TRPV4 channels promote vascular permeability in retinal vascular disease.

This study aimed to determine the role of transient receptor potential vanilloid 4 (TRPV4), a calcium (Ca2+)-permeable cation channel, in the pathophysiology of retinal vascular disease. The retinal vein occlusion (RVO) murine model was created by irradiating retinal veins using lasers. TRPV4 expression and localization were evaluated in RVO mice retinas. In addition, we examined the effects of TRPV4 antagonists (RQ-00317310, HC-067047, GSK2193874, and GSK2798745) on retinal edema, blood flow, and ischemic areas in RVO mice. Furthermore, changes in the retinal expression of tumor necrosis factor (TNF)-α and aquaporin4 (AQP4) by RQ-00317310 were analyzed using Western blot. We also assessed the barrier integrity of epithelial cell monolayers using trans-endothelial electrical resistance (TEER) in Human Retinal Microvascular Endothelial Cells (HRMECs). The expression of TRPV4 was significantly increased and co-localized with glutamine synthetase (GS), a Müller glial marker, in the ganglion cell layer (GCL) of the RVO mice. Moreover, RQ-00317310 administration ameliorated the development of retinal edema and ischemia in RVO mice. In addition, the up regulation of TNF-α and down-regulation of AQP4 were lessened by the treatment with RQ-00317310. Treatment with GSK1016790A, a TRPV4 agonist, increased vascular permeability, while RQ-00317310 treatment decreased vascular endothelial growth factor (VEGF)- or TRPV4-induced retinal vascular hyperpermeability in HRMECs. These findings suggest that TRPV4 plays a role in the development of retinal edema and ischemia. Thus, TRPV4 could be a new therapeutic target against the pathological symptoms of retinal vascular diseases.

A novel model of subretinal edema induced by DL-alpha aminoadipic acid.

In this study we described a new model of subretinal edema induced by single intraocular injection of DL-alpha-aminoadipic acid (DLAAA) that can be employed to study the mechanism of retinal edema and test the efficacy or potential toxicity of treatments. The progression of subretinal edema was evaluated by fundus photography, fluorescein angiography and optical coherence tomography for up to 4 weeks following DLAAA injection. The VEGF, IL-6, TNF-α, Occludin, ZO-1, AQP4, Kir4.1, GFAP and GS levels were examined in DLAAA models by immunostaining, immumohistochemical staining and Western blot. Additionally, bulk RNA-seq was used to detect the mechanism involved in DLAAA-induced retinal Müller cellular injuries. In vivo and vitro assays were further conducted to confirm the sequencing results. Subretinal edema was successfully induced by DLAAA in New Zealand White rabbits (1.29 mg/eye) and C57BL/6 mice (50 or 100 µg/eye). Our results demonstrated that the disruption of blood-retinal-barrier, including vascular hyperpermeability, inflammation, and Müller cell dysfunction of fluid clearance, was involved in subretinal edema formation in the model. Bulk RNA-seq and in vitro studies indicated the activation of p38 MAPK signaling pathway in DLAAA models. This DLAAA-induced subretinal edema model can be used for mechanistic studies or drug screening.

Arctigenin Prevents Retinal Edema in a Murine Retinal Vein Occlusion Model.

