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ZusammenfassungNetzhauteingriffe können zu einem erhöhten Augeninnendruck führen. Die Ursachen hierfür sind vielfältig und schließen mechanische, aber auch pharmakologische Gründe ein. Die Therapie besteht zunächst aus einer Lokaltherapie mit drucksenkenden Augentropfen. Bei unzureichendem Ansprechen sind chirurgische Eingriffe indiziert.

The aim of our prospective off-label, interventional clinical trial was to evaluate the efficacy and safety of the fluocinolone-loop-anchoring technique over two years in eyes with iris-lens diaphragm disruption and pseudophakic cystoid macular edema.In 10 eyes, scleral fixation of fluocinolone implant was performed. Main outcome measures were the development of best-corrected visual acuity (BCVA), central retinal thickness over 24 months, and general safety of the procedure.A significant improvement to 0.57 ± 0.38 log MAR (Snellen 20/80) (range 0-1.30) was observed (P = 0.003) at 1 month. Further improvement to 0.45 ± 036 log MAR (Snellen 20/60) was observed until month 18 (P = 0.081). Mean central retinal thickness decreased by 22% from 601.6 ± 235.5 µm to 449.1 ± 128.9 µm at 1 month. In one patient, the implant has to be removed at Month 7 because of elevated intraocular pressure and one patient after globe rupture had a retinal redetachment at Month 4.In this study, we showed that the treatment of recalcitrant pseudophakic cystoid macular edema with scleral fixated fluocinolone implant in eyes with disruption of the iris-lens diaphragm provides good anatomical and functional results with a reasonable safety profile over 24 months in eyes where pseudophakic cystoid macular edema is otherwise difficult to treat and often left untreated.

Introduction: Tumor recurrence in choroidal melanoma has been associated with decreased overall survival due to metastatic spreading. To detect risk factors of local recurrence and side effects, we analyzed tumor planning and treatment parameters in patients with recurrence of choroidal melanoma after treatment with robotic-assisted radiosurgery (CyberKnife). Methods: Six hundred ninety-four patients treated with CyberKnife between 2005 and 2019 were retrospectively reviewed. Age, gender, best-corrected visual acuity, tumor height, and diameter were recorded. Treatment planning and radiation doses were reviewed. Salvage therapy, overall survival, metastasis, and complications were recorded. Results: Seventy-four patients showed local recurrence. Local recurrence occurred after 42.1 months post CyberKnife treatment (mean; range: 5–100 months). Fourteen out of 74 patients (18.9%) died during follow-up. Recurrence treatment included enucleation in 51 patients (68.9%) and radiosurgery in 19 patients (25.7%). Treatment planning without contrast medium MRI, radiation dose of less than 21 Gy, and insufficient margin delineation were identified as risk factors incrementing local control. Discussion: Robotic-assisted radiosurgery (CyberKnife) is a suitable treatment option for large choroidal melanoma up to 12 mm. Patients with significantly better visual acuity received repeat CyberKnife treatment as salvage therapy and showed an eye retention rate of 81%.

Purpose Patients with extensive submacular hemorrhage (SMH) caused by age-related macular degeneration (AMD) have a poor visual prognosis despite surgical intervention. Systemic blood-thinning drugs, which are commonly prescribed in the same age group, are known to increase the risk of severe hemorrhage in many parts of the body. This study aimed to investigate whether systemic blood-thinning drugs have an impact on the severity of SMH and if there are differences between the different types of blood-thinning medication. Methods We reviewed the medical records of patients who suffered from surgically treated SMH between 2020 and 2022. All patients received a full ophthalmologic examination upon presentation including best-corrected visual acuity (BCVA) and optical coherence tomography. Other characteristics that were recorded included size of hemorrhage, blood-thinning therapy, and reason for intake. Results A total of 115 patients with a mean age of 82 years were included in this retrospective analysis. Eighty-three patients (72.2%) were on blood-thinning therapy. The mean size of SMH was 32.01 mm2. Mean BCVA at initial presentation was 1.63 logMAR and 1.59 logMAR 1 year after surgery. The size of SMH was significantly larger in patients on blood-thinning medication (35.92 mm2 vs. 21.91 mm2) (p = 0.001) and their BCVA postoperatively was worse with 1.68 logMAR compared to 1.30 logMAR after 1 year (p = 0.503). Patients with vitamin K antagonists had larger SMH size and worse outcomes regarding BCVA compared to direct oral anticoagulants. Conclusion Blood thinners in patients with AMD affect the severity of SMH. Consequently, the indication for their intake should be critically evaluated.

