The Complement System as a Therapeutic Target in Retinal Disease.

The complement cascade is a vital system in the human body's defense against pathogens. During the natural aging process, it has been observed that this system is imperative for ensuring the integrity and homeostasis of the retina. While this system is critical for proper host defense and retinal integrity, it has also been found that dysregulation of this system may lead to certain retinal pathologies, including geographic atrophy and diabetic retinopathy. Targeting components of the complement system for retinal diseases has been an area of interest, and in vivo, ex vivo, and clinical trials have been conducted in this area. Following clinical trials, medications targeting the complement system for retinal disease have also become available. In this manuscript, we discuss the pathophysiology of complement dysfunction in the retina and specific pathologies. We then describe the results of cellular, animal, and clinical studies targeting the complement system for retinal diseases. We then provide an overview of complement inhibitors that have been approved by the Food and Drug Administration (FDA) for geographic atrophy. The complement system in retinal diseases continues to serve as an emerging therapeutic target, and further research in this field will provide additional insights into the mechanisms and considerations for treatment of retinal pathologies.

Update on central retinal artery occlusion.

The medical condition referred to as "central retinal artery occlusion" (CRAO) was first documented by Albrecht von Graefe in 1859. Subsequently, CRAO has consistently been identified as a serious medical condition that leads to substantial visual impairment. Furthermore, it is correlated with vascular complications that have the potential to affect crucial organs such as the brain and heart. A considerable amount of research has been extensively published on the various aspects of this topic, which is marked by notable debates and misconceptions, especially regarding its management and outcomes. The primary aim of this review article is to analyze the latest developments in the understanding of CRAO, which includes its causes, techniques for retinal imaging, systemic evaluation, and therapeutic strategies, such as vitrectomy. This review article offers readers a comprehensive learning experience to gain knowledge on the fundamental principles and recent advancements in CRAO.

A journey through the world of vitreous.

Vitreous, one of the largest components of the human eye, mostly contains water. Despite decades of studying the vitreous structure, numerous unanswered questions still remain, fueling ongoing active research. We attempt to provide a comprehensive overview of the current understanding of the development, morphology, biochemical composition, and function of the vitreous. We emphasize the impact of the vitreous structure and composition on the distribution of drugs. Fast developing imaging technologies, such as modern optical coherence tomography, unlocked multiple new approaches, offering the potential for in vivo study of the vitreous structure. They allowed to analyze in vivo a range of vitreous structures, such as posterior precortical vitreous pockets, Cloquet canal, channels that interconnect them, perivascular vitreous fissures, and cisterns. We provide an overview of such imaging techniques and their principles and of some challenges in visualizing vitreous structures. Finally, it explores the potential of combining the latest technologies and machine learning to enhance our understanding of vitreous structures.

Oral HIF-2α Inhibitor Belzutifan in Ocular von Hippel-Lindau Disease: Subgroup Analysis of the Single-Arm Phase 2 LITESPARK-004 Study.

OBJECTIVE: To report the efficacy of oral HIF-2α inhibitor belzutifan in participants with von Hippel-Lindau disease-associated retinal hemangioblastomas in LITESPARK-004. DESIGN: Subgroup analysis of the phase 2, single-arm, open-label LITESPARK-004 study. PARTICIPANTS: Adults with ≥1 von Hippel-Lindau disease-associated measurable renal cell carcinoma tumor not requiring immediate surgical intervention were eligible. METHODS AND INTERVENTION: Participants received oral belzutifan 120 mg once daily until disease progression or unacceptable treatment-related toxicity. MAIN OUTCOME MEASURES: Efficacy of belzutifan in retinal hemangioblastomas was a secondary end point, measured as response (improved, stable, or progressed) by independent reading center certified graders based on color fundus imaging performed every 12 weeks using the investigator's preferred imaging standards. Additional assessments, where available, included optical coherence tomography and ultra-widefield fluorescein angiography. RESULTS: Among 61 participants in LITESPARK-004, 12 had ≥1 evaluable active retinal hemangioblastoma in 16 eyes at baseline per independent reading center. As of April 1, 2022, the median follow-up for participants with ocular von Hippel-Lindau disease at baseline was 37.3 months. All 16 eyes were graded as improved, with a response rate of 100.0% (95% confidence intervals, 79.4-100.0). No new retinal hemangioblastomas or ocular disease progression were reported as of data cutoff date. Eight participants had additional multimodal eye assessments performed at the National Institutes of Health study site. Among this subgroup, 10 of 24 hemangioblastomas in 8 eyes of 6 participants measured ≥500 µm in greatest linear dimension at baseline and were further analyzed. All 10 hemangioblastomas had a mean area reduction of ≥15% by month 12 and ≥30% by month 24. CONCLUSIONS: Belzutifan showed promising activity against ocular von Hippel-Lindau disease, including capacity to control retinal hemangioblastomas, with effects sustained for >2 years while on treatment.