Macular edema causes vision loss in patients with retinal vein occlusion (RVO) and diabetic macular edema (DME). The intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is used for treatment; however, this therapy is invasive, and recurrence occurs in some cases. The establishment of a non-invasive treatment would help to solve these problems. Here, we focused on arctigenin, a lignan polyphenol found in burdock sprout, and has effects on inflammatory and microcirculatory when taken orally. We hypothesized that oral intake of arctigenin could be effective against retinal edema in RVO and DME. In this study, the degree of retinal edema by measuring the total retinal thickness using optical coherence tomography (OCT) and the thickness of the inner nuclear layer (INL) by hematoxylin-eosin (H&E) staining were investigated. Oral administration of arctigenin ameliorated retinal edema in an RVO murine model by inhibiting the decrease in occludin and vascular endothelial (VE)-cadherin. Moreover, in retinas with edema, arctigenin suppressed the induction of VEGF, tumor necrosis factor α (TNFα), and matrix metallopeptidase 9 (MMP9). Next, the effects of arctigenin on barrier function were assessed in human retinal microvascular endothelial cells (HRMECs) by measuring the trans-endothelial electrical resistance (TEER) and conducting fluorescein isothiocyanate (FITC)-dextran permeability assays. Arctigenin showed a protective effect against VEGF-induced barrier dysfunction. In addition, arctigenin inhibited the TNFα-mediated activation of the nuclear factor-kappaB (NF-κB)/p38 mitogen-activated protein kinase (MAPK) pathway. These results suggested that oral administration of arctigenin has beneficial effects on retinal edema by inhibiting vascular hyperpermeability in endothelial cells.

Brolucizumab Intravitreal Injections for Wet Age-Related Macular Degeneration: Real-Life Study on a Cohort of Italian Patients.

Background and Objectives: To report the real-life Brolucizumab therapeutical outcomes of treatment-naïve and non-treatment-naïve eyes with neovascular age-related macular degeneration (nAMD) and to analyze the incidence of therapy-related adverse events. Materials and Methods: A total of 56 eyes of 54 patients diagnosed with nAMD were retrospectively evaluated over a 3-month follow-up. Naïve eyes received a 3-month loading phase, whereas non-naïve eyes were treated with one intravitreal injection + ProReNata scheme. The main outcome measures were best-corrected visual acuity (BCVA) and central retinal thickness (CRT) change. In addition, patients were stratified on the basis of fluid accumulation site, whether intra-retinal (IRF), sub-retinal (SRF), or sub-retinal pigmented epithelium (SRPE), to separately assess the eventual BCVA change in each subgroup. Finally, the incidence of ocular adverse events was evaluated. Results: In naïve eyes, a significant improvement of BCVA (LogMar) was observed at all timepoints from baseline (1 month-Mean Difference (MD): -0.13; 2 months MD: -0.17; 3 months MD: -0.24). In non-naïve eyes, a significant mean change was observed at all timepoints, with the exception of 1-month follow-up (2 months MD: -0.08; 3 months MD: -0.05). CRT significantly changed in both groups at all timepoints at a similar pace within the first two months, with naïve eyes displaying a larger overall thickness decrease at the end of the follow-up (Group 1 = MD: -123.91 µm; Group 2 = MD: -110.33 µm). With respect to the location of the edema, a significant BCVA change was observed in naïve patients with fluid in all three sites at the end of the follow-up (SRPE = MD: -0.13 (p = 0.043); SR = MD: -0.15 (p = 0.019); IR = MD: -0.19 (p = 0.041). Non-naïve patients exhibited significant mean BCVA changes only with respect to SR and IR fluid presence (SRPE = MD: -0.13 (p = 0.152); SR = MD: -0.15 (p = 0.007); IR = MD: -0.06 (p = 0.011). One naïve patient experienced acute-onset anterior and intermediate uveitis which completely resolved after therapy. Conclusions: Brolucizumab was demonstrated to be a safe and efficient alternative in improving both the anatomical and functional parameters of eyes with nAMD in this small, uncontrolled, series of patients.

TIM2 modulates retinal iron levels and is involved in blood-retinal barrier breakdown.

Careful control of iron availability in the retina is central to maintenance of iron homeostasis, as its imbalance is associated with oxidative stress and the progression of several retinopathies. Ferritin, known for its role in iron storage and detoxification, has also been proposed as an iron-transporter protein, through its binding to Scara5 and TIM2 membrane receptors. In this study, the presence and iron-related functions of TIM2 in the mouse retina were investigated. Our results revealed for the first time the presence of TIM2 receptors in the mouse retina, mainly in Müller cells. Experimental TIM2 downregulation in the mouse retina promoted, probably due to a compensatory mechanism, Scara5 overexpression that increased retinal ferritin uptake and induced iron overload. Consecutive reactive oxygen species (ROS) overproduction and vascular endothelial growth factor (VEGF) overexpression led to impaired paracellular and transcellular endothelial transport characterized by tight junction degradation and increased caveolae number. In consequence, blood-retinal barrier (BRB) breakdown and retinal edema were observed. Altogether, these results point to TIM2 as a new modulator of retinal iron homeostasis and as a potential target to counteract retinopathy.

