Search

Background and Objectives : Faricimab is a vascular endothelial growth factor A and angiopoietin-2 bispecific antibody. It is a novel therapeutic approach distinct from previous anti-vascular endothelial growth factor agents. This study aimed to evaluate the efficacy of switching from aflibercept to faricimab in the treatment of diabetic macular edema (DME) refractory to aflibercept, with a specific focus on the resolution of macular edema. Materials and Methods : The medical records of 29 eyes of 21 patients with DME that were refractory to intravitreal injections of aflibercept (IVAs) and who had completed the clinical follow-up of at least four intravitreal injections of faricimab (IVFs) were reviewed. The central retinal thickness (CRT), best-corrected visual acuity (BCVA), and the mean period (weeks) until the next injection were measured after the second-to-last IVA, first-to-last IVA, last IVA, and first to fourth IVFs following the transition to IVF. Results : The mean time from the first IVF to the assessment of effectiveness was significantly shorter than the time to the last IVA; however, no significant difference was found in the time from the second, third, and fourth IVFs to the assessment. The mean CRTs after the first and second IVFs were not significantly different from the CRT after the last IVA, but the mean CRT after the third and fourth IVFs was significantly thinner than that after the last IVA ( p = 0.0025 and p = 0.0076, respectively). The mean BCVAs after the third and fourth IVFs significantly improved compared with that after the last IVA ( p = 0.0050 and p = 0.0052, respectively). Conclusions : When switching the treatment to IVF for eyes with IVA-resistant DME, better treatment outcomes are achieved if IVF is performed three or more times.

Purpose: To assess the impact of intravitreal injections (IVTI) on ocular surface of patients treated with multiple injections., Methods: Prospective, tricentric study conducted in patients treated with unilateral IVTI. An asepsis protocol with povidone-iodine was used for all patients during IVTI. The primary endpoint was the difference between the pre-IVTI Ocular Surface Disease Index (OSDI 1) score and that measured on day one (D1) post-IVTI (OSDI 2). Secondary endpoints were the evaluation of predictive factors for OSDI scores, pain assessment on D1, and the Lacrydiag® analysis of tears from the injected eye versus contralateral eye before IVTI., Results: Two hundred and nineteen patients with a mean age of 75.9 ± 10 years were included. The mean OSDI2-OSDI1 difference was 19.2 ± 20.6 (p < 0.001). The mean noninvasive tear break-up time was 6.41 ± 4.59 seconds in the injected eye versus 7.36 ± 4.36 seconds in the contralateral eye (p < 0.001). In the multivariate analysis, the factors significantly associated with the OSDI 2 score were the OSDI 1 score (p < 0.001), the pain score on D1 (p < 0.001) the number of instilled glaucoma eye drop (p = 0.01) and a centre effect (centres 2 and 3 versus centre 1, p < 0.001)., Conclusion: Our results confirm the impairment of the ocular surface and quality of life immediately after an IVTI. These results suggest 3 levels of action to improve the immediate tolerance: improving the basal status of the ocular surface, reducing the contact time with povidone-iodine that might be toxic to the surface, and improving immediate post-IVTI treatment., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Objective: Vascular endothelial growth factor (VEGF) antagonists have been used for treating metastatic neoplasms. It has also been known that one of its side effects is to cause proteinuria and renal failure in the setting of thrombotic microangiopathy (TMA). The underlying mechanism is likely due to the inhibition of VEGF production in podocytes, resulting in diffuse fusion of foot processes and impaired glomerular endothelial fenestrations, and leading to massive proteinuria and subsequent glomerular endothelium injury. Intravitreal injection of VEGF antagonists (IIVA) has been also used to treat macular degeneration and diabetic retinal neo-vascular proliferation. The majority of patients tolerate the treatment well. However, IIVA can lead to renal dysfunction including proteinuria and gradual renal failure as a rare side effect. The goal of this study was to report two cases related to the nephrotoxicity of IIVA and review the literature associated with this topic., Case Report: The first diabetic patient had elevated serum creatinine at 3.25 mg/dl and proteinuria/creatinine ratio at 6.1 after 48-month treatment of IIVA. The first renal biopsy revealed thrombotic microangiopathy that was correlated with his increased serum creatinine and nephrotic range of proteinuria. The second diabetic patient had increased serum creatinine up to 1.89 mg/dl but low proteinuria. The second biopsy showed acute tubular necrosis that was correlated with his elevated serum creatinine., Conclusion: Intravitreal injection of VEGF antagonist can be associated with thrombotic microangiopathy and acute tubular necrosis, leading to renal dysfunction., (© 2021 by the Association of Clinical Scientists, Inc.)

Background: Eye trauma is an unfortunate and often preventable cause of vision loss. Confetti cannons are common causes of injury. Awareness of ocular hazards of confetti cannons remains low because of limited reports describing ophthalmic injuries following their use., Objectives: To describe outcomes of ocular trauma caused by confetti cannons and to increase recognition of their ocular risks., Methods: A retrospective analysis was conducted of eye injuries caused by confetti cannons presenting to a single medical center between 2016 and 2020. Data collected included age, gender, eye injured, ocular damage, visual outcome, and details of surgeries performed., Results: Overall, six consecutive patients (2 males, mean age 19.5 ± 9.74 years) were identified and studied. In all patients only one eye was injured (3 right eyes) during a private celebration, most commonly (n=5) to a bystander while in the vicinity of a cannon operated by someone else. Most common eye injuries included corneal erosion (n=4), traumatic hyphema (n=4), and retinal edema (n=3). Mean initial logMAR visual acuity in the injured eye was 0.73 ± 0.18, improving to 0.25 ± 0.16 at the final visit (P = 0.125). Two patients underwent eye surgery due to their trauma: one to repair globe penetration and another to undergo intravitreal injection of tissue plasminogen activator and C3F8 for submacular hemorrhage, followed 8 months later by intravitreal bevacizumab injection for choroidal neovascularization., Conclusions: Confetti cannons pose hazards that can cause severe ocular trauma resulting in permanent vision loss. Increasing awareness of device hazards is necessary to prevent eye injuries.

The Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented disruption to the normal operation of the healthcare system. On a worldwide scale, hospitals suspended nonurgent surgeries and outpatient visits to downsize clinical loadings to redistribute manpower to counteract the pandemic's impact. So far, there is no evidence-based guideline defining a clear line between urgent and nonurgent indications of intravitreal injections (IVI). Herein, we aimed to summarize IVI algorithm modifications and discuss the patient prioritization according to medical needs in the hostile environment in the COVID crisis. Assessing current literature, we found that neovascular age-related macular degeneration is considered the utmost priority among conditions that require IVI. Other conditions assigned with a high priority include monocular or quasi-monocular patients (only one eye > 20/40), neovascular glaucoma, and new patients with significant vision loss. Although patients with central retinal vein occlusion and proliferative diabetic retinopathy are not advised to delay treatments, we found no consistent evidence that correlated with a worse outcome. Diabetic macular edema and branch retinal vein occlusion patients undertaking treatment delay should be regularly followed up every 2 to 3 months. Serving as the principle of management behind the algorithm modifications, the reduction of both patient visit and IVI therapy counts should be reckoned together with the risk of permanent visual loss and COVID infection., Competing Interests: Conflicts of interest: Dr. Shih-Hwa Chiou, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Age-related macular degeneration (AMD) is a worldwide leading cause of blindness affecting individuals over 50 years old. The most aggressive form, wet AMD, is characterized by choroidal neovascularization (CNV) and inflammation involving microglia recruitment. By using a laser-induced CNV mouse model, we provide evidence for a key role played by miR-142-3p during CNV formation. MiR-142-3p was overexpressed in murine CNV lesions and its pharmacological inhibition decreased vascular and microglia densities by 46% and 30%, respectively. Consistently, miR-142-3p overexpression with mimics resulted in an increase of 136% and 126% of blood vessels and microglia recruitment. Interestingly, miR-142-3p expression was linked to the activation state of mouse microglia cells as determined by morphological analysis (cell solidity) through a computational method. In vitro , miR-142-3p overexpression in human microglia cells (HMC3) modulated microglia activation, as shown by CD68 levels. Interestingly, miR142-3p modulation also regulated the production of VEGF-A, the main pro-angiogenic factor. Together, these data strongly support the unprecedented importance of miR-142-3p-dependent vascular-inflammation axis during CNV progression, through microglia activation.