Vitreoretinal surgery can lead to elevated intraocular pressure. Causes are multifactorial including both mechanical and pharmacological mechanisms. Therapy initially consists of topical therapy with pressure-lowering eye drops. In case of inadequate response, surgical interventions are indicated.Netzhauteingriffe können zu einem erhöhten Augeninnendruck führen. Die Ursachen hierfür sind vielfältig und schließen mechanische, aber auch pharmakologische Gründe ein. Die Therapie besteht zunächst aus einer Lokaltherapie mit drucksenkenden Augentropfen. Bei unzureichendem Ansprechen sind chirurgische Eingriffe indiziert.

Purpose Vasoproliferative tumours (VPT) are a rare but benign entity that can lead to severe visual acuity deterioration. There is no standard of care, and depending on the degree of clinical features, including tumour size and dissemination, visual acuity and subretinal fluid, treatment options include observation, cryotherapy and brachytherapy. Particularly in larger tumours, brachytherapy has advantages over other options, although higher radiation doses and the need for surgical application are disadvantages of this otherwise effective treatment option. CyberKnife radiosurgery might represent an alternative therapeutic option as no surgical intervention is needed and radiation doses are lower. Methods All patients diagnosed with vasoproliferative tumors who were treated with CyberKnife radiosurgery with a minimum follow-up time of 12 months were included in this case series. We recorded visual acuity, number of lesions, central retinal thickness with optical coherence tomography (OCT) and reflectivity using A-scan standardizes echography every three months. Results A total of four patients with a median age of 34 years (range: 24 - 51) who were observed over an average of 26.5 months (range: 17 - 49 months) matched our inclusion criteria. We appreciated stabilization or increase in visual acuity in all four patients and a regression in tumour thickness with subsequent increase in internal reflectivity as a marker of increasing fibrosis. Conclusion We observed good visual and functional outcome following CyberKnife therapy for VPT. We believe that further studies should be pursued to evaluate CyberKnife therapy for the treatment of VPT not treatable with cryo- or lasertherapy.

Introduction: COVID-19 has had a tremendous impact on our everyday life. A growing body of evidence indicates that subsequent lockdowns and fear of exposure may have impacted patient care. We analyzed data on incidence and time to surgery in cases of rhegmatogenous retinal detachments (RRD) at three defined time points before, during, and 1 year after the first lockdown period in Germany. Methods: In this single-center study, we identified all patients who were admitted and treated for a primary RRD in April and May 2020, the time of the first lockdown period in Germany, and compared them with cases of the same time period in the years 2019 and 2021. The time from first occurrence of symptoms to surgery as well as visual outcome was analyzed. Results: A total of 192 patients presented to our tertiary academic referral center with a RRD during the months of April and May in 2019 (72 patients), 2020 (62 patients), and 2021 (58 patients) and were included in this study. There were no significant differences with regard to gender and age. In 2019, the time interval between occurrence and presentation to our hospital amounted to a mean of 5.96 days and in 2021 to mean of 5.45 days. However, in 2020, the time between occurrence and presentation was significantly longer with a mean of 15.36 days. The number of patients presenting with a macula-on retinal detachment was also lowest in 2020 (39.2%) compared to 2019 (50.7%) and 2021 (50.0%). Furthermore, with 1.24 logMAR the mean BCVA upon initial presentation was lower in 2020 compared to 0.93 logMAR in 2019 and 1.06 logMAR in 2021. Six to twelve weeks following surgery, visual acuity had improved in 56.1% of patients in 2019 and 60.0% of patients in 2021 as compared to 59.0% in 2020. Conclusion: We found significant differences in terms of elapsed time from first symptoms to surgical management for patients in 2020 in comparison with the same time period in 2019 and 2021. Less strict lockdown policies appear to impact patient behavior and patient care. Further measures, such as questionnaires, might help address which measures may provide safer circumstances for patients to consult health care providers in the case of future strict lockdowns.

