TWELVE-MONTH OUTCOMES OF INTRAVITREAL AFLIBERCEPT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Fixed Versus As-needed Dosing.

PURPOSE: To compare the clinical outcomes of aflibercept used with a fixed schedule with a pro-re-nata (PRN) retreatment regimen in patients affected by neovascular age-related macular degeneration. METHODS: This is a prospective multicenter, noninferiority, propensity score-matched study evaluating the 12-month outcomes of aflibercept given either according to labeling or following a PRN regimen. Patients included in the latter group received one initial injection, followed by monthly visits and as-needed retreatment. RESULTS: One-to-one matching resulted in fixed and PRN arms containing 92 eyes each. Visual acuity improved from baseline to 12 months in both the study groups. At Month 4, the fixed regimen was equivalent to the PRN regimen (mean difference: 1.75 Early Treatment Diabetic Retinopathy Study letters, 95% confidence interval: -1.42 to +4.92). The pro-re-nata regimen failed to show noninferiority compared with the fixed regimen at both Month 8 (mean difference: 3.43 Early Treatment Diabetic Retinopathy Study letters, 95% confidence interval: +0.25 to +6.22) and Month 12 (mean difference: 4.83 Early Treatment Diabetic Retinopathy Study letters, 95% confidence interval: +1.37 to +8.29). All patients in the fixed group received seven injections. Patients included in the PRN arm received a mean of 5.5 ± 1.6 treatments. CONCLUSIONS: Aflibercept given with a fixed treatment regimen produces better visual acuity outcomes than an individualized regimen.

Platelet-rich plasma as treatment for persistent ocular epithelial defects.

Platelet- rich plasma (PRP) exhibits regenerative proprieties in wound healing but the biochemical mechanisms are unclear. In this study, autologous PRP with a mean value of 338 × 10(3) platelets/µL was used to treat corneal lesions of different aetiology, while homologous PRP with 1 × 10(6) platelets/µL was used to treat cornel lesions induced by a graft versus host disease. The impact of platelet count on the levels of PDGF AA and BB, VEGF, and EGF in the two PRPs was evaluated after a cycle of freezing/thawing. Treated corneal lesions healed or improved. The levels of PDGF AA and BB, VEGF, and EGF in the autologous PRP raised from 296 ± 61; 201.8 ± 24; 53 ± 14 and 8.9 ± 2 to 1017 ± 253; 924.7 ± 222; 101 ± 46.5 and 174 ± 15.5 pg/mL, while in the homologous PRP were 3.4, 4.5, 3.2 and 2 folds higher, respectively. High level of platelet counts seems not required to treat corneal lesions.

Long-term functional and morphologic retinal changes after ranibizumab and photodynamic therapy in myopic choroidal neovascularization.

PURPOSE: To assess and compare the long-term functional and anatomical outcomes in eyes with myopic choroidal neovascularization (CNV) treated with intravitreal injections of ranibizumab or with photodynamic therapy (PDT). METHODS: Eighty-five eyes of 85 consecutive patients with myopic CNV and treated with either PDT (43/85) or ranibizumab 0.5 mg (42/85) and at least 24 months of follow-up were collected. Data from the best-corrected visual acuity, optical coherence tomography, and fluorescein angiography were compared between the groups. Differences in the regression pattern of myopic CNV and the rate of chorioretinal atrophy development were also compared between the groups. RESULTS: The effect of treatment over time on best-corrected visual acuity and the central retinal thickness was significantly greater in the ranibizumab group (P = 0.0012 and P < 0.0002, respectively), with eyes treated with ranibizumab showing a significant central retinal thickness decrease since the first visit and maintained until 24 months. The proportion of patients showing a complete closure of CNV was similar between the groups (93% [39 of 42 eyes in the ranibizumab group] vs. 88% [38 of 43 eyes in the PDT group], P = 0.48). Both treatments were associated with an increase of chorioretinal atrophy size, which was greater in the PDT-treated eyes (P = 0.016). CONCLUSION: Ranibizumab therapy showed a greater long-term efficacy compared with PDT in myopic CNV eyes, with a fewer proportion of eyes developing an increase of lesion and chorioretinal atrophy size.

Real-World Use of Off-Label MVASI in the Treatment of Patients With Neovascular AMD and DME.