To investigate the influence of age on the function and morphology of patients with myopic choroidal neovascularization (mCNV) and to evaluate the effect and prognostic factors of recurrence of Conbercept treatment on mCNV patients over 50 years. A total of 64 patients (64 eyes) with mCNV were enrolled in this retrospective study. The differences in baseline best-corrected visual acuity (BCVA) and morphological features on imaging between the younger group (˂ 50 years) and the older group (≥ 50 years) were analyzed. Of all, 21 eyes of 21 mCNV patients aged over 50 years who received Conbercept injection were further analyzed. Between the younger and the older group, significant differences were shown in mean BCVA (0.58 ± 0.28 vs 0.77 ± 0.31), subfoveal choroidal thickness (SFCT) (108.17 ± 78.32 μm vs 54.68 ± 39.03 μm) and frequency of vitreoretinal interface abnormalities (VIA) (2 vs 13), respectively (P < 0.05). After treated with Conbercept, the mean BCVA of 21 older mCNV patients increased from 0.83 ± 0.30 at baseline to 0.49 ± 0.24 at one year. Baseline BCVA, external limiting membrane damage, CNV area and CNV location correlated with the visual acuity at the 1-year follow-up. There were 7 (33.3%) recurrent cases during the follow-up and the risk of recurrence in patients with baseline central macular thickness (CMT) ≥ 262.86 μm was 14 times greater than that of patients with CMT < 262.86 μm. The risk of recurrence increased 1.84 times for every 100-μm increment in the CMT. Patients over 50 years with mCNV had a worse BCVA, thinner choroid, and higher risk of VIA than young mCNV patients. The standard Conbercept treatment strategy was safe and effective in mCNV patients over 50 years. As patients over 50 years with a greater CMT have a high risk of recurrence, more attention should be paid on these patients by following them up closely.

Age-related macular degeneration (AMD) is a leading cause of visual impairment. Anti-vascular endothelial growth factor drugs used to treat AMD carry the risk of inducing subretinal fibrosis. We investigated the use of adrenomedullin (AM), a vasoactive peptide, and its receptor activity-modifying protein 2, RAMP2, which regulate vascular homeostasis and suppress fibrosis. The therapeutic potential of the AM-RAMP2 system was evaluated after laser-induced choroidal neovascularization (LI-CNV), a mouse model of AMD. Neovascular formation, subretinal fibrosis, and macrophage invasion were all enhanced in both AM and RAMP2 knockout mice compared with those in wild-type mice. These pathologic changes were suppressed by intravitreal injection of AM. Comprehensive gene expression analysis of the choroid after LI-CNV with or without AM administration revealed that fibrosis-related molecules, including Tgfb, Cxcr4, Ccn2, and Thbs1, were all down-regulated by AM. In retinal pigment epithelial cells, co-administration of transforming growth factor-β and tumor necrosis factor-α induced epithelial-mesenchymal transition, which was also prevented by AM. Finally, transforming growth factor-β and C-X-C chemokine receptor type 4 (CXCR4) inhibitors eliminated the difference in subretinal fibrosis between RAMP2 knockout and wild-type mice. These findings suggest the AM-RAMP2 system suppresses subretinal fibrosis in LI-CNV by suppressing epithelial-mesenchymal transition., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Pathological angiogenesis is the hallmark of many vision-threatening diseases. Anti-VEGF is a primary treatment with substantial beneficial effects. However, such agents require frequent intravitreal injections. Our previous work established a method for effectively modifying exosomes (EXOs) for loading therapeutic peptides. Here, we used this system to load the anti-angiogenic peptide KV11, aiming to establish an EXO-based therapy strategy to suppress neovascularization in the retina. Methods: Using an anchoring peptide, CP05, we linked KV11 to endothelial cell (EC) derived EXOs, yielding EXO KV11 . We tested the delivery efficiency of EXO KV11 via two commonly used ocular injection methods: retro-orbital injection and intravitreal injection. Deploying an oxygen-induced retinopathy (OIR) model and a VEGF injection model, we tested the effects of EXO KV11 on neovascular formation, EC proliferation, and vascular permeability. In vitro experiments were used to test the mechanism and to analyze the effects of EXO KV11 on EC proliferation, migration, and sprouting. Results : By using the EXO loading system, KV11 was more efficiently delivered to the blood vessels of the mouse retina via retro-orbital injection. In both OIR model and VEGF injection model, EXO KV11 was more effective than KV11 alone in inhibiting neovascularization and vessel leakage. The therapeutic effect of retro-orbital injection of EXO KV11 was comparable to the intravitreal injection of VEGF-trap. Mechanistically, KV11 alone inhibited VEGF-downstream signaling, while EXO KV11 showed a stronger effect. Conclusions: We used EXOs as a carrier for intraocular delivery of KV11. We showed that KV11 itself has an anti-angiogenic effect through retro-orbital injection, but that this effect was greatly enhanced when delivered with EXOs. Thus, this system has the potential to treat proliferative retinopathy via retro-orbital injection which is a less invasive manner compared with intravitreal injection., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

To evaluate the effects of intravitreal ranibizumab injection (IVR) on metamorphopsia in patients with branch retinal vein occlusion (BRVO), and to assess the relationship between metamorphopsia and inner retinal microstructure and other factors. Thirty-three treatment-naïve eyes of 33 patients with macular edema caused by BRVO with at least 12 months of follow-up were included. The degree of metamorphopsia was quantified using the M-CHARTS. Retinal microstructure was assessed with spectral-domain optical coherence tomography. Disorganization of the retinal inner layers (DRIL) at the first month after resolution of the macular edema (early DRIL) and at 12 months after treatment (after DRIL) was studied. Central retinal thickness (CRT), and status of the external limiting membrane as well as ellipsoid zone were also evaluated. IVR treatment significantly improved best-corrected visual acuity (BCVA) and CRT, but the mean metamorphopsia score did not improve even after 12 months. Post-treatment metamorphopsia scores showed a significant correlation with pre-treatment metamorphopsia scores (P < 0.005), the extent of early DRIL (P < 0.05) and after DRIL (P < 0.05), and the number of injections (P < 0.05). Multivariate analysis revealed that the post-treatment mean metamorphopsia score was significantly correlated with the pre-treatment mean metamorphopsia score (P < 0.05). IVR treatment significantly improved BCVA and CRT, but not metamorphopsia. Post-treatment metamorphopsia scores were significantly associated with pre-treatment metamorphopsia scores, the extent of DRIL, and the number of injections. Prognostic factor of metamorphopsia was the degree of pre-treatment metamorphopsia.

