Factors associated with serum 25-hydroxyvitamin D concentrations in older people in Europe: the EUREYE study.

BACKGROUND/OBJECTIVES: We aimed to describe serum 25-hydroxyvitamin D (25OHD) concentrations in older Europeans and to investigate associations between 25OHD and lifestyle factors, including dietary intake and supplement use. SUBJECTS/METHODS: Men and women aged ≥ 65 years were recruited from seven centres across north to south Europe. Serum 25OHD2 and 25OHD3 concentrations were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) in 4495 samples and total 25OHD (25OHD2 + 25OHD3) was adjusted for season of blood collection. RESULTS: The mean (25th, 75th quartile) of seasonally adjusted 25OHD was 46 (34, 65) nmol/L, with the highest concentration of 25OHD in Bergen [61 (49, 79) nmol/L], and the lowest in Paris [36 (24, 57) nmol/L)]. Vitamin D deficiency (25-50 nmol/L) and vitamin D insufficiency (50-75 nmol/L) were found in 41 and 33% of the population, respectively. In multivariable analysis controlled for confounders, seasonally adjusted 25OHD concentrations were significantly (p < 0.05) lower in smokers and participants with self-reported diabetes and higher with increasing dietary vitamin D, and supplement use with fish liver oil, omega-3, and vitamin D. Additionally, in further analysis excluding Bergen, 25OHD was associated with higher intakes of oily fish and increasing UVB exposure. We observed low concentrations of 25OHD in older people in Europe. CONCLUSIONS: Our findings of the higher 25OHD concentrations in supplement users (omega-3 fish oil, fish liver oil, vitamin D) add to current recommendations to reduce vitamin D deficiency. We were unable to fully assess the role of dietary vitamin D as we lacked information on vitamin D-fortified foods.

Macular Edema: Definition and Basic Concepts.

Macular edema is the result of an accumulation of fluid in the retinal layers around the fovea. It contributes to vision loss by altering the functional cell relationship in the retina and promoting an inflammatory reparative response. Macular edema may be intracellular or extracellular. Intracellular accumulation of fluid, also called cytotoxic edema, is an alteration of the cellular ionic distribution. Extracellular accumulation of fluid, which is more frequent and clinically more relevant, is directly associated with an alteration of the blood-retinal barrier (BRB). The following parameters are relevant for clinical evaluation of macular edema: extent of the macular edema (i.e., the area that shows increased retinal thickness); distribution of the edema in the macular area (i.e., focal versus diffuse macular edema); central foveal involvement (central area 500 µm); fluorescein leakage (evidence of alteration of the BRB or 'open barrier') and intraretinal cysts; signs of ischemia (broken perifoveolar capillary arcade and/or areas of capillary closure); presence or absence of vitreous traction; increase in retinal thickness and cysts in the retina (inner or outer), and chronicity of the edema (i.e., time elapsed since initial diagnosis and response to therapy). It is essential to establish associations and correlations of all the different images obtained, regardless of whether the same or different modalities are used.

Macular Edema of Choroidal Origin.

Macular edema is most often clinically defined as an accumulation of serous fluid within the neurosensory retina with increased thickness of the central retina. In exudative age-related macular degeneration the leakage of fluid from the choroidal new vessels may be the origin of macular edema. Their abnormal permeability and the inflammatory reaction are mechanisms involved in this accumulation of fluid, which occurs in all layers. Cystoid macular edema is more often associated with subepithelial occult choroidal neovascularization (CNV) than it is with pre-epithelial classic CNV. The simultaneous presence of choroidal new vessels and ME implies a number of cellular dysfunctions especially of Müller cells and subsequently metabolic alterations. The leakage from the choroidal new vessels, predominantly vascular endothelial growth factor (VEGF)-induced, may produce a large accumulation of fluid under the neurosensory retina. It is also likely that the key signaling steps occur prior to the upregulation of VEGF either initiated by, or facilitated by, cytokines, which act under normal basic conditions to counterbalance the integral VEGF effects and, in pathologic circumstances, may either counteract or serve to amplify the process.

