy (PDT).[ 34 ] In cases where PNV is associated with CSCR-like features, treatment response may differ. Specifically, CSCR-predominant PNV has been associated with more favourable outcomes, including a lower recurrence rate of subretinal fluid following PDT or anti-VEGF therapy.[ 35 ] In our cohort, several cases exhibited subretinal fluid fluctuations that appeared independent of anti-VEGF IVT. In such cases, targeted treatments—such as limited-spot PDT or possibly topical corticosteroids—may help reduce subretinal fluid and lower the risk of recurrence.[ 36 , 37 ] However, the efficacy and safety of these approaches in this specific context remain to be established and warrant evaluation in prospective clinical studies. The mechanism underlying the leakage point in these cases is particularly interesting. It closely resembles the leakage point observed above a large choroidal vessel adjacent to Bruch's membrane, where the choriocapillaris is no longer identifiable. While mechanical factors may play a role—given that mechanical stress activates the YAP/TAZ pathway,[ 38 ] which is crucial for maintaining RPE differentiation[ 39 ] —they cannot be considered solely responsible. Serous retinal detachment (SRF) without a detectable leakage point is frequently observed in situations involving mechanical stress, such as dome-shaped macula, large drusenoid PED, or choroidal tumors. In these instances, diffuse RPE dysfunction is the underlying cause of SRF.[ 40 – 42 ] We hypothesize that, in pachychoroid disease, vascular remodelling is associated with—and may even be secondary to—choroidal autonomic neuropathy.[ 43 ] Under physiological conditions, the entire vascular system is regulated by the autonomic nervous system (ANS), and RPE homeostasis and transport activity are modulated by neuropeptides and adrenergic signalling. Large nerves and arteries are typically distant from the RPE, thereby preventing uncontrolled catecholamine discharges from activating the RPE, despite the presence of adrenergic receptors on its surface. In pachychoroid disease, pachyvessels with pathological innervation—similar to the mature neovessels often observed in CSCR[ 44 ]—may serve as a source of abnormal and uncontrolled neural activation due to their proximity to the RPE. From a pathophysiological perspective, dysfunctional vascular neural control may promote microthrombosis of the choriocapillaris, abnormal fibrin clotting, and RPE dysfunction, consistent with histological findings of RPE damage at leakage sites in monkeys.[ 45 , 46 ] Indeed, choroidal haemostasis is under adrenergic control[ 47 ] and the sympathetic nervous system directly produces plasminogen activator around vessels.[ 48 ] Ion transport across RPE in under adrenergic signalling, and excessive epinephrine can induce RPE cell apoptosis.[ 49 ] On the other hand, vasointestinal peptide (VIP) controls RPE homeostasis and barrier function.[ 50 , 51 ] Altogether, these mechanisms suggest that choroidal neuropathy, which may underlie the pachychoroid phenotype, combined with the close proximity of innervated vessels to the RPE, could induce RPE pump dysfunction, alter fibrinolysis, and activate matrix metalloproteinases (MMPs), thereby triggering the development of CSCR. This aligns with the view of CSCR as a maladaptive stress response. A schematic representation of this hypothesis is shown in Fig. 5 . This study has limitations. The retrospective design and small sample size limit statistical generalizability. OCTA may be subject to projection artifacts and false positives, particularly in cases with poor fixation or significant subretinal fluid. The chronology of event could be challenged as non-symptomatic episodes might have occurred without notice. Nevertheless, the consistent multimodal findings across cases support the concept that CNV may act as a triggering factor for CSCR under certain conditions. Ultimately, these findings suggest that CSCR may occasionally result from a neurovascular dysfunction initiated by quiescent CNV or choriocapillaris injury—challenging the traditional view of CNV as a consequence rather than a cause of CSCR. Declarations Ethics approval and consent to participate : The study was approved by the Ethics Committee of the French Society of Ophthalmology (00008855). It adhered to the tenets of the Declaration of Helsinki (1964). Oral informed consent was obtained from all patients prior to inclusion. Consent for publication : Not applicable. Availability of data and materials : The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests : The authors declare no competing interests. Funding : This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors' contributions : A.V.J: Conceptualization, Methodology, Investigation, Screening, Data curation, Formal Analysis, Writing the original draft, Writing – review & editing. E.B. Investigation, Data curation, Writing – review & editing. J.B. Investigation, Data curation, Writing – review & editing. S.M.: Investigation, Data curation, Writing – review & editing F.B.C: Conceptualization, Investigation, Data curation, Writing – review & editing, Supervision. Acknowledgements : Not applicable. References Spitznas M, Huke J. Number, shape, and topography of leakage points in acute type I central serous retinopathy. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1987;225:437–40. Levine R, Brucker AJ, Robinson F. Long-term follow-up of idiopathic central serous chorioretinopathy by fluorescein angiography. Ophthalmology. 1989;96:854–9. Daruich A, Matet A, Dirani A, Bousquet E, Zhao M, Farman N, et al. Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis. Prog Retin Eye Res. 2015;48:82–118. Zhang X, Lim CZF, Chhablani J, Wong YM. Central serous chorioretinopathy: updates in the pathogenesis, diagnosis and therapeutic strategies. Eye Vis Lond Engl. 2023;10:33. Daruich A, Matet A, Marchionno L, De Azevedo J-D, Ambresin A, Mantel I, et al. ACUTE CENTRAL SEROUS CHORIORETINOPATHY: Factors Influencing Episode Duration. Retina Phila Pa. 2017;37:1905–15. Orduña-Azcona J, Pérez-Fernández E, Modamio L, De Manuel-Triantafilo S, Rodríguez-Hernández CF, Gili P. One-year follow-up of choroidal and macular thickness in acute non-treated central serous chorioretinopathy. Clin Exp Optom. 2023;106:47–55. Li Y, Jin P, Lu J, Ma L, Qin X. Analysis of Optical Coherence Tomography in Acute versus Chronic Central Serous Chorioretinopathy. Optom Vis Sci Off Publ Am Acad Optom. 2022;99:267–73. Bijon J, Freund KB. Hyporeflective Subretinal Lucency in Central Serous Chorioretinopathy. Ophthalmology. 2024;131:1481. Parameswarappa DC, Maltsev DS, Goud A, Singh SR, Chhablani J. Characteristics of Central Serous Chorioretinopathy without Leakage. J Curr Ophthalmol. 2021;33:152–7. Yoshioka H, Katsume Y. Experimental central serous chorioretinopathy. III: ultrastructural findings. Jpn J Ophthalmol. 1982;26:397–409. Piccolino FC, Borgia L, Zinicola E, Zingirian M. Indocyanine green angiographic findings in central serous chorioretinopathy. Eye Lond Engl. 1995;9(Pt 3):324–32. Iida T, Hagimura N, Otani T, Ikeda F, Muraoka K. [Choroidal vascular lesions in serous retinal detachment viewed with indocyanine green angiography]. Nippon Ganka Gakkai zasshi. 1996;100:817–24. Pryds A, Sander B, Larsen M. Characterization of subretinal fluid leakage in central serous chorioretinopathy. Invest Ophthalmol Vis Sci. 2010;51:5853–7. Fossataro F, Fossataro C, Abraham N, Fouad Y, Mrejen S, Tan ACS, et al. Pathogenesis of Central Serous Chorioretinopathy and the Link Between Choroidal Hyperpermeability and Retinal Pigment Epithelium Pump Reversal. Am J Ophthalmol. 2024;266:206–17. Mrejen S, Balaratnasingam C, Kaden TR, Bottini A, Dansingani K, Bhavsar KV, et al. Long-term Visual Outcomes and Causes of Vision Loss in Chronic Central Serous Chorioretinopathy. Ophthalmology. 2019;126:576–88. Savastano MC, Rispoli M, Lumbroso B, THE INCIDENCE OF, NEOVASCULARIZATION IN CENTRAL SEROUS CHORIORETINOPATHY BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. Retina Phila Pa. 2021;41:302–8. Bousquet E, Bonnin S, Mrejen S, Krivosic V, Tadayoni R, Gaudric A, OPTICAL, COHERENCE TOMOGRAPHY ANGIOGRAPHY OF FLAT IRREGULAR PIGMENT EPITHELIUM DETACHMENT IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY. Retina Phila Pa. 2018;38:629–38. Azzolini C, Cattaneo J, Premoli L, Metrangolo C, Chiaravalli M, Donati S. The morphology of choroidal neovascularization in chronic central serous chorioretinopathy presenting with flat, irregular pigment epithelium detachment. Int Ophthalmol. 