Background: Previous studies noted that intravitreal injection of S100B triggered a glaucoma-like degeneration of retina and optic nerve as well as microglia activation after 14 days. The precise role of microglia in our intravitreal S100B model is still unclear. Hence, microglia were inhibited through minocycline. The aim is to investigate whether microglia have a significant influence on the degeneration process or whether they are only a side effect in the model studied here., Methods: Minocycline was applied daily in rats by intraperitoneal injection using two different concentrations (13.5 mg/kg body weight, 25 mg/kg body weight). One day after treatment start, S100B or PBS was intravitreally injected in one eye per rat. The naïve groups received no injections. This resulted in a total of five groups (naïve n = 14, PBS n = 14, S100B n = 13, 13.5 mg/kg mino n = 15, 25 mg/kg mino n = 15). At day 14, electroretinogram measurements were performed, followed by immunofluorescence and label-free quantitative proteomics analysis. The focus of these investigations was on the survival of RGCs as well as their axons, the response of the microglia, and the identification of further pathological modes of action of S100B., Results: The best signal transmission was detected via ERG in the 13.5 mg/kg mino group. The inhibition of the microglia protected optic nerve neurofilaments and decreased the negative impact of S100B on RGCs. However, the minocycline treatment could not trigger complete protection of RGCs. Furthermore, in retina and optic nerve, the minocycline treatment reduced the number and activity of S100B-triggered microglia in a concentration-dependent manner. Proteomics analysis showed that S100B application led to numerous metabolic functions and cellular stress, mainly an increased inflammatory response, glycolysis, and mitochondrial dysfunction, which caused oxidative stress in the retina. Importantly, the protective capability of lower dose of minocycline was unraveled by suppressing the apoptotic, inflammatory, and the altered metabolic processes caused by S100B insult in the retina., Conclusion: Intravitreally injected S100B not only led to a pro-inflammatory microglial reaction, but also a mitochondrial and metabolic dysfunction. Also, these results suggest that an excessive microglial response may be a significant degenerative factor, but not the only trigger for increased cell death.

Age-related macular degeneration (AMD) is the leading cause of blindness in older people in the developed world while Stargardt's disease (SD) is a juvenile macular degeneration and an orphan disease. Both diseases are untreatable and are marked by accumulation of lipofuscin advancing to progressive deterioration of the retinal pigment epithelium (RPE) and retina and subsequent vision loss till blindness. We discovered that a small molecule belonging to the tetrahydropyridoether class of compounds, soraprazan renamed remofuscin, is able to remove existing lipofuscin from the RPE. This study investigated the drug penetration, distribution, and elimination into the eyes of a mouse model for increased lipofuscinogenesis, following a single intravitreal injection. We measured the time course of concentrations of remofuscin in different eye tissues using high-performance liquid chromatography combined with mass spectroscopy (HPLC-MS). We also visualized the penetration and distribution of 3 H-remofuscin in eye sections up to 20 weeks post-injection using transmission electron microscopic (TEM) autoradiography. The distribution of silver grains revealed that remofuscin accumulated specifically in the RPE by binding to the RPE pigments (melanin, lipofuscin and melanolipofuscin) and that it was still detected after 20 weeks. Importantly, the melanosomes in choroidal melanocytes only rarely bind remofuscin emphasizing its potential to serve as an active ingredient in the RPE for the treatment of SD and dry AMD. In addition, our study highlights the importance of electron microscopic autoradiography as it is the only method able to show drug binding with a high intracellular resolution., (© 2020 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Proliferative vitreoretinopathy (PVR) is a significant threat for vision recovery from retinal detachment or ocular trauma. Currently, no approved pharmacological intervention to prevent PVR. Daunorubicin (DNR) and dexamethasone (DEX) were sequentially loaded into oxidized porous silicon (pSiO 2 ) particles by covalent conjugation. The DNR + DEX-loaded particles, and control particles loaded with DNR only and DEX only were incubated with RPE-populated collagen for daily gel surface quantitation. Toxicity was monitored by ophthalmic examinations and histological evaluation 21 days after injection. At 3rd week following intravitreal injection, a localized retinal detachment (RD) was created by subretinal injection of Healon in all pretreated eyes in addition to 3 non-interventional control eyes. 10 µg of bromodeoxyuridine (BrdU) was injected into the vitreous 4 h before sacrifice on day 3 after RD induction. Retinal sections were stained for glial fibrillary green protein (GFAP) and BrdU to identify activated glial cells and retinal cell proliferation. The studies demonstrated that all three pSiO 2 particle types were well tolerated in vivo. DNR alone and DNR + DEX combination formulations demonstrated equally strong suppression on gel contraction (least square mean area of the gel: control = 1.71 vs. 30DNR = 1.85 or 30/40Dual = 1.83, p  < .05). Eyes pretreated with pSiO 2 -DNR + DEX exhibited the least GFAP activation (least square mean intensity mm -2 : Dual = 4.03, DNR = 7.76, Dex = 16.23, control = 29.11, p  < .05) and BrdU expression (Mean number of BrdU positive cells per mm of retina: Dual = 2.77, DNR = 4.58, Dex = 4.01, control = 6.16, p  < .05). The synergistic effect of a sustained release pSiO 2 -DNR/DEX showed promise for the prevention of PVR development while reducing the necessary therapeutic concentration of each drug.

Intravitreal delivery can maximize the intensity of therapeutic agents and extend their residence time within ocular tissue. Melatonin is a lipophilic molecule that crosses freely biological barriers and cell membranes. This study intends to investigate the effects of intravitreally delivered melatonin on mouse retina. The visual function of administered mice is assessed by electrophysiological and behavior examinations three weeks after intravitreal delivery. Moreover, multi-electrode array (MEA) was used to assess the electrical activities of retinal ganglion cells (RGCs). We found that intravitreal delivery of high dosage melatonin (400-500 µg/kg) destroyed the retinal architecture and impaired the visual function of mice. Conversely, the melatonin administration at low dose (100-300 µg/kg) did not have any significant effects on the photoreceptor survival or visual function. As shown in the MEA recording, the photoreceptors activity of the central region was more severely disturbed by the high dose melatonin. A pronounced augment of the spontaneous firing frequency was recorded in these mice received high dosage melatonin, indicating that intravitreal delivery of high dosage melatonin would affect the electrical activity of RGCs. Immunostaining assay showed that the vitality of cone photoreceptor was impaired by high dose melatonin. These findings suggest that intravitreal melatonin is not always beneficial for ocular tissues, especially when it is administered at high dosage. These data add new perspectives to current knowledge about melatonin delivery at the ocular level. Further therapeutic strategies should take into consideration of these risks that caused by delivery approach.

This study aimed to assess optical coherence tomography (OCT) parameters associated with vitreomacular traction (VMT) resolution after ocriplasmin intravitreal injection and also associated with the development of vitreomacular complications. Study designed was a retrospective case series. Structural OCT images were acquired at baseline and over the follow-up after treatment. We developed a mathematical model to provide quantitative parameters associated with VMT resolution. Moreover, we adopted the same model to assess the quantitative parameters associated with development of further vitreomacular complications or with the worsening of the coexisting condition. Main outcome measures were BCVA, central macular thickness (CMT), VMT reflectivity, VMT size, VMT resolution, epiretinal membrane (ERM), macular holes. 73 eyes of 73 VMT patients (mean age 73 ± 9 years) were recruited. The mean follow-up duration was 2.6 ± 1.1 years. Mean baseline BCVA was 0.38 ± 0.18 LogMAR, improving to 0.26 ± 0.20 at the end of the follow-up (p < 0.01). Baseline CMT was 431 ± 118 µm, improving to 393 ± 122 µm at the end of the follow-up (p < 0.01). 38/73 eyes (52%) showed only VMT, whereas 35/73 eyes (48%) also showed coexisting alterations at baseline. VMT resolved in 40/73 eyes (55% of cases). Our model disclosed VMT reflectivity as the most involved parameter in VMT resolution. VMT size showed less influence on the success of ocriplasmin treatment. ERM was negatively associated with VMT resolution. Moreover, VMT reflectivity values and ERM represented the most important parameters for the onset of vitreomacular complications.

