Half-dose photodynamic therapy versus 577 nm subthreshold pulse laser therapy in treatment-naive patients with central serous chorioretinopathy.

BACKGROUND: To compare real-life anatomical and functional outcomes of half-dose photodynamic therapy (HD-PDT) and 577 nm subthreshold pulse laser therapy (SPL) in treatment-naïve patients with central serous chorioretinopathy (CSC). METHODS: We retrospectively reviewed consecutive treatment-naïve CSC patients with non-resolving subretinal fluid (SRF) for more than 2 months who received either HD-PDT or SPL treatment. One repetition of the same treatment was allowed in patients with persistent SRF after first treatment. Functional and anatomical outcomes were assessed after first treatment and at final visit. RESULTS: We included 95 patients (HD-PDT group, n = 49; SPL group, n = 46). Complete resolution of SRF after a single treatment was observed in 42.9% of HD-PDT-treated patients (n = 21; median time to resolution 7.1 weeks) and in 41.3% of SPL-treated patients (n = 19; median time to resolution 7.0 weeks). In the HD-PDT-group, 44.9% of patients (n = 22) and in the SPL-group, 43.5% (n = 20) of patients, received a second treatment due to persistent SRF, while 12.2% (n = 6) and 15.2% (n = 7), respectively, opted against a second treatment despite persistent SRF. After the final treatment, complete SRF resolution was observed in 61.2% of all HD-PDT-treated patients (n = 30; median time to resolution 8.8 weeks) and 60.9% of all SPL-treated patients (n = 28; median time to resolution 13.7 weeks, p = 0.876). In the final visit, both groups showed significant improvement of BCVA in comparison to baseline (p < 0.001 for all). The change in BCVA from baseline to final visit was similar for the two groups (HD-PDT, median BCVA change 0.10 logMAR (IQR: 0.0-0.2); in SPL group, median BCVA change 0.10 logMAR (IQR: 0.0-0.2), P = 0.344). The CSC subclassification (simple versus complex) had no influence on the anatomical or functional outcome. CONCLUSIONS: High-density 577 nm SPL resulted in as good anatomical and functional treatment as HD-PDT and may thus represent a treatment alternative to HD-PDT in CSC.

Intravitreal 5-Fluorouracil and Heparin to Prevent Proliferative Vitreoretinopathy: Results from a Randomized Clinical Trial.

PURPOSE: Proliferative vitreoretinopathy (PVR) is the major cause for surgical failure after primary rhegmatogenous retinal detachment (RRD). So far, no therapy has been proven to prevent PVR. Promising results for 5-fluorouracil (5-FU) and low-molecular weight heparin (LMWH) in high-risk eyes have been reported previously. The objective of this trial was to examine the effect of adjuvant intravitreal therapy with 5-FU and LMWH compared with placebo on incidence of PVR in high-risk patients with primary RRD. DESIGN: Randomized, double-blind, controlled, multicenter, interventional trial with 1 interim analysis. PARTICIPANTS: Patients with RRD who were considered to be at high risk for PVR were included. Risk of PVR was assessed by noninvasive aqueous flare measurement using laser flare photometry. METHODS: Patients were randomized 1:1 to verum (200 mg/ml 5-FU and 5 IU/ml dalteparin) and placebo (balanced salt solution) intravitreally applied during routine pars plana vitrectomy. MAIN OUTCOME MEASURES: Primary end point was the development of PVR grade CP (full-thickness retinal folds or subretinal strands in clock hours located posterior to equator) 1 or higher within 12 weeks after surgery. For grading, an end point committee assessed fundus photographs. Secondary end points included best-corrected visual acuity and redetachment rate. A group sequential design with 1 interim analysis was applied using the O'Brien and Fleming boundaries. Proliferative vitreoretinopathy grade CP incidence was compared using a Mantel-Haenszel test stratified by surgeon. RESULTS: A total of 325 patients in 13 German trial sites had been randomized (verum, n = 163; placebo, n = 162). In study eyes, mean laser flare was 31 ± 26 pc/ms. No significant difference was found in PVR rate. Primary analysis in the modified intention-to-treat population results were: verum 28% vs. placebo 23% (including not assessable cases as failures); odds ratio [OR], 1.25; 95% confidence interval [CI], 0.76-2.08; P = 0.77. Those in the per-protocol population were: 12% vs. 12%; OR, 1.05; 95% CI, 0.47-2.34; P = 0.47. None of the secondary end points showed any significant difference between treatment groups. During the study period, no relevant safety risks were identified. CONCLUSIONS: Rate of PVR did not differ between adjuvant therapy with 5-FU and LMWH and placebo treatment in eyes with RRD.