2021;41:2109–16. Guo J, Tang W, Liu W, Chang Q, Xu G, CLINICAL, FEATURES OF FLAT IRREGULAR PIGMENT EPITHELIAL DETACHMENT ASSOCIATED WITH CHOROIDAL NEOVASCULARIZATION IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY. Retina Phila Pa. 2021;41:199–207. Zola M, Bousquet E, Favard C, Gigon A, Mantel I, Behar-Cohen F, INDOCYANINE, GREEN ANGIOGRAPHY OF TYPE 1 MACULAR NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION AND CENTRAL SEROUS CHORIORETINOPATHY REVEALS DIFFERENT DISEASE MECHANISMS. Retina Phila Pa. 2023;43:1255–63. Pang CE, Freund KB. Pachychoroid neovasculopathy. Retina Phila Pa. 2015;35:1–9. Miyake M, Ooto S, Yamashiro K, Takahashi A, Yoshikawa M, Akagi-Kurashige Y, et al. Pachychoroid neovasculopathy and age-related macular degeneration. Sci Rep. 2015;5:16204. Singh SR, Matet A, van Dijk EHC, Daruich A, Fauser S, Yzer S et al. Discrepancy in current central serous chorioretinopathy classification. Br J Ophthalmol. 2018. Sahoo NK, Parameshwarappa DC, Jhingan M, Tatti F, Iovino C, Peiretti E. Interobserver Agreement of Novel Classification of Central Serous Chorioretinopathy. Cureus. 2022;14:e25925. Uchida A, Hu M, Babiuch A, Srivastava SK, Singh RP, Kaiser PK, et al. Optical coherence tomography angiography characteristics of choroidal neovascularization requiring varied dosing frequencies in treat-and-extend management: An analysis of the AVATAR study. PLoS ONE. 2019;14:e0218889. van Rijssen TJ, van Dijk EHC, Yzer S, Ohno-Matsui K, Keunen JEE, Schlingemann RO, et al. Central serous chorioretinopathy: Towards an evidence-based treatment guideline. Prog Retin Eye Res. 2019;73:100770. Kashani AH, Chen C-L, Gahm JK, Zheng F, Richter GM, Rosenfeld PJ, et al. Optical Coherence Tomography Angiography: A Comprehensive Review of Current Methods and Clinical Applications. Prog Retin Eye Res. 2017;60:66–100. Hagag AM, Chandra S, Khalid H, Lamin A, Keane PA, Lotery AJ, et al. Multimodal Imaging in the Management of Choroidal Neovascularization Secondary to Central Serous Chorioretinopathy. J Clin Med. 2020;9:1934. Hagag AM, Rasheed R, Chandra S, Jeffery G, Sivaprasad S. The Diagnostic Accuracy of Double-Layer Sign in Detection of Macular Neovascularization Secondary to Central Serous Chorioretinopathy. Am J Ophthalmol. 2022;236:271–80. Zhou X, Komuku Y, Araki T, Terasaki H, Miki A, Kuwayama S, et al. Risk factors and characteristics of central serous chorioretinopathy with later development of macular neovascularisation detected on OCT angiography: a retrospective multicentre observational study. BMJ Open Ophthalmol. 2022;7:e000976. Feenstra HMA, van Dijk EHC, Cheung CMG, Ohno-Matsui K, Lai TYY, Koizumi H, et al. Central serous chorioretinopathy: An evidence-based treatment guideline. Prog Retin Eye Res. 2024;101:101236. Lejoyeux R, Behar-Cohen F, Mantel I, Ruiz-Medrano J, Mrejen S, Tadayoni R, et al. Type one macular neovascularization in central serous chorioretinopathy: Short-term response to anti-vascular endothelial growth factor therapy. Eye Lond Engl. 2022;36:1945–50. Chhablani J, Cohen FB, Central Serous Chorioretinopathy International Group. Multimodal Imaging-Based Central Serous Chorioretinopathy Classification. Ophthalmol Retina. 2020;4:1043–6. Tanaka N, Azuma K, Aoki S, Kitamoto K, Ueda K, Fujino R, et al. Intravitreal anti-vascular endothelial growth factor and combined photodynamic therapy for pachychoroid neovasculopathy: long-term treatment outcomes. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol. 2024;262:1811–8. Maruyama-Inoue M, Yanagi Y, Inoue T, Kitajima Y, Kadonosono K. Importance of fluorescein angiography as a predictor of treatment response in patients with pachychoroid neovasculopathy. Sci Rep. 2024;14:29157. Zaman M, Mihalache A, Huang RS, Shah N, Popovic MM, Kertes PJ, et al. Safety and Efficacy of Half-dose and Half-fluence Photodynamic Therapy in Chronic Central Serous Chorioretinopathy: A Systematic Review and Meta-analysis. Am J Ophthalmol. 2025;271:233–42. Kim LA, Maguire MG, Weng CY, Smith JR, Jain N, Flaxel CJ, et al. Therapies for Central Serous Chorioretinopathy: A Report by the American Academy of Ophthalmology. Ophthalmology. 2025;132:343–53. Totaro A, Panciera T, Piccolo S. YAP/TAZ upstream signals and downstream responses. Nat Cell Biol. 2018;20:888–99. Lu Q, Scott PA, Vukmanic EV, Kaplan HJ, Dean DC, Li Q. Yap1 is required for maintenance of adult RPE differentiation. FASEB J Off Publ Fed Am Soc Exp Biol. 2020;34:6757–68. Dansingani KK, Balaratnasingam C, Naysan J, Freund KB, EN, FACE IMAGING OF PACHYCHOROID SPECTRUM DISORDERS WITH SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY. Retina Phila Pa. 2016;36:499–516. Viggiano P, Demirel S, Petruzzella G, Pignataro M, Boscia G, Clemente A, et al. Choriocapillaris flow in two different patterns of exudative type 1 macular neovascularization. Eye. 2025;39:556–62. Caillaux V, Gaucher D, Gualino V, Massin P, Tadayoni R, Gaudric A. Morphologic characterization of dome-shaped macula in myopic eyes with serous macular detachment. Am J Ophthalmol. 2013;156:958–e9671. Leclercq B, Weiner A, Zola M, Mejlacowicz D, Lassiaz P, Jonet L et al. The choroidal nervous system: a link between mineralocorticoid receptor and pachychoroid. Acta Neuropathol (Berl). 2023. Bousquet E, Bonnin S, Mrejen S, Krivosic V, Tadayoni R, Gaudric A, OPTICAL, COHERENCE TOMOGRAPHY ANGIOGRAPHY OF FLAT IRREGULAR PIGMENT EPITHELIUM DETACHMENT IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY. Retina Phila Pa. 2018;38:629–38. Yoshioka H, Katsume Y, Akune H. Experimental central serous chorioretinopathy in monkey eyes: fluorescein angiographic findings. Ophthalmol J Int Ophtalmol Int J Ophthalmol Z Augenheilkd. 1982;185:168–78. Yoshioka H, Katsume Y. Experimental central serous chorioretinopathy. III: ultrastructural findings. Jpn J Ophthalmol. 1982;26:397–409. Gatica S, Aravena D, Echeverría C, Santibanez JF, Riedel CA, Simon F. Effects of Adrenergic Receptor Stimulation on Human Hemostasis: A Systematic Review. Adv Exp Med Biol. 2023;1408:49–63. O’Rourke J, Jiang X, Hao Z, Cone RE, Hand AR. Distribution of sympathetic tissue plasminogen activator (tPA) to a distant microvasculature. J Neurosci Res. 2005;79:727–33. Sibayan SA, Kobuch K, Spiegel D, Eckert E, Leser R, Monzer J, et al. Epinephrine, but not dexamethasone, induces apoptosis in retinal pigment epithelium cells in vitro: possible implications on the pathogenesis of central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol. 2000;238:515–9. Koh SM. VIP enhances the differentiation of retinal pigment epithelium in culture: from cAMP and pp60(c-src) to melanogenesis and development of fluid transport capacity. Prog Retin Eye Res. 2000;19:669–88. Maugeri G, D’Amico AG, Gagliano C, Saccone S, Federico C, Cavallaro S, et al. VIP Family Members Prevent Outer Blood Retinal Barrier Damage in a Model of Diabetic Macular Edema. J Cell Physiol. 2017;232:1079–85. Additional Declarations Competing interest reported. Dr Elodie Bousquet: consultant for Abbvie, Bayer Healthcare and Roche, No conflicting relationship exists for other authors. Supplementary Files CNVCSCRSuppIJRV20250901.