Plaque brachytherapy is the most common procedure for the treatment of small choroidal melanoma, especially in posteriorly located tumors. However, there is only little information on outcome after treatment with stereotactic radiosurgery, for example, CyberKnife radiosurgery. We reviewed patients with choroidal melanoma (maximum tumor height 4 mm) treated with CyberKnife radiosurgery. Demographic information, tumor dimension, complications, metastasis and overall survival during the whole follow-up were tracked and analyzed with a specific focus on local tumor control and potential risk factors. One hundred eighty-eight patients (102 female, 54.2%) with a median age of 63 years [interquartile range (IQR): 54-73 years] were analyzed over a median of 46 months (IQR: 24-62 months). Metastasis occurred in 14 patients (7.4%) in median of 18 months after treatment (IQR: 13-47 months) and survival was achieved in 178 patients (94.7%). Within the observation period, eye retention was observed in 166 patients (88.3%). Superior local control was achieved in patients who received a prescription dose of at least 21 Gy or more (91.6%; P = 0.04). Other potential risk factors incrementing local control were treatment planning with missing MRI in advance and too small target delineation during the planning process. Radiosurgery (CyberKnife) in a single, outpatient procedure is suitable for the treatment of small choroidal melanoma. We found local control rate after 3 years compared to the standard treatment with plaque brachytherapy. On the study side, 15 years of CyberKnife treatment allowed to identify risk factors that might increment local control and thus improve treatment regimens.

While proven to be an effective treatment for cystoid macular edema (CME) and diabetic macular edema, intravitreal steroid implants (IVSI) may cause undesirable side effects, including steroid-related glaucoma or migration into the anterior chamber in the case of iris–lens diaphragm disruption. Here we present a new surgical technique that allows for the easy implantation and subsequent fixation of the fluocinolone acetonide intravitreal implant without the risk of migration as a feasible and possibly reversible approach in the treatment of persistent CME in severely damaged eyes. In this single-center, prospective off-label, proof of principle, scleral fixation of the fluocinolone implant was performed in two eyes with disrupted anterior–posterior segment border and persistent CME. Both eyes were then followed monthly in accordance to a detailed protocol. The procedure was overall well tolerated without severe side effects. There was no migration of the implant in the anterior chamber in either eye. Scleral fixation of the fluocinolone implant proved to be a safe and feasible approach in eyes with persistent CME and disrupted anterior–posterior segment border. This new technique also allows for the possible removal of the implant and may therefore be suitable even for eyes at higher risk for side effects, such as glaucoma.

Background:Diabetes prevalence is constantly rising, involving the eyes with damage including development of diabetic macular oedema. Since 2012, intravitreal anti-vascular endothelial growth factor medication is available for diabetic macular oedema treatment. Endocrinological studies have shown that fewer women are affected by diabetes. However, when affected, they exhibit more severe diabetic complications than men. We have investigated gender-related differences in diabetic macular oedema and outcome in an ophthalmological tertiary referral hospital.Methods:We included 88 patients (54 males and 34 females) with 112 eyes (68 male and 44 female) having clinically significant diabetic macular oedema, treated with anti-vascular endothelial growth factor medication. A 1 year follow-up was performed in all patients (visual acuity and optical coherence tomography). Previous retinal surgery was an exclusion criterion, as were other retinal pathologies.Results:The mean visual acuity and mean central retinal thickness at baseline were 0.53 logMAR (male 0.49 and female 0.595) and 469 μm (male 452 μm and female: 494 μm), respectively. After 360 days, mean visual acuity changed by −0.07 (±0.36) logMAR (male −0.11 and female +0.01) and mean central retinal thickness changed by −119 μm (male −113 μm and female −127 μm). For visual acuity, a significant difference was noted at baseline ( p = 0.02) and at 1 year ( p Conclusion:Our study showed that female patients with diabetic macular oedema were diagnosed with and treated for diabetic macular oedema at a stage when visual acuity and optical coherence tomography were worse than those in their male counterparts. This gender difference could not be reduced, despite similar numbers of injections. Female diabetic patients should therefore be assessed early for ophthalmological pathologies.

