HISTORY OF SUNLIGHT EXPOSURE IS A RISK FACTOR FOR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate effects of current and past sunlight exposure and iris color on early and late age-related macular degeneration (AMD). METHODS: Of 3,701 individuals from the EUGENDA database, 752 (20.3%) showed early AMD, 1,179 (31.9%) late AMD, and 1,770 (47.8%) were controls. Information about current and past sunlight exposure, former occupation type, subdivided in indoor working and outdoor working, and iris color were obtained by standardized interviewer-assisted questionnaires. Associations between environmental factors adjusted for age, gender, and smoking and early and late AMD were performed by multivariate regression analysis. RESULTS: Current sunlight exposure showed no association with early AMD or late AMD, but past sunlight exposure (≥8 hours outside daily) was significantly associated with early AMD (odds ratio: 5.54, 95% confidence interval 1.25-24.58, P = 0.02) and late AMD (odds ratio: 2.77, 95% confidence interval 1.25-6.16, P = 0.01). Outside working was found to be associated with late AMD (odds ratio: 2.57, 95% confidence interval 1.89-3.48, P = 1.58 × 10). No association was observed between iris color and early or late AMD. CONCLUSION: Sunlight exposure during working life is an important risk factor for AMD, whereas sunlight exposure after retirement seems to have less influence on the disease development. Therefore, preventive measures, for example, wearing sunglasses to minimize sunlight exposure, should start early to prevent development of AMD later in life.

Immediate Postoperative Intraocular Pressure Changes After Anterior Chamber Air Fill in Descemet Membrane Endothelial Keratoplasty.

PURPOSE: To monitor the intraocular pressure (IOP) changes immediately after anterior chamber air tamponade in Descemet membrane endothelial keratoplasty (DMEK). METHODS: Twenty-four patients undergoing DMEK and 16 patients undergoing rebubbling after DMEK were enrolled (n = 40). All DMEK patients had inferior iridectomy and nearly full intracameral air tamponade with an aimed IOP of 25 mm Hg at the end of surgery. The IOP was measured at 1, 2, 3, 5, 12, 24 hours and 1 week postoperatively. RESULTS: After anterior chamber air fill in DMEK, the IOP increased from preoperative baseline, 12.1 ± 2.9 mm Hg, to 26.3 ± 4.7 mm Hg, P < 0.001. Mean IOP was significantly elevated in the first 2 hours, 19.4 ± 10.5 mm Hg and 17.0 ± 7.4 mm Hg, P = 0.007 and 0.006, respectively. Then, it lowered to the baseline level, 14.0 ± 4.7 mm Hg, P > 0.05, and remained stable during follow-ups. An asymptomatic IOP elevation above 30 mm Hg was detected in 3 patients (12.5%) within the first 2 hours. None had preexisting glaucoma. Most episodes could be controlled by antiglaucoma medications and upright positioning. The pattern of IOP changes after rebubbling was similar to that after DMEK but the IOP dropped sharply to the baseline level after 1 hour and had no incidence of IOP elevations beyond 30 mm Hg. CONCLUSIONS: Adequate inferior iridectomy greatly alleviates the risk and severity of acute IOP rises after nearly full anterior chamber air tamponade in DMEK. Standard IOP adjustment at the end of DMEK surgery with postoperative IOP monitoring especially in the first 2 postoperative hours is advisable when there is no postoperative default air release.

Nutritional risk factors for age-related macular degeneration.

PURPOSE: To evaluate the role of nutritional factors, serum lipids, and lipoproteins in late age-related macular degeneration (late AMD). METHODS: Intake of red meat, fruit, fish, vegetables, and alcohol, smoking status, and body mass index (BMI) were ascertained questionnaire-based in 1147 late AMD cases and 1773 controls from the European Genetic Database. Serum levels of lipids and lipoproteins were determined. The relationship between nutritional factors and late AMD was assessed using logistic regression. Based on multivariate analysis, area-under-the-curve (AUC) was calculated by receiver-operating-characteristics (ROC). RESULTS: In a multivariate analysis, besides age and smoking, obesity (odds ratio (OR): 1.44, P = 0.014) and red meat intake (daily: OR: 2.34, P = 8.22 × 10(-6); 2-6x/week: OR: 1.67, P = 7.98 × 10(-5)) were identified as risk factors for developing late AMD. Fruit intake showed a protective effect (daily: OR: 0.52, P = 0.005; 2-6x/week: OR: 0.58, P = 0.035). Serum lipid and lipoprotein levels showed no significant association with late AMD. ROC for nutritional factors, smoking, age, and BMI revealed an AUC of 0.781. CONCLUSION: Red meat intake and obesity were independently associated with increased risk for late AMD, whereas fruit intake was protective. A better understanding of nutritional risk factors is necessary for the prevention of AMD.