Quantitative assessment of intervortex anastomosis in central serous chorioretinopathy and fellow eyes: Does the size of anastomotic vessels matter for the diagnosis?

PURPOSE: To evaluate the frequency and size of intervortex anastomosis at the posterior pole on en-face spectral domain optical coherence tomography (SD-OCT) images in central serous chorioretinopathy (CSC) cases and their fellow eyes and its associations with choroidal morphology. METHODS: Sixty-five treatment-naive eyes of 65 patients with CSC, 65 fellow eyes, and 55 eyes of healthy age-matched participants were included. The presence of intervortex anastomosis at the watershed zone and asymmetry of the choroidal vessels between the superior and inferior macula were evaluated using 6 × 6 mm en-face SD-OCT. The diameter of the widest Haller vessel and the diameter of the widest anastomotic Haller vessel passing through the watershed zone were measured on en-face SD-OCT images. The choroidal vascularity index (CVI) was assessed using ImageJ software. RESULTS: Intervortex vein anastomosis on the horizontal watershed zone was detected in 75.4% diseased eyes, 61.5% in fellow eyes, and 36.4% in healthy age-matched controls (p < 0.001). The mean CVI was significantly higher in both diseased (74.3 ± 2.3%) and fellow (73.8 ± 2.2%) eyes of CSC cases than in healthy controls (72.5 ± 2.3%) (p = 0.002, p = 0.013, respectively). In the cases with intervortex vein anastomosis, the diameter of the widest anastomotic Haller vessel passing through the watershed zone was 0.40 ± 0.10 mm in diseased eyes, 0.35 ± 0.11 mm in fellow eyes, and 0.30 ± 0.09 mm in healthy age-matched controls (p = 0.001). CONCLUSIONS: Intervortex anastomosis might be seen as a variation in normal eyes, however, its frequency and the size of anastomotic vessels are significant higher in not only CSC but also in fellow eyes.

Screen failures in clinical trials in retina.

PURPOSE: Disparities in clinical trials are a major problem due to significant underrepresentation of certain gender, racial and ethnic groups. Several factors including stringent eligibility criteria and recruitment strategies hinder our understanding of retinal disease. Thus, we aimed to study the various reasons of screen failures and specific patient and study characteristics among screen failures. DESIGN: This is a cross-sectional retrospective study METHODS: Screening data of 87 trials from 6 centers were analyzed. Study characteristics (disease studied, phase of trial, route of drug administration) and patient demographics (age, gender, race, ethnicity, and employment status) were compared among different causes of screen failures. Screen failures were broadly classified into six categories: exclusion due to vision-based criteria, exclusion due to imaging findings, exclusion due to other factors, patient-related criteria, physician related criteria and miscellaneous. Descriptive statistics, Pearson Chi-square test and ANOVA were used for statistical analysis. MAIN OUTCOME MEASURES: Determine the prevalence of various reasons for screen failures in multiple trials and its trend among different study and patient characteristics. RESULTS: Among 87 trials and 962 patients, 465(48.2%) patients were successfully randomized and 497(51.8%) patients were classified as screen failures. The trials were conducted for various retinal diseases. Mean age was 76.50 ±10.45 years and 59.4% were females. Predominantly whites(93.4%) and unemployed/retired patients(66.6%) were screened. Of the 497 screen failures, most were due to patients not meeting inclusion criteria of imaging findings (n=221[44.5%]) followed by inclusion of vision-based criteria (n=73 [14.7%]), exclusion due to other factors (n=75[15.1%]), patient-related (n=34[6.8%]), physician-related (n=28[5.6%]) and miscellaneous reasons (n= 39[17.8%]). Reason for screen failure was not available for 27(5.4%) patients. A higher proportion of patients screened for surgical trials (15%) declined to participate in the study compared to non-invasive trials involving topical drugs and photobiomodulation (0%).(p=0.02) CONCLUSION: Patients not meeting the imaging and vision-cased criteria were the most common reasons for screen failures. Whites and unemployed patients predominantly participated in clinical trials. Patients are more inclined to continue participation in non-invasive clinical trials compared to surgical trials. Better recruitment strategies and careful consideration of study criteria can aid in decreasing the rate of screen failures.