Novel quantitative pigmentation phenotyping enhances genetic association, epistasis, and prediction of human eye colour.

Success of genetic association and the prediction of phenotypic traits from DNA are known to depend on the accuracy of phenotype characterization, amongst other parameters. To overcome limitations in the characterization of human iris pigmentation, we introduce a fully automated approach that specifies the areal proportions proposed to represent differing pigmentation types, such as pheomelanin, eumelanin, and non-pigmented areas within the iris. We demonstrate the utility of this approach using high-resolution digital eye imagery and genotype data from 12 selected SNPs from over 3000 European samples of seven populations that are part of the EUREYE study. In comparison to previous quantification approaches, (1) we achieved an overall improvement in eye colour phenotyping, which provides a better separation of manually defined eye colour categories. (2) Single nucleotide polymorphisms (SNPs) known to be involved in human eye colour variation showed stronger associations with our approach. (3) We found new and confirmed previously noted SNP-SNP interactions. (4) We increased SNP-based prediction accuracy of quantitative eye colour. Our findings exemplify that precise quantification using the perceived biological basis of pigmentation leads to enhanced genetic association and prediction of eye colour. We expect our approach to deliver new pigmentation genes when applied to genome-wide association testing.

Associations between Serum Vitamin D and Genetic Variants in Vitamin D Pathways and Age-Related Macular Degeneration in the European Eye Study.

PURPOSE: To study associations between early and late age-related macular degeneration (AMD) and neovascular AMD (nvAMD) with serum 25-hydroxy vitamin D (25(OH)D) and genetic variants in vitamin D pathway genes. DESIGN: Population-based, cross-sectional study in a random sample aged 65 years or older from 7 European countries. PARTICIPANTS: Of 4753 participants, 4496 (2028 men and 2468 women), with a mean age of 73 years, provided a blood sample; 2137 had no signs of AMD, 2209 had early AMD, and 150 had late AMD, of whom 104 had nvAMD. METHODS: Participants were interviewed to determine smoking and alcohol use, sunlight exposure, and diet; underwent fundus photography. Fundus images were graded using the International Classification System for Age-Related Maculopathy. The 25(OH)D was measured by liquid chromatography-tandem mass spectrometry and categorized as deficient (<30 nmol/l), insufficient (30-50 nmol/l), or adequate (≥50 nmol/l). Genotyping was performed on a subsample of 1284 AMD cases and controls for 93 single nucleotide polymorphisms (SNPs) from 7 genes. Associations were investigated by linear or logistic regression adjusted for potential confounders. MAIN OUTCOME MEASURES: Adjusted odds ratio (OR) for 3 outcomes (early AMD, late AMD, nvAMD). RESULTS: No linear association was found with 25(OH)D and early or late AMD or nvAMD. There was no association between insufficient or deficient status with early or late AMD. Deficient status was associated with nvAMD (adjusted OR, 1.27; 95% confidence interval, 1.1-1.45; P < 0.0001). Significant (P < 0.05) associations with 25(OH)D were found for SNPs in genes GC, VDR, CYP2R1, and CYP27B1. Two SNPs (VDR) were associated with early AMD, 4 SNPs (RXRA) and 1 SNP (VDR) were associated with nvAMD, and 1 SNP (RXRA), 2 SNPs (VDR), and 1 SNP (CYP2R1) were associated with late AMD. After Bonferroni correction, no SNPs were associated with early AMD, late AMD, or nvAMD. CONCLUSIONS: Deficiency in 25(OH)D was associated with nvAMD, but the adjusted OR was small, and we cannot exclude residual confounding. The hypothesis of a causal association of vitamin D with AMD is not supported by clear evidence for an association of vitamin D SNPs with early AMD, late AMD, or nvAMD.

Association Between Myopia, Ultraviolet B Radiation Exposure, Serum Vitamin D Concentrations, and Genetic Polymorphisms in Vitamin D Metabolic Pathways in a Multicountry European Study.

