Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy.

Importance: Anti-vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown. Objective: To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported. Design, Setting, and Participants: Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53; range, 0 [worst] to 100 [best]) without CI-DME. Interventions: Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss. Main Outcomes and Measures: Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years. Results: Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57]; P < .001). The mean (SD) change in visual acuity from baseline to 4 years was -2.7 (6.5) letters with aflibercept and -2.4 (5.8) letters with sham (adjusted mean difference, -0.5 letters [97.5% CI, -2.3 to 1.3]; P = .52). Antiplatelet Trialists' Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants. Conclusions and Relevance: Among patients with NPDR but without CI-DME at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME. Trial Registration: ClinicalTrials.gov Identifier: NCT02634333.

Retinopatía asociada a inhibidor de la proteinquinasa de activación mitogénica (MEKAR). A propósito de un caso / Mitogen-activated protein kinase inhibitor-associated retinopathy (MEKAR). A clinical case

Los inhibidores de la proteína quinasa de activación mitogénica (MEK) son fármacos utilizados para el tratamiento de neoplasias tales como el melanoma metastásico. Su introducción ha mejorado el pronóstico de estas enfermedades, pero su uso no está exento de complicaciones oculares. Se ha descrito una retinopatía asociada a estos fármacos (MEKAR) consistente en la aparición de desprendimientos neurosensoriales (DNS), generalmente bilaterales y múltiples similares a los que aparecen en la coriorretinopatía serosa central (CSC). En la mayoría de los casos la tomografía de coherencia óptica es suficiente para diferenciar esta entidad de una CSC. Presentamos el caso de una paciente de 55 años que, en este contexto, desarrolló DNS bilaterales que asociaron disminución de agudeza visual y que se resolvieron cuando se suspendió la terapia por progresión tumoral (AU)

Mitogen-activated protein kinase kinase (MEK) inhibitors have significantly improved the prognosis of various types of cancer such as metastatic melanoma. However, their use is usually associated with ocular side effects. A retinopathy associated with these agents (MEKAR) has been described, consisting of the development of neurosensory detachments, generally bilateral and multiple, similar to those that appear in the central serous chorioretinopathy (CSC). Generally, optical coherence tomography allows us to differentiate the two conditions. We present the case of a 55-year-old woman in treatment with a MEK inhibitor, who developed bilateral neurosensory detachments and blurred vision, which resolved with the discontinuance of the treatment due to tumour progression (AU)

Arm-to-retina time predicts visual outcome of anti-vascular endothelial growth factor treatment for macular edema due to central retinal vein occlusion.

To explore the factors associated with best-corrected visual acuity (BCVA) after anti-vascular endothelial growth factor (anti-VEGF) treatment for macular edema secondary to central retinal vein occlusion (CRVO). We retrospectively reviewed the medical charts of 22 eyes of 22 treatment-naïve patients with CRVO diagnosed between September 2014 and December 2020. They received anti-VEGF treatment and follow-up for > 12 months. Mean patient age was 64.3 years; 13 (59.1%) were men. Eyes with baseline arm-to-retina (AR) time ≥ 16 s had better BCVA at 12 months (adjusted for baseline BCVA and age; B, - 0.658; 95% confidence interval - 1.058 to - 0.257; P = 0.003), greater mean BCVA change (P = 0.006), lower frequency of residual macular edema at 12 months (P = 0.026) and recurrent and/or unresolved macular edema during 12 months (P = 0.046), and higher frequency of reduction in central retinal thickness ≥ 150 µm at 1 and 12 months (both P = 0.046). Delayed AR time was associated with a better visual outcome and macular edema improvement in CRVO after anti-VEGF treatment regardless of initial BCVA and age. Our results may help understand the pathogenesis and predict the visual prognosis of patients before anti-VEGF therapy initiation.

Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials.

BACKGROUND: Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD). METHODS: TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300). FINDINGS: Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%]). INTERPRETATION: Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD. FUNDING: F Hoffmann-La Roche.

Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials.

BACKGROUND: To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody. METHODS: YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593). FINDINGS: 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]). INTERPRETATION: Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema. FUNDING: F Hoffmann-La Roche.

The impact of compliance among patients with diabetic macular oedema treated with intravitreal aflibercept: a 48-month follow-up study.

