Association of Age-Related Macular Degeneration with a Blood Biomarker of Lipopolysaccharide, a Gut Bacterial Proinflammatory Toxin.

Purpose: Chronic inflammation, immune dysregulation, and oxidative stress are major drivers of age-related macular degeneration (AMD) pathogenesis. Lipopolysaccharide (LPS) is a potent proinflammatory toxin originating from gut bacteria. We assessed the association of a blood biomarker of LPS exposure with incident AMD. Methods: The Alienor Study is a prospective population-based study, including 963 residents of Bordeaux (France), aged 73 years or more at baseline. Esterified 3-hydroxy fatty acids (3-OH FAs) were measured from blood samples as a proxy of LPS burden. AMD was graded from color retinal photographs and spectral domain optical coherence tomography, performed every two years from 2006 to 2017. Cox proportional hazards models were used to estimate associations of between esterified 3-OH FAs, using 722 eyes at risk for incident early AMD and 981 eyes at risk for incident advanced AMD. Results: Higher esterified 3-OH FAs were associated with incident early AMD after adjusting for age and gender (hazard ratio [HR] = 1.21 for 1 standard deviation [SD] increase; 95% confidence interval [CI], 1.01-1.45; P = 0.04) but not with incident advanced AMD (HR = 1.03 for 1 SD increase; 95% CI, 0.73-1.45; P = 0.86). These associations remained stable after multivariate adjustment and imputation for missing covariates (early AMD HR = 1.22 for 1 SD increase; 95% CI, 1.01-1.46; P = 0.04; advanced AMD HR = 0.98 for 1 SD increase; 95% CI, 0.69-1.38; P = 0.91). Conclusions: This study evidenced an association between higher esterified 3-OH FAs and incident early AMD, suggesting that exposure to LPS may be involved in the early pathophysiological processes of AMD.

Incidence of retinopathy of prematurity in Germany: evaluation of current screening criteria.

OBJECTIVE: To evaluate current screening criteria for retinopathy of prematurity (ROP) by investigating the incidence of ROP requiring treatment in infants with gestational age (GA) ≥30 weeks or postmenstrual age (PMA) <32 weeks in Germany. METHODS: Three patient databases were analysed, that is, the German Quality Assurance Procedure in Neonatology (years 2011-2017; n=52 461 infants screened for ROP, 1505 infants treated for ROP), the German Retina.net ROP Registry (years 2011-2018; n=281 treated infants) and the ROP screening programme of two German university hospitals (years 2012-2016; n=837 screened infants). RESULTS: In the analysed cohorts, infants with GA ≥30 weeks represented 33.1%-38.5% of the screening populations but only 1.40%-1.42% of the cases requiring ROP treatment. In a cohort of 281 infants treated for ROP, all 4 infants with GA ≥30 weeks had additional risk factors for ROP including prolonged oxygen supplementation and/or significant comorbidities. Five infants (1.8%) were treated at 32 weeks PMA and none at PMA <32 weeks. CONCLUSIONS: In the investigated cohorts, preterm infants with GA ≥30 weeks carried a very low or no risk for developing treatment-requiring ROP unless additional risk factors were present, and no treatment was performed earlier than 32 weeks PMA. These findings are of relevance for the ongoing re-evaluation of ROP screening criteria.

Retinal findings in neonates with congenital diaphragmatic hernia and extracorporeal membrane oxygenation.

PURPOSE: To evaluate the prevalence of retinal pathologies in neonates with congenital diaphragmatic hernia (CDH) receiving extracorporeal membrane oxygenation (ECMO) therapy. METHODS: This retrospective study included consecutive infants that received ECMO therapy for CDH at our hospital between 2012 and 2018. Retinal changes were assessed by mydriatic indirect funduscopy. Recorded patient parameters include gestational age (GA), type of delivery, duration of ECMO therapy, duration of inhalative oxygen supplementation, and postmenstrual age at fundus examination. RESULTS: Of 54 infants that were treated by ECMO therapy for CDH during the study period, 27 were medically stable enough to receive funduscopic examination and were thus included in the study. Mean GA of these 27 children was 37.3 weeks (range 33.1-40.6) and mean duration of inhalative oxygen supplementation was 12.8 weeks (range 2.7-56.4). Retinal changes were observed in 3 neonates (11.1%). These included multiple midperipheral blot intraretinal hemorrhages in 5 eyes of 3 children and retinopathy of prematurity (ROP) in 2 eyes (stage 3 and stage 2, respectively, without plus disease) of 1 child (GA 35.0 weeks; duration of inhalative oxygen supplementation, 11.9 weeks). In all infants, retinal changes regressed without therapeutic intervention. CONCLUSIONS: Neonates treated with ECMO due to CDH may exhibit retinal hemorrhages, however usually without need for intervention. Prematurely born infants receiving ECMO may develop ROP and thus require ROP screening examinations. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level III.

Non-contact smartphone-based fundus imaging compared to conventional fundus imaging: a low-cost alternative for retinopathy of prematurity screening and documentation.