Purpose Choroidal neovascularizations (CNV) are partially stabilized through a coverage of pericytes leading to a partial anti-VEGF resistence. Drugs licensed for neovascular AMD (nAMD) do not take this mechanical and growth factor-driven CNV stability into account. The purpose of this work was to see if inhibiting the mammalian target of rapamycin (mTOR) may successfully block angiogenic cellular pathways in primary human retinal pericytes in an in vitro model of nAMD. Methods The mTOR inhibitor rapamycin was used to treat human retinal pericytes (HRP) at doses ranging from 0.005 to 15 g/ml. A modified metabolism-based XTT-Assay was used to assess toxicity and anti-proliferative effects. A scratch wound experiment showed the effects on migration. On Cultrex basement membrane gels, the influence of rapamycin on the development of endothelial cell capillary-like structures by human umbilical vein vascular endothelial cells (HUVEC) in the absence and presence of pericytes was investigated. Results Rapamycin showed no signs of toxicity within its range of solubility. The drug showed dose dependent anti-proliferative activity and inhibited migration into the scratch wound. Endothelial cell tube formation in a HUVEC monoculture was effectively inhibited at 45%. A co-culture of HUVEC with pericytes on Cultrex induced endothelial tube stabilization but was disrupted by the addition of rapamycin leading to degradation of 94% of the tubes. Conclusions Rapamycin allows for an efficient modulation of aspects of angiogenesis in pericytes via mTOR-modulation in vitro. Further studies are needed to elucidate whether rapamycin may have an impact on CNV in nAMD in vivo.

This study identifies the endolysosomal two-pore channel TPC2 as a potential novel drug target for age-related macular degeneration (AMD). Inhibition of TPC2 reduces two key clinical hallmarks of the AMD, retinal inflammation and formation of leaky choroi., Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly and can be classified either as dry or as neovascular (or wet). Neovascular AMD is characterized by a strong immune response and the inadequate release of cytokines triggering angiogenesis and induction of photoreceptor death. The pathomechanisms of AMD are only partly understood. Here, we identify the endolysosomal two-pore cation channel TPC2 as a key factor of neovascularization and immune activation in the laser-induced choroidal neovascularization (CNV) mouse model of AMD. Block of TPC2 reduced retinal VEGFA and IL-1β levels and diminished neovascularization and immune activation. Mechanistically, TPC2 mediates cationic currents in endolysosomal organelles of immune cells and lack of TPC2 leads to reduced IL-1β levels in areas of choroidal neovascularization due to endolysosomal trapping. Taken together, our study identifies TPC2 as a promising novel therapeutic target for the treatment of AMD.

PURPOSE We assessed differences in compliance and adherence (lateness of patients, visual acuity, reasons for abstaining) between patients with diabetic macular edema (DME) and patients with age-related macular degeneration (AMD), both under anti-vascular endothelial growth factor therapy. METHODS We included 136 patients with DME (36% women, 65 years, 22 visits, 13.9 injections, and 29.9 months of follow-up) and 109 patients with AMD (59% women, 76 years, 20 visits, 14.7 injections, and 22.3 months of follow-up) (minimum follow-up of 12 months and at least 5 injections). We assessed missed appointments (lateness >14 days) and therapy break-offs (lateness >100 days). All delayed patients were called and interviewed for abstaining reasons. RESULTS Forty-six percent of patients with DME and 22% of patients with AMD had at least one break-off. Thirty-five percent of patients with DME and 50% of patients with AMD were always on schedule. In patients with DME, there was significant correlation (P = 0.017) between the number of break-offs and change of visual acuity. In 60% DME and 38% AMD of break-off cases, visual acuity was worse than the before break-off. The most common reason for abstaining was comorbidities (33% AMD and 20% DME). CONCLUSION There are significant differences between patients with AMD and DME regarding compliance and adherence, which also affects outcome. Strategies to tie patients with DME to costly intravitreal therapy need to be developed to improve outcomes and efficacy.