RetFluidNet: Retinal Fluid Segmentation for SD-OCT Images Using Convolutional Neural Network.

Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness and is characterized by fluid-related accumulations such as intra-retinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED). Spectral-domain optical coherence tomography (SD-OCT) is the primary modality used to diagnose AMD, yet it does not have algorithms that directly detect and quantify the fluid. This work presents an improved convolutional neural network (CNN)-based architecture called RetFluidNet to segment three types of fluid abnormalities from SD-OCT images. The model assimilates different skip-connect operations and atrous spatial pyramid pooling (ASPP) to integrate multi-scale contextual information; thus, achieving the best performance. This work also investigates between consequential and comparatively inconsequential hyperparameters and skip-connect techniques for fluid segmentation from the SD-OCT image to indicate the starting choice for future related researches. RetFluidNet was trained and tested on SD-OCT images from 124 patients and achieved an accuracy of 80.05%, 92.74%, and 95.53% for IRF, PED, and SRF, respectively. RetFluidNet showed significant improvement over competitive works to be clinically applicable in reasonable accuracy and time efficiency. RetFluidNet is a fully automated method that can support early detection and follow-up of AMD.

microRNA-320a prevent Müller cells from hypoxia injury by targeting aquaporin-4.

Müller cells are closely related to diabetic retinopathy (DR). Aquaporin-4 (AQP4) can effectively promote the diffusion of water across cellular membranes. However, the dynamic balance of water plays key role in many diseases, such as cerebral edema. Meanwhile, the unusual expression and distribution of AQP4 in the retina are the significant causes of ocular hypertension and reperfusion injury. To explore the functional significance between microRNA-320a (miR-320a) and AQP4 in pathological hypoxia-induced DR related retinal edema, we hypothesized that miR-320a regulates AQP4 expression and internalization to relieve the edema of Müller cells under the pathological retinal hypoxia stress by targeting AQP4, thereby attenuate the damage of Müller cells. Results demonstrated that miR-320a mimics inhibited the expressions of AQP4 in Müller cells. Furthermore, overexpression miR-320a protected Müller cells by suppressing superoxide anion. In addition, overexpression miR-320a markedly attenuated hypoxia-induced injury, significantly increased the cell viability, and promoted the internalization of AQP4. Furthermore, miR-320a can also regulate the stable anchoring of AQP4 on the cell membrane. Our study indicated that miR-320a may be a potential modulator which can mediate AQP4 expression and attenuate the hypoxia damage of Müller cells. In conclusion, miR-320a may be a potential target for DR therapy by targeting AQP4.

Longitudinal evaluation of immediate inflammatory responses after intravitreal AAV2 injection in rats by optical coherence tomography.

Gene therapy has been proposed as a feasible strategy for RGC survival and optic nerve regeneration. Some preclinical and clinical studies revealed intraocular inflammation after intravitreal injection of adeno-associated virus (AAV) by slit-lamp or indirect ophthalmoscope. Here we evaluate the longitudinal profile of immediate inflammatory responses after AAV2 injection in rat retina and vitreous body by optical coherence tomography (OCT). Adult Fischer F344 rats were intravitreally injected once with saline, AAV2 or zymosan. Retinal thickness and cell infiltration were recorded by OCT longitudinally for 2 months and verified by histological analysis. The transduction rate of single intravitreal AAV2 injection was 21.3 ± 4.9% of whole retina, and the transduction efficiency on RGCs was 91.5 ± 2.5% in the transduced area. Significant increase in cell infiltration was observed from Day 1-3 after AAV2 injection, compared to very few infiltrating cells observed in the saline-injected group. The infiltrating cells ceased at Day 5 after intravitreal injection and remained absent at 2 months. The thicknesses of total and inner retina were increased along Day 1-3 after AAV2 injection, but reverted to normal afterwards. The surviving RGCs in the AAV2-injected groups at Day 14 showed no significant difference compared to saline-injected group. In summary, this study revealed the immediate inflammatory responses and retinal edema after intravitreal AAV2 injection in normal rats, without influencing long-term retinal thickness and RGC survival. OCT can be implemented for the time-lapse in vivo evaluation of inflammatory response after AAV-mediated gene therapy through intravitreal injection.

