Central serous chorioretinopathy (CSCR) is a major cause of vision threat among middle-aged male individuals. Multimodal imaging led to the description of a wide range of CSCR manifestations, and highlighted the contribution of the choroid and pigment epithelium in CSCR pathogenesis. However, the exact molecular mechanisms of CSCR have remained uncertain. The aim of this review is to recapitulate the clinical understanding of CSCR, with an emphasis on the most recent findings on epidemiology, risk factors, clinical and imaging diagnosis, and treatments options. It also gives an overview of the novel mineralocorticoid pathway hypothesis, from animal data to clinical evidences of the biological efficacy of oral mineralocorticoid antagonists in acute and chronic CSCR patients. In rodents, activation of the mineralocorticoid pathway in ocular cells either by intravitreous injection of its specific ligand, aldosterone, or by over-expression of the receptor specifically in the vascular endothelium, induced ocular phenotypes carrying many features of acute CSCR. Molecular mechanisms include expression of the calcium-dependent potassium channel (KCa2.3) in the endothelium of choroidal vessels, inducing subsequent vasodilation. Inappropriate or over-activation of the mineralocorticoid receptor in ocular cells and other tissues (such as brain, vessels) could link CSCR with the known co-morbidities observed in CSCR patients, including hypertension, coronary disease and psychological stress.

Macular edema consists of intra- or subretinal fluid accumulation in the macular region. It occurs during the course of numerous retinal disorders and can cause severe impairment of central vision. Major causes of macular edema include diabetes, branch and central retinal vein occlusion, choroidal neovascularization, posterior uveitis, postoperative inflammation and central serous chorioretinopathy. The healthy retina is maintained in a relatively dehydrated, transparent state compatible with optimal light transmission by multiple active and passive systems. Fluid accumulation results from an imbalance between processes governing fluid entry and exit, and is driven by Starling equation when inner or outer blood-retinal barriers are disrupted. The multiple and intricate mechanisms involved in retinal hydro-ionic homeostasis, their molecular and cellular basis, and how their deregulation lead to retinal edema, are addressed in this review. Analyzing the distribution of junction proteins and water channels in the human macula, several hypotheses are raised to explain why edema forms specifically in the macular region. "Pure" clinical phenotypes of macular edema, that result presumably from a single causative mechanism, are detailed. Finally, diabetic macular edema is investigated, as a complex multifactorial pathogenic example. This comprehensive review on the current understanding of macular edema and its mechanisms opens perspectives to identify new preventive and therapeutic strategies for this sight-threatening condition.

Purpose: To evaluate the influence of clinical and multimodal imaging parameters on the duration of acute central serous chorioretinopathy (CSCR) episodes. Methods: Consecutive patients with first, treatment-naïve central serous chorioretinopathy episodes presenting within 20 days of symptoms onset were prospectively included. They were reevaluated 15 days to 20 days later, followed by monthly evaluation for 6 months. Subfoveal choroidal thickness (SFCT), fluorescein leakage intensity on fluorescein angiography, elevation of retinal pigment epithelium (RPE) lesions at leakage sites, focal/multifocal pattern of indocyanine green angiography (ICGA) at baseline, time-dependent pattern of subretinal fluid (SRF) resorption on OCT using volume segmentation, history of corticosteroid intake and mean blood pressure were evaluated using univariate (Log rank test) and multivariate (Cox proportional hazard regression) survival analysis. Results: Thirty-one patients were included (26 men, 5 women, mean age: 40.0 ± 8.9 years, range: 24–58), of which 26 (84%) had episode resolution by 6 months. Using univariate analysis, episode duration was longer in cases with subfoveal choroidal thickness ≥500 μm (P = 0.0002), retinal pigment epithelium elevation at leakage sites ≥50 μm (P = 0.033), and a peak in subretinal fluid observed during follow-up (P = 0.013), and there was a near-significant association of intense fluorescein leakage (P = 0.074) with longer episodes. Using multivariate analysis, subfoveal choroidal thickness ≥500 μm (P = 0.017), retinal pigment epithelium elevation at leakage sites ≥50 μm (P = 0.010) and patient age ≥40 years (P = 0.010) were significantly and independently associated to longer episodes. Indocyanine green angiography pattern, corticosteroid intake, and blood pressure did not influence episode duration. Conclusion: Older age, higher subfoveal choroidal thickness, and higher degree of retinal pigment epithelium alteration at leakage sites are independent factors of longer acute central serous chorioretinopathy episodes.

