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Background/aims: To investigate the association of commonly used systemic medications with prevalent age-related macular degeneration (AMD) in the general population., Methods: We included 38 694 adults from 14 population-based and hospital-based studies from the European Eye Epidemiology consortium. We examined associations between the use of systemic medications and any prevalent AMD as well as any late AMD using multivariable logistic regression modelling per study and pooled results using random effects meta-analysis., Results: Between studies, mean age ranged from 61.5±7.1 to 82.6±3.8 years and prevalence ranged from 12.1% to 64.5% and from 0.5% to 35.5% for any and late AMD, respectively. In the meta-analysis of fully adjusted multivariable models, lipid-lowering drugs (LLD) and antidiabetic drugs were associated with lower prevalent any AMD (OR 0.85, 95% CI=0.79 to 0.91 and OR 0.78, 95% CI=0.66 to 0.91). We found no association with late AMD or with any other medication., Conclusion: Our study indicates a potential beneficial effect of LLD and antidiabetic drug use on prevalence of AMD across multiple European cohorts. Our findings support the importance of metabolic processes in the multifactorial aetiology of AMD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The objectives of this study were to evaluate the quality-of-life (QoL) impact of eye diseases (keratoconus; neovascular age-related macular degeneration, AMD; retinal vein occlusion, RVO; and diabetic macular edema, DME) using the Impact of Vision Impairment (IVI) questionnaire, and to determine the relationship between the IVI scores and visual acuity., Methods: This cross-sectional, multicentre, real-world study utilised the prospective, web-based Save Sight Registries. The IVI was completed by 1557 patients: 307 with keratoconus, 1049 with AMD, 148 with RVO and 53 with DME. Statistical analysis included Rasch analysis, Welch t-test, one-way ANOVA, Tukey's test, Pearson correlation, and multiple regression., Results: The IVI scales (Overall; Visual Function, VF; Emotional, EM) had robust psychometric properties. The keratoconus patients had the worst Overall (adjusted mean: 48.2 vs. DME 58.8, RVO 64.6, AMD 67.6 units), VF (47.7 vs. DME 59.4, RVO 65.9, AMD 68.9 units) and EM (50.8 vs. DME 63.1, RVO 69.2, AMD 71.8 units) scores (all p < 0.05). The IVI scales scores weakly correlated with better and worse eye visual acuity (Pearson's r 0.24-0.39, all p < 0.05). The correlations were similar in the better eye (Overall 0.35, VF 0.39, EM 0.24) and the worse eye (Overall 0.31, VF 0.33, EM 0.25) visual acuity. Correlations with visual acuity were stronger for VF than for the EM scores., Conclusions: The IVI was a psychometrically robust QoL questionnaire. Keratoconus patients had worse IVI scores than patients with retinal diseases. The low strength of correlations between visual acuity and QoL scores, although statistically significant, suggested that a complex relationship exists., (© 2022 The Authors. Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Ophthalmologists.)

Aim: To assess long-term anatomic and functional outcomes of early lens-sparing vitrectomy (LSV) for stage 4A retinopathy of prematurity (ROP) in infants with aggressive-posterior ROP (AP-ROP) which progressed to retinal detachment despite laser treatment., Methods: Chart review of infants who underwent early 25-gage LSV for stage 4A ROP. Outcomes were anatomic success, mean visual acuity (VA), development of postoperative complications, and refractive changes. Follow-up examinations were performed at 1, 3, 6, 12, and then every 6 months., Results: Ten eyes of seven preterm infants who underwent LSV were included. Mean follow-up was 36 ± 13.4 months and mean postmenstrual age (PMA) at last follow-up was 37 ± 13.7 months. Mean gestational age (GA) and weight at birth was 26 ± 1.4 weeks and 639 ± 180 g. Two eyes had vitreous hemorrhage 4 and 14 days after surgery, respectively. At last follow-up anatomic success was 100%, mean VA was 20/80 and eight eyes (80%) had high myopic refractive correction (mean spherical equivalent -11.25 D)., Conclusion: Early LSV for stage 4A ROP with AP-ROP and progression to retinal detachment is efficacious in terms of anatomic and functional outcomes. Anatomic success is associated with visual improvement despite possible myopic refraction changes during follow-up.

Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial. Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297- 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment. Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a β-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results. Clinical Trial Registration   The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.

Intravitreal antivascular endothelial growth factor drugs represent the current standard of care for neovascular age-related macular degeneration (nAMD). Individualized treatment regimens aim at obtaining the same visual benefits of monthly injections with a reduced number of injections and follow-up visits, and, consequently, of treatment burden. The target of these strategies is to timely recognize lesion recurrence, even before visual deterioration. Early detection of lesion activity is critical to ensure that clinical outcomes are not compromised by inappropriate delays in treatment, but questions remain on how to effectively monitor the choroidal neovascularization (CNV) activity. To assess the persistence/recurrence of lesion activity in patients undergoing treatment for nAMD, an expert panel developed a decision algorithm based on the morphological features of CNV. After evaluating all current retinal imaging techniques, the panel identified optical coherent tomography as the most reliable tool to ascertain lesion activity when funduscopy is not obvious.

Purpose: Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future., Design: Meta-analysis of prevalence data., Participants: A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe., Methods: AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV)., Main Outcome Measures: Prevalence of early and late AMD, BCVA, and number of AMD cases., Results: Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%-5.0%) in those aged 55-59 years to 17.6% (95% CI 13.6%-21.5%) in those aged ≥85 years; for late AMD these figures were 0.1% (95% CI 0.04%-0.3%) and 9.8% (95% CI 6.3%-13.3%), respectively. We observed a decreasing prevalence of late AMD after 2006, which became most prominent after age 70. Prevalences were similar for gender across all age groups except for late AMD in the oldest age category, and a trend was found showing a higher prevalence of CNV in Northern Europe. After 2006, fewer eyes and fewer ≥80-year-old subjects with CNV were visually impaired (P = 0.016). Projections of AMD showed an almost doubling of affected persons despite a decreasing prevalence. By 2040, the number of individuals in Europe with early AMD will range between 14.9 and 21.5 million, and for late AMD between 3.9 and 4.8 million., Conclusion: We observed a decreasing prevalence of AMD and an improvement in visual acuity in CNV occuring over the past 2 decades in Europe. Healthier lifestyles and implementation of anti-vascular endothelial growth factor treatment are the most likely explanations. Nevertheless, the numbers of affected subjects will increase considerably in the next 2 decades. AMD continues to remain a significant public health problem among Europeans., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Autosomal dominant optic atrophy (DOA) is the most frequent form of hereditary optic atrophy, a disease presenting with considerable inter- and intra-familial clinical variability. Although a number of mutations in different genes are now known to cause DOA, many cases remain undiagnosed. In an attempt to identify the underlying genetic defect, whole exome sequencing was performed in a 19-year-old male that had been affected by isolated DOA since childhood. The exome sequencing revealed a pathogenic mutation (p.R468C, c.1402C>T) in the AFG3 like matrix AAA peptidase subunit 2 (AFG3L2) gene, a gene known to be associated with spinocerebellar ataxia. The patient did not show any signs other than DOA. Thus, the result demonstrates the possibility that mutations in the AFG3L2 gene may be a cause of isolated autosomal DOA.

The aim of the present study was to report a novel mutation in the retinoschisin 1 (RS1) gene in a Caucasian family affected by X-linked juvenile retinoschisis (XLRS) and to describe the long-term modification of retinal structure. Two brothers with an early onset maculopathy were diagnosed with XLRS. Fundus photography, fluorescein angiography, spectral domain optical coherence tomography and electroretinogram analyses were performed. Their sister was also examined. All subjects were screened for mutations in the RS1 gene. XLRS patients demonstrated a marked reduction of best-corrected visual acuity. SD-OCT scans reported a cystic degeneration primarily involving the inner nuclear layer, though some cysts were detected in the outer plexiform layer and in the ganglion cell layer. During the ten-year follow-up, a progressive retinal thickening and coalescence of the cysts was observed. Genetic testing revealed a novel mutation (p.Ile212Asn) in the RS1 gene in both XLRS patients, whereas their sister was not a genetic carrier. Several mutations of the RS1 gene were recognized to be responsible for XLRS. Although the correspondence between genotype and phenotype is still under debate, is reasonable that siblings affected by XLRS could share other genetic and/or epigenetic factors capable to influence clinical course of the disease.