Ocular and Systemic Complement Activation during Anti-Vascular Endothelial Growth Factor Treatment and Age-Related Eye Disease Study 2 Dietary Supplementation in Neovascular Age-Related Macular Degeneration.

PURPOSE: The aim of this study was to investigate the influence of dietary supplementation using Age-Related Eye Disease Study 2 (AREDS2) on complement activation in patients with neovascular age-related macular degeneration (nAMD) under ongoing treatment. METHODS: In this prospective, single-center, controlled, open-label investigator-initiated trial, eligible nAMD patients were randomized at a ratio of 1:1 in 2 groups: those with and without dietary AREDS2 supplementation for 4 weeks. Zinc, plasma, and aqueous humor (AH) complement levels were quantified via enzyme-linked immunosorbent assays. RESULTS: Fifty of 62 enrolled patients completed the trial (AREDS2 n = 27, controls n = 23). Systemic zinc and complement levels were not different at baseline between the 2 groups (p > 0.1). At the final visit, systemic zinc levels were significantly higher in the AREDS2 group (10.16 ± 2.08 µmol/L; 8.66 ± 1.17 µmol/L; p = 0.007), whereas systemic and AH complement levels were not different (p > 0.1). In both groups, no significant change was observed in systemic levels of C3, C3a, FH, FI, and sC5b-9 (p > 0.1). Only systemic complement component Ba showed an increase from baseline to the end visit (p = 0.01). This increase was higher in the control group (p = 0.02) than in the AREDS2 group (p = 0.23). CONCLUSIONS: Short-term dietary AREDS2 supplementation leads to a significant increase in systemic zinc levels without any influence on complement activation levels.

Genetic and environmental risk factors for reticular pseudodrusen in the EUGENDA study.

PURPOSE: The purpose of this study was to analyze genetic and nongenetic associations with reticular pseudodrusen (RPD) in patients with and without age-related macular degeneration (AMD). METHODS: This case-control study included 2,719 consecutive subjects from the prospective multicenter European Genetic Database (EUGENDA). Color fundus photographs and optical coherence tomography (OCT) scans were evaluated for the presence of AMD and RPD. Association of RPD with 39 known AMD polymorphisms and various nongenetic risk factors was evaluated. Stepwise backward variable selection via generalized linear models (GLMs) was performed based on models including the following: a) age, sex, and genetic factors and b) all predictors. Receiver operating characteristic (ROC) curves and the areas under the curve (AUCs) were determined. RESULTS: RPD were present in 262 cases (no AMD, n = 9 [0.7%; early/intermediate AMD, n = 75 [12.4%]; late AMD, n = 178 [23.8%]). ROC analysis of the genetic model including age, APOE rs2075650, ARMS2 rs10490924, CFH rs800292, CFH rs12144939, CFI rs10033900, COL8A1 rs13081855, COL10A1 rs3812111, GLI3 rs2049622, and SKIV2L rs4296082 revealed an AUC of 0.871. Considering all possible predictors, backward selection revealed a slightly different set of genetic factors, as well as the following nongenetic risk factors: smoking, rheumatoid arthritis, steroids, antiglaucomatous drugs, and past sunlight exposure; the results showed an AUC of 0.886. CONCLUSIONS: RPD share a variety of genetic and nongenetic risk factors with AMD. Future AMD grading systems should integrate RPD as an important risk phenotype.

Association of imaging biomarkers and local activation of complement in aqueous humor of patients with early forms of age-related macular degeneration.