BackgroundBrolucizumab has recently been approved in Europe as a novel treatment for patients with neovascular age-related macular degeneration (nAMD). We report on early experiences with real-world outcomes of switch to brolucizumab therapy in previously anti-vascular endothelial growth factor (anti-VEGF)-treated patients.MethodsPatients with recalcitrant nAMD were switched to brolucizumab therapy. Functional and structural parameters 4 weeks after first brolucizumab injection were evaluated including best-corrected visual acuity (BCVA (logMAR)), foveal centre point (FCP (µm)), central subfield retinal thickness (CSRT (µm)) and macular volume (mm³).ResultsSixty-three eyes of 57 patients with nAMD (52.6% females) with a mean (±SD) age of 79.5±6.7 years were included. Mean change of BCVA was 0.03±0.14 logMAR (p=0.115). Significant reductions were recorded for FCP with a mean (±SD) change of −66.81±72.63 µm, −66.76±60.71 µm for CSRT and −0.27±0.24 mm³ for macular volume (all pConclusionsThe results of the SHIFT study indicate that switch to brolucizumab may represent a treatment option in patients with nAMD poorly responsive to other anti-VEGF agents. Further long-term analyses appear prudent to assess efficacy and safety of brolucizumab in a routine clinical setting.

Keratoconus is a progressive ectatic corneal disorder, which can result in severe visual impairment. The new ABCD keratoconus classification system allows differentiated description of the disease. Aim of the study was to evaluate the components of this novel staging system (ARC, PRC, thinnest pachymetry) as well as topometric indices, deviation of normality indices, and other parameters in terms of repeatability and reliability. 317 eyes with keratoconus were examined twice with a Scheimpflug device (Pentacam, Oculus). Bland Altman analysis and intraclass correlations were carried out to evaluate the parameters repeatability and reliability. Apart from IHA (ICC = 0.730), all parameters showed excellent reliability (ICC > 0.900). ARC, PRC, thinnest pachymetry, Kmax, CKI, KI, Rmin, and Progression Avg were the best repeatable parameters with relative repeatability values

BACKGROUND Hyperglycemia, insulin insensitivity, and low IGF1 levels in extremely preterm infants are associated with an increased risk of retinopathy of prematurity (ROP), but the interactions are incompletely understood. METHODS In 117 extremely preterm infants, serum glucose levels and parenteral glucose intake were recoded daily in the first postnatal week. Serum IGF1 levels were measured weekly. Mice with oxygen-induced retinopathy alone versus oxygen-induced retinopathy plus streptozotocin-induced hyperglycemia/hypoinsulinemia were assessed for glucose, insulin, IGF1, IGFBP1, and IGFBP3 in blood and liver. Recombinant human IGF1 was injected to assess the effect on glucose and retinopathy. RESULTS The highest mean plasma glucose tertile of infants positively correlated with parenteral glucose intake [r(39) = 0.67, P < 0.0001]. IGF1 plasma levels were lower in the high tertile compared with those in low and intermediate tertiles at day 28 (P = 0.038 and P = 0.03). In high versus lower glucose tertiles, ROP was more prevalent (34 of 39 versus 19 of 39) and more severe (ROP stage 3 or higher; 71% versus 32%). In oxygen-induced retinopathy, hyperglycemia/hypoinsulinemia decreased liver IGF1 expression (P < 0.0001); rh-IGF1 treatment improved normal vascular regrowth (P = 0.027) and reduced neovascularization (P < 0.0001). CONCLUSION In extremely preterm infants, high early postnatal plasma glucose levels and signs of insulin insensitivity were associated with lower IGF1 levels and increased ROP severity. In a hyperglycemia retinopathy mouse model, decreased insulin signaling suppressed liver IGF1 production, lowered serum IGF1 levels, and increased neovascularization. IGF1 supplementation improved retinal revascularization and decreased pathological neovascularization. The data support IGF1 as a potential treatment for prevention of ROP. TRIAL REGISTRATION ClinicalTrials.gov NCT02760472 (Donna Mega). FUNDING This study has been supported by the Swedish Medical Research Council (14940, 4732, 20144-01-3, and 21144-01-3), a Swedish government grant (ALFGB2770), Lund medical faculty grants (ALFL, 11615 and 11601), the Skåne Council Foundation for Research and Development, the Linnéa and Josef Carlsson Foundation, the Knut and Alice Wallenberg Foundation, the NIH/National Eye Institute (EY022275, EY017017, EY017017-13S1, and P01 HD18655), European Commission FP7 project 305485 PREVENT-ROP, Deutsche Forschungsgemeinschaft (CA-1940/1-1), and Stiftelsen De Blindas Vänner., In extremely preterm infants, high early postnatal plasma glucose levels and signs of insulin insensitivity were associated with lower IGF1 levels and increased retinopathy of prematurity severity.