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 11 Oct, 2025 Reviews received at journal 03 Oct, 2025 Reviewers agreed at journal 28 Sep, 2025 Reviewers agreed at journal 28 Sep, 2025 Reviewers agreed at journal 28 Sep, 2025 Reviewers agreed at journal 28 Sep, 2025 Reviews received at journal 16 Sep, 2025 Reviewers agreed at journal 07 Sep, 2025 Reviewers invited by journal 04 Sep, 2025 Editor assigned by journal 04 Sep, 2025 Submission checks completed at journal 03 Sep, 2025 First submitted to journal 31 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7502868","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":512488096,"identity":"d08cdd9f-8713-4814-9d49-c8d4e7674dc5","order_by":0,"name":"Aliénor Vienne-Jumeau","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYFACxgYQKccmf4DxQQKDHPFajPkkGJgNPjAYE29X4jwJBjbJGcRo4Z+R3Pi4cIdNept0A4M0D4NBPkEtEjcSm41nnknLbZM5wGAM1GLZQFDPmYNt0rxth3PbGPI/JPMw/DEgqEP+zMH237xt/9PZGBIYDgNtIazF4HhjGzNv24EENokExsYZxGgxPN7YDHRYsmEbzwFmhg8GRGiRO8z+8DNvm528fHsD+4+ECiK0oLuTVA2jYBSMglEwCrACAGLrNSS3iFx4AAAAAElFTkSuQmCC","orcid":"","institution":"Centre hospitalier national d'ophtalmologie des Quinze-Vingts","correspondingAuthor":true,"prefix":"","firstName":"Aliénor","middleName":"","lastName":"Vienne-Jumeau","suffix":""},{"id":512488097,"identity":"f0f75e04-5703-4195-8521-7270c3ca5fb9","order_by":1,"name":"Elodie Bousquet","email":"","orcid":"","institution":"Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris","correspondingAuthor":false,"prefix":"","firstName":"Elodie","middleName":"","lastName":"Bousquet","suffix":""},{"id":512488098,"identity":"f6dfc708-56fa-4c2d-a7a3-8abc150561af","order_by":2,"name":"Jacques Bijon","email":"","orcid":"","institution":"Fondation Ophtalmologique Adolphe de Rothschild","correspondingAuthor":false,"prefix":"","firstName":"Jacques","middleName":"","lastName":"Bijon","suffix":""},{"id":512488099,"identity":"b921acf5-1bbe-41c3-864b-4ea529b8dd1f","order_by":3,"name":"Sarah Mrejen","email":"","orcid":"","institution":"Centre hospitalier national d'ophtalmologie des Quinze-Vingts","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Mrejen","suffix":""},{"id":512488100,"identity":"9236803c-b053-4f42-af09-8225dce3ad29","order_by":4,"name":"Francine Behar-Cohen","email":"","orcid":"","institution":"Cochin Hospital, Université Paris Cité","correspondingAuthor":false,"prefix":"","firstName":"Francine","middleName":"","lastName":"Behar-Cohen","suffix":""}],"badges":[],"createdAt":"2025-08-31 21:53:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7502868/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7502868/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91075106,"identity":"0002370a-9801-4dad-81d7-0f7e73cbb7f2","added_by":"auto","created_at":"2025-09-11 11:05:43","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":688746,"visible":true,"origin":"","legend":"\u003cp\u003eMultimodal follow-up imaging of the left eye in Case 1. Fluorescein angiography (FA) in the early, mid, and late phases (A–C) shows several hyperfluorescent pinpoint areas, including one with more intense leakage, while indocyanine green angiography (ICGA) in the early, mid, and late phases (D–F) reveals a parafoveal area of choroidal hyperfluorescence. Spectral-domain optical coherence tomography (SD-OCT) B-scans at the level of the leaking point (blue line) demonstrate subretinal fluid and a flat, irregular pigment epithelial detachment (FIPED) at baseline (G) and after several months of observation (H), with a magnified view highlighting a retinal pigment epithelium (RPE) break (red asterisk, I). OCT angiography (OCTA, J) and OCTA overlaid on FA (K) colocalize the choroidal neovascularization (CNV) with the leakage point (red arrow).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7502868/v1/baa3dfc7def7b9e00a9cf00d.jpeg"},{"id":91078928,"identity":"92bc715a-dcc1-477f-870a-a475b9fb1694","added_by":"auto","created_at":"2025-09-11 11:21:43","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":612144,"visible":true,"origin":"","legend":"\u003cp\u003eMultimodal follow-up imaging of the left eye in Case 2. Fluorescein angiography (FA) in the early, mid, and late phases (A–C) shows a retrofoveal focal leakage, while indocyanine green angiography (ICGA) in the early, mid, and late phases (D–F) reveals prominent pachyvessels. (G–L) Serial spectral-domain optical coherence tomography (SD-OCT) B-scans through the leakage site (blue line in B) illustrate disease evolution : 60 months before baseline (G, M–60), choroidal thickening with a flat, irregular pigment epithelial detachment (FIPED) and no subretinal fluid; 12 months before baseline (H, M–12), early FIPED formation; at baseline (I, M0, day of angiography), new subretinal fluid and photoreceptor outer segment elongation; 2 months later (J, M+2), increased fluid; 32 months later (K, M+32), persistent fluid despite three intravitreal anti-VEGF injections; and 66 months later (L, M+66), complete and durable resolution four months after initiating daily topical prednisone, maintained without recurrence for three years. OCT angiography (OCTA, M) and OCTA overlaid on FA (N) demonstrate the colocalized choroidal neovascularization (CNV) and leakage point (red arrow).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7502868/v1/150f7367cb235c42c3cd93f6.jpeg"},{"id":91075116,"identity":"6afb859c-c45c-4a78-9292-73a1d652ece1","added_by":"auto","created_at":"2025-09-11 11:05:43","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":565025,"visible":true,"origin":"","legend":"\u003cp\u003eMultimodal follow-up imaging of the left eye in Case 3. Fluorescein angiography (FA) in the early, mid, and late phases (A–C) shows a focal hyperfluorescent leakage point, while indocyanine green angiography (ICGA) in the corresponding phases (D–F) reveals a parafoveal area of choroidal hyperfluorescence. Serial spectral-domain optical coherence tomography (SD-OCT) B-scans at the level of the leaking point (blue line, G–J) demonstrate subretinal fluid and a flat, irregular pigment epithelial detachment (FIPED) with associated fluid at presentation, which progressively resolves over time. Optical coherence tomography angiography (OCTA, K) and OCTA overlaid on FA (L) colocalize the choroidal neovascularization (CNV) with the leakage point (red arrow).\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7502868/v1/2af125e21fa7b6180597e2bc.jpeg"},{"id":91075109,"identity":"f4c8c01c-219a-4ca1-955f-134c31585db8","added_by":"auto","created_at":"2025-09-11 11:05:43","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":562868,"visible":true,"origin":"","legend":"\u003cp\u003eMultimodal follow-up imaging of the left eye in Case 4. Fluorescein angiography (FA) in the early, mid, and late phases (A–C) shows a subtle hyperfluorescent point, while indocyanine green angiography (ICGA) in the corresponding phases (D–F) reveals late hyperfluorescence at the leakage site. Spectral-domain optical coherence tomography (SD-OCT) B-scans at the level of the leaking point (blue line) demonstrate subretinal fluid and a flat, irregular pigment epithelial detachment (FIPED) at baseline (G) and after follow-up at 3 months, 2 years, 5 years, and 7 years (H–K), with a magnified view highlighting a retinal pigment epithelium (RPE) break (red asterisk, L). Optical coherence tomography angiography (OCTA, M) and OCTA overlaid on FA (N) colocalize the choroidal neovascularization (CNV) with the leakage point (red arrow).\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7502868/v1/bacc5bba2cf9d2b4e7b47071.jpeg"},{"id":91075111,"identity":"67e86e38-bb2f-4e37-82e6-d8ed4e49b486","added_by":"auto","created_at":"2025-09-11 11:05:43","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":300411,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic representation of the proposed hypothesis linking choroidal nerve signaling to leakage from choroidal neovascularization. Choroidal nerves release epinephrine, which activates matrix metalloproteinase-9 via VIP receptors on the retinal pigment epithelium (RPE). This disrupts RPE barrier integrity, facilitating fluid leakage. Simultaneously, choroidal microthrombosis contributes to local ischemia and inflammation, further promoting leakage.\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7502868/v1/33d6683145d04e3515077753.jpeg"},{"id":91080072,"identity":"7ed69470-5376-454c-b54e-9d7632110b7e","added_by":"auto","created_at":"2025-09-11 11:29:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3388748,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7502868/v1/d53ad90a-4a30-4fa4-8653-5818698409ab.pdf"},{"id":91078927,"identity":"51360b98-0959-4913-8a78-5b4ea9a6cceb","added_by":"auto","created_at":"2025-09-11 11:21:43","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":852279,"visible":true,"origin":"","legend":"","description":"","filename":"CNVCSCRSuppIJRV20250901.docx","url":"https://assets-eu.researchsquare.com/files/rs-7502868/v1/f8bfc3c7e01379085d99df39.docx"}],"financialInterests":"Competing interest reported. Dr Elodie Bousquet: consultant for Abbvie, Bayer Healthcare and Roche, No conflicting relationship exists for other authors.","formattedTitle":"Choroidal Neovascularization as a Trigger for Central Serous Chorioretinopathy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAcute central serous chorioretinopathy (CSCR) is defined by the occurrence of serous retinal detachment associated with a leak on fluorescein angiography (FA), showing active dye passage through one or more areas of the retinal pigment epithelium (RPE) barrier break.