PURPOSE: To investigate a possible correlation between established imaging biomarkers for age-related macular degeneration and local complement system activation, measured in aqueous humor (AH) of patients with early stages of age-related macular degeneration (AMD) and controls. METHODS: This analysis included prospectively acquired AH samples of 106 eyes (35 with early/intermediate AMD, 71 controls). The levels of complement protein 3 (C3), 4 (C4), 5 (C5); activation products of complement factor 3a (C3a) and Ba, C3b/iC3b; complement factors B, D, H, I (CFB, CFD, CFH, CFI); and total protein concentration were analyzed. Quantitative levels of complement factors were correlated to the presence of reticular pseudodrusen (RPD), the presence of hyperreflective foci (HRF), and total drusen volume (DV) graded on imaging by spectral-domain optical coherence tomography and using Spearman's rank correlation test. RESULTS: DV correlated with C3b/iC3b (r = 0.285; P = 0.034), C3a (r = 0.200; P = 0.047), Ba (r = 0.262; P = 0.009), and C5 (r = 430; P = 0.005), and showed a tendency towards correlation with C3a (r = 0.198; P = 0.057). HRF correlated significantly with C5 (r = 0.388; P = 0.011) and RPD showed a tendency towards correlation with CFB (r = 0.196; P = 0.050). CONCLUSION: In patients with early AMD, HRF and drusen parameters but not RPD show low to fair levels of correlation with local complement activation in patients' AH. Better understanding of complement activation could provide some insights into the pathogenesis of AMD. Imaging biomarkers could be useful to identify suitable patients for future clinical trials with complement-modulating therapies.

SALIVARY ALPHA-AMYLASE LEVELS MAY CORRELATE WITH CENTRAL SEROUS CHORIORETINOPATHY ACTIVITY.

PURPOSE: To investigate and compare the salivary alpha-amylase (sAA) activity as an indicator of the sympathetic activity and stress response in patients with central serous chorioretinopathy (CSC) and healthy control subjects. METHODS: Prospective multicenter case series, including 80 CSC patients and 88 healthy control subjects. Central serous chorioretinopathy status was classified as either active or inactive, depending on the presence of subretinal fluid on optical coherence tomography. Salivary samples were collected in the morning from patients and control subjects of the main cohort and at midnight for the additional cohort. Salivary alpha-amylase activity was determined in all patients and control subjects. RESULTS: Morning sAA activity was significantly higher in patients with active CSC compared with inactive CSC (P = 0.049) and to healthy control subjects (P = 0.012). There was no significant difference in sAA activity between patients with inactive CSC and control subjects (P = 1.0). Nocturnal sAA activity did not show any significant difference between patients with active CSC and either inactive CSC or control subjects (P = 0.139). CONCLUSION: Morning sAA activity is increased in patients with active CSC, although diurnal rhythmicity is preserved. Measurement of sAA is easy to perform and might be an eligible tool to further investigate the relation between stress and CSC.

Genetic and environmental risk factors for extramacular drusen.

PURPOSE: To analyze risk factors for extramacular drusen (EMD) in patients with age-related macular degeneration (AMD) and healthy control individuals. METHODS: This case-control study included 1,520 patients from the prospective multicenter European Genetic Database (EUGENDA). Color fundus photographs and optical coherence tomography scans were evaluated for the presence of AMD and EMD. EMD was considered present if ten or fewer drusen including at least one intermediate-sized drusen were detected outside the macula. Association of EMD was evaluated with various genetic and non-genetic risk factors (31 single nucleotide polymorphisms, systemic complement activation, smoking, cardiovascular factors, and sunlight exposure) using logistic regression models adjusted for age, gender, and AMD. RESULTS: EMD was found in 608 subjects (40%) and AMD in 763 (50%) of 1,520 participants. EMD was strongly associated with AMD (p = 2.83 × 10-63, odds ratio [OR] 7.63). After adjustment for AMD, age (p = 0.06, OR 1.02), female gender (p = 3.34 × 10-24, OR 4.44), history of sunlight exposure ≥ 8 h /day (p = 0.0004, OR 1.99), serum complement activation (p = 0.004, OR 1.61), and polymorphisms in ARMS2 (p = 0.00016, OR 1.43) and CFI (p = 0.043, OR 1.20) were identified as risk factors for EMD. The final prediction model including these variants showed an area under the curve of 0.820. CONCLUSIONS: The comprehensive analysis of various risk factors revealed a common genetic and pathological pathway of EMD with AMD. Future longitudinal studies are needed to evaluate the role of EMD in otherwise healthy subjects as an expanded phenotype of AMD.

