Intravitreal Injection Research Articles

Pigment epithelium-derived factor exerts neuroprotection in oxygen-induced retinopathy by targeting endoplasmic reticulum stress and oxidative stress

Endoplasmic reticulum (ER) stress and oxidative stress have been involved in the occurrence of neuronal apoptosis in ischemic retinopathy. Pigment epitheliu-derived factor (PEDF) is well known for its multifunctional properties, including neuroprotection, anti-inflammation and antioxidant. However, the association between PEDF and ER stress or oxidative stress in ischemic retinopathy remain incompletely understood. In this study, the concentration of the key factor of ER stress C/EBP homologous protein (CHOP) in aqueous humor (AqH) and vitreous samples of proliferative diabetic retinopathy (PDR) patients were measured by ELISA assays. Oxygen-induced retinopathy (OIR) mice model was established and PEDF intravitreal injections were conducted. Primary bone marrow derived macrophages (BMDMs) were isolated and cultured under hypoxic conditions in vitro. Western blotting, real-time RT-PCR, immunofluorescence, transmission electron microscopy (TEM), TUNEL assays were performed to explore roles of PEDF on ER stress and oxidative stress, as well as subsequently neuronal apoptosis under hypoxic conditions in vivo and in vitro. The results revealed that ER stress and oxidative stress were notably activated under hypoxic conditions. We also observed that hypoxia evoked ultrastructural damage of ER and mitochondrion in the retina. However, PEDF significantly prevented ER stress and oxidative stress, as well as the damage of ultrastructure, resulting in diminution of photoreceptor apoptosis in OIR retinas. These results indicate that PEDF may play its neuroprotection role through inhibiting ER stress and oxidative stress in ischemic retinopathy, which is a novel molecular mechanism of PEDF protecting photoreceptors from ischemic damage, thereby suggesting that PEDF is an effective therapeutic agent for the treatment of neuron damage in ischemic retinal diseases.

High Intraocular Concentration of Fibrinogen Regulates Retinal Function Via the ICAM-1 Pathway.

Diabetic retinopathy (DR) is a significant complication of diabetes mellitus that can lead to progressive visual impairment. This study aimed to elucidate the role of fibrinogen, a protein whose serum and intraocular concentrations are elevated in patients with diabetes and DR, in the pathogenesis of DR. The changes in the protein levels of the neuronal marker tubulin-β3 (TUBB3) and retinal response induced by the intravitreal injections of 1× phosphate-buffered saline, 40mg/mL of fibrinogen, and 40mg/mL of fibrinogen in combination with anti-intracellular adhesion molecule-1 (ICAM-1) antibody in normal mice were observed using immunofluorescence, western blotting, and electroretinography. High concentrations of fibrinogen led to a decrease in the expression of TUBB3 in immunofluorescence and western blotting. The amplitudes of the positive scotopic threshold response and b-wave were notably reduced after the injection of fibrinogen, indicating potential damage to the retinal ganglion cells. The co-administration of anti-ICAM-1 antibody effectively mitigated these fibrinogen-induced changes, indicating that fibrinogen-induced damage is mediated via the ICAM-1 pathway. The present study underscores the significance of elevated intraocular fibrinogen levels as a pathogenic factor in DR. Involvement of the fibrinogen/ICAM-1 pathway presents new avenues for therapeutic intervention, especially in patients with treatment-resistant conditions.

Effect of intravitreal injection of anti-interleukin (IL)-6 antibody in experimental autoimmune uveitis in mice

PurposeThe aim of this study was to assess the functional and clinical impact of intravitreal administration of a neutralizing anti-IL-6 antibody in the treatment of experimental autoimmune uveitis (EAU) in mice.MethodsEAU was induced in 17 female B10.RIII mice by administering Inter-Photoreceptor-Binding-Protein (IRBP) in complete Freund’s adjuvant, followed by a boost with Pertussis toxin. Intravitreal injections of anti-Interleukin (IL)-6 antibody were administered on days 10, 13, and 16 after EAU induction (day 0) into the randomized treatment eye, with an isotype antibody similarly injected into the fellow control eye. Visual acuity was assessed using the optomotor reflex via OptoDrum, and clinical scoring was performed via fundus imaging (utilizing 6 EAU grades) in a single-blinded manner on days 0, 10, 13, 16, and 18.ResultsUveitis developed in all 17 mice. Significantly higher visual acuity was observed in treated eyes compared to control eyes on days 13, 16, and 18. The most pronounced effect was noted on days 16 and 18 (p < 0.001). On days 13, 16, and 18 the number of eyes with lower EAU-score was significantly higher in the treatment group, with the most notable effect observed on day 18 (p < 0.003).ConclusionIntravitreal administration of anti-IL-6 treatment notably mitigates experimental autoimmune uveitis in mice, both functionally and clinically. Further investigations are warranted to assess the potential of intravitreal anti-IL-6 therapy as a treatment option for non-infectious uveitis in humans.