IMPORTANCE: Myopia is becoming increasingly common globally and is associated with potentially sight-threatening complications. Spending time outdoors is protective, but the mechanism underlying this association is poorly understood. OBJECTIVE: To examine the association of myopia with ultraviolet B radiation (UVB; directly associated with time outdoors and sunlight exposure), serum vitamin D concentrations, and vitamin D pathway genetic variants, adjusting for years in education. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional, population-based random sample of participants 65 years and older was chosen from 6 study centers from the European Eye Study between November 6, 2000, to November 15, 2002. Of 4187 participants, 4166 attended an eye examination including refraction, gave a blood sample, and were interviewed by trained fieldworkers using a structured questionnaire. Myopia was defined as a mean spherical equivalent of -0.75 diopters or less. Exclusion criteria included aphakia, pseudophakia, late age-related macular degeneration, and vision impairment due to cataract, resulting in 371 participants with myopia and 2797 without. EXPOSURES: Exposure to UVB estimated by combining meteorological and questionnaire data at different ages, single-nucleotide polymorphisms in vitamin D metabolic pathway genes, serum vitamin D3 concentrations, and years of education. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) of UVB, serum vitamin D3 concentrations, vitamin D single-nucleotide polymorphisms, and myopia estimated from logistic regression. RESULT: Of the included 3168 participants, the mean (SD) age was 72.4 (5) years, and 1456 (46.0%) were male. An SD increase in UVB exposure at age 14 to 19 years (OR, 0.81; 95% CI, 0.71-0.92) and 20 to 39 years (OR, 0.7; 95% CI, 0.62-0.93) was associated with a reduced adjusted OR of myopia; those in the highest tertile of years of education had twice the OR of myopia (OR, 2.08; 95% CI, 1.41-3.06). No independent associations between myopia and serum vitamin D3 concentrations nor variants in genes associated with vitamin D metabolism were found. An unexpected finding was that the highest quintile of plasma lutein concentrations was associated with a reduced OR of myopia (OR, 0.57; 95% CI, 0.46-0.72). CONCLUSIONS AND RELEVANCE: Increased UVB exposure was associated with reduced myopia, particularly in adolescence and young adulthood. The association was not altered by adjusting for education. We found no convincing evidence for a direct role of vitamin D in myopia risk. The relationship between high plasma lutein concentrations and a lower risk of myopia requires replication.

Mediterranean Diet Score and Its Association with Age-Related Macular Degeneration: The European Eye Study.

PURPOSE: To examine associations between adherence to a Mediterranean diet and prevalence of age-related macular degeneration (AMD) in countries ranging from Southern to Northern Europe. DESIGN: Cross-sectional, population-based epidemiologic study. PARTICIPANTS: Of 5060 randomly sampled people aged 65 years or older from 7 study centers across Europe (Norway, Estonia, United Kingdom, France, Italy, Greece, and Spain), full dietary data were available in 4753. The mean age of participants was 73.2 years (standard deviation, 5.6), and 55% were women. METHODS: Participants underwent an eye examination and digital retinal color photography. The images were graded at a single center. Dietary intake during the previous 12 months was assessed by using a semiquantitative food-frequency questionnaire (FFQ). A previously published Mediterranean Diet Score (MDS) was used to classify participants according to their responses on the FFQ. Multivariable logistic regression was used to investigate the association of the MDS score and AMD, taking account of potential confounders and the multicenter study design. MAIN OUTCOME MEASURES: Images were graded according to the International Classification System for age-related maculopathy and stratified using the Rotterdam staging system into 5 exclusive stages (AMD 0-4) and a separate category of large drusen (≥125 µm). Age-related macular degeneration 4 included neovascular AMD (nvAMD) and geographic atrophy (GA). RESULTS: Increasing MDS was associated with reduced odds of nvAMD in unadjusted and confounder-adjusted analysis. Compared with the lowest MDS adherence (≤4 score), those in the highest category MDS adherence (>6 score) showed lower odds of nvAMD (odds ratio, 0.53; 0.27-1.04; P trend = 0.01). The association with MDS did not differ by Y204H risk allele (P = 0.89). For all early AMD (grade 1-3), there was no relationship with MDS (P trend = 0.9). There was a weak trend (P = 0.1) between MDS and large drusen; those in the highest category of MDS had 20% reduced odds compared with those in the lowest (P = 0.05). CONCLUSIONS: This study adds to the limited evidence of the protective effect of adherence to a Mediterranean dietary pattern in those with late AMD, although it does not support previous reports of a relationship with genetic susceptibility. Interventions to encourage the adoption of the Mediterranean diet should be developed, and methods by which such behavior change can be achieved and maintained investigated.