PURPOSE: This study aimed to compare anatomical and functional outcomes between patients with non-proliferative diabetic retinopathy (NPDR) with diabetic macular oedema (DME) who adhered to intravitreal aflibercept therapy and patients lost to follow-up (LTFU). METHODS: We enrolled 200 patients and recorded the interval between each procedure and the subsequent follow-up visit. Moreover, visual acuity (VA) and anatomical outcomes were measured at each follow-up examination. RESULTS: Among the patients, 103 (51%) patients adhered to intravitreal aflibercept therapy and follow-up examination while 97 (49%) patients were LTFU. Forty-six (47%) patients LTFU who returned for further treatment showed a significant decrease in VA from 0.51 (±0.46) to 0.89 (±0.38) logarithm of the minimum angle of resolution (logMAR) after 48 months (p = 0.004). Compared with the adherent group, the return group showed a worse VA at 48 months (p = 0.036). Further, 1 (1%) patient in the adherent group and 8 (17%) patients in the return group developed a proliferative DR. Patients who were LTFU had a 13.0 times greater chance to develop a proliferative DR (p = 0.022). CONCLUSIONS: Patients who did not adhere to intravitreal aflibercept therapy for DME showed significantly worse visual outcomes compared to patients with good therapy adherence. Moreover, patients with LTFU had a 13 times higher risk of developing a proliferative DR. Considering the potential disease progress, better strategies should be applied to optimize the functional outcome of patients at risk of reduced adherence.

Topical treatment of diabetic retinopathy: a systematic review.

Diabetic retinopathy (DR) is the most common microvascular complication in diabetes and may cause severe visual impairment. Until late stages of DR, treatment options are limited. The aim of the present review was to investigate whether changes of DR might be influenced by topical treatment with eye drops. This systematic review included both randomized and non-randomized human clinical studies on the subject. A systematic search of PubMed Medline, Embase and Scopus databases yielded 710 studies. No inclusion criteria regarding classification of DR were defined. Reference lists as well as first authors were screened for the inclusion of additional studies. Potential bias of the randomized studies was assessed using the Cochrane Risk of Bias tool. Nineteen studies suitable for inclusion were identified. Seven studies were randomized trials. These examined 11 different pharmacological groups of drugs in DR. A favourable effect of corticosteroid eye drops in diabetic macular oedema (DMO) was reported in four studies, and another study reported a positive trend. Eye drops with non-steroidal anti-inflammatory drugs were also reported to have a favourable effect in DMO, but not in non-center involving DMO. Application of neuroprotective agents was found effective in patients with pre-existing neurodegeneration in three studies. The remaining studies of DMO and DR were heterogeneous in both designs and results. Studies on treatment of DR with topical eye drops vary with regards to patient population, interventional drugs, study design, and outcome measures. Treatment of DR with eye drops was found effective in the aforementioned cases, but there is still a need for further investigations of long-term, randomized controlled trials in any of the reported pharmacological group.

A Pilot, Phase II, Observational, Case-Control, 1-Month Study on Asthenopia in Video Terminal Operators without Dry Eye: Contrast Sensitivity and Quality of Life before and after the Oral Consumption of a Fixed Combination of Zinc, L-Carnitine, Extract of Elderberry, Currant and Extract of Eleutherococcus.

The aims of the study were to investigate the ability and effectiveness of an oral intake of a fixed combination of zinc, L-carnitine, elderberry extract, black currant and Eleutherococcus extract in controlling the symptoms of eyestrain in videoterminal (VDT) users and to record its effects on contrast sensitivity. A single-center, phase II, observational, case-control, 1-month study in VDT workers without dry eye disease was carried out. Demographics and number of actual hours at VDT/day were taken into account. All subjects underwent a complete ophthalmic examination, including assessment of contrast sensitivity, and completed the computer vision symptom scale questionnaire at baseline and one month later. A total of 30 Caucasian subjects adhered to the required inclusion criteria and completed the study; 15 subjects were treated (T) and 15 were controls (C). All clinical data at baseline were similar in both groups (p > 0.05): after one month, all subjects had stable visual acuity, refractive defect and intraocular pressure (IOP); screen exposure time was unchanged. Regarding symptoms, at randomization, the groups had a similar score: 33.1 ± 3.3 in T and 32.8 ± 5.6 in C. One month later, the computer vision symptom scale (CVSS) questionnaire score decreased by -14.1 ± 3, 1 (p = 0.000) and -2.3 ± 1.8 (p = 0.568), respectively. Regarding contrast sensitivity, in group C the values of spatial frequencies remained unchanged, while they improved in almost all the cycles per degree stimuli in the treated group. Oral intake of a fixed combination of zinc, L-carnitine, elderberry extract, black currant and eleutherococcus extract can significantly improve contrast sensitivity and symptoms in VDT workers with no signs of dry eye disease.