Purpose: To evaluate sensitivity, specificity and the safest cut-offs of three predictive algorithms (WINROP, ROPScore and CHOP ROP) for retinopathy of prematurity (ROP)., Methods: A retrospective study was conducted in three centres from 2012 to 2014; 445 preterms with gestational age (GA) ≤ 30 weeks and/or birthweight (BW) ≤ 1500 g, and additional unstable cases, were included. No-ROP, mild and type 1 ROP were categorized. The algorithms were analysed for infants with all parameters (GA, BW, weight gain, oxygen therapy, blood transfusion) needed for calculation (399 babies)., Results: Retinopathy of prematurity (ROP) was identified in both eyes in 116 patients (26.1%), and 44 (9.9%) had type 1 ROP. Gestational age and BW were significantly lower in ROP group compared with no-ROP subjects (GA: 26.7 ± 2.2 and 30.2 ± 1.9, respectively, p < 0.0001; BW: 839.8 ± 287.0 and 1288.1 ± 321.5 g, respectively, p = 0.0016). Customized alarms of ROPScore and CHOP ROP correctly identified all infants having any ROP or type 1 ROP. WINROP missed 19 cases of ROP, including three type 1 ROP. ROPScore and CHOP ROP provided the best performances with an area under the receiver operating characteristic curve for the detection of severe ROP of 0.93 (95% CI, 0.90-0.96, and 95% CI, 0.89-0.96, respectively), and WINROP obtained 0.83 (95% CI, 0.77-0.87). Median time from alarm to treatment was 11.1, 5.1 and 9.1 weeks, for WINROP, ROPScore and CHOP ROP, respectively., Conclusion: ROPScore and CHOP ROP showed 100% sensitivity to identify sight-threatening ROP. Predictive algorithms are a reliable tool for early identification of infants requiring referral to an ophthalmologist, for reorganizing resources and reducing stressful procedures to preterm babies., (© 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Although many studies have been published about specific lesions characterizing von Hippel-Lindau(VHL) disease, none have dealt with the natural history of the whole disease and the consequent disabilities. We aim to define the comprehensive natural history of VHL disease and to describe the functional disabilities and their impact upon patients' quality of life, thereby tailoring the follow-up schedule accordingly., Methods: We performed a prospective analysis on 128 VHL-affected patients beginning in 1996. For each affected organ, we defined intervals between the first and subsequent VHL-related manifestations and compared them with current VHL surveillance protocols. We looked for any association of the number of involved organs with age, sex, type of VHL gene mutation, and functional domain mutation. Ultimately, we assessed the organ-specific disabilities caused by VHL disease., Results: Hemangioblastomas show different patterns of progression depending on their location, whereas both renal cysts and carcinomas have similar progression rates. Surgery for pheochromocytoma and CNS hemangioblastoma is performed earlier than for pancreatic or renal cancer. The number of involved organs is associated with age but not with sex, type of VHL gene mutation, or functional domain mutation. A thorough analysis of functional disabilities showed that age is related to the first-appearing functional impairment, but it is not predictive of the final number of disabilities., Conclusions: Our study defines the disease progression and provides a comprehensive view of the syndrome over time. We analyzed for the first time the functional disability of VHL patients, assessing the progression for each function., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Occult macular dystrophy (OMD) is an inherited macular disease characterized by progressive visual decline with the absence of visible retinal abnormalities. Typical alterations of the retinal structure are detectable by spectral domain optical coherence tomography (SD‑OCT). Mutations in the RP1L1 gene have been identified to be responsible for the disease in Asian subjects. The present study assessed the role of mutations in the RP1L1 gene in an Italian family with OMD. One patient with OMD and five related subjects (two male offspring affected by progressive visual decline and three asymptomatic siblings of the patient) were subjected to complete ophthalmological examination. SD‑OCT was also performed. All subjects were screened for OMD‑associated genetic mutations in the RP1L1 gene. The OMD patient and the two symptomatic offspring presented with a reduced best‑corrected visual acuity. Although no fundus abnormalities were observed, SD‑OCT examination showed that the external limiting membrane and the inner segment/outer segment band were not clearly identifiable and a focal disruption of the photoreceptor layer was present. The degree of photoreceptor alterations was correlated with the severity of visual impairment. Clinical and tomographic results in the three asymptomatic relatives were normal. A p.Arg45Trp mutation in the RP1L1 gene was identified in the OMD patient, in the two symptomatic offspring and also in two of the asymptomatic siblings of the patient. The identification of RP1L1 mutations in subjects with OMD may improve the accuracy of diagnosis of this rare condition and may aid in enhancing the efficacy of genetic counseling.