Purpose: The purpose of this study was to evaluate the efficacy and safety of bevacizumab-awwb in the off-label treatment of neovascular age-related macular degeneration (n-AMD) and diabetic macular edema (DME). Methods: All patients with n-AMD and DME treated in the maintenance phase according to the "treat and extend" strategy, who underwent forced drug substitution from bevacizumab to bevacizumab-awwb from October 2022 to April 2023 at the Tor Vergata Polyclinic in Rome, were evaluated in a retrospective study. The primary outcome was changes in central retinal thickness (CRT) over time following drug substitution. The secondary outcomes were variations in drug durability, best corrected visual acuity (BCVA) and retinal fluid, and the incidence of drug-related local and systemic serious adverse events. Results: Of 80 eyes of 76 patients with n-AMD and 55 eyes of 44 patients with DME included, before and after drug substitution, the average CRT did not statistically differ; the proportion of patients within time intervals of q8, q12, and q16 was not different; and the mean BCVA remained constant. Of a cumulative 3496 bevacizumab-awwb treatments (2154 for patients with n-AMD and 1342 for patients with DME), no local severe complications were detected. Out of a total of 544 patients (342 affected by n-AMD and 202 affected by DME), no serious adverse events were reported. Conclusions: In our cohort of patients with n-AMD and DME in the maintenance phase, bevacizumab-awwb seems to represent a viable and cost-effective intravitreal therapy with comparable efficacy and safety to the originator. Translational Relevance: This study provides a preliminary assessment of the efficacy and safety of intravitreal bevacizumab-awwb, which is widely used off-label in retinal vascular diseases.

Combined reduced fluence photodynamic therapy and intravitreal ranibizumab for polypoidal choroidal vasculopathy.

PURPOSE: We performed a prospective noncomparative study to report the results of reduced fluence photodynamic therapy (PDT) combined with intravitreal ranibizumab in patients with polypoidal choroidal vasculopathy with active exudation and hemorrhage. METHODS: Seventeen polypoidal choroidal vasculopathy eyes were treated, and follow-up for all patients was 12 months. Photodynamic therapy was administered with reduced fluence (exposure time of 70'') and followed (48 hours later) by intravitreal ranibizumab (0.5 mg in 50 µL). Intravitreal ranibizumab, with or without reduced fluence PDT, was repeated as indicated by clinical and angiographic findings. RESULTS: During the follow-up, the mean best-corrected visual acuity significantly improved from 0.45 ± 0.29 logarithm of the minimum angle of resolution at baseline to 0.29 ± 0.28 logarithm of the minimum angle of resolution at 12 months. The mean total macular volume (documented by optical coherence tomography retinal map examination) decreased from 7.5 ± 1.18 mm to 6.7 ± 0.8 mm. In 95% of the cases, best-corrected visual acuity remained stable or improved. CONCLUSION: Reduced fluence PDT limits laser exposure, minimizing the risks of PDT-induced adverse effects. Intravitreal injections of ranibizumab 0.5 mg reduced bleeding and leakage in polypoidal choroidal vasculopathy eyes and interfere with rebound upregulation of vascular endothelial growth factor because of PDT-induced choroidal hypoperfusion. Combined treatment may improve treatment outcomes in polypoidal choroidal vasculopathy while minimizing ocular and systemic complications of treatment.

Persistent epithelial defect after penetrating keratoplasty caused by adenoviral infectious keratitis.

A causal role of herpes simplex infection in persistent epithelial defect following penetrating keratoplasty (PKP) has been documented in the past. Instead, not much information is available on the role of adenovirus infection in delayed epithelization following PKP. Here, we describe a case of persistent epithelial defect due to adenoviral infection keratitis confirmed by PCR analysis. Adenovirus keratitis can be an unusual cause of delayed epithelization after PKP.

Indocyanine Green Angiography and Optical Coherence Tomography Angiography of Choroidal Neovascularization in Age-Related Macular Degeneration.