Effect of Platelet-Rich Plasma on Corneal Epithelial Healing after Phototherapeutic Keratectomy: An Intraindividual Contralateral Randomized Study.

PURPOSE: To assess the effect of platelet-rich plasma (PRP) on the healing response of the corneal epithelium in eyes undergoing phototherapeutic keratectomy (PTK). METHODS: We prospectively examined 20 eyes of 10 patients undergoing bilateral PTK for granular corneal dystrophy or band keratopathy. Patients were randomly assigned to start topical administration of PRP ophthalmic suspension (PRP group) or artificial tears (control group) 4 times daily for 2 weeks. Immediately, 1, and 2 days, and 1 week after PTK, we quantitatively measured the staining area of the corneal epithelium, using slit-lamp photography. We also determined the subjective symptoms and the satisfaction, using the visual analogue system (VAS). RESULTS: The staining area in the PRP group was significantly smaller than that in the control group on days 1 and 2 (Wilcoxon signed-rank test, p = 0.022 and p = 0.017, respectively), but not on day 7 (p = 0.317). The recovery rate of the corneal epithelium in the PRP group was significantly higher than that in the control group on days 1 and 2 (p = 0.022 and p = 0.017, respectively), but not on day 7 (p = 0.317). We found no significant differences in pain (p = 0.139), foreign body sensation (p = 0.108), epiphora (p = 1.000), or satisfaction (p = 0.295), between the two groups. Postoperative complications did not occur in any of the eyes in the study. CONCLUSIONS: The PRP treatment was effective for enhancing corneal epithelial recovery in the early postoperative period, without significant adverse events, in post-PTK-treated eyes, suggesting that it may hold promise as one of the treatment options for treating such postsurgical patients.

Effectiveness of microperimetry in evaluating anti-vascular endothelial growth factor therapy for diabetic macular edema patients with relatively good vision: A retrospective observational study.

ABSTRACT: No studies have evaluated the retinal sensitivity (RS) for diabetic macular edema (DME) patients with good vision. Therefore, this study aimed to determine the effectiveness of microperimetry in evaluating the effectiveness of anti-vascular endothelial growth factor (anti-VEGF) treatment for DME patients with relatively good vision.Twenty-seven eyes of 27 patients (mean age, 61.3 ±â€Š11.2 years) with DME and decimal best-corrected visual acuity (BCVA) ≥0.6 were studied. All patients received 3 consecutive monthly injections of intravitreal anti-VEGF agents. The BCVA, central subfield macular thickness (CMT), and RS were evaluated by microperimetry (MAIA) within the 10 degree of the foveal center. To determine significant differences between the values, we used paired t tests.Patients were evaluated at baseline and 4 weeks after the third injection. The BCVA improved significantly from 0.18 ±â€Š0.06 logarithm of the minimum angle of resolution (logMAR) units to 0.13 ±â€Š0.13 logMAR units (P = .002; paired t test). The CMT decreased significantly from 464.3 ±â€Š91.8 µm to 393.4 ±â€Š129.0 µm (P = .005), and the RS also improved significantly from 21.8 ±â€Š3.1 dB to 24.1 ±â€Š2.8 dB at 4 weeks after treatment (P = .006). Among the patients with a decimal BCVA of 0.7 or better at baseline, there was no significant improvement in the BCVA (P = .28). However, the CMT decreased significantly from 479.5 ±â€Š79.1 µm to 394.0 ±â€Š99.8 µm at 4 weeks after treatment (P = .007). The RS also improved significantly from 22.0 ±â€Š2.4 dB to 24.0 ±â€Š3.1 dB at 4 weeks after treatment (P = .004).Measuring RS by microperimetry is a good option for evaluating the effectiveness of anti-VEGF treatment for DME patients with a relatively good BCVA.