Nongenetic risk factors for neovascular age-related macular degeneration.

PURPOSE: To create a risk model for neovascular age-related macular degeneration (nAMD) based on nongenetic factors. METHODS: In this case-control study, 1459 individuals were included, 445 patients showed nAMD and 1014 were healthy controls. Participants were randomly assigned into a training set (containing two-thirds of individuals) and a validation set. Stepwise logistic regression analysis was performed for 25 environmental risk factors in the training set. The risk model with the remaining factors was then validated in the validation set using receiver operating characteristics (ROC) curve and Hosmer-Lemeshow-Test. Additionally, a genetic risk model including variants in the complement factor H gene (CFH, rs1061170) and the age-related maculopathy susceptibility 2 gene (ARMS2, rs10490924) was generated. RESULTS: The environmental risk model with the factors age, alcohol use, allergy, education, sunlight exposure, fish consumption, and physical exercise showed an AUC of 0.80 (95% confidence interval [CI] 0.76-0.84) in the training set. Validation of the model showed adequate calibration (Hosmer-Lemeshow P = 0.81). The AUC for the genetic model was 0.77 (95% CI 0.730-0.808), for the combined environmental and genetic model 0.92 (95% CI 0.887-0.947). CONCLUSIONS: Seven nongenetic factors are able to provide equivalent discrimination between nAMD patients and controls to genetic risk models. Most of them are modifiable and give the opportunity for counseling patients.

Environmental and genetic risk factors for retinal angiomatous proliferation.

PURPOSE: To identify genetic and environmental risk factors in patients with retinal angiomatous proliferation (RAP), a clinical subtype of age-related macular degeneration (AMD). METHODS: In this case-control study, 108 AMD cases with RAP, 258 AMD patients with choroidal neovascularization (CNV) without RAP and 443 healthy controls were evaluated. Single nucleotide polymorphisms in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) and various environmental risk factors were analysed. Statistical analysis was performed by univariate and multivariate regression analysis. RESULTS: High age, female sex and genetic variants in CFH and ARMS2 were identified as risk factors for developing any CNV. In RAP patients, arterial hypertension was also identified as a risk factor (OR 2.39; p = 0.0005). Compared with the 'non-RAP' CNV group, the association with high age (OR 1.05; p = 0.008) and arterial hypertension (OR 1.82; p = 0.02) was significantly higher in RAP patients, while the association with CFH risk alleles (homozygous OR 0.40; p = 0.003) was significantly lower, which was confirmed in a multivariate analysis (OR 0.41; p = 0.03 for the heterozygous risk allele and OR 0.38; p = 0.03 for the homozygous risk allele). CONCLUSION: The association with the CFH Y402 risk allele was less pronounced in RAP patients than in 'non-RAP' CNV patients, while the association with high age and arterial hypertension appeared to be stronger. These findings stress the importance of detailed phenotyping in AMD to identify homogeneous AMD subtypes and their different risk factors and disease mechanisms.

Impact of the common genetic associations of age-related macular degeneration upon systemic complement component C3d levels.