Investigation of the therapeutic mechanism of subthreshold micropulse laser irradiation in retina.

PURPOSE: Subthreshold micropulse laser irradiation has been used for the treatment of retinal edema; however, there are few reports about the mechanism of its therapeutic effect. In this study, we compared threshold short pulse and subthreshold micropulse laser irradiation in mice and investigated their mechanism. METHODS: Nine to 12-week-old male C57BL/6J mice were used in this study. After general anesthesia, threshold short pulse or subthreshold micropulse laser irradiation was performed on the right eye using IQ577. Enucleation was performed 24 h after the laser irradiation, and histological and gene expression analyses were carried out. RESULTS: Coagulation spots and atrophy of the retinal pigment epithelium were observed after threshold short pulse laser irradiation but not after subthreshold micropulse laser irradiation. Twenty-four hours after laser, aquaporin (AQP) 1, 2, 7, and 11 levels were significantly elevated by 1.7- to 3-fold in the threshold short pulse laser group compared with non-treated control group. AQP 3 was increased significantly and prominently by 100-fold. VEGF-A and VEGFR2 were upregulated 1.5- and 2.3-fold, respectively. In the subthreshold micropulse laser group, AQP 3 was increased by 6-fold compared with the non-treated control group. Angiopoietin-1 and the adrenomedullin (AM) receptor CLR were decreased by 0.6-fold and 0.5-fold, respectively. CONCLUSION: Threshold short pulse laser irradiation caused retinal damage and prominent changes in the expression of various genes. Contrarily, subthreshold micropulse laser irradiation did not induce retinal damage; it upregulated AQP 3, which might have improved retinal edema by drainage of subretinal fluid.

Triamcinolone acetonide-chitosan coated liposomes efficiently treated retinal edema as eye drops.

Macular edema (ME), which is present in various retinal diseases, leads to permanent retinal structural damage and threatens vision. The intravitreal/periocular injection of triamcinolone acetonide (TA) can improve the prognosis of ME; however, further exploration of noninvasive delivery systems is essential. Therefore, as a continuation of our previous study using TA-chitosan coated liposomes (TA-CHLs) as a topical drug delivery system, the present study aimed to determine the drug safety, stability, permeability, and bioavailability of TA-CHLs. The study was based on detecting the delivery of a fluorescent dye to the retina using optical coherence tomography angiography in rats. Marked cellular uptake was observed in cell lines. TA-CHL toxicity was investigated in cell culture. Clinical ocular safety was evaluated by measuring the corneal thickness and intraocular pressure. In preclinical studies on a laser-induced retinal edema rat model, the TA-CHL eye drops had dramatic therapeutic effect in remission of retinal edema over 10 days. These results demonstrated that TA-CHL was nontoxic and had good bioavailability in vitro and in vivo. The results of the present study indicated that this formulation could be an effective therapeutic approach and the TA-CHL eye drops may represent a new option for retinal diseases.

Implication of VEGF and aquaporin 4 mediating Müller cell swelling to diabetic retinal edema.