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Other characteristic clinical signs are visual impairment such as contrast loss, color vision impairment, micropsia, and focal blurring, without major loss of visual acuity.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Spectral-Domain Optical Coherence Tomography (SD-OCT) examination confirms the diagnosis when characteristic choroidal signs are present, such as thickened choroid compared to fellow eye or age-matched controls and the presence of dilated veins that obscure the choriocapillaris (pachyvessels)[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and are associated with the serous detachment. On SD-OCT, the leakage site(s) observed on FA often correspond to structural changes such as a pigment epithelial detachment (PED), focal RPE disruption, areas of outer segment \u0026lsquo;erosion\u0026rsquo; or elongation[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and, in some cases, adjacent hyporeflective subretinal lucencies.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] In acute forms, FA typically reveals a focal site of RPE leakage. A high intensity of leakage is generally indicative of an episode that will resolve within a few months[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In contrast, diffuse RPE dysfunction without a clearly identified leakage site is more suggestive of chronic episodes and more complex disease forms[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The exact mechanisms of \u0026ldquo;leakage,\u0026rdquo; which is transient in acute forms, are not fully understood. Histological analysis of adrenaline-induced CSCR-like disease in monkey showed that spots of fluorescein leakage coincided with focal RPE cell degeneration over area of choriocapillaris endothelial defects with fibrin deposits within the Bruch\u0026rsquo;s membrane, suggesting that coagulation cascade and macromolecular transports could be involved.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Indocyanine green angiography (ICGA) in patients with acute CSCR confirmed choriocapillaris involvement with area of capillaries hypoperfusion and leakage at the site of RPE leak.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] Several mechanisms have been hypothesized, including bulk fluid flow[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and reverse of retinal pigment epithelium pump[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], which could be promoted by mechanical stresses from the dilated and engorged choroid.\u003c/p\u003e\u003cp\u003eThe development of choroidal neovascularization (CNV) is a sight threatening complication of CSCR, being responsible for a reduced visual acuity during a long-term follow-up.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] Using multimodal imaging, CNV was detected in up to 40% of \u0026ldquo;chronic\u0026rdquo; or complex forms of CRSC.[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] The detection of CNV can indeed be difficult, and it is the presence of a flat irregular PED (FIPED), partially hyperreflective, that should raise suspicion.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] Detection of choroidal neovascularization (CNV) is notably easier with OCT-Angiography (OCT-A), which enables visualization in approximately 35% of cases, compared to 25% with ICGA. This is because, unlike in age-related macular degeneration (AMD), type 1 CNV in these conditions does not frequently form hyperfluorescent plaques in the late phase of ICGA.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] Although FIFED have been identified in around 40% of acute CSCR, the exact occurrence of CNV in these cases has been poorly documented. Within the pachychoroid spectrum, another entity has been recognized: pachychoroid neovasculopathy (PNV). These are patients who have no history of CSCR but present mature neovascularization secondary to pachychoroid and area of ICGA hyperpermeability, with or without associated epitheliopathy and no exudative detachment.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] Differential diagnosis with AMD can be difficult, and it is the thickness of the choroid and the absence of drusen that will guide this diagnosis, the boundary with AMD currently being debated.[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eIn this ever-expanding spectrum of pachychoroid disease, the definition of different forms of CSCR is an ongoing process.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003csup\u003e,\u003c/sup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] We report here the cases of patients presenting with a first episode of acute CRSC and an active FA leakage site located on the edge of a neovascular membrane. Based on these cases, we discuss the mechanisms, diagnostic methods, and implications for management.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003eEthics Statement.\u003c/b\u003e The study was approved by the Ethics Committee of the French Society of Ophthalmology (00008855). It adhered to the tenets of the Declaration of Helsinki (1964). Oral informed consent was obtained from all patients prior to inclusion.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy Design.\u003c/b\u003e This retrospective observational study was conducted at the Department of Ophthalmology, Cochin Hospital (Paris), and the Department of Ophthalmology, Centre Hospitalier National d\u0026rsquo;Ophtalmologie des Quinze-Vingts (Paris). All patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years who presented with either a new diagnosis or follow-up of central serous chorioretinopathy (CSCR) associated with choroidal neovascularization (CNV) between December 2024 and April 2025 were retrospectively reviewed for inclusion.\u003c/p\u003e\u003cp\u003e\u003cb\u003ePatients.\u003c/b\u003e Patients were eligible if diagnosed with acute CSCR associated with concurrent CNV. Inclusion criteria were: no prior history of CSCR, absence of clinical or imaging signs of complex CSCR, and presence of at least one leakage point located within the neovascular network. Multimodal imaging\u0026mdash;including fluorescein angiography (FA), indocyanine green angiography (ICGA), spectral-domain optical coherence tomography (SD-OCT; Spectralis\u0026reg;, Heidelberg), and optical coherence tomography angiography (OCTA)\u0026mdash;had to be performed within one month of CSCR diagnosis.\u003c/p\u003e\u003cp\u003e\u003cem\u003eData Collection\u003c/em\u003e: For each patient, the following data were collected: age at diagnosis, gender, CNV maturity, contralateral eye choroidal characteristics, and refractive error (spherical equivalent). CNV maturity was defined on OCTA as vascular morphology graded into immature (tangled or rosette-like cluster of indistinct capillary vessels) or mature (presence of a prominent, dilated core vessel within a more organized vascular network).[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] The leaking point was defined as a focal area of hyperfluorescence with an increased in size over time on FA as previously described.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] CNV was defined on OCTA as abnormal flow within the outer retinal slab.[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] When necessary, the outer retina and choriocapillaris slabs were manually adjusted to refine segmentation. CNV lesions were classified based on en face OCTA projections (ORCC slab) according to established vascular morphology criteria. Following identification of the leaking point and CNV, the OCTA was accurately realigned with the angiographic images by referencing the retinal vessels at the level of the superficial microvasculature, in order to precisely localize the site of leakage.