Occurrence of macular hematoma after ranibizumab treatment for age-related macular degeneration.

PURPOSE: To report the occurrence and study the characteristics of macular hematoma after ranibizumab (anti-VEGF) intravitreal injection for subfoveal choroidal neovascularization in age-related macular degeneration (AMD). METHODS: The charts of 6000 patients treated with ranibizumab (0.5 mg) for exudative AMD were reviewed. Inclusion criteria were a minimum follow-up of 1 year after the first injection and the occurrence of a large macular hematoma involving the fovea in patients with macular lesions considered stabilized or still active. All patients had a complete ophthalmologic assessment including Early Treatment of Diabetic Retinopathy Study visual acuity (VA) measurement, fundus photography, fundus fluorescein angiography, scanning laser ophthalmoscopy-infracyanine green angiography, and spectral-domain optical coherence tomography. RESULTS: Of the 6000 eyes, 24 (0.4%) developed macular hematoma during follow-up. There were 8 men (33.3%) and 16 women (66.7%). The mean age at the time of initial presentation was 76.7 ± 3.8 years (range 61-81 years). The mean time to occurrence of macular hematoma after the last injection was 4.8 months. Spectral-domain optical coherence tomography showed the presence of a retinal pigment epithelium (RPE) tear in 19 eyes (79.1%). Vitreomacular traction (VMT) was only present in 4 eyes (17%). Final VA after macular hematoma resorption was <20/50 in 17 cases (70.9%) and ≥20/50 in 7 cases (29.1%). CONCLUSIONS: Macular hematoma may follow intravitreal anti-VEGF injection for exudative AMD with large occult neovascularization, especially if a large RPE tear is found. The occurrence does not seem to be linked to anticoagulation treatment or the presence of VMT.

Retreatment with Ozurdex for macular edema secondary to retinal vein occlusion.

PURPOSE: To review the current practice of retreatment with Ozurdex injections in patients with macular edema (ME) secondary to retinal vein occlusion (RVO), and to recommend simple guidelines for Ozurdex reinjection in management of RVO. METHODS: This was a multicenter retrospective study of patients who received more than 2 Ozurdex injections for the treatment of ME in RVO. Recorded parameters included percent of patients with a 15-letter gain, visual acuity (VA) improvement from baseline, change in central macular thickness (CMT), time to reinjection, and occurrence of any complications. RESULTS: A total of 128 patients were included, 58 (45.3%) with central RVO (CRVO) and 70 (54.7%) with branch RVO (BRVO). Mean interval for Ozurdex reinjection was 5.9 months following the first injection and 8.7 months following the second. A >15-letter gain in VA was observed in 34 (48.8%) patients with CRVO and 16 (28%) patients with BRVO. Mean overall VA improvement at month 6 did not show significance (p>0.05); however, a significantly better mean VA improvement was seen in treatment-naïve eyes (p<0.03). The CMT was significantly reduced compared to baseline. The mean CMT decreased by 214.6 µm in eyes with BRVO (n = 53) and by 355.1 µm in eyes with CRVO (n = 63) (p = 0.002). Complication rates were very low. CONCLUSIONS: Repeated injections of Ozurdex are effective and have a favorable safety profile. In current practice, the retreatment interval with Ozurdex injections might be too long, precluding the full therapeutic potential of this treatment modality. A strategy for managing RVO patients treated with Ozurdex on an as-needed basis is provided.