Dnajc3 (HSP40) Enhances Axon Regeneration in the Mouse Optic Nerve.

A forward genetics approach was used to identify genomic elements enhancing axon regeneration in the BXD recombinant mouse strains. Axon regeneration was induced by knocking down Pten in retinal ganglion cells (RGCs) using adeno-associated virus (AAV) to deliver an shRNA followed by an intravitreal injection of Zymosan with CPT-cAMP that produced a mild inflammatory response. RGC axons were damaged by optic nerve crush (ONC). Following a 12-day survival period, regenerating axons were labeled by intravitreal injection of Cholera Toxin B (CTB) conjugated with Alexa Fluor 647. Two days later, labeled axons within the optic nerve were examined to determine the number of regenerating axons and the distance they traveled down the optic nerve. The analysis revealed a surprising difference in the amount of axonal regeneration across all 33 BXD strains. There was a 7.5-fold difference in the number of regenerating axons and a 4-fold difference in distance traveled by regenerating axons. These data were used to generate an integral map defining genomic loci modulating the enhanced axonal regeneration. A quantitative trait locus modulating axon regeneration was identified on Chromosome 14 (115 to 119 Mb). Within this locus were 16 annotated genes. Subsequent testing revealed that one candidate gene, Dnajc3 , modulates axonal regeneration. Dnajc3 encodes Heat Shock Protein 40 (HSP40), which is a molecular chaperone. Knocking down Dnajc3 in the high regenerative strain (BXD90) led to a decreased regeneration response, while overexpression of Dnajc3 in a low regenerative strain (BXD34) resulted in an increased regeneration response. These findings suggest that Dnajc3 not only increases the number of regenerating axons, it also increases the distance those axons travel. This may prove to be critical for functional recovery in large mammals, where the distance axons travel to their target is considerably longer than that of the mouse. Thus, Dnajc3 may play a critical role for functional recovery in humans by increasing the number of regenerating axons and the distance the regenerating axons travel.

Impaired axonal transport at the optic nerve head contributes to neurodegeneration in a novel Cre-inducible mouse model of myocilin glaucoma.

Elevation of intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction, leading to neurodegeneration, is the pathological hallmark of primary open-angle glaucoma (POAG). Impaired axonal transport is an early and critical feature of glaucomatous neurodegeneration. However, a robust mouse model that replicates these human POAG features accurately has been lacking. We report the development and characterization of a novel Cre-inducible mouse model expressing a DsRed-tagged Y437H mutant of human myocilin (Tg.CreMYOCY437H). A single intravitreal injection of HAd5-Cre induced selective MYOC expression in the TM, causing TM dysfunction, reducing outflow facility, and progressively elevating IOP in Tg.CreMYOCY437H mice. Sustained IOP elevation resulted in significant retinal ganglion cell (RGC) loss and progressive axonal degeneration in Cre-induced Tg.CreMYOCY437H mice. Notably, impaired anterograde axonal transport was observed at the optic nerve head before RGC degeneration, independent of age, indicating that impaired axonal transport contributes to RGC degeneration in Tg.CreMYOCY437H mice. In contrast, axonal transport remained intact in ocular hypertensive mice injected with microbeads, despite significant RGC loss. Our findings indicate that Cre-inducible Tg.CreMYOCY437H mice replicate all glaucoma phenotypes, providing an ideal model for studying early events of TM dysfunction and neuronal loss in POAG.