Age-related macular degeneration (AMD) is a common condition that leads to severe vision loss and dysregulation of the complement system is thought to be associated with the disease. To investigate associations of polymorphisms in AMD susceptibility genes with systemic complement activation, 2655 individuals were genotyped for 32 single nucleotide polymorphisms (SNPs) in or near 23 AMD associated risk genes. Component 3 (C3) and its catabolic fragment C3d were measured in serum and AMD staging was performed using multimodal imaging. The C3d/C3 ratio was calculated and associations with environmental factors, SNPs and various haplotypes of complement factor H (CFH) genes and complement factor B (CFB) genes were analyzed. Linear models were built to measure the influence of genetic variants on the C3d/C3 ratio. The study cohort included 1387 patients with AMD and 1268 controls. Higher C3d/C3 ratios were found for current smoker (p = 0.002), higher age (p = 1.56 × 10(-7)), AMD phenotype (p = 1.15 × 10(-11)) and the two SNPs in the C3 gene rs6795735 (p = 0.04) and rs2230199 (p = 0.04). Lower C3d/C3 ratios were found for diabetes (p = 2.87 × 10(-6)), higher body mass index (p = 1.00 × 10(-13)), the SNPs rs1410996 (p = 0.0001), rs800292 (p = 0.003), rs12144939 (p = 4.60 × 10(-6)) in CFH, rs4151667 (p = 1.01 × 10(-5)) in CFB and individual haplotypes in CFH and CFB. The linear model revealed a corrected R-square of 0.063 including age, smoking status, gender, and genetic polymorphisms explaining 6.3% of the C3d/C3 ratio. After adding the AMD status the corrected R-square was 0.067. In conclusion, none of the evaluated genetic polymorphisms showed an association with increased systemic complement activation apart from two SNPs in the C3 gene. Major genetic and non-genetic factors for AMD were not associated with systemic complement activation.

Genetic and environmental risk factors for age-related macular degeneration in persons 90 years and older.

PURPOSE: We studied associations of genetic polymorphisms in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) in nonagenarians with age-related macular degeneration (AMD). METHODS: This case-control study comprised 2737 persons (1204 controls, 1433 AMD cases), including 166 nonagenarians (52 controls, 114 AMD cases). Single nucleotide polymorphisms (SNPs) in the genes ARMS2 and CFH were determined. Risk scores were computed by multiple logistic regression analysis, including genetic and environmental risk factors (smoking, hypertension, body mass index, diabetes) for different age groups (<70, 70-79, 80-89, ≥ 90 years [nonagenarians]). RESULTS: In nonagenarians, ARMS2 showed the weakest associations with AMD (odds ratio [OR] = 1.52, P = 0.127) compared to the other groups (OR, 70 years = 2.23, P = 1.03 × 10(-13); OR, 70-79 years = 2.70, P = 1.00 × 10(-13); OR, 80-89 years = 3.11, P = 6.56 × 10(-8)). For CFH, ORs for AMD increased with age (<70 years OR = 1.96, P = 1.80 × 10(-11); 70-79 years OR = 1.89, P = 4.48 × 10(-13); 80-89 years OR = 2.71, P = 1.28 × 10(-7)), but decreased again in the nonagenarians (OR = 2.21, P = 0.005). Compared to the group <70 years, reduced minor allele frequencies (MAFs) for AMD patients were observed in the nonagenarians (CFH 0.54 vs. 0.43, P = 0.009; ARMS2 0.44 vs. 0.29, P = 2.97 × 10(-5)), while the MAFs in controls were not significantly different. The genetic risk score revealed the lowest discriminative power in the nonagenarians with an area-under-curve (AUC) of 0.658 for receiver-operating characteristics (AUC 80-89 years = 0.768, 70-79 years = 0.704, <70 years = 0.682), while no significant difference was seen for the environmental risk score (AUC < 70 years = 0.579, 70-79 years = 0.567, 80-89 years = 0.600, >90 years = 0.608). CONCLUSIONS: Risk alleles in CFH and ARMS2 have a significantly smaller effect on AMD development in nonagenarians, while environmental factors retain a similar effect.

Allergy is a protective factor against age-related macular degeneration.