PURPOSE: Aquaporin 4 (AQP4), a water channel protein, is known to be expressed in retinal Müller cells. The purpose of this study was to determine the effects of VEGF and AQP4 channels on the volumetric changes in Müller cells. METHODS: Retinas from diabetic rats and a cultured Müller cell line, TR-MUL5, were used in this study. Intravitreal injections of VEGF or PBS were performed on either streptozotocin (STZ)-induced diabetic or normoglycemic rats. Retinal sections were immunostained for anti-glial fibrillary acidic protein (GFAP), anti-AQP4, and anti-VEGF. VEGF protein levels from collected retinas were determined by western blot analysis. Volumetric changes and nitric oxide (NO) levels in cultured Müller cells were determined using flow cytometry (FACS), in the presence or absence of VEGF and TGN-020, a selective AQP4 inhibitor. RESULTS: In the diabetic rat retina, VEGF immunoreactivity was concentrated in the internal retinal layers, and AQP4 immunoreactivity was higher than controls. The expressions of AQP4 were colocalized with GFAP. Protein levels of VEGF in the hyperglycemic rat retina were significantly higher than controls. FACS analyses showed that exposure to VEGF enlarged Müller cells, while exposure to TGN-020 suppressed the enlargement. Intracellular levels of NO were increased after exposure to VEGF, which was suppressed following the addition of TGN-020. CONCLUSION: The observed Müller cell swelling is mediated by VEGF and AQP4.

Exudative vascular anomalous complex-like lesion of the peripapillary area.

PURPOSE: Perifoveal exudative vascular anomalous complex is an uncommon retinal lesion of idiopathic origin characteristically described as an isolated, aneurysmal lesion of the perifoveal region. We report an unusual presentation of an exudative vascular anomalous complex-like lesion affecting the peripapillary area. CASE DESCRIPTION: A 69-year-old diabetic woman presented with blurred vision in her left eye for two months. Fundus examination of the left eye showed a small, reddish-orange lesion just supratemporal to the optic disc with perifoveal hard exudates and retinal thickening. Fundus fluorescein angiography demonstrated a peripapillary hyperfluorescent lesion with minimal leakage. Ocular coherence tomography showed an oval structure extending throughout the outer and inner plexiform and nuclear layers with a hyper-reflective wall accompanied by subfoveal and intraretinal fluid suggestive of an eVAC-like lesion in the peripapillary area. Intravitreal anti-vascular endothelial growth factor injection was given, and the lesion persisted even three weeks after the injection. Later, focal laser photocoagulation of the aneurysmal lesion was done. At 6 weeks follow-up, a complete resolution of the aneurysmal lesion with a marked decrease in retinal edema and an improvement of the visual acuity was observed. CONCLUSION: Exudative intraretinal aneurysmal lesions can occur in areas other than perifoveal area. OCT is an useful investigation for knowing their characteristics and the response to treatment. These aneurysmal lesions irrespective of their location can be called by the name eVAC-like or more aptly retinal capillary macro aneurysms (RCM).

Exploring the mechanism of Bushen Huoxue prescription in the treatment of early diabetic retinal edema from the perspective of inner blood-retinal barrier injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic retinopathy (DR) is one of the most severe complications of diabetes mellitus, diabetes belongs to the category of "emaciation-thirst disease" in traditional Chinese medicine (TCM). Bushen Huoxue Prescription (BHP) is composed of traditional Chinese materia medica, which has therapeutic effects on DR and early diabetic retinal edema (EDRE). However, the therapeutic mechanism is unclear. AIM OF THE STUDY: Exploring the mechanism of BHP against EDRE. METHODS: Feeding Sprague Dawley (SD) rats a high-fat, high-sugar diet as well as providing intraperitoneal injections of streptozotocin (STZ) to promote inner blood-retinal barrier (iBRB) damage that can trigger EDRE, evaluating the therapeutic effect of BHP by the level of expressiveness of TJ proteins (ZO-1,Occludin) of the iBRB and the leakage of rhodamine B isothiocyanate (RITC) in the retina. The combination of network pharmacology and metabolomics was employed to study the mechanism of BHP in preventing of EDRE, then four proteins which were closely to the damage of iBRB were chosen for the validation by employing Western Blot (WB). RESULTS: Research of network pharmacology had shown that BHP had efficacy against EDRE by regulating targets such as AKT1, ALB, TNF, PPARG, etc, its potential pathways mainly involving signaling pathways such as HIF-1. In untargeted metabolomics analysis of serum, 15 differential metabolites were identified, with the metabolic pathways focusing on ketone body metabolism and synthesis, sphingolipid metabolism and phenylalanine metabolism. The conclusions of metabolomics and network pharmacology revealed that BHP can treat EDRE by alleviating hypoxia and oxidative stress and exerting protection of the iBRB. Finally, BHP's protection behavior of the iBRB was validated by WB experiments. CONCLUSION: Through integrating pharmacodynamics, network pharmacology and metabolomics, BHP was discovered to have a crucial function in EDRE therapy by preserving the integrity of iBRB. This comprehensive strategy also provided a reasonable way to reveal the multi-components, multi-targets, multi-pathways mechanism of TCM.