Progression of macular retinoschisis following intravitreal aflibercept injection for myopic macular neovascularization-a case report and review of literature.

BACKGROUND: Macular retinoschisis (MRS) and myopic macular neovascularization (mMNV) are both potentially blinding complications of high myopia. In this case report, we highlight the progression of MRS after intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment for mMNV, as well as an extensive review of the literature on this topic. CASE DESCRIPTION: A 49-year-old woman presented with two weeks of recent onset blurring and metamorphopsia in her right eye. She had high myopia in both eyes (right eye - 20/60 with - 16D, left eye - 20/20 with - 13D). Slit-lamp ophthalmoscopy found a normal anterior segment in both eyes. On fundus examination, features of pathological myopia with posterior staphyloma and peripapillary atrophy were observed in both eyes. An active mMNV, as well as intraretinal fluid, minimal perifoveal inner and outer MRS, and focal posterior vitreous traction along the inferotemporal retinal arcade, were detected on optical coherence tomography (OCT) of the right eye. The patient received an intravitreal injection of Aflibercept (2 mg/0.05 ml). RESULTS: OCT scans at two- and four-month follow-up visits revealed regressed mMNV with a taut epiretinal membrane, progressive worsening of outer MRS, and the development of multiple perifoveal retinal detachment inferior to the fovea. Pars plana vitrectomy surgery was performed for the progressive MRS with good anatomical (resolved MRS) and functional outcome (maintained visual acuity at 20/60) at the last one-month post-surgery visit. CONCLUSION: Intravitreal anti-VEGF injections for mMNV can cause vitreoretinal interface changes, exacerbating MRS and causing visual deterioration. Vitrectomy for MRS could be one of several treatment options.

Understanding the relationship between pachychoroid spectrum disorders and retinitis pigmentosa: A review of the evidence.

This study aims to investigate the relationship between pachychoroid spectrum disorders and retinitis pigmentosa (RP) or rod-cone dystrophy through a comprehensive literature review. The purpose is to explore the association between these disorders, understand their underlying mechanisms, and summarize the existing hypotheses and opinions. A thorough review of the literature was conducted using PubMed, focusing on articles related to central serous chorioretinopathy (CSC), RP, pachychoroid pigment epitheliopathy, pachychoroid neovasculopathy, polypoidal choroidal vasculopathy, focal choroidal excavation, peripapillary pachychoroid neovasculopathy, and peripheral exudative hemorrhagic chorioretinopathy. Relevant studies were selected for a detailed narrative review and analysis. Several studies have reported the coexistence of CSC and RP, indicating a potential association between the two conditions. The dysfunction of the retinal pigment epithelium is proposed as a common factor. Choroidal thinning is observed in RP, but conflicting results exist regarding choroidal thickness (CT). While some studies support choroidal thinning in RP, others suggest preserved or increased thickness. Additionally, cases of pachychoroid neovasculopathy and polypoidal choroidal vasculopathy in RP have been reported, suggesting an overlap between these conditions. The literature suggests conflicting reports on CT changes in RP. Future research should focus on large-scale studies using comprehensive imaging techniques, genetic analysis, and long-term follow-up to uncover the underlying mechanisms and determine the prevalence of pachychoroid spectrum disorders in RP patients.

Artificial intelligence in chorioretinal pathology through fundoscopy: a comprehensive review.

BACKGROUND: Applications for artificial intelligence (AI) in ophthalmology are continually evolving. Fundoscopy is one of the oldest ocular imaging techniques but remains a mainstay in posterior segment imaging due to its prevalence, ease of use, and ongoing technological advancement. AI has been leveraged for fundoscopy to accomplish core tasks including segmentation, classification, and prediction. MAIN BODY: In this article we provide a review of AI in fundoscopy applied to representative chorioretinal pathologies, including diabetic retinopathy and age-related macular degeneration, among others. We conclude with a discussion of future directions and current limitations. SHORT CONCLUSION: As AI evolves, it will become increasingly essential for the modern ophthalmologist to understand its applications and limitations to improve patient outcomes and continue to innovate.

Viscoelastics Enable Dissection of Anterior Closed Funnels in Proliferative Vitreoretinopathy: A Retrospective Case Series.