Iris melanoma is a rare form of uveal melanoma with potential metastic spread. Treatment options include surgical resection, enucleation or irradiation. We analysed visual outcome, complication appearance and management in eight patients with iris melanoma following robotic-assisted CyberKnife treatment. Consecutive patients from the Department of Ophthalmology at University of Munich were included in the study if they had an iris melanoma that was treated with CyberKnife and had a minimum follow-up of 12 months. We evaluated tumor thickness, largest diameter, visual acuity and complications. 8 patients were included in this report. The median age was 74 years (range: 53–86 years). The median follow-up was 23 months (range 12–48 months). Tumor thickness decreased from 2.1 to 1.4 mm on average. Four out of eight patients showed stable or increased visual acuity compared to visual acuity at first visit. We did not find a correlation of applied radiation volume or radiation dose on visual outcome. Radiation keratopathy was the most common complication in five patients. No recurrences were noted. Robotic-assisted radiosurgery following CyberKnife is a promising non-invasive, single session treatment option for iris melanoma with comparable results regarding recurrence rate or complications to brachytherapy and proton beam therapy. All included patients showed good visual outcome.

Purpose Clinical practice guidelines provide recommendations for the management of diseases. In orphan conditions such as uveal melanoma (UM), guideline developers are challenged to provide practical and useful guidance even in the absence of high-quality evidence. Here, we assessed the methodological quality and identified deficiencies of international guidelines on UM as a base for future guideline development. Methods A systematic search was carried out in guideline databases, Medline and Embase until 27th May 2019 for guidelines on UM published between 2004 and 2019. Five independent reviewers assessed the methodological quality of the identified guidelines using the instruments “Appraisal of Guidelines for Research and Evaluation II” (AGREE II) and AGREE-REX (Recommendation EXcellence). Descriptive analysis was performed and subgroup differences were explored with the Kruskal–Wallis (H) test. The relationship between the individual domains and items of the instruments were examined using Spearman’s correlation. Results Five guidelines published from 2014 to 2018 by consortia of the United States of America, Canada and the United Kingdom (UK) were included. The highest scores were obtained by the UK guideline fulfilling 48–86% of criteria in AGREE II and 30–60% for AGREE-REX. All guidelines showed deficiencies in the domains “editorial independence”, “applicability”, and “recommendation”. Subgroup differences were identified only for the domain “editorial independence”. Conclusion The UK guideline achieved the highest scores with both instruments and may serve as a basis for future guideline development in UM. The domains “editorial independence”, “recommendation”, and “applicability” were identified as methodological weaknesses and require particular attention and improvement in future guidelines.

Ciliary body melanoma have the worst prognosis among all uveal melanoma (UM). In this report we share our experience with CyberKnife and show that the outcome is not considerably worse than with UM located elsewhere.

Retinal neuronal abnormalities occur before vascular changes in diabetic retinopathy. Accumulating experimental evidence suggests that neurons control vascular pathology in diabetic and other neovascular retinal diseases. Therefore, normalizing neuronal activity in diabetes may prevent vascular pathology. We investigated whether fibroblast growth factor 21 (FGF21) prevented retinal neuronal dysfunction in insulin-deficient diabetic mice. We found that in diabetic neural retina, photoreceptor rather than inner retinal function was most affected and administration of the long-acting FGF21 analog PF-05231023 restored the retinal neuronal functional deficits detected by electroretinography. PF-05231023 administration protected against diabetes-induced disorganization of photoreceptor segments seen in retinal cross section with immunohistochemistry and attenuated the reduction in the thickness of photoreceptor segments measured by optical coherence tomography. PF-05231023, independent of its downstream metabolic modulator adiponectin, reduced inflammatory marker interleukin-1β (IL-1β) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2–related factor 2 pathway and reduced IL-1β expression in stressed photoreceptors. PF-05231023 administration did not change retinal expression of vascular endothelial growth factor A, suggesting a novel therapeutic approach for the prevention of early diabetic retinopathy by protecting photoreceptor function in diabetes.