SD-OCT stages of progression of type 2 macular telangiectasia in a patient followed for 3 years.

PURPOSE: To describe the natural course of type 2 idiopathic macular telangiectasia (MT) using spectral-domain optical coherence tomography (SD-OCT). METHODS: Analysis of the different stages of progression of type 2 MT during a period of 3 years using multimodal imaging, including SD-OCT correlated with angiographic and autofluorescence images. The analysis of the different steps was obtained initially from the first eye, then successively from the fellow eye when progressive changes appeared. RESULTS: The earliest visible alteration at SD-OCT was the interruption of the interface between inner segment and ellipsoid (IS/EL) (stage 1). The second stage was characterized by the complete interruption of both IS/EL interface and external limiting membrane (stage 2). At the next step, a wide disruption of the outer nuclear layer was noted (stage 3). The fourth stage showed a complete disorganization of the inner layers with aspect of fusion of the inner retinal layers associated with progressive atrophy of the outer layers (stage 4). Hyper-reflective deposits were found in both the internal and external retinal layers (stage 5). Small intraretinal cystoid spaces appeared in the different retinal layers (stage 6). This last feature was an earlier manifestation of the typical intraretinal cysts that are the well-known OCT appearance of type 2 MT. CONCLUSIONS: We describe the 6 steps of progression from earlier SD-OCT findings that led to a complete disorganization and fusion of the inner layers (probably due to changes in the Müller cells) to the typical intraretinal cysts.

Association analysis of CFH and ARMS2 gene polymorphisms in a Brazilian cohort with age-related macular degeneration.

PURPOSE: To investigate the association between the CFH and ARMS2 gene polymorphisms and age-related macular degeneration (AMD) in a Brazilian cohort. METHODS: We examined 163 individuals with AMD and 154 controls recruited at the Department of Ophthalmology of the Universidade Federal de Minas Gerais, at the Instituto da Visão, and at the Centro Especializado em Olhos, in Brazil, between 2007 and 2012. Genotyping for CFH rs1061170 and ARMS2 rs10490924 single-nucleotide polymorphisms was performed. The odds ratios (OR) for all of the studied genotypes (heterozygous and homozygous) of both genes were calculated compared to homozygous ancestral alleles. RESULTS: Homozygosity for the CFH and ARMS2 at-risk allele was 33.3 and 23.6%, respectively, for AMD individuals and 10.3 and 7.1%, respectively, for controls (p < 0.0001). The OR was 7.2 (95% CI 3.6-14.5; p < 0.001) for the CFH at-risk genotype (CC) and 5.5 (95% CI 2.6-11.8; p < 0.0001) for ARMS2 (TT). Subjects homozygous for both polymorphisms had a much higher risk of developing AMD (n = 14 patients, OR 33.3, 95% CI 12.8-86.4). The proportion of ancestry in each group indicated that AMD patients had a higher European (Caucasian) component than controls. CONCLUSION: CFH and ARMS2 polymorphisms were strongly associated with AMD in this Brazilian cohort.

ARMS2 increases the risk of early and late age-related macular degeneration in the European Eye Study.