Destabilizing domains (DDs) have been used successfully to conditionally control the abundance of proteins of interest (POIs) in a small-molecule-dependent manner in mice, worms ( Caenorhabditis elegans ), and Drosophila . However, development of such systems must account for delivery of the DD-POIs to the target tissue, accessibility of the target tissue to the small molecule, and quantification of stabilization. Here, we describe the considerations and steps to take in order to effectively implement a DD-POI in mouse ocular and hepatic tissue. For complete details on the use and execution of this protocol, please refer to Datta et al. (2018), Ramadurgum and Hulleman (2020), and Ramadurgum et al. (2020)., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

Aims: To confirm the therapeutic efficacy of conbercept for the treatment of macular edema (ME) secondary to retinal vein occlusion (RVO) by using optical coherence tomography angiography (OCTA) and to find out the differences in therapeutic efficacy between ischemic and nonischemic retinal vein occlusion (iRVO or non-iRVO) after conbercept treatment., Methods: In this prospective, randomized, and comparative study, 60 unilateral eyes suffered from RVO combined with macular edema were included and fellow eye as controls. After an initial intravitreal injection of conbercept (IVIC), a pro re nata (PRN) strategy was adopted, and the follow-up time was 6 months. The foveal avascular zone (FAZ), vascular density of superficial capillary plexus (SCP), and vascular density of deep retinal capillary plexus (DCP), nonperfused areas (NPAs) were evaluated with OCTA on baseline and after treatment., Results: The mean intravitreal injection number was 2.9 ± 0.89 times during six months in iRVO patients and 2.1 ± 0.86 times in non-iRVO patients, with statistically significant difference ( p < 0.05). On baseline, central macular thickness (CMT) and FAZ were significantly thickened and enlarged compared to those of healthy fellow eyes; the vascular density of SCP and DCP were significantly decreased, and the differences were statistically significant ( p < 0.05). Compared to baseline, after treatment, the best-corrected visual acuity (BCVA) was improved in either iRVO or non-iRVO (-0.601 ± 0.387, -0.241 ± 0.341 logMAR, p < 0.05). In iRVO, the improvement was more substantial than that of the non-iRVO group. FAZ in the non-iRVO group had significantly decreased compared to that in iRVO group (-0.044 ± 0.040 versus 0.014 ± 0.043 mm 2 , p < 0.05). CMT, the vascular density of SCP, and DCP had no significant difference., Conclusions: The changes of microvascular structure can be quantitatively evaluated by using OCTA for the patients with RVO. Conbercept had a significant effect on treatment of RVO with macular edema. A more profound effect was achieved in the iRVO group on visual improvement and FAZ reduction in the non-iRVO group after conbercept treatment., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Wenqi Song et al.)

Comparison of a customized disposable kit with a conventional stainless steel instrument was performed for an intravitreal injection. A total of 2700 eyes of 2250 patients were enrolled in two groups. Comfort level of the patients was assessed using a 'Pain Scale' and any post intravitreal injection complications were examined clinically by a slit lamp biomicroscopy. Surgeon's ease was assessed by a questionnaire. In group A, no pain was recorded in 1231(82.06%) eyes, mild pain was d escribed in 184(12.27%), moderate pain was documented in 78 (5.2%) while, severe pain was noticed in 7(0.47%). In group B, no pain was seen in 1014(84.5%), mild pain was present in 123(10.25%), moderate pain was perceived in 58 (4.83%) while, severe pain was recorded in 5 (0.42%). With respect to surgeon's ease, 6 out of the 7 surgeons found the kit to be more convenient and cost effective as compared to the conventional instruments. Disposable intravitreal kit is beneficial for both the patients as well as the surgeons.

Introduction: Coats disease is a sporadic, retinal vascular abnormality, causing blindness. Several interventional methods, including laser photocoagulation, have been proposed; however, the use of intravitreal dexamethasone in refractory Coats disease is not well described., Patient Concerns: A 38-year-old man presented with a painless reduction in visual acuity in his right eye, commencing 15 days prior to initial assessment., Diagnosis: Clinical manifestations and multimodal imaging indicated Coats disease., Interventions: Retinal laser photocoagulation was performed in the nonperfused areas, 15 months later, the exudative retinal detachment, and macular edema remained, the patient was then treated with an intravitreal slow-release dexamethasone implant., Outcomes: The exudative retinal detachment and macular edema had resolved, and the BCVA had also improved., Conclusion: Dexamethasone intravitreal implantation was effective in treating refractory Coats disease.

An extremely premature baby boy born at 23 weeks' gestational age was treated with unilateral low dose of 0.16 mg/0.025 mL intravitreal bevacizumab in the left eye for aggressive retinopathy of prematurity (ROP). He developed photographically documented changes in his contralateral right eye on imaging 5 days later. Second eye treatment was at 12 days. He has development assessment and ophthalmic review beyond age 2, which is normal. Systemic absorption of the drug caused an end organ effect to slow down and reverse ROP in his untreated right eye. Both eyes vascularised fully. His normal Bayley III developmental score at age 2 is uncommon for a 23-week gestation baby. Even at a low dose, bevacizumab has the potential for end organ effect on the second eye, and therefore other organs. In this case, there are no medium-term measurable neurodevelopmental side-effects. We suggest longer term follow-up is required before excluding unwanted side-effects., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Administering anti-vascular endothelial growth factor (anti-VEGF) by intraocular injection has been shown to have a safe systemic profile. Nevertheless, incidents of acute kidney injury following anti-VEGF injection have been reported. We assessed the long-term effect of multiple intravitreal anti-VEGF injections on measures of renal function in patients with diabetes including rate of change of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR)., Methods: A retrospective review of patients receiving diabetic macular oedema (DMO) treatment was undertaken. Serum creatinine, ACR, number of intravitreal anti-VEGF injections and clinical characteristics were collected from electronic healthcare records (EHR). A co-efficient of eGFR and ACR change with time was calculated over a mean duration of 2.6 years. Regression modelling was used to assess variation in the number of anti-VEGF injections and change in eGFR and ACR., Results: The EHR of 85 patients with DMO (59% male, 78% type 2 diabetes mellitus [T2DM]) were reviewed. On average, 26.8 intravitreal anti-VEGF injections were given per patient over a mean duration of 31 months. No association between increasing number of anti-VEGF injections and rate of eGFR decline (beta = 0.04, 95% confidence intervals [CI]: - 0.02, 0.09; p = 0.22) or ACR change over time (beta = 0.02, CI: - 0.19, 0.23; p = 0.86) was detected, following adjustment for hypertension, cerebrovascular disease, T2DM, and medications taken., Conclusion: Our data suggests regular long-term intravitreal VEGF inhibition does not significantly alter the rate of change in eGFR and/or ACR with increasing number of treatment injections.

Background: Age-related macular degeneration (AMD) is the third largest cause of blindness worldwide, accounting for 8.7% of all cases. A considerable number of preventive or therapeutic interventions have been used for AMD., Objective: This study presents a critical view of the interventions that have been assessed through Cochrane systematic reviews., Design and Setting: Review of systematic reviews, conducted in the Discipline of Evidence-Based Medicine, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP)., Methods: Review of Cochrane systematic reviews about interventions for AMD., Results: The 18 systematic reviews included assessed the effects of surgical techniques, laser/photo/radiotherapy, intravitreal injections, systemic drugs and phytotherapy/vitamins/supplements., Conclusion: The Cochrane systematic reviews found evidence that use of bevacizumab, ranibizumab, pegaptanib, laser photocoagulation, photodynamic therapy and multivitamin compounds may present some benefits for treating AMD. There was insufficient evidence for supporting the use of macular translocation, submacular surgery, steroid implantation, radiotherapy, intravitreal aflibercept, interferon alfa, statins or omega-3 fatty acids for treating AMD; or the use of multivitamin antioxidant vitamins or mineral supplementation for preventing AMD. Future randomized controlled trials are imperative to reduce the uncertainty in several clinical questions regarding AMD.