Severe retinal hemorrhages at various levels with a serous retinal detachment in a pediatric patient with aplastic anemia-A case report.

Background: Aplastic anemia can cause ophthalmic abnormalities in patients. Vision loss in a child with aplastic anemia due to massive retinal hemorrhages at various levels is rare. Case presentation: A pediatric patient with aplastic anemia presented with retinal hemorrhages at multiple levels along with a serous retinal detachment in both eyes and subsequent retinal changes after pars plana vitrectomy. Conclusion: Anemia and thrombocytopenia in aplastic anemia could cause severe retinal hemorrhages and result in retinal atrophy and retinal edema. Vitrectomy can be performed to remove vitreous hemorrhage, but risk factors for retinal atrophy and edema need further investigation.

Longitudinal changes in peri-papillary retinal nerve fiber layer thickness in patients with unilateral branch retinal vein occlusion.

Background: Associations between retinal venous occlusion (RVO), elevated intraocular pressure, and glaucoma have been reported. Further investigations into structural alterations in the fellow eyes of individuals with unilateral RVO have revealed that the peripapillary retinal nerve fiber layer is thinner than in healthy eyes, suggesting that there may be systemic risk factors common to both RVO and glaucoma. We aimed to evaluate changes in peripapillary retinal nerve fiber layer thickness (pRNFLT) among individuals with unilateral branch retinal vein occlusion (BRVO). Methods: This prospective observational study recruited 30 individuals (60 eyes) with newly diagnosed unilateral BRVO and macular edema, and a control group of 30 healthy individuals (30 eyes) with no abnormalities on fundus examination or concurrent systemic comorbidities. After baseline measurements, the participants were reassessed at 6, 12, and 24 months by measuring global and sectoral pRNFLT using spectral-domain optical coherence tomography. Results: The mean age and sex distributions were comparable between the patient and control groups (both P > 0.05). When compared to fellow eyes, global and sectoral pRNFLT in eyes with BRVO were significantly higher at baseline (all P < 0.05). Over time, pRNFLT decreased dramatically, and by the conclusion of the two-year follow-up, there was a significant reduction from baseline in the affected eyes (all P < 0.05). Likewise, affected eyes experienced a significant improvement in best-corrected distance visual acuity and central macular thickness over the two-year follow-up (both P ≤ 0.001). Comparing the global and all-sector pRNFLT of fellow eyes in the patient group with those of normal eyes in the control group, there were no significant differences at any visit, except in the temporal sector, which revealed a significant reduction in pRNFLT at 24 months in the fellow eyes of patients with unilateral BRVO (P = 0.02). Conclusions: Patients with unilateral BRVO experienced a significant reduction in pRNFLT in the affected eyes and, to a lesser extent, in the fellow eyes, compared with that of the control arm, suggesting that they are prone to retinal nerve fiber layer damage. The reduction in pRNFLT in the normal fellow eyes of patients with BRVO may be attributed to age or concurrent systemic comorbidities. Further studies with long follow-up periods are required to shed light on the etiology of functional and structural changes in both the retinal nerve fiber layer and ganglion cell complex in the normal and affected eyes of patients with unilateral BRVO.

Ocular Injuries in Pediatric Patients Admitted With Abusive Head Trauma.