OBJECTIVE: To study associations between severity stages of early and late age-related macular degeneration (AMD) and genetic variations in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) and to investigate potential interactions between smoking and ARMS2. DESIGN: Population-based, cross-sectional European Eye Study in 7 countries in Europe. PARTICIPANTS: Four thousand seven hundred fifty participants, 65 years of age and older, recruited through random sampling. METHODS: Participants were classified on the basis of the more severely affected eye into 5 mutually exclusive AMD severity stages ranging from no AMD, 3 categories of early AMD, and late AMD. History of cigarette smoking was available and allowed classification into never, former, and current smokers, with the latter 2 groups combined into a single category of ever smokers for analysis. Genotyping was performed for single nucleotide polymorphisms rs10490924 and rs4146894 in ARMS2 and rs1061170 in CFH. Associations were analyzed by logistic regression. MAIN OUTCOME MEASURES: Odds ratios (ORs) for stage of AMD associated with genetic variations in ARMS2 and CFH and interactions between ARMS2 and smoking status. RESULTS: Early AMD was present in 36.4% and late AMD was present in 3.3% of participants. Data on both genotype and AMD were available for 4276 people. The ORs for associations between AMD stage and ARMS2 increased monotonically with more severe stages of early AMD and were altered little by adjustment for potential confounders. Compared with persons with no AMD, carriers of the TT genotype for rs10490924 in ARMS2 had a 10-fold increase in risk of late AMD (P<3 × 10(-20)). The ORs for associations with CFH were similar for stage 3 early AMD and late AMD. Interactions between rs10490924 in ARMS2 and smoking status were significant in both unadjusted and adjusted models (P = 0.001). The highest risk was observed in those doubly homozygous for rs10490924 and rs1061170 in CFH (OR, 62.3; 95% confidence interval, 16-242), with P values for trend ranging from 0.03 (early AMD, stage 1) to 1 × 10(-26) (late AMD). CONCLUSIONS: A strong association was demonstrated between all stages of AMD and genetic variation in ARMS2, and a significant gene-environment interaction with cigarette smoking was confirmed.

Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema.

OBJECTIVE: To assess long-term efficacy and safety of intravitreal inserts releasing 0.2 µg/d (low dose) or 0.5 µg/d (high dose) fluocinolone acetonide (FAc) in patients with diabetic macular edema (DME). DESIGN: Two randomized, sham injection-controlled, double-masked, multicenter clinical trials. PARTICIPANTS: Subjects with persistent DME despite ≥1 macular laser treatment were randomized 1:2:2 to sham injection (n = 185), low-dose insert (n = 375), or high-dose insert (n = 393). METHODS: Subjects received study drug or sham injection and after 6 weeks were eligible for rescue laser. Based on retreatment criteria, additional study drug or sham injections could be given after 1 year. MAIN OUTCOME MEASURES: Percentage of patients with improvement of ≥15 letters from baseline. Secondary outcomes included other parameters of visual function and foveal thickness. RESULTS: At month 36, the percentage of patients who gained ≥15 in letter score using the last observation carried forward method was 28.7% (low dose) and 27.8% (high dose) in the FAc insert groups compared with 18.9% (P = 0.018) in the sham group, and considering only those patients still in the trial at month 36, it was 33.0% (low dose) and 31.9% (high dose) compared with 21.4% in the sham group (P = 0.030). Preplanned subgroup analysis demonstrated a doubling of benefit compared with sham injections in patients who reported duration of DME ≥3 years at baseline; the percentage who gained ≥15 in letter score at month 36 was 34.0% (low dose; P<0.001) or 28.8% (high dose; P = 0.002) compared with 13.4% (sham). An improvement ≥2 steps in the Early Treatment Diabetic Retinopathy Study retinopathy scale occurred in 13.7% (low dose) and 10.1% (high dose) compared with 8.9% in the sham group. Almost all phakic patients in the FAc insert groups developed cataract, but their visual benefit after cataract surgery was similar to that in pseudophakic patients. The incidence of incisional glaucoma surgery at month 36 was 4.8% in the low-dose group and 8.1% in the high-dose insert group. CONCLUSIONS: In patients with DME FAc inserts provide substantial visual benefit for up to 3 years and would provide a valuable addition to the options available for patients with DME.

Macular edema in central retinal vein occlusion: correlation between optical coherence tomography, angiography and visual acuity.