Disminución de la agudeza visual tras un procedimiento odontológico: A propósito de un caso / Unilateral visual impairment after a dental procedure: Case report

El uso de anestésicos locales para la realización de procedimientos odontológicos es una práctica ampliamente extendida que puede causar efectos adversos. Sin embargo, muy infrecuentemente puede causar complicaciones oculares como diplopía, ptosis, visión borrosa, miosis, disminución de la agudeza visual o amaurosis. Presentamos un caso de un paciente varón de 26 años que se presentó a la consulta por una disminución de la agudeza visual en su ojo derecho 48h después de una intervención odontológica del lado ipsilateral, logrando una recuperación de la misma en los 6 meses posteriores, sin tratamiento alguno. Diferentes teorías que justifiquen la aparición de complicaciones oculares como consecuencia de esta clase de procedimientos han sido propuestas en la literatura. En nuestro caso, una inyección intravenosa inadvertida habría sido la causa posible del hecho (AU)

The use of intra-oral local anaesthetics for dental procedures is a widely extended practice that may cause side effects. As such, in rare cases it may cause ocular complications such as diplopia, ptosis, blurry vision, miosis, vision loss, or amaurosis. (Most of them are transient, recovering after several hours or days). A case is presented of a 26 year-old male patient who had visual impairment in the right eye 2 days after a dental procedure was performed. Six months later he had a complete restoration of the previous visual acuity, despite the fact that he had not received any treatment. Several ways have been proposed in the literature that may explain the appearance of ocular complications following these kinds of procedures. In this case, inadvertent intravenous injection is believed to have been the cause (AU)

Inflammatory Factors of Macular Atrophy in Eyes With Neovascular Age-Related Macular Degeneration Treated With Aflibercept.

Background: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness in older people. Low-grade inflammation is well-known as one of the pathogenic mechanisms in nAMD. Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for nAMD, although macula atrophy (MA) developed under anti-VEGF therapy causes irreversible visual function impairment and is recognized as a serious disorder. Here, we show specific expression patterns of aqueous humor (AH) cytokines in nAMD eyes developing MA under intravitreal injection of aflibercept (IVA) as an anti-VEGF antibody and present predictive cytokines as biomarkers for the incidence of MA in nAMD eyes under IVA treatment. Methods: Twenty-eight nAMD patients received three consecutive monthly IVA, followed by a pro re nata regimen for 2 years. AH specimens were collected before first IVA (pre-IVA) and before third IVA (post-IVA). AH cytokine levels, visual acuity (VA), and central retinal thickness (CRT) were measured. Results: Two-year incidence of MA was 21.4%. In nAMD eyes developing MA [MA (+) group], pre-IVA levels of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1ß, VEGF and post-IVA level of MCP-1 were higher than those in nAMD eyes without MA [MA (-) group]. In hierarchical cluster analysis, pre-IVA MCP-1 and VEGF were grouped into the same subcluster, as were post-IVA MCP-1 and CRT. In principal component analysis, principal component loading (PCL) of pre-IVA interferon-γ-inducible protein 10 (IP-10) was 0.61, but PCL of post-IVA IP-10 decreased to -0.09. In receiver operating characteristic analysis and Kaplan-Meier curves, pre-IVA MCP-1, MIP-1ß, and VEGF and post-IVA interleukin-6, MCP-1, and MIP-1ß were detected as predictive factors for MA incidence. In 2-year clinical course, changes of VA in groups with high levels of pre-IVA MIP-1ß (over 39.9 pg/ml) and VEGF (over 150.4 pg/ml) were comparable to those in MA (+) group. Conclusion: Substantial loss of IP-10 effects and persistent inflammation contribute to incidence of MA, and screening of AH cytokine levels could be a useful method to predict MA incidence in nAMD eyes under anti-VEGF therapy.

Ellipsoid Zone Integrity and Visual Acuity Changes during Diabetic Macular Edema Therapy: A Longitudinal Study.