PURPOSE: To investigate the role of allergy on AMD. METHODS: Age-related macular degeneration staging was performed for 3585 individuals (1878 from Cologne, Germany, and 1707 from Nijmegen, The Netherlands). Interviewer-assisted questionnaires were evaluated for the factors smoking, use of corticosteroids, and history of allergy, including causative allergens. Serum complement component C3d and C3 levels were measured and the C3d:C3 ratio was calculated. Associations of allergy with AMD/late AMD were assessed by logistic regression analysis; C3d:C3 ratio was compared between groups. RESULTS: The discovery cohort from Cologne included 864 AMD patients and 1014 controls; 495 patients had late AMD. Positive history of allergy showed strong protective effects on the phenotype AMD (OR 0.52; P = 3.42 × 10(-9)) and late AMD (OR 0.32; P = 2.57 × 10(-13)). Subclassification in allergy-provoking agents showed significant protective effects in all groups. After adjustment for age, sex, smoking, and corticosteroid use, protective effects for AMD (OR 0.75; P = 0.018) and late AMD (OR 0.49; P = 2.87 × 10(-5)) were confirmed. Although the C3d:C3 ratio was higher in AMD/late AMD patients (both P < 0.001), there was no association with allergy in AMD (P = 0.22). The protective effect of allergy on AMD was confirmed in the replication cohort from Nijmegen (P = 0.002 for AMD; P = 0.0001 for late AMD). CONCLUSIONS: Allergy has a protective effect on the development of AMD independent of the provoking allergen, which cannot be explained by complement activation. Further investigations are necessary to elucidate the molecular mechanisms underlying the protective effect of allergy on AMD.

Response to anti-VEGF therapy in patients with subretinal fluid and pigment epithelial detachment on spectral-domain optical coherence tomography.

PURPOSE: To analyse the long-term functional and morphological response of a specific choroidal neovascular membrane (CNV) phenotype to anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Data from 30 eyes of 30 consecutive patients with subretinal fluid (SRF) and fibrovascular pigment epithelial detachment (PED) due to CNV on spectral-domain optical coherence tomography (SDOCT) with a follow-up of at least 20 months were retrospectively collected. Main outcome measures included change in visual acuity, quantitative and qualitative parameters on SDOCT [photoreceptor layer, outer nuclear layer (ONL), choroid, PED, SRF] and on fluorescein angiography (CNV activity). Subjects were divided into responders and non-responders based on morphological and functional aspects. RESULTS: An average number of 20.23 ± 9.9 anti-VEGF injections were administered during a mean follow-up of 40.25 ± 13.5 months. Fourteen eyes were categorized as morphological non-responders, 12 as functional non-responders and eight as complete non-responders. Complete non-responders were significantly younger than complete responders (68.5 ± 4.5 vs 74.3 ± 6.8 years; p < 0.05) and presented thinner baseline ONL values (68.43 ± 15.2 vs103.5 ± 32.8 µm; p < 0.05). Intermediate or large drusen as typical features for age-related macular degeneration (AMD) were less frequently present in complete non-responders; however, this was not statistically significant (62.5 % vs 91.7 %; p = 0.25). CONCLUSIONS: Our preliminary findings indicate that eyes with the specific SDOCT phenotype with isolated fibrovascular PED and SRF frequently demonstrate non-response to anti-VEGF therapy, and the underlying disease mechanism may be different from AMD. Larger prospective trials are required to validate those results, and to develop strategies to improve the morphological as well as functional outcome.

Aqueous flare is increased in patients with clinically significant cystoid macular oedema after cataract surgery.

BACKGROUND: To analyse the relationship of clinically significant cystoid macular oedema (CME after phacoemulsification to blood-aqueous barrier breakdown as determined by aqueous flare, visual acuity and retinal thickness in optical coherence tomography (OCT). MATERIALS AND METHODS: 30 eyes of 30 consecutive patients with clinically significant CME and vision loss were included. 46 pseudophakic and 45 phakic eyes without CME served as controls. Clinical data included age, gender, best-corrected visual acuity (BCVA) and spectral domain OCT volume scans. Retinal thickness measuring of the foveal central subfield was determined. Aqueous flare was measured quantitatively with the Kowa FM-500 Laser Flare-Cell Meter. RESULTS: Patients with CME had significantly higher flare values compared with pseudophakic patients (p<0.0001). For patients with CME, aqueous flare values correlated significantly with BCVA (Spearman rs=0.4, p=0.041), while there was no correlation with retinal thickness. Using flare values to predict CME, receiver operating characteristic analysis returned an area under the curve of 0.976. CONCLUSIONS: Aqueous flare as a marker for inflammation and breakdown of the blood-retinal barrier is increased in patients with CME after cataract surgery.