To analyze the characteristics and the course of macular edema secondary to central retinal vein occlusion (CRVO) using optical coherence tomography (OCT) and to determine correlations between clinical, tomographic and angiographic data, in particular including retinal ischemia. In this retrospective study, 53 consecutive patients with CRVO were included. At each follow-up visit, patients underwent complete ophthalmological examination, including best-corrected visual acuity (BCVA) and OCT. Fluorescein angiography was performed at baseline and on demand during follow-up. 243 OCTs were analyzed. Mean age was 61 years and mean follow-up 13 months. The first structural change, observed very early after the onset of the occlusion, was a diffuse increase at the level of the outer nuclear layer without change at the level of the inner retina. This early change seemed characteristic of retinal vein occlusion. Cystoid spaces were subsequently observed in all retinal layers and were combined with serous retinal detachment in 51 %. During the first 6 months, central retinal thickness was higher in ischemic CRVO (mean, 691 µm) than in non-ischemic CRVO (mean, 440 µm, p < 0.01). In eyes with foveal thickness (central retinal thickness without subretinal fluid) of 700 µm or greater, peripheral ischemia was present in 69 % of eyes, final BCVA was 20/200 or less in 75 % and never reached 20/40 during follow-up. The integrity of the junction of the photoreceptors' inner and outer segments was correlated with a better prognosis (p < 0.05). Foveal thickness was inversely correlated to BCVA at each visit and could have a prognostic value. OCT examination in CRVO revealed useful data for the diagnosis of CRVO and its prognosis. The largest macular edemas seemed to be the hallmark of ischemic CRVO.

Optical coherence tomography in tadalafil-associated retinal toxicity.

PURPOSE: Tadalafil (Cialis) is a potent phosphodiesterase type 5 inhibitor that is widely used to treat erectile dysfunction. Phosphodiesterase-5 inhibitors have long been recognized to cause temporary and minor visual changes. METHODS: We report for the first time a case of visual disturbances due to reversible damage to the parafoveal photoreceptors following the use of tadalafil. The patient was examined using confocal scanning laser ophthalmoscopy combined with spectral domain optical coherence tomography (OCT). RESULTS: Spectral domain OCT of the right eye revealed a hyperreflective dense area and the appearance of a serous retinal detachment (SRD). The photoreceptors' internal segment-outer segment (IS-OS) interface was thickened and markedly hyperreflective without distinguishable deposits. The increased hyperreflectivity of the IS-OS interface created a hyporeflective space behind which mimicked the appearance of a SRD. The use of tadalafil was discontinued and the patient examined 2 months later. Spectral domain OCT revealed disappearance of the dense area and the pseudo-SRD. The associated symptoms resolved rapidly with discontinuation of the drug. CONCLUSIONS: Tadalafil use may be associated with reversible damage to the photoreceptors and corresponding visual symptoms.

Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype.

BACKGROUND: Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case-control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking. METHODS: To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, 'Y402H') with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26,494 individuals, including 14,174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene-smoking interaction; and 16 published studies from non-European ancestry. RESULTS: In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10-2.45; P = 1.1 x 10(-161)]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies. CONCLUSION: The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.

Associations between aspirin use and aging macula disorder: the European Eye Study.

OBJECTIVE: To study associations between aspirin use and early and late aging macula disorder (AMD). DESIGN: Population-based cross-sectional European Eye Study in 7 centers from northern to southern Europe. PARTICIPANTS: In total, 4691 participants 65 years of age and older, collected by random sampling. METHODS: Aspirin intake and possible confounders for AMD were ascertained by a structured questionnaire. Ophthalmic and basic systemic measurements were performed in a standardized way. The study classified AMD according to the modified International Classification System on digitized fundus images at 1 grading center. Nonfasting blood samples were analyzed in a single laboratory. Associations were analyzed by logistic regression. MAIN OUTCOME MEASURES: Odds ratios (ORs) for AMD in aspirin users. RESULTS: Early AMD was present in 36.4% of the participants and late AMD was present in 3.3% of participants. Monthly aspirin use was reported by 1931 (41.2%), at least once weekly by 7%, and daily use by 17.3%. For daily aspirin users, the ORs, adjusted for potential confounders, showed a steady increase with increasing severity of AMD grades. These were: grade 1, 1.26 (95% confidence interval [CI], 1.08-1.46; P<0.001); grade 2, 1.42 (95% CI, 1.18-1.70), and wet late AMD, 2.22 (95% CI, 1.61-3.05). CONCLUSIONS: Frequent aspirin use was associated with early AMD and wet late AMD, and the ORs rose with increasing frequency of consumption. This interesting observation warrants further evaluation of the associations between aspirin use and AMD. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Intravitreal ranibizumab for macular oedema secondary to retinal vein occlusion: a retrospective study of 34 eyes.