Major Predictive Factors for Progression of Early to Late Age-Related Macular Degeneration.

INTRODUCTION: We present a prediction model for progression from early/intermediate to advanced age-related macular degeneration (AMD) within 5.9 years. OBJECTIVES: To evaluate the combined role of genetic, nongenetic, and phenotypic risk factors for conversion from early to late AMD over ≥5 years. METHODS: Baseline phenotypic characteristics were evaluated based on color fundus photography, spectral-domain optical coherence tomography, and infrared images. Genotyping for 36 single-nucleotide polymorphisms as well as systemic lipid and complement measurements were performed. Multivariable backward logistic regression resulted in a final prediction model. RESULTS AND CONCLUSIONS: During a mean of 5.9 years of follow-up, 22.4% (n = 52) of the patients (n = 232) showed progression to late AMD. The multivariable prediction model included age, CFH variant rs1061170, pigment abnormalities, drusenoid pigment epithelial detachment (DPED), and hyperreflective foci (HRF). The model showed an area under the curve of 0.969 (95% confidence interval 0.948-0.990) and adequate calibration (Hosmer-Lemeshow test, p = 0.797). In addition to advanced age and carrying a CFH variant, pigment abnormalities, DPED, and HRF are relevant imaging biomarkers for conversion to late AMD. In clinical routine, an intensified monitoring of patients with a high-risk phenotypic profile may be suitable for the early detection of conversion to late AMD.

GENETIC RISK FACTORS IN ACUTE CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To investigate genetic associations in white patients with acute central serous chorioretinopathy (aCSC) and to assess genetic differences between aCSC and chronic CSC (cCSC). METHODS: A total of 135 aCSC patients, 272 cCSC patients, and 1,385 control individuals were included. Eight single nucleotide polymorphisms were genotyped for ARMS2 (rs10490924), CFH (rs800292, rs1061170, rs1065489, rs1329428, rs2284664, rs3753394), and NR3C2 (rs2070951). Also, C4B gene copy numbers were analyzed. RESULTS: Three single nucleotide polymorphisms in the CFH gene were significantly associated with aCSC: rs800292 (P = 0.003, odds ratio = 1.53 [95% confidence interval = 1.15-2.03]), rs1061170 (P = 0.002, odds ratio = 0.64 [95% confidence interval = 0.48-0.86]), and rs1329428 (P = 5.87 × 10, odds ratio = 1.83 [95% confidence interval = 1.40-2.38]). A significant difference was found in the distribution of C4B gene copy numbers in aCSC patients compared with controls (P = 0.0042). No differences could be found among the selected variants between aCSC and cCSC patients. CONCLUSION: Three variants in the CFH gene and copy number variations in C4B were found to be significantly associated with the risk of aCSC development. Despite the differences in clinical presentation, acute and chronic CSC may share a similar genetic predisposition based on our present analysis. Other genetic and/or nongenetic risk factors may be more influential in the differentiation toward an acute or a chronic phenotype of CSC.

Onset of Retinal Pigment Epithelium Atrophy Subsequent to Anti-VEGF Therapy in Patients with Neovascular Age-Related Macular Degeneration.

PURPOSE: The aim of this study was to evaluate risk factors for the development of retinal pigment epithelium (RPE) atrophy in patients with neovascular age-related macular degeneration (nAMD). PROCEDURES: This post hoc analysis of the prospective RESPONSE study includes 52 therapy-naive nAMD patients without baseline RPE atrophy, who were treated with ≥9 anti-vascular endothelial growth factor (VEGF) injections for ≥3 years. RPE atrophy was assessed via multimodal imaging. Baseline aqueous VEGF and serum complement levels (C3d/C3) were measured. Risk factors for atrophy development were evaluated via logistic regression analysis. RESULTS: Atrophy onset was significantly associated with the duration of nAMD (mean 5.34 years; odds ratio = 1.83, p = 0.012). Anti-VEGF injection number, age, C3d/C3 ratio, baseline intraocular VEGF, or delay to the first treatment had no influence on RPE atrophy. CONCLUSIONS: The duration of treatment-requiring nAMD was identified as primary risk factor for the onset of concomitant RPE atrophy after commencing therapy. Targeting concomitant atrophy in nAMD patients might improve the long-term prognosis of the disease.