PURPOSE: Ellipsoid zone (EZ) integrity is identified as a potential biomarker for therapy surveillance and outcome prediction of visual acuity (VA). However, only a few studies report long-term results of over 1 year of clinical and anatomical changes in patients with diabetic macular edema (DME). This study is aimed at describing the long-term VA and anatomical outcomes in spectral domain optical coherence tomography (OCT) (relative ellipsoid zone reflectivity ratio, central macular thickness, and volume) in patients with DME treated with antivascular endothelial growth factor (anti-VEGF) therapy. Furthermore, we studied the correlation between EZ integrity and changes in visual acuity. METHODS: 71 eyes of 71 patients were included in this retrospective study. Clinical characteristics were reviewed yearly. OCT data were assessed at baseline and after 1, 3, and 5 years. EZ parameters were quantified automatically. OCT parameters and visual outcome were correlated and analyzed in multivariable regression models. RESULTS: EZ reflectivity ratio correlated with functional outcome in DME patients from baseline to fifth year at all time points (for all p < 0.05). EZ reflectivity improved the most in the first year of treatment (0.68 to 0.75; p < 0.05) and declined gradually until year 5 of therapy (0.71; compared to baseline p > 0.05). Similarly, best VA was achieved after 1 year (0.40 logarithm of the minimum angle of resolution (logMAR) to 0.28 logMAR; p < 0.001) and declined gradually until year 5. Final VA in year 5 was comparable to baseline (0.45 logMAR, compared to baseline p > 0.05). Together with baseline VA, baseline EZ parameters did predict VA outcome after 1 year (p < 0.05). Concordantly, VA and EZ parameters from year 1 were associated with VA outcome in year 2. CONCLUSION: This study described the long-term course of EZ changes during anti-VEGF treatment in DME patients. In addition, our results underlined the potential of EZ parameters as novel OCT biomarkers for prediction of VA outcomes during therapy.

Effectiveness of anti-vascular endothelial growth factors in neovascular age-related macular degeneration and variables associated with visual acuity outcomes: Results from the EAGLE study.

OBJECTIVE: To assess the overall effectiveness of anti-vascular endothelial growth factor (VEGF) therapy in treatment-naïve patients with neovascular age-related macular degeneration (nAMD) in a clinical practice setting. STUDY DESIGN: EAGLE was a retrospective, 2-year, cohort observational, multicenter study conducted in Italy that analyzed secondary data of treatment-naïve patients with nAMD. The primary endpoint evaluated the mean annualized number of anti-VEGF injections at Years 1 and 2. The main secondary endpoints analyzed the mean change in visual acuity (VA) from baseline and variables associated with visual outcomes at Years 1 and 2. RESULTS: Of the 752 patients enrolled, 745 (99.07%) received the first dose of anti-VEGF in 2016. Overall, 429 (57.05%) and 335 (44.5%) patients completed the 1- and 2-year follow-ups, respectively. At baseline, mean (standard deviation, SD) age was 75.6 (8.8) years and the mean (SD) VA was 53.43 (22.8) letters. The mean (SD) number of injections performed over the 2 years was 8.2 (4.1) resulting in a mean (SD) change in VA of 2.45 (19.36) (P = 0.0005) letters at Year 1 and -1.34 (20.85) (P = 0.3984) letters at Year 2. Linear regression models showed that age, baseline VA, number of injections, and early fluid resolution were the variables independently associated with visual outcomes at Years 1 and 2. CONCLUSIONS: The EAGLE study analyzed the routine clinical practice management of patients with nAMD in Italy. The study suggested that visual outcomes in clinical practice may be improved with earlier diagnosis, higher number of injections, and accurate fluid resolution targeting during treatment induction.

Night Vision and Carotenoids (NVC): A Randomized Placebo Controlled Clinical Trial on Effects of Carotenoid Supplementation on Night Vision in Older Adults.