Retinoblastoma is the most frequent intraocular malignancy in children, originating from a maturing cone precursor in the developing retina. Little is known on the molecular basis underlying the biological and clinical behavior of this cancer. Here, using multi-omics data, we demonstrate the existence of two retinoblastoma subtypes. Subtype 1, of earlier onset, includes most of the heritable forms. It harbors few genetic alterations other than the initiating RB1 inactivation and corresponds to differentiated tumors expressing mature cone markers. By contrast, subtype 2 tumors harbor frequent recurrent genetic alterations including MYCN-amplification. They express markers of less differentiated cone together with neuronal/ganglion cell markers with marked inter- and intra-tumor heterogeneity. The cone dedifferentiation in subtype 2 is associated with stemness features including low immune and interferon response, E2F and MYC/MYCN activation and a higher propensity for metastasis. The recognition of these two subtypes, one maintaining a cone-differentiated state, and the other, more aggressive, associated with cone dedifferentiation and expression of neuronal markers, opens up important biological and clinical perspectives for retinoblastomas.

Uveal melanoma (UM) arises from malignant transformation of melanocytes in the uveal tract of the eye. This rare tumor has a poor outcome with frequent chemo-resistant liver metastases. BAP1 is the only known predisposing gene for UM. UMs are generally characterized by low tumor mutation burden, but some UMs display a high level of CpG>TpG mutations associated with MBD4 inactivation. Here, we explored the incidence of germline MBD4 variants in a consecutive series of 1093 primary UM case patients and a series of 192 UM tumors with monosomy 3 (M3). We performed MBD4 targeted sequencing on pooled germline (n = 1093) and tumor (n = 192) DNA samples of UM patients. MBD4 variants (n = 28) were validated by Sanger sequencing. We performed whole-exome sequencing on available tumor samples harboring MBD4 variants (n = 9). Variants of unknown pathogenicity were further functionally assessed. We identified 8 deleterious MBD4 mutations in the consecutive UM series, a 9.15-fold (95% confidence interval = 4.24-fold to 19.73-fold) increased incidence compared with the general population (Fisher exact test, P = 2.00 × 10^–5, 2-sided), and 4 additional deleterious MBD4 mutations in the M3 cohort, including 3 germline and 1 somatic mutations. Tumors carrying deleterious MBD4 mutations were all associated with high tumor mutation burden and a CpG>TpG hypermutator phenotype. We demonstrate that MBD4 is a new predisposing gene for UM associated with hypermutated M3 tumors. The tumor spectrum of this predisposing condition will likely expand with the addition of MBD4 to diagnostic panels. Tumors arising in such a context should be recognized because they may respond to immunotherapy.

Purpose: To determine the prevalence, clinical characteristics and nature of subfoveal nodules in Coats' disease and the associated impact on the long-term visual outcome. Methods: Consecutive cases of Coats' disease with foveal exudation were retrospectively reviewed. The presence of a subfoveal nodule or macular fibrosis was recorded. Clinical characteristics, retinal imaging, and outcome were analyzed by comparative analysis. The histopathological description of an enucleated eye with subfoveal nodule was performed. Results: Among 40 patients presenting unilateral Stage 2B or 3A1 Coats' disease, a subfoveal nodule was detected in 21 patients (52.5%). The median follow-up was 4.7 years. Nineteen patients (47.5%) did not present a subfoveal nodule. Three patients (15.8%) without subfoveal nodule and 21 patients (100%) with subfoveal nodule progressed to a macular fibrotic scar (P < 0.0001), and the mean time of macular fibrosis onset was 11.0 ± 2.6 months. Final visual acuity was significantly worse in patients who presented a subfoveal nodule at diagnosis (P = 0.01). Of 18 cases with subfoveal nodule who underwent fluorescein angiography, retinal–retinal anastomosis and neovascularization were detected in 13 (72.2%) and 2 eyes (11.1%), respectively. Histopathological analysis of a subfoveal nodule revealed an aggregate of proteinaceous material including fibrin, spindle cells, macrophages, and pigmented cells. Conclusion: The presence of a subfoveal nodule at presentation is a predictive factor for macular fibrosis development and worse visual outcome in patients with Coats' disease. These observations suggest an updated classification introducing two subcategories within Stage 2B: without subfoveal nodule (Stage 2B1) and with subfoveal nodule (Stage 2B2).