HO-1-Mediated Ferroptosis Regulates Retinal Neovascularization via the COX2/VEGFA Axis

Retinal neovascularization (RNV) is a key pathological process in many blinding disorders. This study aims to investigate the potential mechanisms of heme oxygenase-1 (HO-1) on ferroptosis during RNV. Through bioinformatics analysis, differentially expressed ferroptosis-related genes were identified in the oxygen-induced retinopathy (OIR) mouse model. Ferroptosis was assessed in the OIR model and the human retinal microvascular endothelial cells (HRECs) with the treatment of H2O2. The mRNA and protein levels were measured through RT-qPCR and western blot. Lipid peroxidation was assessed through C11-BODIPY staining. HO-1 expression was knocked down by intravitreal injection with a self-complementary adeno-associated virus in the OIR model and small interfering RNA in HRECs. The pathological neovascular area and avascular area were assessed through immunofluorescent staining. The cellular functions of HRECs were evaluated with migration and tube formation assays. Our results demonstrate that HO-1 was significantly upregulated in the OIR model. 4-HNE upregulation and GPX4 downregulation were observed in the OIR model. The H2O2-induced oxidative stress resulted in lipid peroxidation, GPX4 downregulation, and mitochondrial morphology changes in HRECs. HO-1 knockdown induced GPX4 upregulation, and decreased lipid peroxidation in vitro and in vivo. Furthermore, HO-1 inhibition reduced pathological RNV in the OIR model and attenuated migration and tube formation in HRECs. Treatment with 6-OHDA restored the decrease of VEGFA, migration, and tube formation caused by HO-1 knockdown in HRECs. Overall, HO-1-mediated ferroptosis can regulate RNV through the COX2/VEGFA signal axis. These findings suggest that targeting HO-1 may serve as a promising approach for treating retinal neovascular diseases.

Term infant brain MRI after ROP treatment by anti-VEGF injection versus laser therapy.

Intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents is used to treat posterior type 1 retinopathy of prematurity (ROP). Recent reports indicate that anti-VEGF therapy may be associated with white matter brain injury, according to animal studies, and neurodevelopmental impairments in children born preterm. We investigated whether type 1 ROP treated with bevacizumab is associated with structural brain injury on infant term magnetic resonance images (MRIs) in very low birth weight infants compared with those treated with laser ablation. We retrospectively reviewed the medical records of very low birth weight infants from 2006 to 2021 with type 1 ROP who had been treated with laser or anti-VEGF therapy. Intravitreal bevacizumab injection was used for type 1 ROP in zone 1 or very posterior zone 2 or when laser treatment was not feasible. A pediatric neuroradiologist reviewed brain MRIs at term equivalent age (36-46 weeks' postmenstrual age) and classified infants for severity (no/mild vs moderate/severe) of overall brain and white matter injury using the validated Kidokoro scoring system. Fifty-two infants met inclusion criteria: 35 (67%) treated with laser and 17 (33%) with bevacizumab. Moderate-to-severe brain injury scores were not statistically different between bevacizumab and laser treatment groups in either continuous or binary adjusted analyses, for either the overall score or the white matter subscore. Severity of structural injury on term brain MRI (total and white matter) did not differ between infants with type 1 ROP treated with anti-VEGF agent (bevacizumab) and those treated with laser ablation.

Safety and Efficiency of Anti-VEGF with Dexamethasone Intravitreal Implant for Non-Ischemic Retinal Vein Occlusion: A Prospective, Case-controlled, Cohort Study.

This study aimed to assess the efficacy and safety of anti-VEGF combined with dexamethasone implant for the retinal vein occlusion patients with macular edema. In this prospective, case-controlled, cohort clinical trial (Register ID: ChiCTR2400080048), patients with non-ischemic retinal vein occlusion were enrolled from the Sanmenxia Central Hospital from August 2020 to April 2023. The patients were randomized into two groups. All the patients received ranibizumab intravitreal injection in the first 3 consecutive months. For the ranibizumab group, anti-VEGF injections were as needed thereafter in case of recurrence of macular edema; For the combination group, the patients received an intravitreal dexamethasone implant injection at 15 days after the first ranibizumab injection. The primary outcome measurements were improvement in best corrected visual acuity (BCVA) and reduction in central macular thickness (CMT). The secondary outcomes were recurrence of macular edema, number of intravitreal injections, and injection interval. Safety profiles were also recorded. A total of 124 patients were included, of which 73 patients completed all follow-ups. Both the ranibizumab monotherapy and the combination therapy significantly improved BCVA at all time points, compared to the baseline. The combined group achieved more BCVA improvement in 3 months, 6 months, and 12 months, compared to the ranibizumab alone group. Compared to the baseline, both groups achieved significant reductions in CMT at all follow-ups. However, the combination group showed more CMT reduction at 1 week post injection, compared to the ranibizumab group. The combination group had a significantly longer injection interval, lower injection time, and recurrence of macular edema. Ocular hypertension was the most common adverse events. Lastly, intraocular pressure was all well controlled by 1-3 glaucoma medications without surgical intervention. The combination therapy could significantly improve the BCVA and reduce the CMT with a good safety profile.