Genome-Wide Association Study Reveals Variants in CFH and CFHR4 Associated with Systemic Complement Activation: Implications in Age-Related Macular Degeneration.

PURPOSE: To identify genetic variants associated with complement activation, which may help to select age-related macular degeneration (AMD) patients for complement-inhibiting therapies. DESIGN: Genome-wide association study (GWAS) followed by replication and meta-analysis. PARTICIPANTS: AMD patients and controls (n = 2245). METHODS: A GWAS on serum C3d-to-C3 ratio was performed in 1548 AMD patients and controls. For replication and meta-analysis, 697 additional individuals were genotyped. A model for complement activation including genetic and non-genetic factors was built, and the variance explained was estimated. Haplotype analysis was performed for 8 SNPs across the CFH/CFHR locus. Association with AMD was performed for the variants and haplotypes found to influence complement activation. MAIN OUTCOME MEASURES: Normalized C3d/C3 ratio as a measure of systemic complement activation. RESULTS: Complement activation was associated independently with rs3753396 located in CFH (Pdiscovery = 1.09 × 10-15; Pmeta = 3.66 × 10-21; ß = 0.141; standard error [SE] = 0.015) and rs6685931 located in CFHR4 (Pdiscovery = 8.18 × 10-7; Pmeta = 6.32 × 10-8; ß = 0.054; SE = 0.010). A model including age, AMD disease status, body mass index, triglycerides, rs3753396, rs6685931, and previously identified SNPs explained 18.7% of the variability in complement activation. Haplotype analysis revealed 3 haplotypes (H1-2 and H6 containing rs6685931 and H3 containing rs3753396) associated with complement activation. Haplotypes H3 and H6 conferred stronger effects on complement activation compared with the single variants (P = 2.53 × 10-14; ß = 0.183; SE = 0.024; and P = 4.28 × 10-4; ß = 0.144; SE = 0.041; respectively). Association analyses with AMD revealed that SNP rs6685931 and haplotype H1-2 containing rs6685931 were associated with a risk for AMD development, whereas SNP rs3753396 and haplotypes H3 and H6 were not. CONCLUSIONS: The SNP rs3753396 in CFH and SNP rs6685931 in CFHR4 are associated with systemic complement activation levels. The SNP rs6685931 in CFHR4 and its linked haplotype H1-2 also conferred a risk for AMD development, and therefore could be used to identify AMD patients who would benefit most from complement-inhibiting therapies.

Genetic screening for macular dystrophies in patients clinically diagnosed with dry age-related macular degeneration.

It can be clinically challenging to distinguish dry age-related macular degeneration (AMD) from AMD-mimicking dystrophies, and sometimes misdiagnosis occurs. With upcoming therapies for dry AMD it is important to exclude patients with a different retinal disease from clinical trials. In this study we evaluated the occurrence of AMD-mimicking dystrophies in an AMD cohort. Whole-exome sequencing (WES) was performed in 218 patients with intermediate AMD or geographic atrophy secondary to AMD and 133 control individuals. WES data was analyzed for rare variants in 19 genes associated with autosomal dominant and recessive macular dystrophies mimicking AMD. In three (1.4%) of 218 cases we identified a pathogenic heterozygous variant (PRPH2 c.424C > T; p.R142W) causal for autosomal dominant central areolar choroidal dystrophy (CACD). Phenotypically, these patients all presented with geographic atrophy. In 12 (5.5%) of 218 cases we identified a heterozygous variant of unknown clinical significance, but predicted to be highly deleterious, in genes previously associated with autosomal dominant macular dystrophies. The distinction between AMD and AMD-mimicking dystrophies, such as CACD, can be challenging based on fundus examination alone. Genetic screening for genes associated with macular dystrophies, especially PRPH2, can be beneficial to help identify AMD-mimicking dystrophies.

Early Changes of Retinal Morphology in Therapy of Neovascular Age-Related Macular Degeneration with Three Commonly Used Anti-VEGF Agents.