Twilight and low luminance levels are visually challenging environments for the elderly, especially when driving at night. Carotenoid rich diets are known to increase macular pigment optical density (MPOD), which in turn leads to an improvement in visual function. It is not known whether augmenting MPOD can lead to a decrease in vision related night driving difficulties. Additionally, it is unknown if carotenoid supplementation provides additional measurable benefits to one's useful field of view (UFOV) along with a decreased composite crash risk score. The aim of the study was to evaluate changes in night vision function and UFOV in individuals that took carotenoid vitamin supplements for a six-month period compared to a placebo group. METHODS: A prospective, randomized, double-blind, six-month trial of a 14 mg zeaxanthin/7 mg lutein-based supplement was carried out. Participants were randomized into active or placebo group (approx 2:1). RESULTS: n = 33 participants (26 males/7 females) participated with 93% capsule intake compliance in the supplemented group (n = 24) and placebo group (n = 9). MPOD (mean/standard error SE) in the active group increased in the Right eye from 0.35 density units (du)/0.04 SE to 0.41 du/0.05 SE; p < 0.001 and in the Left eye from 0.35 du/0.05 SE to 0.37 du, p > 0.05). The supplemented group showed significant improvements in contrast sensitivity with glare in both eyes with improvements in LogMAR scores of 0.147 and 0.149, respectively (p = 0.02 and 0.01, respectively), monocularly tested glare recovery time improved 2.76 and 2.54 s, respectively, (p = 0.008 and p = 0.02), and we also noted a decreased preferred luminance required to complete visual tasks (p = 0.02 and 0.03). Improvements in UFOV scores of divided attention (p < 0.001) and improved composite crash risk score (p = 0.004) were seen in the supplemented group. The placebo group remained unchanged. CONCLUSIONS: The NVC demonstrates that augmenting MPOD in individuals with difficulty in night vision showed measurable benefits in numerous visual functions that are important for night vision driving in this small sample RCT. Additionally, we observed an improvement in UFOV divided attention test scores and decreased composite risk scores.

Vitamin A cycle byproducts impede dark adaptation.

Impaired dark adaptation (DA), a defect in the ability to adjust to dimly lit settings, is a universal hallmark of aging. However, the mechanisms responsible for impaired DA are poorly understood. Vitamin A byproducts, such as vitamin A dimers, are small molecules that form in the retina during the vitamin A cycle. We show that later in life, in the human eye, these byproducts reach levels commensurate with those of vitamin A. In mice, selectively inhibiting the formation of these byproducts, with the investigational drug C20D3-vitamin A, results in faster DA. In contrast, acutely increasing these ocular byproducts through exogenous delivery leads to slower DA, with otherwise preserved retinal function and morphology. Our findings reveal that vitamin A cycle byproducts alone are sufficient to cause delays in DA and suggest that they may contribute to universal age-related DA impairment. Our data further indicate that the age-related decline in DA may be tractable to pharmacological intervention by C20D3-vitamin A.

Does ganciclovir exert retinal toxicity after multiple continuous intravitreal injections?

BACKGROUND: The objective of this study is to report a case of acute retinal necrosis in which abnormalities in visual function did not correspond to retinal anatomical outcomes. CASE PRESENTATION: A 39-year-old female diagnosed with acute retinal necrosis underwent repeated (nine rounds) intravitreal ganciclovir injection (3 mg/0.1 ml) into the left eye, one injection every 2 weeks. During the therapy, the patient noticed her visual acuity declining gradually. The best corrected visual acuity in the left eye was 20/33. The visual field showed massive visual damage. There was no posterior necrotizing involvement, no macular edema or exudation, and only slight abnormity of the interdigitation zone in the fovea area was visible on OCT. Angio-OCT revealed normal capillary density of three retinal capillary and choriocapillaris layers. The visually evoked potential was normal. The photopic single-flash response showed a declined amplitude of a-wave and b-wave. The amplitudes of photopic 30 Hz flicker were decreased. Multifocal electroretinography revealed macular dysfunction. CONCLUSION: Ganciclovir-associated photoreceptor damage may induce abnormalities in retinal function in response to multiple continuous intravitreal ganciclovir injections at a relatively high dosage (3 mg/0.1 ml).