Introduction: The present study aimed to describe a case series of patients in which a cohesive ophthalmic viscous device (OVD) was used to viscodissect and posteriorly displace the retina in cases of total retinal detachment complicated by proliferative vitreoretinopathy, operated with minimally invasive pars plana vitrectomy. Case Presentations: Three patients with a mean age of 67 years were included in the present study. One eye was aphakic, while the others were pseudophakic. OVD injection was performed through the limbus in the aphakic eye and via pars plana in the pseudophakic eyes. In all cases, the OVD injection led to a posterior displacement of the detached retina with a smooth dissection. No complications related to the surgery were observed. At the last follow-up visit, the retina was attached in all cases, with an improvement in visual acuity. Conclusion: To conclude, the injection of a cohesive OVD anterior to the detached retina allowed to posteriorize and viscodissect to some extent the retina, facilitating the implant of trocars.

Quantification of Choroidal Vascular Hyperpermeability on Ultra-Widefield Indocyanine Green Angiography in Macular Neovascularization.

To obtain a quantitative parameter for the measurement of choroidal vascular hyperpermeability (CVH) on ultra-widefield indocyanine green angiography (UWICGA) using an objective analysis method in macular choroidal neovascularization (CNV). A total of 113 UWICGA images from 113 subjects were obtained, including with 25 neovascular age-related macular degeneration (nAMD), 37 with polypoidal choroidal vasculopathy (PCV) (19 with thin-choroid and 18 with thick-choroid), 33 with pachychoroid neovasculopathy (PNV), and 18 age-matched controls. CVH was quantified on a gray image by the subtraction of 2 synchronized UWICGA images of early and late phases. The measured CVH parameter was compared with human graders and among CNV subtypes and correlated with choroidal vascular density (CVD) and subfoveal choroidal thickness (SFCT). The mean CVH values were 28.58 ± 4.97, 33.36 ± 8.40, 33.61 ± 11.50, 42.19 ± 13.25, and 43.59 ± 7.86 in controls and patients with nAMD, thin-choroid PCV, thick-choroid PCV, and PNV, respectively (p < 0.001). CVH was higher in thick-choroid PCV and PNV compared to the other groups (all p ≤ 0.006). The measured CVH value positively correlated with those reported by human graders (p < 0.001), CVD, and SFCT (p = 0.001 and p < 0.001, respectively). CVH can be measured objectively using quantitative UWICGA analysis. The CVH parameter differs among macular CNV subtypes and correlates with CVD and SFCT.

Safety and Efficacy of Photodynamic Therapy with Chlorin E6 in Chronic Central Serous Chorioretinopathy.

PURPOSE: To evaluate the efficacy and safety of photodynamic therapy (PDT) with chlorin E6 in chronic central serous chorioretinopathy (CSCR). METHODS: This single-center, retrospective cohort study. All patients received standard PDT with 6 mg of chlorin E6 (Fotoran E6) for each m2 of body surface area with 50 J/cm2 fluence and a treatment time of 83 seconds. The changes in central retinal thickness (CRT), subfoveal choroidal thickness (SCT), and best-corrected visual acuity (BCVA) were evaluated at the end of the follow-up. Main outcome measure was the presence of subretinal fluid (SRF) at three months after PDT. RESULTS: Thirty-nine eyes (32 males and 7 females, 43.7 ± 10.0 years) were included. In total, 50 PDT sessions were performed. At three months of follow-up, 31 out of 39 (79.5%) study eyes showed complete resolution of SRF. Mean follow-up period after PDT was 15.3 ± 7.8 months. At the end of follow-up, a complete resolution of SRF was observed in 32 out of 39 (82.7%) eyes. Mean change in CRT, SCT, and BCVA at the end of the follow-up was -139.7 ± 136.4 µm, -66.8 ± 36.2 µm, and -0.05 ± 0.08 LogMAR, respectively (p < 0.001). Neither systemic nor ocular adverse events were observed, nor were local reactions seen. CONCLUSION: Standard PDT with chlorin E6 is an effective and safe option in the management of chronic CSCR and may be considered as an alternative to the standard PDT with Visudyne.

Three-dimensional choroidal contour mapping in healthy population.