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003eAmong 202 eligible patients with CSCR and CNV seen between December 2024 and April 2025, four patients met the inclusion criteria (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e\u003cp\u003eThe cohort comprised two men and two women (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The age at CSCR onset ranged from 54 to 58 years. In all cases, only one eye was affected. The left eye was involved in two patients and the right eye in two. All patients were either emmetropic or mildly hyperopic, with absolute refractive errors\u0026thinsp;\u0026lt;\u0026thinsp;3 diopters.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u0026ndash; Description of included patients\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"11\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEye\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDiagnosis fellow eye\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAge at CSCR diagnosis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003evessel type at diagnosis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eVessel location\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNumber of leaking point(s)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMid-phase hyperfluorescent plaque (ICGA)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eLate-phase hyperfluorescent plaque (ICGA)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eTime to CSCR\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePNV\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003emature \u0026ldquo;dead-tree\u0026rdquo;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eRetrofoveal (temporal)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eAt diagnosis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eFCE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eintermediate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eRetrofoveal (infero-temporal)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUncomplicated pachychoroid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eimmature \u0026ldquo;corallike\"\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTemporal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eAt diagnosis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient 4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePPE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003emature \u0026ldquo;dead-tree\u0026rdquo;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eRetrofoveal (temporal)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eAt diagnosis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eSE : Spheric equivalent; PPE : Pachychoroid pigment epitheliopathy; PNV : Pachychoroid neovascularization; CSCR: Central serous chorioretinopathy.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eCSCR diagnosis and diagnosis in the Fellow Eye\u003c/h3\u003e\n\u003cp\u003eAll cases presented with a first episode of CSCR, which by definition manifests as serous detachment associated with an angiographic leaking point in the context of pachychoroid. No signs of chronicity or complexity were observed, such as outer retinal atrophy or widespread and/or multifocal RPE atrophy (\u0026ge;\u0026thinsp;2 disc diameters) (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA-F, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA-D, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-D, \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA-D). The fellow eye of each patient showed distinct pachychoroid spectrum features. One patient had PNV, another had focal choroidal excavation (FCE), while the remaining two exhibited either pachychoroid pigment epitheliopathy (PPE) or uncomplicated pachychoroid. The patient with contralateral PNV manifest as a subtle flat irregular PED overlying a large and mature CNV and no sign or symptoms of an episode of subretinal fluid (Supplementary Fig.\u0026nbsp;2).\u003c/p\u003e\n\u003ch3\u003eCNV and Leaking Points\u003c/h3\u003e\n\u003cp\u003eIn all cases, the CNV lesions were located close to the fovea, with three classified as retrofoveal (cases 1, 2, 4) and one as temporal (case 3). The morphology of the vessels varied: two patients had mature, \u0026ldquo;dead-tree\u0026rdquo; type vessels (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eG, \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE) and two had immature \u0026ldquo;coral-like\u0026rdquo; or intermediate pattern (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eEach patient exhibited a single fluorescein angiography-confirmed leakage point. In all cases, the leakage site colocalized precisely with the neovascular lesion identified on OCTA. Multimodal imaging for each case, including FA and OCTA overlay, demonstrated the clear spatial association between the area of FA-confirmed leakage and the corresponding CNV lesion. Other signs of leakage were observed on SD-OCT such as lucency in cases 1 and 3, outer segment erosion above RPE in case 3 and RPE break in cases 1 and 4 (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eI, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eL).\u003c/p\u003e\n\u003ch3\u003eTiming of CSCR Onset and Serous Fluid Fluctuations\u003c/h3\u003e\n\u003cp\u003eIn three patients, CSCR was diagnosed at the same time as the CNV. In the remaining case, CSCR developed 12 months after the initial identification of CNV in a patient with FCE.\u003c/p\u003e\u003cp\u003eFluctuations in subretinal fluid were observed in all four cases, occurring independently of anti-VEGF IVT injections. These changes were not temporally associated with injections, suggesting a mechanism not solely driven by VEGF-dependent CNV exudative activity. In one case (Case 4), the subretinal fluid persisted despite monthly anti-VEGF injections (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eF\u0026ndash;K).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis series of rare cases highlights a potential pathogenic link between CNV and the onset of acute CSCR in the context of pachychoroid. In these patients, FA revealed that the leaking point associated with and possibly responsible for subretinal fluid was located at the site of an RPE elevation above a CNV lesion. This spatial colocalization and the chronology of the events suggest that CNV may not merely be a late complication of chronic CSCR, but may instead act as a direct trigger for acute CSCR\u003c/p\u003e\u003cp\u003eCNV has been typically recognized as a complication of complex/ chronic CSCR[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] in about 36% of cases and presenting as elevated RPE with double sign layer[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In a prospective longitudinal study, CNV complicated about 13% of CRSC, with higher risks for chronic cases, long-lasting fluid during the first year, older age and foveal involvement[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In the time course of chronic CSCR complicated by CNV, episodes of leakage can occur, often located in area of mid-phase ICG hyperpermeability, near or far from the neovessels and despite ongoing anti-VEGF treatment. It is therefore important to accurately locate the areas of leakage that could be treated by laser or focal PDT.[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] The multifactorial origin of the subretinal fluid in these cases could explain an incomplete response to anti-VEGF[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. On the other hand, Pang and Freund described ten years ago, the PNV phenotype as the presence of type 1 CNV underlying a shallow RPE elevation in eyes with thick choroid and no evidence of exudative detachment or autofluorescence changes suggestive of previous or actual CSCR.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] The angiographic characteristics of PNV are a late fluorescein leakage with undetermined origin, and a typical late staining plaque on ICGA.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] The clinical presentation of our cases does not correspond to any of these descriptions and appears rather as a simple and acute form of CRSC whose leakage point overlooks a neovessel. Although not formally described, this clinical form was suggested, as neovessels could be added signs in simple or complex forms of CRSC when we proposed reclassifying the disease.