Clinical Characteristics of K. pneumoniae Related Endogenous Endophthalmitis in China.

To investigate the clinical characteristics and systemic risk factors of K. pneumoniae related endogenous endophthalmitis (KPREE) in China and explore the possible pathophysiological mechanisms. This was a retrospective comparative study. All enrolled KPREE patients were followed up for at least 1 month to observe their clinical characteristics, unfavorable prognosis, and risk factors, and were compared with intraocular surgery-related postoperative endophthalmitis (ISRPE). Finally, a total of 15 eyes (3 both eyes) from 12 patients were enrolled in KPREE group, and 11 eyes (none both eyes) from 11 patients were enrolled in ISRPE group. Compared to the ISRPE group, the KPREE group had a higher percentage of fever (100% vs 9.09%, P = 0.000), liver abscess (91.67% vs 0%, P = 0.000), lung involvement (50.00% vs 0%, P = 0.024), and lower plasma albumin levels (24.1 [17.8, 31.7] vs 44.0 [37.7, 48.4], P = 0.001). Furthermore, Pearson's partial correlation analysis showed that fever (adjusted r = 0.592, adjusted P = 0.026) and plasma albumin (adjusted r = -0.658, adjusted P = 0.011) were independent factors associated with KPREE. In the KPREE group, ten eyes received 1-3 intravitreal antibiotic injections within one month. In the ten eyes that underwent injections, due to poor treatment reaction, four eyes experienced evisceration, and two eyes underwent vitrectomy with silicone oil tamponade at 1-month follow-up. And one eye developed sympathetic ophthalmia at 8-month visit. Patients with K. pneumoniae infection with hypoproteinemia or fever should be highly vigilant about the occurrence of KPREE, and more attention should be paid to the contralateral risk of KPREE or sympathetic ophthalmia.

Bilateral Anti VEGF on Same Day-Investigation on Safety in Retinopathy of Prematurity (BASISROP)- A Multicenter retrospective study

PurposeTo report incidence of procedure related complications in preterm infants with ROP treated with intravitreal anti vascular endothelial growth factors (anti VEGF) injection in both eyes on same day DesignRetrospective, multicenter case series SubjectsPreterm infants with ROP treated with anti VEGF bilaterally on same day MethodsIntervention: All included infants underwent intravitreal anti VEGF injection in both eyes under aseptic precautions in ophthalmic operation theatre (OT) or neonatal intensive care unit (NICU). Postoperative examination was performed to look for procedure related complications Main Outcome MeasuresIncidence of procedure related complication (Presumed endophthalmitis, intraocular inflammation, lens injury, vitreous hemorrhage, retinal tear) in the study cohort. To study association of indication, type of anti VEGF, type of needle used, setting of procedure, site of injection (distance from limbus) and experience of the treating ophthalmologist with the complications. Results9984 eyes of 4992 infants were analysed. The procedure was most commonly performed in ophthalmic OT (8258, 82.7%) using 29G (4514, 45.2%) needle between 1-1.5 mm (9984, 100%) from limbus. Aggressive retinopathy of prematurity was the most common indication for anti VEGF use (4866, 48.7%) while Bevacizumab was the most commonly used anti VEGF agent (8642, 86.6%). Overall, 26 eyes (0.3%) had procedure related complications. Lens injury (15, 0.15%) and presumed endophthalmitis (7, 0.07%) were most common complications. One eye had culture proven endophthalmitis with Pseudomonas aeruginosa. No case of bilateral endophthalmitis was noted. Endophthalmitis was not associated with setting of procedure or type of anti VEGF used, while risk of lens injury was seven times higher when performed in NICU and 30 times higher when performed by an ophthalmologist with < 1year of experience in injecting anti VEGF in preterm infants. ConclusionsThe incidence of presumed endophthalmitis after bilateral same day anti VEGF in infants with ROP is 0.07%. These infants can be treated in both eyes on same day with the anti VEGFs and needles (29-32G) evaluated in this study, with emphasis on the direction of needle parallel to visual axis. Extra precaution is advocated if the procedure is planned in NICU or by an ophthalmologist with limited experience.