Purpose was to study 3-dimensional choroidal contour at choroidal inner boundary (CIB) and choroidal outer boundary (COB) in healthy eyes. Healthy eyes imaged on wide field swept-source optical coherence tomography were included. Delineation of CIB and COB was done based on our previously reported methods. Quantitative analysis of the surfaces of CIB and COB was based on analyzing best fit spherical radius (R) (overall and sectoral). One hundred and seven eyes of 74 subjects with a mean age of 46.4 ± 19.3 years were evaluated. Overall, R COB (mean ± SD: 22.5 ± 4.8 mm) < R CIB (32.4 ± 9.4 mm). Central sector had the least R at COB (7.2 ± 5.9 mm) as well as CIB (25.1 ± 14.3 mm) across all age groups. Regression analysis between R (CIB) and age (r = -0.31, r2 = 0.09) showed negative correlation (P < 0.001) and that between R (COB) and age was positive (r = 0.26, r2 = 0.07) (P = 0.01). To conclude, central sector is the steepest sector in comparison to all the other sectors. This is indicative of a prolate shape of choroidal contour at CIB and COB. Outer boundary of choroid is steeper than inner boundary across all age groups. However, with ageing, outer boundary becomes flatter and inner boundary becomes steeper.

Internal limiting membrane separation and posterior vitreous hyperreflective dots: novel OCT findings in Purtscher-like retinopathy.

BACKGROUND: Purtscher or Purtscher-like retinopathy is diagnosed by retinal hemorrhages and areas of retinal whitening on fundus examination, as well as a reduction in visual acuity due to microvascular occlusion of the precapillary retinal arterioles. We describe novel optical coherence tomography (OCT) findings of internal limiting membrane (ILM) separation and posterior hyperreflective dots in a case of Purtscher-like retinopathy in this report. METHODS: A 33-year-old man with acute pancreatitis and alcohol-induced liver disease presented to the retina department complaining of four days of painless vision loss in both eyes. Both eyes' anterior segment examination and intraocular pressure were normal. Dilated fundus examination of both eyes revealed confluent areas of retinal whitening, hemorrhages, and cotton-wool spots over the posterior pole, indicating Purtscher-like retinopathy. OCT scans through the macula revealed dense inner retinal reflectivity, thickening, and loss of retinal layer stratification, as well as outer retinal layer shadowing and islands of ILM separation, posterior vitreous hyperreflective dots, and minimal subfoveal fluid, all of which corresponded to areas of retinal whitening on fundus photographs. The patient was given a brief course of systemic steroids. RESULTS: On the tenth day after the presentation, visual acuity in the right eye had improved to 6/18 and finger counting at 1 m in the left eye. The retinal findings had faded. The retina had reverted to its normal thickness on the OCT scans, with minimal hyperreflectivity remaining. The ILM separation and posterior vitreous hyperreflective dots were no longer present. CONCLUSION: Following Purtscher or Purtscher-like retinopathy, we believe inflammation could play a major role in the development of these two novel OCT findings. This case offers an additional perspective on the underlying mechanisms responsible for the retinal manifestations observed in Purtscher or Purtscher-like retinopathy.

Comparison of pigment epithelium detachment composition indices between neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

PURPOSE: To compare changes in the fibrous component of pigment epithelium detachment composition indices (PEDCI-F) in neovascular age-related macular degeneration (n-AMD) and polypoidal choroidal vasculopathy (PCV) over 12 months. METHODS: This was a retrospective chart review of treatment-naïve n-AMD and PCV eyes treated with anti-vascular endothelial growth factor (anti-VEGF) agents. Optical coherence tomography (OCT) images were recorded at baseline and at 3, 6, and 12 months. OCT images were processed by filtering followed by pigment epithelium detachment (PED) segmentation and analysis of PED lesion heterogeneity based on the composition (PEDCI-F). RESULTS: A total of 74 eyes with n-AMD (36) and PCV (38) were included. Overall, PEDCI-F increased minimally in both n-AMD and PCV groups (both p > 0.05). The majority, i.e., 58.3% and 60.5%, of n-AMD and PCV eyes, respectively, showed an increase in PEDCI-F at 12 months. An increase in PEDCI-F was associated with improved BCVA logMAR (n-AMD, r = -0.79; p < 0.001 and PCV, r = - 0.06; p = 0.74) and the need for fewer anti-VEGF injections (n-AMD, r = - 0.53; p < 0.001 and PCV, r = - 0.09; p = 0.58). CONCLUSION: PEDCI-F increases in the majority of eyes with n-AMD and PCV through 12 months following treatment with anti-VEGF injections. This group had better visual acuity compared to the other subset with reduction in PEDCI-F requiring more anti-VEGF injections and worse visual acuity, possibly due to fibrovascular PED (FVPED) collapse and atrophy or a relative increase in other PEDCI constituents at 12 months.