BACKGROUND: Pediatric abusive head trauma (AHT) refers to head injury from intentional blunt force or violent shaking in children aged five years or less. We sought to evaluate the epidemiology of ocular injuries in AHT. METHODS: This retrospective analysis of the National Trauma Data Bank (2008 to 2014) identified children aged five years or less with AHT and ocular injuries using ICD-9-CM codes. Demographic data, types of ocular and nonocular/head injuries, geographic location, length of hospital admission, injury severity, and Glasgow Coma scores were tabulated and analyzed. RESULTS: A total of 10,545 children were admitted with AHT, and 2550 (24.2%) had associated ocular injuries; 58.7% were female. The mean age was 0.5 (±1.0) years. Most (85.7%) were aged one year or less. Common ocular injuries included contusion of eye/adnexa (73.7%) and retinal edema (59.3%), and common head injuries were subdural hemorrhage (SDH) (72.8%) and subarachnoid hemorrhage (22.9%). Retinal hemorrhages occurred in 5.3%. About 42.8% of children had injury severity scores greater than 24 (very severe), and the mortality rate was 19.2%. Children aged one year or less had the greatest odds of retinal hemorrhages (odds ratio [OR] = 2.44; P = 0.008) and SDH (OR = 1.55; P < 0.001), and the two- to three-year-old group had the greatest odds of contusions (OR = 1.68; P = 0.001), intracerebral hemorrhages (OR = 1.55; P = 0.002), and mortality (OR = 1.78; P < 0.001). For all ages, SDH occurred most frequently with retinal edema compared with other ocular injuries (OR = 2.25; P < 0.001). CONCLUSIONS AND RELEVANCE: Ocular injuries varied with age and were variably associated with nonocular injury. The youngest group was most frequently affected; however, the two- to three-year-old group was most likely to succumb to injuries.

Long-Term Oral Treatment with Non-Hypoglycemic Dose of Glibenclamide Reduces Diabetic Retinopathy Damage in the Goto-KakizakiRat Model.

Diabetic retinopathy (DR) remains a major cause of vision loss, due to macular edema, retinal ischemia and death of retinal neurons. We previously demonstrated that acute administration of glibenclamide into the vitreous, or given orally at a non-hypoglycemic dose, protected the structure and the function of the retina in three animal models that each mimic aspects of diabetic retinopathy in humans. In this pilot study, we investigated whether one year of chronic oral glibenclamide, in a non-hypoglycemic regimen (Amglidia®, 0.4 mg/kg, Ammtek/Nordic Pharma, 5 d/week), could alleviate the retinopathy that develops in the Goto-Kakizaki (GK) rat. In vivo, retinal function was assessed by electroretinography (ERG), retinal thickness by optical coherence tomography (OCT) and retinal perfusion by fluorescein and indocyanin green angiographies. The integrity of the retinal pigment epithelium (RPE) that constitutes the outer retinal barrier was evaluated by quantitative analysis of the RPE morphology on flat-mounted fundus ex vivo. Oral glibenclamide did not significantly reduce the Hb1Ac levels but still improved retinal function, as witnessed by the reduction in scotopic implicit times, limited diabetes-induced neuroretinal thickening and the extension of ischemic areas, and it improved the capillary coverage. These results indicate that low doses of oral glibenclamide could still be beneficial for the prevention of type 2 diabetic retinopathy. Whether the retinas ofpatients treated specifically with glibenclamideare less at risk of developing diabetic complications remains to be demonstrated.

Optical coherence tomography-based determination of ischaemia onset - the temporal dynamics of retinal thickness increase in acute central retinal artery occlusion.