Endomucin regulates the endothelial cytoskeleton independently of VEGF

The endothelial glycocalyx, lining the apical surface of the endothelium, is involved in a host of vascular processes. The glycocalyx is comprised of a network of membrane-bound proteoglycans and glycoproteins along with associated plasma proteins. One such glycoprotein is endomucin (EMCN), which our lab has revealed is a modulator of VEGFR2 function. Intravitreal injection of siEMCN into the eyes of P5 mice impairs vascular development. In vitro silencing of EMCN suppresses VEGF-induced proliferation and migration. Signaling pathways that drive cell migration converge on cytoskeletal remodeling. By coupling co-immunoprecipitation with liquid chromatography/mass spectrometry, we identified interactions between EMCN and proteins associated with actin cytoskeleton organization. The aim of the study was to investigate the influence of EMCN on cytoskeleton dynamics in angiogenesis. EMCN depletion resulted in reduction of F-actin levels, whereas overexpression of EMCN induced increased membrane protrusions in cells that were rich in stress fibers. The reorganization of the actin filaments did not depend on VEGFR2 signaling, suggesting that EMCN connects the cytoskeleton and the glycocalyx.

ADMINISTERING INTRAVITREAL BEVACIZUMAB FOR RETINOPATHY OF PREMATURITY: 8-Year Cognitive Outcomes In A Prospective Cohort.

Determine whether intravitreal injection of bevacizumab exerts long-term effects on neurodevelopmental outcomes in children with retinopathy of prematurity (ROP) when reaching the age of 8 years. In total, 277 children were enrolled. Patients were stratified into full-term, preterm without ROP, ROP without treatment, or ROP with treatment groups, based on gestational age and ROP status. Children under the gestational age of 37 weeks were considered premature. Patients' cognitive outcomes were evaluated using a full-scale intelligence quotient (full score and percentile) generated by the Wechsler Intelligence Scale for Children-Fourth Edition every 1 year to 2 years. At the mean age of 7.8 years, ROP without and with treatment groups demonstrated lower full-scale intelligence quotient scores and percentiles, compared with full-term and premature groups (both P < 0.05). Full-scale intelligence quotient scores and percentiles did not significantly differ between patients who received different treatments for ROP (full score P = 0.19; percentile P = 0.37). After adjusting for gestational age, logMAR best-corrected visual acuity was negatively associated with full-scale intelligence quotient scores ( P = 0.0008) and percentiles ( P = 0.0002). At the mean age of 8 years, patients with ROP undergoing injection of bevacizumab did not exhibit worse cognitive outcomes than those who underwent laser photocoagulation or both treatments. Gestational age and best-corrected visual acuity correlated with cognitive development in children.

ONS-5010 (bevacizumab-vikg) Safety and Efficacy in Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration.