Purpose: To determine the characteristics of diabetic macular edema (DME) patients refractory to intravitreal bevacizumab (IVB) treatments and an additional dexamethasone implant., Methods: We classified 119 DME patients according to whether or not they are responsive to 3 consecutive monthly anti-VEGF treatments and/or an additional dexamethasone implant. We compared their concentrations of IL (interleukin)-1β, IL-8, IL-10, IL-17, placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) in the aqueous humor as well as their optical coherence tomography (OCT) findings, and baseline characteristics. We used logistic regression analyses to identify preoperative factors related to refractoriness to treatments., Results: Of 119 treatment-naïve DME patients, 50 (42.02%) patients showed responsiveness [central subfield thickness (CST) < 300μm] after 3 IVBs, and 59 (49.58%) patients showed responsiveness after an additional dexamethasone implant, but 10 (8.40%) patients showed CST 300 ≥ μm even after both treatments. Refractory DME patients showed significantly higher number of hyperreflective foci (HF) in the OCT and higher average level of aqueous IL-1β at baseline (p<0.001 and p = 0.042, respectively). In the logistic regression analysis, higher number of HF in the OCT was associated with the refractoriness to both treatments (odds ratio [OR]: 7.03, p = 0.007)., Conclusions: Higher number of HF in the OCT at the initial visit was associated with poor responses to IVBs and an additional dexamethasone implant., Competing Interests: The authors received financial support from the fund of Aju Pharm from Catholic Medical Center Research Foundation in the program year of 2018. The fund is involved with writing the article and publication charge. We declare that all the authors do not have financial or non financial competing interest that occurred within years and outside of 5 year time frame of conducting the research under consideration, or preparing the article for publication. Additionally, we declare that all the authors do not have competing interest regarding employment, consultancy, patents, products in development, marketed products, etc. Also, this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Currently, the two primary patient-derived xenograft (PDX) models of glioblastoma are established through intracranial or subcutaneous injection. In this study, a novel PDX model of glioblastoma was developed via intravitreal injection to facilitate tumor formation in a brain-mimicking microenvironment with improved visibility and fast development. Glioblastoma cells were prepared from the primary and recurrent tumor tissues of a 39-year-old female patient. To demonstrate the feasibility of intracranial tumor formation, U-87 MG and patient-derived glioblastoma cells were injected into the brain parenchyma of Balb/c nude mice. Unlike the U-87 MG cells, the patient-derived glioblastoma cells failed to form intracranial tumors until 6 weeks after tumor cell injection. In contrast, the patient-derived cells effectively formed intraocular tumors, progressing from plaques at 2 weeks to masses at 4 weeks after intravitreal injection. The in vivo tumors exhibited the same immunopositivity for human mitochondria, GFAP, vimentin, and nestin as the original tumors in the patient. Furthermore, cells isolated from the in vivo tumors also demonstrated morphology similar to that of their parental cells and immunopositivity for the same markers. Overall, a novel PDX model of glioblastoma was established via the intravitreal injection of tumor cells. This model will be an essential tool to investigate and develop novel therapeutic alternatives for the treatment of glioblastoma.

The present review focuses on recent clinical trials that analyze the efficacy of intravitreal therapeutic agents for the treatment of dry age-related macular degeneration (AMD), such as neuroprotective drugs, and complement inhibitors, also called immunomodulatory or anti-inflammatory agents. A systematic literature search was performed to identify randomized controlled trials published prior to January 2019. Patients affected by dry AMD treated with intravitreal therapeutic agents were included. Changes in the correct visual acuity and reduction in geographic atrophy progression were evaluated. Several new drugs have shown promising results, including those targeting the complement cascade and neuroprotective agents. The potential action of the two groups of drugs is to block complement cascade upregulation of immunomodulating agents, and to prevent the degeneration and apoptosis of ganglion cells for the neuroprotectors, respectively. Our analysis indicates that finding treatments for dry AMD will require continued collaboration among researchers to identify additional molecular targets and to fully interrogate the utility of pluripotent stem cells for personalized therapy.

This retrospective study was to compare the efficacy of intravitreal injection of ranibizumab and aflibercept for patients with pachychoroid neovasculopathy. 54 eyes were initially treated with 3 monthly loading injections of ranibizumab or aflibercept. Treatment switching from ranibizumab to aflibercept, and aflibercept to photodynamic therapy was done at 3 months in case of incomplete fluid absorption. At 3 months, the rate of complete fluid absorption was significantly higher in the aflibercept-treated group than in the ranibizumab-treated group (82.6% vs 51.6%, p = 0.018). The mean reduction of subfoveal choroidal thickness was significantly greater in the aflibercept group than in the ranibizumab group (-35 µm vs -9 µm, p = 0.013). There was no significant difference between the two groups in terms of visual improvement or decrease in central macular thickness. Complete fluid absorption was achieved after switching from ranibizumab to aflibercept in 13 of 15 eyes (86.7%). Adjunctive photodynamic therapy was required in 6 eyes. In conclusion, treatment mainly with anti-vascular endothelial growth factor effectively improved visual acuity within 12 months (from 20/56 to 20/44 at 3 months and to 20/36 at 12 months). Aflibercept was superior to ranibizumab in achieving dry macula and reducing choroidal thickness at 3 months.

This study aimed to investigate whether the transplantation of genetically engineered bone marrow-derived mesenchymal stromal cells (MSCs) to overexpress brain-derived neurotrophic factor (BDNF) could rescue the chronic degenerative process of slow retinal degeneration in the rd6 (retinal degeneration 6) mouse model and sought to identify the potential underlying mechanisms. Rd6 mice were subjected to the intravitreal injection of lentivirally modified MSC-BDNF or unmodified MSC or saline. In vivo morphology, electrophysiological retinal function (ERG), and the expression of apoptosis-related genes, as well as BDNF and its receptor (TrkB), were assessed in retinas collected at 28 days and three months after transplantation. We observed that cells survived for at least three months after transplantation. MSC-BDNF preferentially integrated into the outer retinal layers and considerably rescued damaged retinal cells, as evaluated by ERG and immunofluorescence staining. Additionally, compared with controls, the therapy with MSC-BDNF was associated with the induction of molecular changes related to anti-apoptotic signaling. In conclusion, BDNF overexpression observed in retinas after MSC-BDNF treatment could enhance the neuroprotective properties of transplanted autologous MSCs alone in the chronically degenerated retina. This research provides evidence for the long-term efficacy of genetically-modified MSC and may represent a strategy for treating various forms of degenerative retinopathies in the future.

The effect of triamcinolone acetonide (TA) on the peripheral retinochoroidal thickness was determined after pars plana vitrectomy (PPV) with scatter photocoagulation in eyes with proliferative diabetic retinopathy. The peripheral retinochoroidal thickness was measured at 5 mm from the limbus in the four quadrants using anterior segment optical coherence tomography before, and 3 days, and 1 and 2 weeks after the surgery. The total peripheral thickness was significantly thicker than the baseline thickness after PPV alone (P < 0.001; 18 eyes), PPV combined with intravitreal TA injection (IVTA; P = 0.011; 19 eyes), and PPV combined with sub-tenon TA injection (STTA; P = 0001; 23 eyes). The total peripheral thickness in the PPV group at 3 days after surgery was significantly thicker than that of the PPV + IVTA (P = 0.015) and of the PPV + STTA groups (P = 0.016). Multiple linear regression analyses showed that the injection of TA by the two routes and the number of photocoagulation burns were significantly correlated with the total peripheral thicknesses at 3 days after the surgery. The results indicate that the PPV with large number of intraoperative scatter photocoagulation burns caused an increase in the total peripheral thickness and an administration of either IVTA and STTA can reduced the degree of thickening.