PURPOSE: To compare changes of retinal morphology in the first weeks following injection of anti-VEGF agents for neovascular age-related macular degeneration (nAMD). PROCEDURES: In a prospective study 50 patients with active choroidal neovascularization secondary to nAMD were monitored weekly by spectral-domain optical coherence tomography for 3 weeks after treatment. Twenty-two patients received bevacizumab, 15 ranibizumab, and 13 aflibercept. Morphological parameters of retinal compartments were compared. RESULTS: Mean central retinal thickness (391.22 ± 123.41 µm) was reduced by -26.15 µm (p < 0.001) after 1 week, by -12.54 µm (p < 0.001) after 2 weeks, and by -3.52 µm (p = 0.09) after 3 weeks. Mean intraretinal layer thickness changed only significantly between baseline and week 1 (p < 0.001). Mean subretinal thickness also decreased between weeks 1 and 2 (p = 0.01). CONCLUSIONS: Early morphological changes occur primarily in the first 14 days after treatment. This information could be clinically helpful to evaluate early non-response.

Retinal Nerve Fiber Loss in Anti-VEGF Therapy for Age-Related Macular Degeneration Can Be Decreased by Anterior Chamber Paracentesis.

PURPOSE: To analyze peripapillary retinal nerve fiber layer thickness (RNFLT) change after long-term intravitreal anti-VEGF therapy. Patients with regular anterior chamber paracentesis (ACP) prior to intravitreal injections (IVIs) were compared to those without ACP. METHODS: Neovascular age-related macular degeneration (nAMD) was treated in a pro re nata regimen with a minimum of 9 IVIs. RNFLT change was determined in spectral domain optical coherence tomography. RESULTS: In 32 patients without ACP, mean RNFLT loss (-2.16 ± 3.60 µm) was significantly higher than in 44 patients with regular ACP (0.16 ± 3.60; p = 0.029). Both groups were comparable in age (75.0 vs. 76.8 years; p = 0.35), number of IVIs (16.2 vs. 16.6; p = 0.98), and observational time (30.0 vs. 32.3 months; p = 0.32). In patients without ACP, RNFLT loss was higher compared to IVI-naive fellow eyes (p = 0.005), whereas in ACP patients, no difference was detected (p = 0.5). CONCLUSIONS: A moderate RNFLT loss is found in nonglaucomatous patients after injection therapy for nAMD. As it is decreased with regular ACP, tight management of intraocular pressure seems advisable.

Implications of Ocular Confounding Factors for Aqueous Humor Proteomic and Metabolomic Analyses in Retinal Diseases.

Purpose: To assess the impact of ocular confounding factors on aqueous humor (AH) proteomic and metabolomic analyses for retinal disease characterization. Methods: This study recruited 138 subjects (eyes): 102 with neovascular age-related macular degeneration (nAMD), 18 with diabetic macular edema (DME), and 18 with cataract (control group). AH samples underwent analysis using Olink Target 96 proteomics and Metabolon's metabolomics platform Data analysis included correlation, differential abundance, and gene-set analysis. Results: In total, 756 proteins and 408 metabolites were quantified in AH. Total AH protein concentration was notably higher in nAMD (3.2-fold) and DME (4.1-fold) compared to controls. Pseudophakic eyes showed higher total AH protein concentrations than phakic eyes (e.g., 1.6-fold in nAMD) and a specific protein signature indicative of matrix remodeling. Unexpectedly, pupil-dilating drugs containing phenylephrine/tropicamide increased several AH proteins, notably interleukin-6 (5.4-fold in nAMD). Correcting for these factors revealed functionally relevant protein correlation clusters and disease-relevant, differentially abundant proteins across the groups. Metabolomics analysis, for which the relevance of confounder adjustment was less apparent, suggested insufficiently controlled diabetes and chronic hyperglycemia in the DME group. Conclusions: AH protein concentration, pseudophakia, and pupil dilation with phenylephrine/tropicamide are important confounding factors for AH protein analyses. When these factors are considered, AH analyses can more clearly reveal disease-relevant factors. Translational Relevance: Considering AH protein concentration, lens status, and phenylephrine/tropicamide administration as confounders is crucial for accurate interpretation of AH protein data.