[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] The recognition of CNV-induced acute CSCR is important, as it may carry therapeutic implications and raise intriguing pathogenic hypotheses. From a diagnostic perspective, while SD-OCT is widely used in routine cases of acute or simple CSCR, it does not allow precise localization of leakage sites (as seen on FA) or direct visualization of CNV, which is better detected with OCT-A. However, the interpretation of OCT-A can be limited by signal attenuation in areas of subretinal fluid, making repeat imaging after fluid resolution often necessary. The best therapeutic option in this clinical presentation is uncertain and whether an initial combination of anti-VEGF and PDT would lead to more favourable outcome would need to be evaluated. PNV can be managed with either anti-VEGF or photodynamic therapy (PDT).[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] In cases where PNV is associated with CSCR-like features, treatment response may differ. Specifically, CSCR-predominant PNV has been associated with more favourable outcomes, including a lower recurrence rate of subretinal fluid following PDT or anti-VEGF therapy.[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] In our cohort, several cases exhibited subretinal fluid fluctuations that appeared independent of anti-VEGF IVT. In such cases, targeted treatments\u0026mdash;such as limited-spot PDT or possibly topical corticosteroids\u0026mdash;may help reduce subretinal fluid and lower the risk of recurrence.[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] However, the efficacy and safety of these approaches in this specific context remain to be established and warrant evaluation in prospective clinical studies.\u003c/p\u003e\u003cp\u003eThe mechanism underlying the leakage point in these cases is particularly interesting. It closely resembles the leakage point observed above a large choroidal vessel adjacent to Bruch's membrane, where the choriocapillaris is no longer identifiable. While mechanical factors may play a role\u0026mdash;given that mechanical stress activates the YAP/TAZ pathway,[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] which is crucial for maintaining RPE differentiation[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] \u0026mdash;they cannot be considered solely responsible. Serous retinal detachment (SRF) without a detectable leakage point is frequently observed in situations involving mechanical stress, such as dome-shaped macula, large drusenoid PED, or choroidal tumors. In these instances, diffuse RPE dysfunction is the underlying cause of SRF.[\u003cspan additionalcitationids=\"CR41\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eWe hypothesize that, in pachychoroid disease, vascular remodelling is associated with\u0026mdash;and may even be secondary to\u0026mdash;choroidal autonomic neuropathy.[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e] Under physiological conditions, the entire vascular system is regulated by the autonomic nervous system (ANS), and RPE homeostasis and transport activity are modulated by neuropeptides and adrenergic signalling. Large nerves and arteries are typically distant from the RPE, thereby preventing uncontrolled catecholamine discharges from activating the RPE, despite the presence of adrenergic receptors on its surface. In pachychoroid disease, pachyvessels with pathological innervation\u0026mdash;similar to the mature neovessels often observed in CSCR[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u0026mdash;may serve as a source of abnormal and uncontrolled neural activation due to their proximity to the RPE. From a pathophysiological perspective, dysfunctional vascular neural control may promote microthrombosis of the choriocapillaris, abnormal fibrin clotting, and RPE dysfunction, consistent with histological findings of RPE damage at leakage sites in monkeys.[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] Indeed, choroidal haemostasis is under adrenergic control[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e] and the sympathetic nervous system directly produces plasminogen activator around vessels.[\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e] Ion transport across RPE in under adrenergic signalling, and excessive epinephrine can induce RPE cell apoptosis.[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e] On the other hand, vasointestinal peptide (VIP) controls RPE homeostasis and barrier function.[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] Altogether, these mechanisms suggest that choroidal neuropathy, which may underlie the pachychoroid phenotype, combined with the close proximity of innervated vessels to the RPE, could induce RPE pump dysfunction, alter fibrinolysis, and activate matrix metalloproteinases (MMPs), thereby triggering the development of CSCR. This aligns with the view of CSCR as a maladaptive stress response. A schematic representation of this hypothesis is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThis study has limitations. The retrospective design and small sample size limit statistical generalizability. OCTA may be subject to projection artifacts and false positives, particularly in cases with poor fixation or significant subretinal fluid. The chronology of event could be challenged as non-symptomatic episodes might have occurred without notice. Nevertheless, the consistent multimodal findings across cases support the concept that CNV may act as a triggering factor for CSCR under certain conditions.\u003c/p\u003e\u003cp\u003eUltimately, these findings suggest that CSCR may occasionally result from a neurovascular dysfunction initiated by quiescent CNV or choriocapillaris injury\u0026mdash;challenging the traditional view of CNV as a consequence rather than a cause of CSCR.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e: The study was approved by the Ethics Committee of the French Society of Ophthalmology (00008855). It adhered to the tenets of the Declaration of Helsinki (1964). Oral informed consent was obtained from all patients prior to inclusion.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Not applicable.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e:\u0026nbsp;The authors declare no competing interests.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e: A.V.J: Conceptualization, Methodology, Investigation, Screening, Data curation, Formal Analysis, Writing the original draft, Writing \u0026ndash; review \u0026amp; editing. E.B. Investigation, Data curation, Writing \u0026ndash; review \u0026amp; editing. J.B. Investigation, Data curation, Writing \u0026ndash; review \u0026amp; editing. S.M.: Investigation, Data curation, Writing \u0026ndash; review \u0026amp; editing F.B.C: Conceptualization, Investigation, Data curation, Writing \u0026ndash; review \u0026amp; editing, Supervision.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: Not applicable.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSpitznas M, Huke J. Number, shape, and topography of leakage points in acute type I central serous retinopathy. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol. 1987;225:437\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLevine R, Brucker AJ, Robinson F. Long-term follow-up of idiopathic central serous chorioretinopathy by fluorescein angiography. Ophthalmology. 1989;96:854\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDaruich A, Matet A, Dirani A, Bousquet E, Zhao M, Farman N, et al. Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis. Prog Retin Eye Res. 2015;48:82\u0026ndash;118.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang X, Lim CZF, Chhablani J, Wong YM. Central serous chorioretinopathy: updates in the pathogenesis, diagnosis and therapeutic strategies. Eye Vis Lond Engl. 2023;10:33.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDaruich A, Matet A, Marchionno L, De Azevedo J-D, Ambresin A, Mantel I, et al. ACUTE CENTRAL SEROUS CHORIORETINOPATHY: Factors Influencing Episode Duration. Retina Phila Pa. 2017;37:1905\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOrdu\u0026ntilde;a-Azcona J, P\u0026eacute;rez-Fern\u0026aacute;ndez E, Modamio L, De Manuel-Triantafilo S, Rodr\u0026iacute;guez-Hern\u0026aacute;ndez CF, Gili P. One-year follow-up of choroidal and macular thickness in acute non-treated central serous chorioretinopathy. Clin Exp Optom. 