BACKGROUND The aim of this study was to compare the alterations in intraocular pressure (IOP) values during the early postoperative period after intravitreal ranibizumab, aflibercept, or dexamethasone implant injections. MATERIAL AND METHODS In this retrospective study, a total of 188 patients were grouped into 3 groups: the ranibizumab group, the aflibercept group, and the dexamethasone group. Ocular axial length (AXL) and anterior chamber depth (ACD) were measured in the pre-injection period. IOP was measured just before the injection at 1 minute,10 minutes, 1 hour, 1 day, and 1 month after injection. RESULTS There was a transient peak in the ranibizumab group and the aflibercept group at 1 minute that started to decrease at 10 minutes and IOP values returned to preoperative values at approximately 1 hour. Similar alterations were also determined for the dexamethasone group with a lesser increase noted. In the correlation analysis, only alterations in IOP levels at 1 minute were negatively correlated with preoperative AXL values. There was not any correlation between preoperative AXL or ACD values and IOP alterations at any other time points. CONCLUSIONS There was a sudden, transient increase in IOP values after intravitreal ranibizumab or aflibercept injections; which return to normal values in a short time without requirement of any medical treatments. This transient peak was determined to be negatively correlated with the preoperative AXL.

Fungal endophthalmitis remains a significant cause of vision impairment and blindness. Moreover, the prognosis is poor, in part due to delay in diagnosis and to limited availability of effective antifungal agents with good ocular penetration. Thus, it is imperative to evaluate the therapeutic efficacy in fungal endophthalmitis of newer antifungal agents. In this study, we assessed the efficacy of isavuconazole in treating Aspergillus fumigatus endophthalmitis in an exogenous mouse model of the disease. Briefly, endophthalmitis was induced by intravitreal (IVT) injection of A. fumigatus spores into immunocompetent C57BL/6 (B6) mouse eyes. Mice were randomized into five groups that received isavuconazole via (i) oral gavage, (ii) IVT injections, (iii) intravenous injection, (iv) IVT injection followed by oral gavage, and (v) IVT injection followed by intravenous injection. Our data showed that isavuconazole treatment via all routes reduced fungal burden in A. fumigatus -infected eyes. This coincided with the preservation of retinal structural integrity (histology analysis) and retinal function (electroretinography [ERG] analysis), resulting in significantly improved disease outcome. Furthermore, isavuconazole treatment reduced the levels of inflammatory cytokines (tumor necrosis factor α [TNF-α], interleukin 1β [IL-1β], and IL-6) and cellular infiltration in the eyes. Notably, oral administration of isavuconazole was as effective in ameliorating endophthalmitis as intravitreal injection of the drug. Collectively, our study demonstrates that isavuconazole is effective in treating A. fumigatus endophthalmitis in mice, indicating its potential use in human ocular infections., (Copyright © 2018 American Society for Microbiology.)

BACKGROUND This article discusses the effectiveness of phacoemulsification cataract surgery with intraocular lens implantation in patients with wet age-related macular degeneration in the inactive phase of the disease. MATERIAL AND METHODS Forty-nine patients (50 eyes) aged 78.94±5.54 years, previously treated with intravitreal injections of anti-vascular endothelial growth factor agents, were qualified for a prospective, randomized 12-month study. The participants were divided into 2 groups. Group I consisted of 25 patients (25 eyes) who were subjected to phacoemulsification cataract surgery. Group II consisted of 24 patients (25 eyes) who were not subjected to phacoemulsification cataract surgery despite having a lens opacity of grade II or higher according to the Lens Opacities Classification System. RESULTS After 12 months of follow-up, patients in group I gained on average 8.04 letters (p<0.001). Furthermore, 20% of the eyes had a significant improvement in best corrected visual acuity of ≥15 Early Treatment of Diabetic Retinopathy Study Chart letters. Patients in group II lost on average 1.96 letters (p>0.05). No significant differences between central retinal thickness values in either group (p>0.05) were noted. The mean number of intravitreal injections of anti-vascular endothelial growth factor agents during the study was 2.64±1.98 in group I and 2.92±2.40 in group II (p>0.05). CONCLUSIONS Phacoemulsification performed in eyes with wet age-related macular degeneration during the inactive phase of the disease significantly improves visual acuity. In addition, it does not significantly influence the frequency of intravitreal injections of anti-vascular endothelial growth factor agents or disease activity.

Background: Recent years have seen major changes in the diagnosis and treatment of solid intraocular tumors, mainly owing to an improved molecular biological understanding of their pathogenesis, new therapeutic approaches for the local treatment of tumors in children, and long-term follow-up observations in clinical trials., Methods: This review is based on pertinent publications retrieved by a selective search in PubMed., Results: Retinoblastoma is the most common type of primary intraocular tumor, with approximately 8000 new cases per year around the world, while malignant melanoma of the uvea is the most common primary intraocular tumor in adults, with approximately 7000 new cases per year around the world. Intraocular metastases of malignant tumors are ten times more common, in terms of incidence, than primary intraocular tumors and are therefore the most common intraocular tumors overall. Improved methods of intraocular biopsy, diagnostic imaging, and molecular genetic investigation have led to steady improvement in clinical and predictive diagnostic assessment. In the treatment of retinoblastoma, local techniques including brachytherapy and intra-arterial and intravitreal chemotherapy play a prominent role. Prognostic molecular-genetic testing now enables the highly selective identification of uveal melanomas that have a high potential to metastasize. Cutaneous and uveal melanomas differ both in their clinical behavior and in their basic biological features; to date, effective systemic treatment has been established for melanoma of the skin, but not for metastatic melanoma of the uvea. Intraocular metastases are common and often the initial manifestation of an extraocular tumor, particularly lung cancer., Conclusion: Modern diagnostic and therapeutic concepts for intraocular tumors can only be implemented through the close interdisciplinary collaboration of ophthal - mologists, oncologists, radiologists, radiotherapists, pathologists, and human geneticists.

Blinding retinal diseases become more epidemic as the population ages. These diseases, such as diabetic retinopathy and macular edema, are of chronic nature and require protracted drug presence at the disease site. A sustained intravitreal porous silicon delivery system with dexamethasone (pSiO 2 -COO-DEX) was evaluated in a new rabbit model of proliferative vitreoretinopathy (PVR) in a real treatment design. In contrast to the pretreatment design model, pSiO 2 -COO-DEX was intravitreally injected into the eyes with active inflammation. Subretinal injection of vascular endothelial growth factor (VEGF) and Matrigel induced a late-onset vitreoretinal inflammation that gradually developed into PVR. This method mimics the human disease better than PVR induced by either intravitreal cell injection or trauma. The pSiO 2 -COO-DEX intervened eyes had minimal PVR, while balanced saline solution or free dexamethasone intervened eyes had significantly more PVR formation. In addition, adding VEGF to the Matrigel for subretinal injection induced greater inflammation and retinal neovascularization in comparison to only Matrigel injected under the medullary ray. Clinical and pathological examinations, including fundus fluorescein angiography and optical coherence tomography, confirmed these changes. In the current study, neither subretinal injection of Matrigel or subretinal injection of VEGF and Matrigel induced choroidal neovascularization. However, the current PVR model demonstrates a chronic course with moderate severity, which may be useful for drug screening studies.

The burden of intravitreal injections has increased tremendously over the past few years. Since traditionally the operation theatre setup is currently used for this procedure, it is increasingly becoming difficult to manage such a patient load in the theatres. To overcome this challenge, office-based setup for intravitreal injection was started. This study was planned to determine the incidence of endophthalmitis after office-based intravitreal bevacizumab injection and to compare it with previously reported incidence of endophthalmitis after operation theatre-based intravitreal injections. The study was conducted at Al-Ehsan Eye Hospital, Lahore, Pakistan, from July 2015 to June 2016, and comprised patients who received intravitreal injections of bevacizumab (Avastin) for different ocular indications. A total of 1,047 intravitreal injections were given in an office-based set-up. Of them, 2(0.19%) cases of clinically suspected endophthalmitis were identified. Office-based set-up for intravitreal bevacizumab injection was found to have comparable safety profile with traditional operation theatre-based set-up.