The neural cells and factors determining normal vascular growth are not well defined even though vision‐threatening neovessel growth, a major cause of blindness in retinopathy of prematurity (ROP) (and diabetic retinopathy), is driven by delayed normal vascular growth. We here examined whether hyperglycemia and low adiponectin (APN) levels delayed normal retinal vascularization, driven primarily by dysregulated photoreceptor metabolism. In premature infants, low APN levels correlated with hyperglycemia and delayed retinal vascular formation. Experimentally in a neonatal mouse model of postnatal hyperglycemia modeling early ROP, hyperglycemia caused photoreceptor dysfunction and delayed neurovascular maturation associated with changes in the APN pathway; recombinant mouse APN or APN receptor agonist AdipoRon treatment normalized vascular growth. APN deficiency decreased retinal mitochondrial metabolic enzyme levels particularly in photoreceptors, suppressed retinal vascular development, and decreased photoreceptor platelet‐derived growth factor (Pdgfb). APN pathway activation reversed these effects. Blockade of mitochondrial respiration abolished AdipoRon‐induced Pdgfb increase in photoreceptors. Photoreceptor knockdown of Pdgfb delayed retinal vascular formation. Stimulation of the APN pathway might prevent hyperglycemia‐associated retinal abnormalities and suppress phase I ROP in premature infants.

Neovascular eye diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration, threaten the visual health of children and adults. Current treatment options, including anti–vascular endothelial growth factor therapy and laser retinal photocoagulation, have limitations and are associated with adverse effects; therefore, the identification of additional therapies is highly desirable. Both clinical and experimental studies show that dietary ω-3 (n–3) long-chain polyunsaturated fatty acids (LC-PUFAs) reduce retinal and choroidal angiogenesis. The ω-3 LC-PUFA metabolites from 2 groups of enzymes, cyclooxygenases and lipoxygenases, inhibit [and the ω-6 (n–6) LC-PUFA metabolites promote] inflammation and angiogenesis. However, both of the ω-3 and the ω-6 lipid products of cytochrome P450 oxidase 2C promote neovascularization in both the retina and choroid, which suggests that inhibition of this pathway might be beneficial. This review summarizes our current understanding of the roles of ω-3 and ω-6 LC-PUFAs and their enzymatic metabolites in neovascular eye diseases.

Pathological neovessels growing into the normally avascular photoreceptors cause vision loss in many eye diseases. Sun et al. find that a master inflammatory regulator, c-Fos, in photoreceptor controls retinal blood vessel growth into the photoreceptors through the inflammatory signal–induced STAT3/VEGFA pathway., Pathological neovessels growing into the normally avascular photoreceptors cause vision loss in many eye diseases, such as age-related macular degeneration and macular telangiectasia. Ocular neovascularization is strongly associated with inflammation, but the source of inflammatory signals and the mechanisms by which these signals regulate the disruption of avascular privilege in photoreceptors are unknown. In this study, we found that c-Fos, a master inflammatory regulator, was increased in photoreceptors in a model of pathological blood vessels invading photoreceptors: the very low-density lipoprotein receptor–deficient (Vldlr−/−) mouse. Increased c-Fos induced inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor (TNF), leading to activation of signal transducer and activator of transcription 3 (STAT3) and increased TNFα–induced protein 3 (TNFAIP3) in Vldlr−/− photoreceptors. IL-6 activated the STAT3/vascular endothelial growth factor A (VEGFA) pathway directly, and elevated TNFAIP3 suppressed SOCS3 (suppressor of cytokine signaling 3)–activated STAT3/VEGFA indirectly. Inhibition of c-Fos using photoreceptor-specific AAV (adeno-associated virus)-hRK (human rhodopsin kinase)–sh_c-fos or a chemical inhibitor substantially reduced the pathological neovascularization and rescued visual function in Vldlr−/− mice. These findings suggested that the photoreceptor c-Fos controls blood vessel growth into the normally avascular photoreceptor layer through the inflammatory signal–induced STAT3/VEGFA pathway.