PURPOSE: Acute central retinal artery occlusion (CRAO) induces ischaemic retinal oedema. The purpose of this study was to define sensitivity and specificity of optical coherence tomography (OCT) based retinal thickness analysis in determining ischaemia onset in CRAO. METHODS: The relative retinal thickness increase (RRTI) in comparison with the fellow eye was analysed retrospectively in OCT scans of 66 patients diagnosed with CRAO between January 2010 and December 2019 within 48 hr of ischaemia onset. The natural course of RRTI and the sensitivity and specificity of OCT-based determination of ischaemia onset in identifying CRAO within 4.5 hr using the RRTI were evaluated. RESULTS: Relative retinal thickness increase (RRTI) in acute CRAO follows a hyperbolic curve with a steep incline within the early phase after which it reaches a plateau. Optical coherence tomography (OCT)-based retinal thickness analysis in CRAO allows to differentiate patients with ischaemia onset within the past 4.5 hr or thereafter with a sensitivity of 100% and a specificity of 94.3%. CONCLUSION: Relative retinal thickness increase (RRTI) allows to identify CRAO patients that are eligible for a potentially beneficial reperfusion therapy within a therapeutic window of 4.5 hr with a high accuracy. Especially in patients with unknown ischaemia onset, this diagnostic tool could be of major importance in the future clinical management.

Intravitreal Aflibercept versus Ranibizumab for Diabetic Macular Edema in a Taiwanese Health Service Setting.

Purpose: To compare the visual and anatomical outcomes between intravitreal aflibercept and ranibizumab for diabetic macular edemaMethods: A total of 194 eyes from 194 patients (aflibercept n = 95, ranibizumab n = 99) were retrospectively enrolled in the study. All eyes fulfilled the key criteria including a baseline best-corrected visual acuity (BCVA) between 20 and 70 ETDRS letters, a central subfield thickness (CST) 300 µm or more. Primary outcomes were BCVA and CST at 1, 3, 6, and 12 months. Maintenance of vision was defined as visual loss of less than 5 letters over 6 to 12 months. Predictors for final visual acuity and visual maintenance were analyzed using multivariate regression models.Results: Both agents achieved comparable visual and anatomical outcomes at any time point over the course of follow-up (all p > .05). At 12 months, aflibercept group had higher proportions of visual gains 5, 10 and 15 letters or more (p = .014, p = .011, and p = .034, respectively). The mean number of injections was 5.0 ± 1.9 in ranibizumab group and 4.5 ± 1.9 in aflibercept group (p = .09). Ranibizumab predicted poor maintenance of vision (p = .009), but not the final visual acuity (univariate p = .1). Ranibizumab was more likely to have recurrence of subretinal fluid than aflibercept in 12 months after resolution of subretinal fluid at baseline (p = .016). Both aflibercept and ranibizumab had similar rates of loss to follow-up (p = .47) and occurrence of vitreous hemorrhage (p = .21).Conclusion: While both agents improved vision with resolution of edema, aflibercept maintained vision more effectively with less recurrence of subretinal fluid at 12 months in real-world settings.

Topical sustained drug delivery to the retina with a drug-eluting contact lens.

Intravitreal injections and implants are used to deliver drugs to the retina because therapeutic levels of these medications cannot be provided by topical administration (i.e. eye drops). In order to reach the retina, a topically applied drug encounters tear dilution, reflex blinking, and rapid fluid drainage that collectively reduce the drug's residence time on the ocular surface. Residing under the tears, the cornea is the primary gateway into the eye for many topical ophthalmic drugs. We hypothesized that a drug-eluting contact lens that rests on the cornea would therefore be well-suited for delivering drugs to the eye including the retina. We developed a contact lens based dexamethasone delivery system (Dex-DS) that achieved sustained drug delivery to the retina at therapeutic levels. Dex-DS consists of a dexamethasone-polymer film encapsulated inside a contact lens. Rabbits wearing Dex-DS achieved retinal drug concentrations that were 200 times greater than those from intensive (hourly) dexamethasone drops. Conversely, Dex-DS demonstrated lower systemic (blood serum) dexamethasone concentrations. In an efficacy study in rabbits, Dex-DS successfully inhibited retinal vascular leakage induced by intravitreal injection of vascular endothelial growth factor (VEGF). Dex-DS was found to be safe in a four-week repeated dose biocompatibility study in healthy rabbits.