Purpose: To compare the capability of indocyanine green angiography (ICGA) and optical coherence tomography angiography (OCTA) in detecting choroidal neovascularization (CNV). Methods: In this prospective study, patients with CNV detected with fluorescein angiography (FA) underwent ICGA and OCTA, spectral domain OCT (SD-OCT), and infrared or fundus color photographs. CNV lesions were outlined on ICGA and OCTA images, and the composition and size of the CNV was documented. Results: One hundred eighty-two eyes were included. With ICGA, well-defined lesions were observed in 37.9%, partly defined in 44.5%, and undefined in 17% of eyes. On OCTA, well-defined, partly defined, and undefined vessels were observed in 53.8%, 27.5%, and 18.7% of eyes, respectively. There was a good correlation between CNV size measured with the two instruments (r = 0.84). However, OCTA underestimated CNV area by about 4.5% (slope coefficient with linear regression: 0.55, 95% confidence interval [CI]: 0.46 to 0.65; intercept: 0.27, 95% CI: -0.2 to 0.56). On ICGA, CNV composition was capillary in 28%, mature in 14.3%, and mixed (capillary and major neovascular complex) in 57.7% of eyes. Similarly, OCTA revealed capillary, mature, and mixed CNV in 28.9%, 15.9%, and 55.5% of eyes, respectively. Conclusions: OCTA provides the clinician the ability to perform precise structural and vascular assessment of CNV noninvasively. Our study is, to our knowledge, the largest OCTA analysis to date of CNV secondary to neovascular AMD analyzed simultaneously by ICGA and OCTA.

A cluster of presumed, noninfectious endophthalmitis after intravitreal injection of bevacizumab: long-term follow-up.

PURPOSE: To report the outcome of 5 consecutive cases of presumed, noninfectious endopththalmitis following intravitreal injection of bevacizumab (IVB). METHODS: Ten pre-loaded syringes of bevacizumab (1.25 mg/50 µL) furnished by a compounding pharmacy were injected intravitreally. Treatments were performed in the operating room by the same surgeon on 2 consecutive days. RESULTS: Of 10 eyes, 5 showed moderate to severe ocular inflammation within a few days of injection. All patients were treated in the same surgical session. Vitreous tap performed in the patient presenting with the most severe grade of inflammation was negative for bacteria and fungi. At the time of the vitreous biopsy, this patient was injected with vancomycin 1 mg/100 µL in the vitreous cavity. Other eyes with moderate inflammation received topical and systemic antibiotics and topical steroid treatment. Visual acuity returned to pre-endophthalmitis or better levels in all eyes within 1 month. The other 5 patients treated with IVB from the same batch in the other surgical session did not develop inflammation. CONCLUSIONS: IVB can induce noninfectious endophthalmitis. The use of compounded syringes can explain clustering of the inflammation. We were unable to identify the reasons for the variable grade of inflammation we observed in our patients.

Visual disability and quality of life in glaucoma patients.

Glaucoma is an optic neuropathy that can result in progressive and irreversible vision loss, thereby affecting quality of life (QoL) of patients. Several studies have shown a strong correlation between visual field damage and visual disability in patients with glaucoma, even in the early stages of the disease. Visual impairment due to glaucoma affects normal daily activities required for independent living, such as driving, walking, and reading. There is no generally accepted instrument for assessing quality of life in glaucoma patients; different factors involved in visual disability from the disease are difficult to quantify and not easily standardized. This chapter summarizes recent works from clinical and epidemiological studies, which describe how glaucoma affects the performance of important vision-related activities and QoL.

The effect of corneal flap on optical aberrations.

PURPOSE: To evaluate the changes in ocular aberrations induced by corneal flap creation. DESIGN: Prospective interventional nonrandomized clinical trial. METHODS: This study included 15 patients who were scheduled for laser in situ keratomileusis. A nasal hinge flap was created, using the Nidek MK-2000 microkeratome and then replaced without performing laser ablation. The ocular aberrations were measured before and after flap creation using the Nidek Optical Path Difference Scanning System ARK-10000. RESULTS: The root mean square wavefront errors of the higher-order optical aberrations (third-, fourth-, fifth-, and sixth-order aberrations) were not significantly altered at 1 week postsurgery compared with the preoperative values (P >.35). CONCLUSIONS: Creating a corneal flap with the Nidek MK-2000 microkeratome did not induce changes in higher-order optical aberrations as measured with the Nidek Optical Path Difference Scanning System ARK-10000 during the early postoperative period.

Age-related macular degeneration: insights into inflammatory genes.

Age-related macular degeneration (AMD) is a progressive neurodegenerative disease that affects approximately 8.7% of elderly people worldwide (>55 years old). AMD is characterized by a multifactorial aetiology that involves several genetic and environmental risk factors (genes, ageing, smoking, family history, dietary habits, oxidative stress, and hypertension). In particular, ageing and cigarette smoking (including oxidative compounds and reactive oxygen species) have been shown to significantly increase susceptibility to the disease. Furthermore, different genes (CFH, CFI, C2, C3, IL-6, IL-8, and ARMS2) that play a crucial role in the inflammatory pathway have been associated with AMD risk. Several genetic and molecular studies have indicated the participation of inflammatory molecules (cytokines and chemokines), immune cells (macrophages), and complement proteins in the development and progression of the disease. Taking into consideration the genetic and molecular background, this review highlights the genetic role of inflammatory genes involved in AMD pathogenesis and progression.