PURPOSE: To evaluate the efficacy and the safety of intravitreal ranibizumab injection (Lucentis) in eyes with macular oedema secondary to central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO). METHODS: The files of consecutive patients (34 eyes, 15 CRVO, 19 BRVO) were retrospectively analysed. Intravitreal injections of 0.5 mg ranibizumab were administered; retreatment was based on acuity visual changes and optical coherence tomography findings. Patients received 2-4 injections (mean, 2.1). Mean follow-up was 7 months. RESULTS: After the first injection, mean best-corrected visual acuity (BCVA) improved from 20/160 to 20/80 and mean central retinal thickness (CRT) decreased significantly from 549 to 301 µm (p < 0.01). For each injection, BCVA improvement was on average nine letters (p < 0.01) and macular oedema reduction was 195 µm CRT (p < 0.01). The decrease in CRT was similar in CRVO and BRVO, but the improvement in BCVA was larger in BRVO. No local or systemic adverse effect was detected. Final visual acuity was correlated to initial visual acuity and to visual acuity measured after the first injection. The change in CRT was correlated to the number of injections and to initial CRT. CONCLUSION: Intravitreal injections of ranibizumab appeared to be a safe and effective option in the treatment of macular oedema secondary to retinal vein occlusion. Nevertheless, because the natural course has demonstrated a possible improvement in vision in almost one quarter of affected eyes at 3 years, further controlled and prospective studies are necessary to compare this treatment to the natural course with a longer follow-up.

Randomized clinical trial France DMLA2: effect of trimetazidine on exudative and nonexudative age-relatedmacular degeneration.

PURPOSE: To evaluate the effect of trimetazidine (TMZ) in a randomized, double-blind, placebo-controlled clinical trial on the occurrence of choroidal neovascularization or geographic atrophy in age-related macular degeneration. METHODS: A total of 1,086 patients from France, Belgium, and Spain with soft drusen and/or retinal pigment epithelium abnormalities in the study eye and choroidal neovascularization in the contralateral eye were randomly assigned to receive orally placebo or TMZ 70 mg daily (35 mg × 2) and followed-up for 3 years to 5 years. RESULTS: Treatment duration ranged between 0.4 months and 67.8 months with a mean ± SD of 38 ± 16 months. Three hundred and fifty-eight patients developed choroidal neovascularization (incidence per 100 patient-years: TMZ 10.86; placebo 11.13). Trimetazidine did not prevent the choroidal neovascularization (hazard ratio = 0.97; 95% confidence interval, 0.77-1.20; P = 0.781). However, there was a trend favoring TMZ for retinal atrophy, a secondary endpoint (HR = 0.76; 95% confidence interval, 0.56-1.02; P = 0.069). Overall, the difference in atrophy incidence between TMZ and placebo was not statistically different. Differences within some prespecified subgroups of patients showed superiority of TMZ in men (HR = 0.50; 95% confidence interval, 0.28-0.89; p = 0.016), in patients aged ≤75 years (HR = 0.58; 95% confidence interval, 0.38-0.88; p = 0.010), or in patients presenting with isolated pigmentary changes (HR = 0.19; 95% confidence interval, 0.05-0.70; p = 0.005). CONCLUSION: Trimetazidine failed to prevent choroidal neovascularization. Subgroup analyses suggest that this drug could be tested as preventive therapy for geographic atrophy, although the overall comparison showed no statistically significant differences in the progression of geographic atrophy.