Recommendations for diabetic macular edema management by retina specialists and large language model-based artificial intelligence platforms.

PURPOSE: To study the role of artificial intelligence (AI) in developing diabetic macular edema (DME) management recommendations by creating and comparing responses to clinicians in hypothetical AI-generated case scenarios. The study also examined whether its joint recommendations followed national DME management guidelines. METHODS: The AI hypothetically generated 50 ocular case scenarios from 25 patients using keywords like age, gender, type, duration and control of diabetes, visual acuity, lens status, retinopathy stage, coexisting ocular and systemic co-morbidities, and DME-related retinal imaging findings. For DME and ocular co-morbidity management, we calculated inter-rater agreements (kappa analysis) separately for clinician responses, AI-platforms, and the "majority clinician response" (the maximum number of identical clinician responses) and "majority AI-platform" (the maximum number of identical AI responses). Treatment recommendations for various situations were compared to the Indian national guidelines. RESULTS: For DME management, clinicians (ĸ=0.6), AI platforms (ĸ=0.58), and the 'majority clinician response' and 'majority AI response' (ĸ=0.69) had moderate to substantial inter-rate agreement. The study showed fair to substantial agreement for ocular co-morbidity management between clinicians (ĸ=0.8), AI platforms (ĸ=0.36), and the 'majority clinician response' and 'majority AI response' (ĸ=0.49). Many of the current study's recommendations and national clinical guidelines agreed and disagreed. When treating center-involving DME with very good visual acuity, lattice degeneration, renal disease, anaemia, and a recent history of cardiovascular disease, there were clear disagreements. CONCLUSION: For the first time, this study recommends DME management using large language model-based generative AI. The study's findings could guide in revising the global DME management guidelines.

Successful resolution of serous macular detachment following glaucoma-filtering surgery alone for acquired optic disc pit maculopathy.

PURPOSE: To describe a case of acquired glaucomatous optic disc pit-related maculopathy successfully treated with glaucoma filtering surgery alone. CASE DESCRIPTION: A 67-year-old male was diagnosed with advanced primary open angle glaucoma in both eyes, with a cup: disc ratio of 0.85 in the right eye and 0.95 in the left eye. Visual acuity at presentation was 20/60, and intraocular pressure was 14 mm Hg in the left eye. The fundus of the left eye revealed a serous macular retinal detachment due to an acquired optic disc pit. RESULTS: The left eye of the patient underwent combined cataract and glaucoma filtering surgery. The serous macular detachment resolved completely 15 months after surgery, with a documented visual acuity of 20/40 and intraocular pressure of 10 mm Hg without the use of additional antiglaucoma medications. There was no recurrence of serous macular detachment even after the two-year follow-up visit. CONCLUSION: This case demonstrates that controlling intraocular pressure alone resulted in complete resolution of serous macular detachment in acquired optic disc pit maculopathy without the need for pars plana vitrectomy.

Central serous chorioretinopathy: An evidence-based treatment guideline.

Central serous chorioretinopathy (CSC) is a relatively common disease that causes vision loss due to macular subretinal fluid leakage and it is often associated with reduced vision-related quality of life. In CSC, the leakage of subretinal fluid through defects in the retinal pigment epithelial layer's outer blood-retina barrier appears to occur secondary to choroidal abnormalities and dysfunction. The treatment of CSC is currently the subject of controversy, although recent data obtained from several large randomized controlled trials provide a wealth of new information that can be used to establish a treatment algorithm. Here, we provide a comprehensive overview of our current understanding regarding the pathogenesis of CSC, current therapeutic strategies, and an evidence-based treatment guideline for CSC. In acute CSC, treatment can often be deferred for up to 3-4 months after diagnosis; however, early treatment with either half-dose or half-fluence photodynamic therapy (PDT) with the photosensitive dye verteporfin may be beneficial in selected cases. In chronic CSC, half-dose or half-fluence PDT, which targets the abnormal choroid, should be considered the preferred treatment. If PDT is unavailable, chronic CSC with focal, non-central leakage on angiography may be treated using conventional laser photocoagulation. CSC with concurrent macular neovascularization should be treated with half-dose/half-fluence PDT and/or intravitreal injections of an anti-vascular endothelial growth factor compound. Given the current shortage of verteporfin and the paucity of evidence supporting the efficacy of other treatment options, future studies-ideally, well-designed randomized controlled trials-are needed in order to evaluate new treatment options for CSC.