This was a prospective multicenter, randomized, double-masked, active-controlled study, the aim of which was to demonstrate the efficacy and safety of intravitreal ONS-5010 (bevacizumab-vikg) in eyes with neovascular age-related macular degeneration (nAMD). This was a phase III trial on ONS-5010 (NORSE TWO). Treatment-naïve nAMD patients aged 50 years and older with a best-corrected distance visual acuity (BCVA) of 25 to 67 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and evidence of disease activity were included. Subjects randomized to ONS-5010 received monthly intravitreal doses of 1.25 mg of ONS-5010, bevacizumab-vikg (Outlook Therapeutics) for 12 months. Subjects randomized to ranibizumab received 0.50 mg of ranibizumab on days 0, 30, 60, 150, and 240 based on the PIER study dosing regimen. The primary end point was the proportion of subjects who gained ≥ 15 letters from baseline in BCVA at 11 months, and evaluating the safety and tolerability of intravitreal injections of ONS-5010 administered monthly from baseline to 12 months. One hundred thirteen subjects were included in the ONS-5010 group and 115 subjects were included in the ranibizumab group. Respectively, 41.7% and 23.1% of patients gained ≥ 15 letters (3 lines) of visual acuity, with a risk difference of 0.1859 [95% CI = 0.0442, 0.3086]; P = 0.0052. The change in BCVA from baseline to 11 months was found to be 11.2 ± 12.19 and 5.8 ± 14.80 ETDRS letters, respectively. The number of subjects gaining ≥ 5 and ≥ 10 letters and subjects losing < 15 letters was significantly higher in the ONS-5010 group. Similarly, subjects with a Snellen visual acuity equivalent of 20/200 (35 ETDRS letters) or worse at 11 months were significantly fewer in the ONS-5010 group. Only one subject in the ONS-5010 group had a study-related serious ocular adverse event (SAE), namely, elevated intraocular pressure. The most common adverse event in the ONS-5010 group was conjunctival hemorrhage (8.8%), and reduced visual acuity in the ranibizumab group (12.2%). In the prescribed treatment plan, ONS-5010 exhibited strong effectiveness in improving or stabilizing visual acuity and was also well tolerated. Bevacizumab and ranibizumab displayed a comparable safety profile. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Stakeholder insights on cost, quality, and incorporating patient voice in managed care decisions on neovascular (wet) age-related macular degeneration: Findings from the AMCP Market Insights program.

Wet age-related macular degeneration (AMD) is an acquired degeneration of the retina that can lead to central vision impairment. It is primarily treated with intravitreal injections of vascular endothelial growth factor inhibitors. Although vascular endothelial growth factor inhibitors can effectively prevent progression of vision loss in many patients, they require ongoing regular administration and are therefore associated with considerable treatment burden. To gain insights into the impact of wet AMD and its treatment, AMCP convened an expert panel of managed care stakeholders in April 2024 through its Market Insights program. Key issues related to wet AMD identified by participants included cost and affordability, provider-related considerations, biosimilar adoption, measuring and improving quality, and incorporating the patient voice. Suggested payer best practices related to these issues in wet AMD also emerged from the discussion.

Development of puerarin-loaded poly(lactic acid) microspheres for sustained ocular delivery: In vitro/vivo evaluation

Diabetic retinopathy, an ocular complication of diabetes, is an important cause of blindness in adults. Puerarin is considered to have promising potential for clinical use in treating diabetic retinopathy. In this study, we designed a novel puerarin-loaded poly(lactic acid) sustained-release microspheres suitable for ocular administration, and we assessed itsin vitro and in vivo properties. The preparation of puerarin-loaded microspheres was optimized by Box-Behnken response surface design. The encapsulation efficiency and drug loading of microspheres were 35.71% and 3.85%, respectively. The microspheres exhibited good dispersion and high safety, making it suitable for ocular drug delivery. In vitro release demonstrated that microspheres had a well-sustained release effectiveness, and its release behavior complied with the zero-order kinetic characteristics. The results of ocular tissue distribution revealed that the CmaxandAUC0-∞ of the microspheres group in the retina and choroid were considerably higher than those of the solution group and the intravenous injection group. This research revealed that intravitreal injection of microspheres can significantly prolong the half-life of puerarin in eye tissues and achieve sustained drug release. Therefore, intravitreal injection of microspheres has positive implications for the treatment of diabetic retinopathy.

Submacular hemorrhage: My personal journey to the goal.