2023;106:47\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi Y, Jin P, Lu J, Ma L, Qin X. Analysis of Optical Coherence Tomography in Acute versus Chronic Central Serous Chorioretinopathy. Optom Vis Sci Off Publ Am Acad Optom. 2022;99:267\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBijon J, Freund KB. Hyporeflective Subretinal Lucency in Central Serous Chorioretinopathy. Ophthalmology. 2024;131:1481.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eParameswarappa DC, Maltsev DS, Goud A, Singh SR, Chhablani J. Characteristics of Central Serous Chorioretinopathy without Leakage. J Curr Ophthalmol. 2021;33:152\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoshioka H, Katsume Y. Experimental central serous chorioretinopathy. III: ultrastructural findings. Jpn J Ophthalmol. 1982;26:397\u0026ndash;409.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePiccolino FC, Borgia L, Zinicola E, Zingirian M. Indocyanine green angiographic findings in central serous chorioretinopathy. Eye Lond Engl. 1995;9(Pt 3):324\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIida T, Hagimura N, Otani T, Ikeda F, Muraoka K. [Choroidal vascular lesions in serous retinal detachment viewed with indocyanine green angiography]. Nippon Ganka Gakkai zasshi. 1996;100:817\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePryds A, Sander B, Larsen M. Characterization of subretinal fluid leakage in central serous chorioretinopathy. Invest Ophthalmol Vis Sci. 2010;51:5853\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFossataro F, Fossataro C, Abraham N, Fouad Y, Mrejen S, Tan ACS, et al. Pathogenesis of Central Serous Chorioretinopathy and the Link Between Choroidal Hyperpermeability and Retinal Pigment Epithelium Pump Reversal. Am J Ophthalmol. 2024;266:206\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMrejen S, Balaratnasingam C, Kaden TR, Bottini A, Dansingani K, Bhavsar KV, et al. Long-term Visual Outcomes and Causes of Vision Loss in Chronic Central Serous Chorioretinopathy. Ophthalmology. 2019;126:576\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSavastano MC, Rispoli M, Lumbroso B, THE INCIDENCE OF, NEOVASCULARIZATION IN CENTRAL SEROUS CHORIORETINOPATHY BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. Retina Phila Pa. 2021;41:302\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBousquet E, Bonnin S, Mrejen S, Krivosic V, Tadayoni R, Gaudric A, OPTICAL, COHERENCE TOMOGRAPHY ANGIOGRAPHY OF FLAT IRREGULAR PIGMENT EPITHELIUM DETACHMENT IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY. Retina Phila Pa. 2018;38:629\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAzzolini C, Cattaneo J, Premoli L, Metrangolo C, Chiaravalli M, Donati S. The morphology of choroidal neovascularization in chronic central serous chorioretinopathy presenting with flat, irregular pigment epithelium detachment. Int Ophthalmol. 2021;41:2109\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGuo J, Tang W, Liu W, Chang Q, Xu G, CLINICAL, FEATURES OF FLAT IRREGULAR PIGMENT EPITHELIAL DETACHMENT ASSOCIATED WITH CHOROIDAL NEOVASCULARIZATION IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY. Retina Phila Pa. 2021;41:199\u0026ndash;207.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZola M, Bousquet E, Favard C, Gigon A, Mantel I, Behar-Cohen F, INDOCYANINE, GREEN ANGIOGRAPHY OF TYPE 1 MACULAR NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION AND CENTRAL SEROUS CHORIORETINOPATHY REVEALS DIFFERENT DISEASE MECHANISMS. Retina Phila Pa. 2023;43:1255\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePang CE, Freund KB. Pachychoroid neovasculopathy. Retina Phila Pa. 2015;35:1\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMiyake M, Ooto S, Yamashiro K, Takahashi A, Yoshikawa M, Akagi-Kurashige Y, et al. Pachychoroid neovasculopathy and age-related macular degeneration. Sci Rep. 2015;5:16204.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSingh SR, Matet A, van Dijk EHC, Daruich A, Fauser S, Yzer S et al. Discrepancy in current central serous chorioretinopathy classification. Br J Ophthalmol. 2018.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSahoo NK, Parameshwarappa DC, Jhingan M, Tatti F, Iovino C, Peiretti E. Interobserver Agreement of Novel Classification of Central Serous Chorioretinopathy. Cureus. 2022;14:e25925.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUchida A, Hu M, Babiuch A, Srivastava SK, Singh RP, Kaiser PK, et al. Optical coherence tomography angiography characteristics of choroidal neovascularization requiring varied dosing frequencies in treat-and-extend management: An analysis of the AVATAR study. PLoS ONE. 2019;14:e0218889.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003evan Rijssen TJ, van Dijk EHC, Yzer S, Ohno-Matsui K, Keunen JEE, Schlingemann RO, et al. Central serous chorioretinopathy: Towards an evidence-based treatment guideline. Prog Retin Eye Res. 2019;73:100770.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKashani AH, Chen C-L, Gahm JK, Zheng F, Richter GM, Rosenfeld PJ, et al. Optical Coherence Tomography Angiography: A Comprehensive Review of Current Methods and Clinical Applications. Prog Retin Eye Res. 2017;60:66\u0026ndash;100.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHagag AM, Chandra S, Khalid H, Lamin A, Keane PA, Lotery AJ, et al. Multimodal Imaging in the Management of Choroidal Neovascularization Secondary to Central Serous Chorioretinopathy. J Clin Med. 2020;9:1934.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHagag AM, Rasheed R, Chandra S, Jeffery G, Sivaprasad S. The Diagnostic Accuracy of Double-Layer Sign in Detection of Macular Neovascularization Secondary to Central Serous Chorioretinopathy. Am J Ophthalmol. 2022;236:271\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhou X, Komuku Y, Araki T, Terasaki H, Miki A, Kuwayama S, et al. Risk factors and characteristics of central serous chorioretinopathy with later development of macular neovascularisation detected on OCT angiography: a retrospective multicentre observational study. BMJ Open Ophthalmol. 2022;7:e000976.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFeenstra HMA, van Dijk EHC, Cheung CMG, Ohno-Matsui K, Lai TYY, Koizumi H, et al. Central serous chorioretinopathy: An evidence-based treatment guideline. Prog Retin Eye Res. 2024;101:101236.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLejoyeux R, Behar-Cohen F, Mantel I, Ruiz-Medrano J, Mrejen S, Tadayoni R, et al. Type one macular neovascularization in central serous chorioretinopathy: Short-term response to anti-vascular endothelial growth factor therapy. Eye Lond Engl. 2022;36:1945\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChhablani J, Cohen FB, Central Serous Chorioretinopathy International Group. Multimodal Imaging-Based Central Serous Chorioretinopathy Classification. Ophthalmol Retina. 2020;4:1043\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTanaka N, Azuma K, Aoki S, Kitamoto K, Ueda K, Fujino R, et al. Intravitreal anti-vascular endothelial growth factor and combined photodynamic therapy for pachychoroid neovasculopathy: long-term treatment outcomes. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol. 2024;262:1811\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaruyama-Inoue M, Yanagi Y, Inoue T, Kitajima Y, Kadonosono K. Importance of fluorescein angiography as a predictor of treatment response in patients with pachychoroid neovasculopathy. Sci Rep. 2024;14:29157.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZaman M, Mihalache A, Huang RS, Shah N, Popovic MM, Kertes PJ, et al. Safety and Efficacy of Half-dose and Half-fluence Photodynamic Therapy in Chronic Central Serous Chorioretinopathy: A Systematic Review and Meta-analysis. Am J Ophthalmol. 2025;271:233\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKim LA, Maguire MG, Weng CY, Smith JR, Jain N, Flaxel CJ, et al. Therapies for Central Serous Chorioretinopathy: A Report by the American Academy of Ophthalmology. Ophthalmology. 