Haplotypes in IL-8 Gene Are Associated to Age-Related Macular Degeneration: A Case-Control Study.

BACKGROUND: Age-related macular degeneration (AMD) is the main cause of blindness in the developed world. The etiology of AMD is multifactorial due to the interaction between genetic and environmental factors. IL-8 has a role in inflammation and angiogenesis; we report the genetic characterization of IL-8 allele architecture and evaluate the role of SNPs or haplotypes in the susceptibility to wet AMD, case-control study. METHODS: Case-control study including 721 AMD patients and 660 controls becoming from Italian population. Genotyping was carried out by Real Time-PCR. Differences in the frequencies were estimated by the chi-square test. Direct sequencing was carried out by capillary electrophoresis trough ABI3130xl. RESULTS: rs2227306 showed a p-value of 4.15*10(-5) and an Odds Ratio (OR) for T allele of 1.39 [1.19-1.62]. After these positive results, we sequenced the entire IL-8 regulatory and coding regions of 60 patients and 30 controls stratified for their genotype at rs2227306. We defined two different haplotypes involving rs4073 (A/T), rs2227306 (C/T), rs2227346 (C/T) and rs1126647 (A/T): A-T-T-T (p-value: 2.08*10(-9); OR: 1.68 [1.43-1.97]) and T-C-C-A (p-value: 7.07*10(-11); OR: 0.60 [0.51-0.70]). To further investigate a potential functional role of associated haplotypes, we performed an expression study on RNA extracted from whole blood of 75 donors to verify a possible direct correlation between haplotype and gene expression, failing to reveal significant differences. CONCLUSIONS: These results suggest a possible secondary role of IL-8 gene in the development of the disease. This paper outlines the importance of association between inflammation and AMD. Moreover IL-8 is a new susceptibility genomic biomarker of AMD.

Compassionate use of intravitreal pegaptanib in patients with age-related macular degeneration.

The study aim was to evaluate the short-term safety and efficacy of pegaptanib sodium injections (Macugen, Eyetech Pharmaceuticals, Inc., New York, NY) in the compassionate-use therapy of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Intravitreal pegaptanib was used to treat 41 eyes in 40 patients with CNV. Injections were given every 6 weeks, and a minimum of three injections were planned. The mean change in BCVA for all lesions was a loss of 0.03 Snellen lines. Seven eyes (17.1%) gained more than 3 lines, three (7.31%) lost 6 lines or more, and in 75.6% the BCVA stabilized or improved.

Typing of ARMS2 and CFH in age-related macular degeneration: case-control study and assessment of frequency in the Italian population.

OBJECTIVES: To determine the effects of the polymorphisms CFH Tyr402His and ARMS2 del443ins54 on susceptibility to age-related macular degeneration (AMD) and to find the frequencies of these single-nucleotide polymorphisms in an Italian population that was not examined clinically. METHODS: A total of 286 control subjects (126 men and 160 women) and 159 white patients (73 men and 86 women) harboring exudative AMD in 1 eye were recruited. A third group of 182 DNA samples from blood donors of the same geographical areas were also typed to assess the frequency of CFH Tyr402His and ARMS2 del443ins54 polymorphisms in the general population. The data were analyzed statistically by a standard 2 x 2 table, Fisher exact tests, and odds ratios. RESULTS: The deletion-insertion at chromosome 10q26 (del443ins54) showed the strongest association with AMD in terms of both P value and odds ratio (P = 2.7 x 10(-15); odds ratio = 3.25), and a highly significant association was also confirmed for Tyr402His at the CFH locus (P = 9.9 x 10(-13); odds ratio = 2.86). We found no differences in allele and genotype association between classic and occult choroidal neovascularization. We also observed that 39% of the samples in the general Italian population were at least 5.4 times more likely than control subjects to develop AMD. CONCLUSIONS: To our knowledge, this is the first confirmation of the association of del443ins54 in Italian patients with AMD, and we also confirmed the association of Tyr402His with CFH. Genetic analysis of the general population suggested that analysis of the ARMS2 and CFH risk alleles alone may be helpful in differentiating high-risk individuals (odds ratio > 5.00) from low-risk individuals (odds ratio < 0.45). CLINICAL RELEVANCE: Individuals at high risk for developing AMD could be identified and selected for specific prevention programs. In this context, the development of prevention programs based on dietary antioxidants or on close monitoring of at-risk individuals should be considered or suggested.