Long-term outcomes of ranibizumab vs. aflibercept for neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

To evaluate the long-term outcomes of ranibizumab (RBZ) vs. aflibercept (AFL) in treatment-naïve eyes with typical neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV). This multicenter, retrospective, matched-cohort analysis was conducted on data  up to 4 years of follow-ups. The primary outcome was the visual acuity (VA) change from baseline. The secondary outcomes included the number of injections, proportion of eyes without a yearly injection, and the number of eyes with treatment switching. Subgroup analyses were performed for typical nAMD and PCV. Typical nAMD was defined as nAMD other than PCV. We included VA-matched 215 eyes of 209 patients (131 and 84 eyes with RBZ and AFL, respectively). The crude mean VA changes from baseline were + 6.7 vs. + 2.6, + 2.1 vs. - 0.4, - 1.3 vs. - 1.8, and - 2.2 vs. - 5.0 letters in the RBZ and AFL groups, at 1, 2, 3, and 4 years, respectively (p > 0.05). The adjusted predicted VA by linear mixed model, proportion of eyes stratified by VA, and the survival curve for significant vision loss were comparable during the 4-year follow-up (p > 0.05). The mean number of injections were similar between the RBZ and AFL groups (2.9 vs. 3.0, respectively, p = 0.692). The subgroup analysis for typical nAMD and PCV showed similar results between the groups. The visual outcomes did not differ between RBZ and AFL during 4 years with comparable numbers of injections. Our study reflects the long-term, real-world clinical practice and treatment pattern of two treatments for typical nAMD and PCV.

Carotenoids in the Management of Glaucoma: A Systematic Review of the Evidence.

Primary open-angle glaucoma (POAG) remains a leading cause of irreversible blindness globally. Recent evidence further substantiates sustained oxidative stress, and compromised antioxidant defenses are key drivers in the onset of glaucomatous neurodegeneration. Overwhelming oxidative injury is likely attributed to compounding mitochondrial dysfunction that worsens with age-related processes, causing aberrant formation of free radical species. Thus, a compromised systemic antioxidant capacity exacerbates further oxidative insult in glaucoma, leading to apoptosis, neuroinflammation, and subsequent tissue injury. The purpose of this systematic review is to investigate the neuroprotective benefits of the macular carotenoids lutein, zeaxanthin, and meso-zeaxanthin on glaucomatous neurodegeneration for the purpose of adjunctive nutraceutical treatment in glaucoma. A comprehensive literature search was conducted in three databases (PubMed, Cochrane Library, and Web of Science) and 20 records were identified for screening. Lutein demonstrated enhanced neuroprotection on retinal ganglion cell survival and preserved synaptic activity. In clinical studies, a protective trend was seen with greater dietary consumption of carotenoids and risk of glaucoma, while greater carotenoid levels in macular pigment were largely associated with improved visual performance in glaucomatous eyes. The data suggest that carotenoid vitamin therapy exerts synergic neuroprotective benefits and has the capacity to serve adjunctive therapy in the management of glaucoma.

Influence of bevacizumab therapy and intraretinal hemorrhage in long-term outcomes of hemorrhagic retinal arterial macroaneurysm.

This study aimed to evaluate the long-term visual outcomes of hemorrhagic retinal arterial macroaneurysm (RAM), particularly focusing on the influence of bevacizumab therapy and intraretinal hemorrhage (IRH) on the outcomes. This retrospective study included 49 patients diagnosed with hemorrhagic RAM. Patients were divided into the bevacizumab group and observation group depending on the whether they were administered bevacizumab treatment and the IRH group and the non-IRH group based on the presence of IRH at the fovea. Best-corrected visual acuity (BCVA) at diagnosis was compared with that at the final visit. Further, the BCVA at the final visit was compared between the study groups. Multivariate analysis was also performed to identify factors associated with poor BCVA at the final visit. The mean follow-up period was 24.8 ± 15.3 months. The mean logarithm of minimal angle of resolution BCVA was significantly improved from 1.37 ± 0.70 at diagnosis to 0.72 ± 0.62 at the final visit (P < 0.001). There was no significant difference in the BCVA at the final visit between the bevacizumab group and observation group (P = 0.576). However, the BCVA at the final visit was significantly worse in the IRH group than in the non-IRH group (P = 0.002). In multivariate analysis, the presence of IRH was significantly associated with poor BCVA (P = 0.007). Significant long-term visual improvement was noted in hemorrhagic RAM. However, the presence of IRH at the fovea was associated with poor visual prognosis. Bevacizumab therapy did not significantly influence the outcomes.