Purpose: To study the suitability of injectable microspheres based on poly(ester amide) (PEA) or poly lactic-co-glycolic acid (PLGA) as potential vehicles for intravitreal drug delivery in rat eyes. Dexamethasone-loaded PEA microspheres (PEA + DEX) were also evaluated., Methods: Forty male Sprague Dawley rats were divided into four groups that received different intravitreally injected microspheres: PEA group (n = 12); PLGA group (n = 12); PEA + DEX group (n = 8); and control group (no injection, n = 8). Electroretinography (ERG), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (sdOCT) were performed at baseline, weeks 1 and 2, and months 1, 2, and 3 after intravitreal injection. Eyes were histologically examined using light microscopy and transmission electron microscopy at the end of the in vivo study., Results: There were no statistically significant changes in ERG among the groups. Abnormal FAF pattern and abnormal deposits in OCT were observed after injection but almost completely disappeared between week 2 and month 3 in all injected groups. GFAP staining showed that Müller glia cell activation was most pronounced in PLGA-injected eyes. Increased cell death was not observed by TUNEL staining at month 1. In electron microscopy at month 3, the remnants of microparticles were found in the retinal cells of all injected groups, and loss of plasma membrane was seen in the PLGA group., Conclusions: Although morphological changes such as mild glial activation and material remnants were observed histologically 1 month and 3 months after injection in all injected groups, minor cell damage was noted only in the PLGA group at 3 months after injection. No evidence of functional abnormality relative to untreated eyes could be detected by ERG 3 months after injection in all groups. Changes observed in in vivo imaging such as OCT and FAF disappeared after 3 months in almost all cases., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Competing Interests: There are no conflicts of interest.

Background: Ozurdex is a 700 mcg dexamethasone intravitreal implant, approved for the management of macular edema secondary to retinal vein occlusion, and other related pathoglogiesAnterior chamber dislocation of Ozurdex represents an uncommon complication of the intravitreal injection, which can be managed by repositioning the implant into the vitreous cavity. We describe the case of a successful repositioning of an Ozurdex implant by mobilization and subsequent balanced saline solution injection in the anterior chamber., Case Presentation: An 83-year-old white woman presented to our Emergency Unit complaining of pain and vision loss in herright eye lasting a week. Her anamnesis revealed a history of persistent cystoid macular edema after phacoemulsification with scleral-fixated posterior chamber intraocular lens implantation, recently treated with an intravitreal Ozurdex implant. She also took a long-distance flight 2 days after the injection. An anterior segment examination showed corneal edema and the rod implant adherent to corneal endothelium. To avoid corneal decompensation, we opted for a implant repositioning. Under topical anesthesia, a 30-gauge needle was introduced through a limbar incisionto mobilize the dislocated rod. Balanced saline solution was injected, with a successful repositioning of the implant into the vitreous cavity. Topical 5 % hypertonic saline solution and 0.2 % betamethasone associated with 0.5 % chloramphenicol drops were administered four times a day. To prevent redislocation of the Ozurdex implant, she was instructed to avoid prone position, any kind of physical effort, and not to undertake long-distance flights during the first postoperative week. One week after surgery, an anterior segment examination showed an improvement of corneal edema. Funduscopy showed that the Ozurdex implant was settled into the vitreous cavity., Conclusions: Anterior chamber dislocation of Ozurdex from the vitreous cavity is rare. In our patient, in addition to the posterior capsule tearing, the long-distance flight could have contributed to implant dislocation. Repositioning of the implant is necessary to avoid endothelial decompensation. It can be carried out by using saline balanced solution with the same efficacy as other surgical procedures reported in the literature. A possible disadvantage of this procedure could be implant migration.

Introduction: Non-physicians such as nurses are trained to give injections into the vitreous body of the eye to meet the increasing demand for intravitreal therapy with vascular endothelial growth factor inhibitors against common eye diseases, e.g. age-related macular degeneration and diabetic retinopathy. We systematically reviewed the existing literature to provide an overview of the experiences in this transformational process., Methods: We searched for literature on 22 September 2015 using PubMed, Embase, the Cochrane Library, CINAHL and the Web of Science. Eligible studies had to address any outcome based on non-physician delivered intravitreal therapy regardless of the study design. Being non-physician was defined as the injecting personnel not being a physician, but no further restrictions were made., Results: Five studies were included with a total of 31,303 injections having been performed by 16 nurses. The studies found that having nurses perform the intravitreal injections produced to a short-term capacity improvement and liberated physicians for other clinical work. Training was provided through courses and direct supervision. The rates of endophthalmitis were 0-0.40‰, which is comparable to reported rates when the intravitreal therapy is given by physicians., Conclusion: Non-physician delivered intravitreal therapy seems feasible and safe.

A standard treatment for patients with primary intraocular lymphoma (PIOL) remains unclear. This study retrospectively analyzed the clinical features and outcomes of 19 patients with PIOL who were treated with a first-line therapy comprising combined intravenous high-dose methotrexate and intravitreal methotrexate between January 2003 and December 2013. Thirteen (68.4 %) patients were female, and the median age at diagnosis was 57 (39-77 years). Diagnoses were based on the identification of abnormal lymphoid cells in vitreous fluid. Ten (52.6 %) patients had bilateral eye involvement, and six had concurrent central nervous system (CNS) involvement. All 19 patients achieved complete remission (CR) as confirmed by cytological examination of vitreous and cerebrospinal fluid and brain imaging if CNS was involved. Patients with concurrent brain involvement required a longer time to achieve CR. However, the duration of complete remission did not differ between patients with and without CNS involvement. The 5-year overall survival rate was 55.8 % for the total cohort and was higher (68.8 %) in patients with isolated PIOL than in those with concurrent CNS involvement. In all patients, methotrexate treatment was well tolerated, with manageable side effects. We conclude that combined intravitreal methotrexate and systemic high-dose methotrexate treatment is effective in patients with PIOL.

There is increasing use of the vitreous cavity as a reservoir for drug delivery. We study the intraocular migration and distribution of triamcinolone acetonide (TA) after injection into silicone oil tamponade agent during and after vitrectomy surgery ex vivo (pig eye) and in vitro (glass bottle). For ex vivo assessment, intraocular migration of TA was imaged using real-time FLASH MRI scans and high-resolution T2W imaging and the in vitro model was monitored continuously with a video camera. Results of the ex vivo experiment showed that the TA droplet sank to the interface of silicone oil and aqueous almost immediately after injection and remained inside the silicone oil bubble for as long as 16 minutes. The in vitro results showed that, after the shrinkage of the droplet, TA gradually precipitated leaving only a lump of whitish crystalline residue inside the droplet for about 100 minutes. TA then quickly broke the interface and dispersed into the underlying aqueous within 15 seconds, which may result in a momentary increase of local TA concentration in the aqueous portion and potentially toxic to the retina. Our study suggests that silicone oil may not be a good candidate as a drug reservoir for drugs like TA.

Intravitreal (IVT) injection of therapeutic agents has become one of the most commonly performed procedures in ophthalmology. Over the past decade, a number of guidelines have been published that recommend proper techniques to increase the safety of IVT injections. Among the various complications of IVT injections, endophthalmitis can be sight threatening. The reported endophthalmitis rates after IVT injection range from 0.020% to 0.085%, which are higher than what would be expected from a simple, fast, and relatively atraumatic procedure. The 2 key issues involved in the prevention of endophthalmitis are pre-IVT injection disinfection using povidone-iodine (PVI) and the use of topical antibiotics as prophylaxis. Whereas 5% PVI for 5 minutes is most commonly used in cataract surgery for disinfection, the duration in IVT injection is much less and can be as short as 30 seconds. Further studies seem warranted to investigate whether longer duration of PVI application in IVT injection can lower the endophthalmitis rate. Recent data suggest that there is inadequate evidence to support the routine use of prophylactic pre-, peri-, or postinjection antibiotics to reduce the risk of endophthalmitis. However, as many confounding factors such as the PVI regimens were not standardized in previous studies, it is too soon to make a concrete conclusion. Despite the availability of published guidelines, considerable variations still exist in real-life clinical situations. In this article, we describe our IVT injection practice protocol and compare it with the most recent international guidelines. Finally, a summary table that shows the clinical features of true, sterile, and pseudoendophthalmitis is presented.