Acute submacular hemorrhage (SMH) can be caused by various diseases including age-related macular degeneration (AMD), polypoidal choroidal vasculopathy (PCV), and retinal arterial microaneurysm (RAM). The natural course of submacular hemorrhage is generally poor. Animal studies have suggested that the removal of subretinal hemorrhage may effectively reduce retinal damage caused by hemorrhage in humans and removal of submacular hemorrhage have been performed with limited visual outcomes. Pneumatic displacement involving intravitreal expansile gas with or without adjunctive intravitreal injection of tissue plasminogen activator (tPA) has demonstrated effective displacement of SMH and improvement in visual acuity in the majority of cases. Although tPA may not be indispensable, its use may facilitate displacement. Combining pneumatic displacement with vitrectomy and subretinal injection of tPA may achieve superior displacement of SMH compared to pneumatic displacement of SMH, implying that pneumatic displacement of SMH with vitrectomy and subretinal injection may offer enhanced effectiveness in SMH displacement,while noobvious different was found in visual outcomes between the two treatments.Complications associated with these procedures encompass breakthrough hemorrhage, retinal detachment and macular hole formation. Breakthrough hemorrhage is more commonly observed following pneumatic displacement whereas retinal detachment appears to be more prevalent following vitrectomy. Macular hole formation subsequent to vitrectomy represents a significant complication, particularly in eyes with SMH attributed to ruptured retinal arterial microaneurysm. Both pneumatic displacement and vitrectomy present advantages and disadvantages, and the superiority between the two remains undetermined. Sequential strategy for the treatment of submacular hemorrhage is another option. As the initial step, pneumatic displacement of SMH should be attempted, and if displacement is insufficient, pneumatic displacement following vitrectomy with subretinal injection of tPA may be pursued. Further investigations are warranted to ascertain optimal management strategies for SMH leading to improved outcomes. KEY MESSAGES: What is known • Pneumatic displacement with/without intravitreal tPA injection, and vitrectomy with subretinal tPA injection and gas are the two major treatments for submacular hemorrhage. What is new • No obvious different was found in visual outcomes between vitrectomy, subretinal tPA injection and gas, and intravitreal tPA injection and gas while vitrectomy with subretinal tPA injection and gas may achieve better displacement of submacular hemorrhage. • Macular hole formation is a specific complication for submacular hemorrhage due to ruptured retinal arterial macroaneurysm.

Association between renal function and the Treatment of Diabetic Macular Edema in Long-Term Cohort Study

To determine the correlation between the severity of chronic kidney disease (CKD) and treatment of diabetic macular edema (DME). The retrospective 2-year cohort study included eyes with DME confirmed using spectral-domain optical coherence tomography in Taipei Veterans General Hospital, Taiwan, between 2010 and 2020. All the eyes were treated with an intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) during regular follow-up around 2 years. They were categorized into 3 different groups: an estimated glomerular filtration rate ≥ 60 (mL/min per 1.73 m2) (group A), < 60 (group B), and patients undergoing hemodialysis (group C). The main outcome measures were (1) visual improvement, (2) structural improvement, and (3) the injection frequency of anti-VEGF in the different groups. In this study, 167 eyes from 120 patients were enrolled. Compared with groups B and C, the eyes in group A experienced the only significant visual improvement at month 3, month 6, and month 12 (P = 0.0001, 0.0002, 0.0013, respectively). The presence of subretinal fluid and intraretinal cysts was significantly decreased in groups A and B. In the treatment frequency analysis, the number of injections was the highest in group A and lowest in group C during the study period (P = 0.04). The severity of CKD had an impact on the DME treatment. The less severe CKD was, the greater the visual improvement that could be achieved. In addition, relatively poor renal function required a lower anti-VEGF injection frequency. The active prevention of the progression of CKD may play a key role in DME treatment.

IDIOPATHIC RETINAL VASCULITIS, ANEURYSMS, AND NEURORETINITIS COMPLICATED BY CILIORETINAL ARTERY OCCLUSION: MULTIMODAL IMAGING AND 5-YEAR FOLLOW-UP.

To describe a multimodal imaging and a 5-year follow-up of a case of cilioretinal artery occlusion (CLRAO) in a 40-year-old woman with idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome. Fundus photography, indocyanine green and fluorescein angiography, optical coherence tomography (OCT), OCT angiography (OCTA), and a literature review of retinal artery occlusions associated with IRVAN syndrome were performed. Fundus examination revealed bilateral blurred margins of the discs and peri-vascular hard exudates. Fluorescein angiography (FA) demonstrated peripheral capillary nonperfusion areas in both eyes (OU). It also revealed an aberrant cilioretinal artery in the right eye (OD). OCT showed attenuation of the inner retinal layers and disruption of the outer retinal layers secondary to CLRAO in OD. OCTA allowed a clear identification of macular hypoperfusion in OU. Laser photocoagulation, along with anti-VEGF and corticosteroid intravitreal injections, was administered in OU. Best-corrected visual acuity remained stable, with no evidence of progression or development of neovascularization after a 5-year follow-up. IRVAN syndrome may be complicated by CLRAO, resulting in poor final visual acuity despite reperfusion of the occluded artery. In such cases, multimodal imaging allows the identification of complications such as macular atrophy on OCT and hypoperfusion areas that may not be detected on FA on OCTA.