Genetic Risk of Reticular Pseudodrusen in Age-Related Macular Degeneration: HTRA1 /lncRNA BX842242.1 dominates, with no evidence for Complement Cascade involvement.

Age-related macular degeneration (AMD) is a multifactorial retinal disease with a large genetic risk contribution. Reticular pseudodrusen (RPD) is a sub-phenotype of AMD with a high risk of progression to late vision threatening AMD. In a genome-wide association study of 2,165 AMD+/RPD+ and 4,181 AMD+/RPD-compared to 7,660 control participants, both chromosomes 1 ( CFH ) and 10 ( ARMS2/HTRA1 ) major AMD risk loci were reidentified. However association was only detected for the chromosome 10 locus when comparing AMD+/RPD+ to AMD+/RPD-cases. The chromosome 1 locus was notably absent. The chromosome 10 RPD risk region contains a long non-coding RNA (ENSG00000285955/BX842242.1) which colocalizes with genetic markers of retinal thickness. BX842242.1 has a strong retinal eQTL signal, pinpointing the parafoveal photoreceptor outer segment layer. Whole genome sequencing of phenotypically extreme RPD cases identified even stronger enrichment for the chromosome 10 risk genotype.

Visual complaints in pregnancy: (pre)eclampsia as a chameleon.

Objective: The visual system often is affected in patients with preeclampsia and even more in cases of eclampsia, a life-threatening pregnancy complication. Symptoms include blurred vision and deterioration of visual acuity. Pregnancy can also affect pre-existing conditions, such as diabetic retinopathy. In this case series, we describe three patients with the same underlying condition, i.e. (pre)eclampsia who experienced acute visual disturbance whereas the final diagnosis was different: disseminated intravascular coagulopathy (DIC), posterior reversible encephalopathy syndrome (PRES), and diabetic retinopathy. Methods and results: All patients underwent a thorough slit lamp examination and ocular coherence tomography (OCT). All patients presented with acute impaired vision and subretinal fluid and-/or fibrin. Conclusions: These cases highlight the importance of early involvement of ophthalmologists when pregnant women complain about visual disorders.

The Effect of Genetic Variants Associated With Age-Related Macular Degeneration Varies With Age.

Purpose: The prevalence of age-related macular degeneration (AMD) increases dramatically with age. This large collaborative study investigates the effects of 51 late-AMD-associated genetic variants in different ages, focusing on individuals above the age of 90 years. Methods: The study included 27,996 individuals of the International AMD Genomics Consortium; 14,539 showed late AMD (51.9%) and 13,457 were controls (48.1%). Four age groups were compiled: 60 to 69 years, n = 6514, AMD = 2210 (33.9%); 70 to 79 years, n = 12228, AMD = 6217 (51.7%); 80 to 89 years, n = 8285, AMD = 5326 (64.3%); and ≥90 years, n = 969, AMD = 686 (70.8%). The effect sizes of 51 AMD-associated genetic variants were calculated for all age groups and were compared among the age groups. Results: Six variants were associated with late AMD in individuals ≥ 90 years of age (P ≤ 0.0006). For rs10922109 and rs570618 (both in CFH), the minor allele (MA) was protective, and minor allele frequency (MAF) increased with age in cases and controls. For rs116503776 in C2/CFB/SKIV2L, the MA was protective, and MAF increased in cases. For rs3750846 in ARMS2/HTRA1, the MA increased risk, and MAF was lower in cases with increasing age. For rs6565597 in NPLOC4/TSPAN10, the MA increased risk. For rs5754227 in SYN3/TIMP3, the MA was protective, and there was no consistent variation in MAF with age. Variants in CFH and ARMS2 showed lower effect sizes at greater age. Interaction analysis showed strong age-related effects for rs570618 (P = 2.24 × 10-7) and rs3750846 (P = 0.001). Total genetic risk was lower in individuals ≥ 90 years old (area under the curve [AUC], 0.795) than in those 70 to 79 years old (AUC, 0.831; P = 0.03). Conclusions: Effect sizes and MAF of genetic risk factors for late AMD differed among the age groups. These results could guide future work on AMD risk assessment in older individuals.