Delivery of therapeutic agents to posterior segment of the eyes is challenging due to the anatomy and physiology of ocular barriers and thus long-acting implantable formulations are much desired. In this study, a thermogelling system composed of two poly(lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock copolymers was developed as an injectable matrix for intravitreal drug delivery. The thermogel was prepared by mixing a sol and a precipitate of PLGA-PEG-PLGA triblock copolymers with different block ratios, among which a hydrophobic glucocorticoid, dexamethasone (DEX), was incorporated. The DEX-loaded thermogel was a low-viscous liquid at low temperature and formed a non-flowing gel at body temperature. The in vitro release rate of DEX from the thermogel could be conveniently modulated by varying the mixing ratio of the two copolymers. The long-lasting intraocular residence of the thermogel was demonstrated by intravitreal injection of a fluorescence-labeled thermogel to rabbits. Compared with a DEX suspension, the intravitreal retention time of DEX increased from a dozen hours to over 1week when being loaded in the thermogel. Additionally, intravitreal administration of the thermogel did not impair the morphology of retina and cornea. This study reveals that the injectable PLGA-PEG-PLGA thermogel is a biocompatible carrier for sustained delivery of bioactive agents into the eyes, and provides an alternative approach for treatment of posterior segment diseases., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

A 33-year-old man presented with vision loss in his right eye due to rhegmatogenous retinal detachment, for which he underwent pars plana vitrectomy with silicone oil injection. Three months later, the patient presented with sudden vision loss. On examination, his visual acuity was 20/200 with presence of subretinal haemorrhage with attached retina and silicone oil in situ. Fluorescein angiography confirmed the diagnosis of choroidal neovascularisation (CNV). The patient underwent intravitreal ranibizumab injection (0.5 mg per 0.05 mL). He subsequently underwent oil removal along with intravitreal bevacizumab injection (1.25 mg per 0.05 mL). The CNV completely regressed. At 7 years follow-up, the patient's best corrected visual acuity was 20/50 with attached retina and macular scar due to regressed CNV. His other eye was within normal limits throughout the follow-up period. This unique case demonstrates the successful outcome of intravitreal ranibizumab injection in a silicone oil-filled eye with myopic CNV., (2015 BMJ Publishing Group Ltd.)

Purpose: We assessed the effects of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy on scleral architecture using spectral domain anterior segment optical coherence tomography (OCT)., Methods: A total of 35 eyes of 35 patients treated with at least 30 intravitreal injections in one eye in the inferotemporal quadrant with ranibizumab or aflibercept and 10 or less intravitreal injections in the fellow eye attending the intravitreal injection clinic were included. Enhanced depth imaging anterior segment OCT was used to measure scleral thickness. For each eye the sclera was measured in four quadrants at 3 mm from the limbus. In addition axial eye length was measured in all subjects using partial coherence interferometry., Results: The mean number of intravitreal injections was 42 (range, 30-73) and 1.6 (range, 0-9) in the fellow eyes. In the study eyes with more than 30 injections the average scleral thickness in the inferotemporal quadrant was 568.4 μm (SD ± 66 μm) and 590.6 μm (SD ± 75 μm) in the fellow eyes with 10 or less injections (P = 0.003). The mean average scleral thickness in the other three quadrants (inferonasal, superotemporal, and superonasal) was 536.6 μm in the study eyes (SD ± 100 μm) and 545.2 μm (SD ± 109 μm) in the fellow eyes (P = 0.22). There was a borderline association of the total number of injections with scleral thickness change in the inferotemporal quadrant (r = 0.3, P = 0.052)., Conclusions: Intravitreal injections may lead to scleral changes when applied repeatedly in the same quadrant. Thus, alternating the injection site should be considered in patients requiring multiple intravitreal injections., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

Background: The aim of this study was to design a self-retaining rat contact lens to simplify intravitreous injection in rats., Material/methods: A self-retaining, plane-concave prism contact lens customized for rats was designed. Forty diabetic rats were randomly divided into 2 groups and received the intravitreous injection of 10 μl of a cell suspension containing bone marrow-derived stroma cell (BMSC). Group A: used a microsyringe and a rat contact lens (n=20). Group B: used the same microsyringe and a traditional cover-slip (n=20).The duration of the intravitreous injection course and the success rate of intravitreous injection were observed., Results: With the use of a self-retaining rat contact lens, a clear and stable view of the rat fundus was provided and the intravitreous injection course of rats quickly achieved, averaging 4.65±0.53 min in Group A and 12.33±2.79 min in Group B. The difference was statistically significant, and the time saved averaged 7.68 min. None of the Group A rats had retinal bleeding or lens injury; whereas 2 of 20 Group B rats had bleeding and 1 of 20 had lens injury. There was no significant difference between the rats in Group A and Group B., Conclusions: A self-retaining rat contact lens is a potentially powerful instrument that allows high-quality observation of the rat fundus and simplifies the course of intravitreal injection.

The clinical efficacy of one or two intravitreal injections of a continued deliverance dexamethasone 700 μg implant in ten patients with persistent macular edema following uncomplicated phacoemulsification was evaluated. Complete ophthalmological examination and spectral domain optical coherence tomography were carried out. Follow-up was at day 7 and months 1, 2, 4, 6, 8, and 12. At baseline mean best corrected visual acuity was 62 Early Treatment Diabetic Retinopathy Study Chart letters, which showed statistically significant improvement at each follow-up, except at month 6, to reach 79 letters at month 12 (P = 0.018). Prior to treatment mean central foveal thickness was 622 μm, which showed statistically significant improvement at each follow-up to reach a mean value of 282 μm (P = 0.012) at month 12. Five patients received a second dexamethasone implant at month 7. Two patients were excluded from the study at months 4 and 8. Intraocular pressure remained stable during the study period with the exception of mild increase in two patients requiring topical therapy. In conclusion there was statistically significant improvement of best corrected visual acuity and mean central foveal thickness with one or two intravitreal dexamethasone implants over 12 months.

Purpose: To describe retinal changes during Spectral Domain Optical Coherence Tomography (SD-OCT) guided bevacizumab treatment for neovascular age- related macular degeneration (AMD)., Settings and Design: Single center observational study., Materials and Methods: We confirmed wet AMD in 47 eyes of 45 patients by fluorescein angiography and SD-OCT. After bevacizumab injection, we examined the patients at 4-week intervals. During each follow-up control, we performed SD-OCT and a complete ophthalmic examination. Criteria for reinjection were visual acuity loss of more than five ETDRS letters, and/or increase of central retinal thickness, sub-retinal fluid, intra-retinal fluid, pigment epithelium detachment. If reinjection criteria were not met, we advised the patient to return in 4 weeks' time for the next scheduled follow-up. We used 3-dimensional SD-OCT to measure photoreceptor defects and sub-retinal fibrosis. The main efficacy endpoints were the SD-OCT measurements of the size of photoreceptor defects, the size of external membrane defects and the central retinal thickness., Results: Over the 12 months study period, the percentage of scans in 3-D imaging mode showing visible defects of the junction between inner and outer segments of photoreceptors increased from 38.96 to 53.8%. The percentage of scans in 3-D imaging mode with visible sub-retinal fibrosis increased from 33 to 52% and mean central retinal thickness decreased from 333 μm (96-900 μm) to 272 μm (P = 0.011)., Conclusion: In long-term anti- Vascular endothelial growth factor (VEGF) treatment for neovascular AMD, photoreceptor defects and fibrosis progress despite a decrease in central retinal thickness and improvements in visual acuity. We would encourage further discussion as to whether this is the natural course of the disease or a result of the treatment.