A New Ray of Hope in the Treatment of Seasonal Hyperacute Panuveitis: Could Intravitreal Triple Combination Therapy of an Antibiotic with Dual Steroids Play a Pivotal Role?

ABSTRACT Introduction Seasonal Hyperacute Panuveitis (SHAPU) is a blinding disease in Nepal with unknown aetiology. Henceforth, we proposed to study the treatment outcome of a triple intravitreal combination therapy of dual steroids triamcinolone (long-acting steroid) and dexamethasone (short-acting steroid) along with antibiotic moxifloxacin for patients with severe stage of SHAPU. Methods A prospective study was conducted among the SHAPU patients presenting in severe stages during the September to December 2023 outbreak. Intravitreal injection of 4-mg preservative-free triamcinolone acetonide (4 mg/0.1 ml) with intravitreal dexamethasone injection (0.4 mg/0.1 ml) and 0.5 mg/0.1 ml of moxifloxacin was given in the operating theatre. Best corrected visual acuity, intraocular pressure measurements, vitreous haze and fundus evaluation, were assessed to determine the treatment outcome on examination on day 7 and day 30 following intravitreal combination therapy. Result A total of 6 patients (2 female and 4 male) were enrolled. At presentation, the mean BCVA was 2.40 ± 0.30 logMAR, mean intraocular pressure was 12.8 mmHg and vitreous haze was 4+ haze in all cases. The evaluation on the 7th day and 30th after injection showed significant improvement in BCVA (p value = 0.039; p value = 0.040, respectively). The change in the IOP at day 7 (p value = 0.85) was insignificant. However, the IOP change was significant at day 30 (p value = 0.5). Similarly, there was a marked reduction in the vitreous haze with better fundus visibility after treatment. Conclusion This study depicted that steroids prevent the dreaded complication of hypotony due to ciliary shutdown by combating severe inflammation, thus adding new hope to the armamentarium of SHAPU management.

Omiganan-Based Synthetic Antimicrobial Peptides for the Healthcare of Infectious Endophthalmitis.

Bacterial endophthalmitis is a severe infection of the aqueous or vitreous humor of the eye that can lead to permanent vision loss. Due to the rapid emergence of antibiotic resistance and dose-limiting toxicities, the standard treatment of bacterial endophthalmitis via the intravitreal injection of broad-spectrum antibiotics remains inadequate. Membrane active cationic antimicrobial peptides (AMPs) have emerged as a promising class of effective and broad-spectrum antimicrobial agents with potential to overcome antibiotic resistance. In this work, we investigate, for the first time, the use of omiganan (IK-12), a 12-amino acid indolicidin derivative for the treatment of bacterial endophthalmitis. Additionally, IK-12 was used as a template to perform amino acid rearrangements, without altering the length or type of amino acids, to yield a series of new derivative AMPs with varying extents of secondary structure formation under membrane mimicking conditions. IK-12 and its derivatives demonstrated strong and broad-spectrum antibacterial activities against a panel of clinically isolated Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus commonly implicated in bacterial endophthalmitis. Interestingly, two of the new IK-12 derivatives, IP-12 and WP-12, showed lower geometric mean minimum inhibitory concentration and higher 50% hemolysis concentration values, which effectively translated into 2- to 3.4-fold higher bacterial selectivity than the parent IK-12. Furthermore, the intravitreal injection of IK-12, IP-12, and WP-12 in a rabbit model of MRSA-induced endophthalmitis led to considerably improved clinical presentation and reduced recruitment of inflammatory cells. In all, these results demonstrate the potential of IK-12 and its derivatives, IP-12 and WP-12, as promising candidates for the treatment of bacterial endophthalmitis.