Modulation of Ku70/80, clusterin/ApoJ isoforms and Bax expression in indocyanine-green-mediated photo-oxidative cell damage.

PURPOSE: In order to characterize the biological effects and molecular mechanism underlying indocyanine-green (ICG)-mediated photo-oxidative cell damage, human cultured retinal pigmented epithelium (RPE) cells preloaded with ICG were exposed to 810-nm laser irradiation. Cell viability and death induction were examined, as well as the modulation of proteins involved in cell death and DNA repair. METHODS: ARPE-19 cells preloaded with 100 microM ICG were irradiated using continuous and micropulsed 810-nm laser for the dye photoactivation, and cell viability and apoptosis were evaluated. The expression and subcellular localization of Bax, Ku70, Ku80 and clusterin/ApoJ were analyzed by immunocytochemistry and Western blot. RESULTS: ICG photoactivation induced apoptosis in RPE cells. The micropulsed laser irradiation induced a higher percentage of cell killing as compared to continuous wave. Cell killing was inhibited by sodium azide, suggesting the involvement of reactive oxygen species in the laser-induced cell damage. Bax was strongly induced after 4 and up to 24 h of treatment. The nuclear proapoptotic isoform of clusterin/ApoJ was selectively upregulated after 24 h of treatment. The DNA repair machinery was upregulated after 4 and up to 24 h. CONCLUSION: These data elucidate some molecular mechanisms involved in cell death induced by ICG photosensitization. The increase and relocalization of Bax into the mitochondria and the upregulation and translocation of the proapoptotic isoform of clusterin/ApoJ in the nucleus demonstrated the involvement of these proteins in the photo-oxidative cell death pathway. These data point out new molecular targets and suggest potential applications in the therapy of the retinal diseases that could benefit by selective RPE treatment.

A microbiological and confocal microscopy study documenting a slime-producing Staphylococcus epidermidis isolated from a nylon corneal suture of a patient with antibiotic-resistant endophthalmitis.

BACKGROUND: We describe a case of posttraumatic endophthalmitis unresponsive to systemic (amoxicillin+clavulanic acid and piperacillin/tazobactam), intra-ocular (vancomycin) and topical (ofloxacin, tetracycline and sulfametoxazole) antibiotic therapy. Microbiological and confocal microscopy studies of a nylon corneal suture revealed the presence of a slime-producing strain of Staphylococcus epidermidis. METHODS: We describe the history and clinical presentation of a 77-year-old man in whom a high-grade posttraumatic endophthalmitis resolved only after the removal of a single nylon corneal suture. Microbiological investigations of the aqueous, vitreous and suture were performed, and the propensity of the suture-associated isolate to form biofilm was assessed using confocal microscopy. RESULTS: A single stain of S. epidermidis was isolated from both aqueous and vitreous specimens and from the suture. The planktonic form of the isolate was susceptible in vitro to the antibiotics administered to the patient, but the strain was capable of forming biofilms and this phenotype showed resistance to high concentrations of the same antibiotics. CONCLUSIONS: The presence of a slime-producing strain of S. epidermidis should be considered in endophthalmitis that is unresponsive to specific antibiotic therapy, especially in cases in which an intra-ocular foreign body (e.g., a suture) is present.

Low contrast visual acuity in pseudophakic patients implanted with an anterior surface modified prolate intraocular lens.

PURPOSE: To determine whether implantation of a new intraocular lens (IOL) with a modified prolate anterior surface, designed to reduce the positive spherical aberration of the pseudophakic eyes, results in improved contrast sensitivity assessed in terms of low contrast visual acuity (VA). METHODS: We carried out an intraindividual study of 12 patients with bilateral cataracts, randomized to receive a prolate anterior surface IOL (Tecnis Z9000, Pharmacia) in one eye and a biconvex spherical surface IOL (CeeOn 911 A, Pharmacia) in the other. High and low contrast VA was assessed under photopic conditions, before and after pupil dilation. RESULTS: After mydriasis, the Technis Z9000 provided significantly better low contrast VA at contrast levels < or = 25%. No significant difference was found under normal pupil conditions. CONCLUSION: Our results confirm the hypothesis that the spherical aberration of the eye after cataract surgery can be reduced by an anterior prolate surface IOL.