The European Eye Epidemiology (E3) consortium is a recently formed consortium of 29 groups from 12 European countries. It already comprises 21 population-based studies and 20 other studies (case-control, cases only, randomized trials), providing ophthalmological data on approximately 170,000 European participants. The aim of the consortium is to promote and sustain collaboration and sharing of data and knowledge in the field of ophthalmic epidemiology in Europe, with particular focus on the harmonization of methods for future research, estimation and projection of frequency and impact of visual outcomes in European populations (including temporal trends and European subregions), identification of risk factors and pathways for eye diseases (lifestyle, vascular and metabolic factors, genetics, epigenetics and biomarkers) and development and validation of prediction models for eye diseases. Coordinating these existing data will allow a detailed study of the risk factors and consequences of eye diseases and visual impairment, including study of international geographical variation which is not possible in individual studies. It is expected that collaborative work on these existing data will provide additional knowledge, despite the fact that the risk factors and the methods for collecting them differ somewhat among the participating studies. Most studies also include biobanks of various biological samples, which will enable identification of biomarkers to detect and predict occurrence and progression of eye diseases. This article outlines the rationale of the consortium, its design and presents a summary of the methodology.

Aim: To investigate the association of diet and other modifiable risk factors with the prevalence of age-related macular degeneration (ARMD) in rural and urban communities of a Mediterranean population in the northeast of Italy., Methods: A cross-sectional population-based study was conducted among subjects aged over 60 years. A food frequency questionnaire (FFQ) was used to assess the consumption of different food categories, i.e., protective (P), risky (R), lutein-rich (L) and neutral (N). Smoking habit and alcohol intake were also examined. Macular pigment was measured by Raman spectroscopy., Results: P food intake reduced the risk of large drusen (ARM2; OR 0.93; 95% CI 0.89-0.96) within the rural community. In this sub-group, R foods resulted in a slight association with large drusen, though the R/P food ratio was highly correlated with ARM2 (OR 1.21; 95% CI 1.12-1.31). Raman measures showed an age-dependent decrease but did not correlate with lutein intake. Smoking habit showed a positive association with ARM2 among women (OR 2.40; 95% CI 1.54-3.75), whereas alcohol consumption resulted in protective odds (OR 0.72; 95% CI 0.60-0.86)., Conclusion: FFQ analysis confirmed the role of P and R foods and the benefit of a Mediterranean diet in ARMD. Moderate alcohol consumption showed a beneficial effect, whereas the deleterious role of a smoking habit was more evident in females., (© 2015 S. Karger AG, Basel.)

Purpose: To investigate whether genetic and non-genetic risk factors influence 12-month response to ranibizumab treatment for exudative age-related macular degeneration (AMD)., Methods: A cohort of 94 Caucasian patients with unilateral exudative AMD received intravitreal ranibizumab. After a three-injection loading phase, a PRN regimen was followed. Patients were genotyped for three single-nucleotide polymorphisms: CFH rs1061170, ARMS2 rs10490924 and C3 rs2230199. Non-genetic risk factors [choroidal neovascularization (CNV) phenotype, smoking habit, hypertension and body mass index] were considered. The selected end-point was the 12-month variation of number of ETDRS letters., Results: Complement factor H (CFH) risk alleles, smoking history and arterial hypertension each independently influenced treatment response, with worse 12-month BCVA outcomes (p = 0.036, 0.037, 0.043, respectively). A significant cumulative effect of these risk factors was also observed: patients homozygous for the CFH risk alleles and with a positive smoking history showed a mean loss of 8.0 ETDRS letters (p = 0.010). Patients with CFH risk alleles, smoking history and hypertension had a mean loss of 13.9 ETDRS letters (p = 0.013). CNV phenotypes did not influence visual outcomes, nor were they associated with other genetic/non-genetic risk factors., Conclusions: Complement factor H risk alleles, smoking history and hypertension affect the mid-term response to ranibizumab in exudative AMD., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)