2025;132:343\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTotaro A, Panciera T, Piccolo S. YAP/TAZ upstream signals and downstream responses. Nat Cell Biol. 2018;20:888\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLu Q, Scott PA, Vukmanic EV, Kaplan HJ, Dean DC, Li Q. Yap1 is required for maintenance of adult RPE differentiation. FASEB J Off Publ Fed Am Soc Exp Biol. 2020;34:6757\u0026ndash;68.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDansingani KK, Balaratnasingam C, Naysan J, Freund KB, EN, FACE IMAGING OF PACHYCHOROID SPECTRUM DISORDERS WITH SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY. Retina Phila Pa. 2016;36:499\u0026ndash;516.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eViggiano P, Demirel S, Petruzzella G, Pignataro M, Boscia G, Clemente A, et al. Choriocapillaris flow in two different patterns of exudative type 1 macular neovascularization. Eye. 2025;39:556\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCaillaux V, Gaucher D, Gualino V, Massin P, Tadayoni R, Gaudric A. Morphologic characterization of dome-shaped macula in myopic eyes with serous macular detachment. Am J Ophthalmol. 2013;156:958\u0026ndash;e9671.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLeclercq B, Weiner A, Zola M, Mejlacowicz D, Lassiaz P, Jonet L et al. The choroidal nervous system: a link between mineralocorticoid receptor and pachychoroid. Acta Neuropathol (Berl). 2023.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBousquet E, Bonnin S, Mrejen S, Krivosic V, Tadayoni R, Gaudric A, OPTICAL, COHERENCE TOMOGRAPHY ANGIOGRAPHY OF FLAT IRREGULAR PIGMENT EPITHELIUM DETACHMENT IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY. Retina Phila Pa. 2018;38:629\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoshioka H, Katsume Y, Akune H. Experimental central serous chorioretinopathy in monkey eyes: fluorescein angiographic findings. Ophthalmol J Int Ophtalmol Int J Ophthalmol Z Augenheilkd. 1982;185:168\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoshioka H, Katsume Y. Experimental central serous chorioretinopathy. III: ultrastructural findings. Jpn J Ophthalmol. 1982;26:397\u0026ndash;409.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGatica S, Aravena D, Echeverr\u0026iacute;a C, Santibanez JF, Riedel CA, Simon F. Effects of Adrenergic Receptor Stimulation on Human Hemostasis: A Systematic Review. Adv Exp Med Biol. 2023;1408:49\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eO\u0026rsquo;Rourke J, Jiang X, Hao Z, Cone RE, Hand AR. Distribution of sympathetic tissue plasminogen activator (tPA) to a distant microvasculature. J Neurosci Res. 2005;79:727\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSibayan SA, Kobuch K, Spiegel D, Eckert E, Leser R, Monzer J, et al. Epinephrine, but not dexamethasone, induces apoptosis in retinal pigment epithelium cells in vitro: possible implications on the pathogenesis of central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol. 2000;238:515\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKoh SM. VIP enhances the differentiation of retinal pigment epithelium in culture: from cAMP and pp60(c-src) to melanogenesis and development of fluid transport capacity. Prog Retin Eye Res. 2000;19:669\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaugeri G, D\u0026rsquo;Amico AG, Gagliano C, Saccone S, Federico C, Cavallaro S, et al. VIP Family Members Prevent Outer Blood Retinal Barrier Damage in a Model of Diabetic Macular Edema. J Cell Physiol. 2017;232:1079\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-retina-and-vitreous","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"IJRV","sideBox":"Learn more about [International Journal of Retina and Vitreous](https://jneurodevdisorders.biomedcentral.com/)","snPcode":"40942","submissionUrl":"https://submission.nature.com/new-submission/40942/3","title":"International Journal of Retina and Vitreous","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Choroidal Neovascularization, Pachychoroid neovascularization, Central Serous Chorioretinopathy, Leaking point, Optical coherence tomography","lastPublishedDoi":"10.21203/rs.3.rs-7502868/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7502868/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackgrounds:\u003c/strong\u003e To investigate whether choroidal neovascularization (CNV) can act as a trigger for central serous chorioretinopathy (CSCR) in patients with pachychoroid features, by analyzing cases where fluorescein angiography (FA)-confirmed leakage originated directly within the CNV lesion.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We retrospectively reviewed patients with no prior history or signs of CSCR who presented with a first episode of CSCR and coexisting CNV. Inclusion required at least one FA-confirmed leakage point located within the neovascular complex. Multimodal imaging—including FA, spectral-domain optical coherence tomography (SD-OCT), and OCT angiography (OCTA)—was performed to detect CNV and evaluate its topographical relationship with leakage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Among 202 patients screened, four met inclusion criteria (two males, two females; age range 54–58 years). All presented with a unilateral first episode of CSCR. In each case, FA and OCTA demonstrated precise colocalization of the leakage point within the CNV lesion. CNV was predominantly retrofoveal and appeared mature in morphology. Three patients were diagnosed simultaneously with CSCR and a neovascular membrane, while one developed CSCR during follow-up of a previously identified PNV. Subretinal fluid fluctuations were observed in all cases and often appeared independent of anti-VEGF treatment, suggesting a mechanism not exclusively driven by VEGF-mediated CNV activity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e This case series suggests that, within the pachychoroid spectrum, CNV may not only complicate chronic or complex CSCR but may also act as a direct trigger of acute episodes. These findings underscore the importance of multimodal imaging, particularly FA and OCTA, for comprehensive assessment of CSCR.\u003c/p\u003e","manuscriptTitle":"Choroidal Neovascularization as a Trigger for Central Serous Chorioretinopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-11 11:05:38","doi":"10.21203/rs.3.rs-7502868/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-11T08:56:05+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-03T17:23:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"288924896995423871428735606551187014580","date":"2025-09-28T17:15:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"16034549835540751351476492448591985355","date":"2025-09-28T17:11:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"253557574745791704675813635224157127952","date":"2025-09-28T11:08:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"28486780255581377489423730185517778795","date":"2025-09-28T09:42:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-16T13:06:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"19064755902650143584300646298512951792","date":"2025-09-07T19:38:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-04T08:25:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-04T08:21:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-03T12:01:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Retina and Vitreous","date":"2025-08-31T21:39:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-retina-and-vitreous","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"IJRV","sideBox":"Learn more about [International Journal of Retina and Vitreous](https://jneurodevdisorders.biomedcentral.com/)","snPcode":"40942","submissionUrl":"https://submission.nature.com/new-submission/40942/3","title":"International Journal of Retina and Vitreous","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4801cfff-0bd9-4987-8c5a-6839467a0d86","owner":[],"postedDate":"September 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-11-09T13:38:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-11 11:05:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7502868","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7502868","identity":"rs-7502868","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}