Retinopathy of prematurity (ROP) is a frequent cause of treatable childhood blindness. The current dependency of telemedicine-based ROP screening on cost-intensive equipment does not meet the needs in economically disadvantaged regions. Smartphone-based fundus imaging (SBFI) allows for affordable and mobile fundus examination and, therefore, could facilitate cost-effective telemedicine-based ROP screening in low-resources settings. We compared non-contact SBFI and conventional contact fundus imaging (CFI) in terms of feasibility for ROP screening and documentation. Twenty-six eyes were imaged with both SBFI and CFI. Field-of-view was smaller (ratio of diameters, 1:2.5), level of detail was equal, and examination time was longer for SBFI as compared to CFI (109.0 ± 57.8 vs. 75.9 ± 36.3 seconds, p < 0.01). Good agreement with clinical evaluation by indirect funduscopy was achieved for assessment of plus disease and ROP stage for both SBFI (squared Cohen's kappa, 0.88 and 0.81, respectively) and CFI (0.86 and 0.93). Likewise, sensitivity/specificity for detection of plus disease and ROP was high for both SBFI (90%/100% and 88%/93%, respectively) and CFI (80%/100% and 100%/96%). SBFI is a non-contact and low-cost alternative to CFI for ROP screening and documentation that has the potential to considerably improve ROP care in middle- and low-resources settings.

Optical coherence tomography angiography (OCT-A) in an animal model of laser-induced choroidal neovascularization.

Aim of the study was to compare optical coherence tomography angiography (OCT-A) and conventional fluorescein angiography (FA) for quantitative analysis of the retinal and choroidal vasculature in the animal model of laser-induced choroidal neovascularization (CNV). Therefore, Dark Agouti rats underwent argon laser photocoagulation to induce CNV at D0. In vivo imaging using combined confocal scanner laser ophthalmoscopy (cSLO)-based FA and OCT-A (Heidelberg Engineering GmbH, Heidelberg, Germany) was performed before and immediately after laser treatment as well as at day 2, 7, 14 and 21. OCT-A en-face images were compared to cSLO images obtained by conventional FA topographic uptake recorded using a series of different pre-defined focus settings. For a quantitative comparison of CNV imaging by OCT-A and FA, CNV area, vessel density, number of vessel junctions, total vessel length and number of vessel end points were analyzed. Subsequent ex vivo analyses of the CNV included immunofluorescence staining of vessels in retinal and RPE/choroidal/scleral flatmount preparations. We found, that OCT-A allowed for high-resolution non-invasive imaging of the superficial, intermediate and deep retinal capillary plexus as well as the choroidal blood vessels in rats. Compared with OCT-A, visualization of CNV progression by invasive FA was less accurate, in particular the deep vascular plexus was visualized in more detail by OCT-A. The area of neovascularization was mainly detected in the deep retinal vascular plexus, outer nuclear layer (ONL), ellipsoid zone (EZ) and the choroid. Within the laser lesions, signs of CNV formation occurred at day 7 with progression in size and number of small vessels until day 21. Due to leakage and staining effects, CNV areas appeared significantly larger in FA compared to OCT-A images (p ≤ 0.0001 for all tested layers). Vessel density, number of vessel junctions, total vessel length and number of vessel end points were significantly higher in intermediate vascular plexus (IVP) and deep vascular plexus (DVP) in OCT-A compared to FA images. Overall, CNV area in flatmounts was similar to OCT-A results and much smaller compared to the area of dye leakage by FA. This study demonstrates that in vivo OCT-A imaging in small animals is feasible and allows for precise analysis of the formation of new blood vessel formation in the animal model of laser-induced CNV. Given its superior axial resolution, sensitivity and non-invasiveness compared to conventional FA imaging, OCT-A opens the door for a more detailed evaluation of CNV development in such a model and, thus, enables the analysis of the response to novel therapeutic interventions in longitudinal in vivo studies.

Correction to: Visual impairment and blindness in institutionalized elderly in Germany.

The original version of this article inadvertently contained a mistake. Authors incorrectly listed in PDF version while correctly presented in the html version.

Efficacy of novel selective NLRP3 inhibitors in human and murine retinal pigment epithelial cells.

NLRP3 inflammasome activation in the retinal pigment epithelium (RPE) is observed in atrophic age-related macular degeneration (AMD), and pharmacological NLRP3 inhibition may provide a therapeutic strategy to halt disease progression. We tested selective NLRP3 inhibitors (IFM-514, IFM-632, and CRID3) for their efficacy in human and murine RPE cells. Inflammasome activation was induced in primary human RPE cells and ARPE-19 cells following priming with IL-1α by different stimuli, including lysosomal membrane permeabilization by leucyl-leucine methyl ester (Leu-Leu-OMe), oxidative damage induced by hydrogen peroxide, lipofuscin-mediated photooxidative damage induced by incubation with 4-hydroxynonenal-modified photoreceptor outer segments and subsequent blue light irradiation, and P2X7 receptor activation by benzoylbenzoyl-ATP. Independent of the applied activation mechanism, treatment with the NLRP3 inhibitors IFM-632, IFM-514, and CRID3 resulted in a significant suppression of inflammasome activation as assessed by IL-1ß and LDH release. Likewise, inflammasome activation in blue light-irradiated Abca4-/- mouse and Leu-Leu-OMe-treated wild-type mouse RPE/choroid/sclera eye cups was significantly reduced by treatment with the NLRP3 inhibitors. These results indicate that the investigated selective NLRP3 inhibitors are effective in human and murine RPE cells, thus representing promising agents for the future evaluation of inflammasome inhibition as a therapeutic strategy in atrophic AMD. KEY MESSAGES: • NLRP3 inhibitors suppress inflammasome activation in human RPE cells independent of trigger. • Light-induced inflammasome activation in Abca4-/- mouse eye cups is reduced by NLRP3 inhibitors. • Novel selective NLRP3 inhibitors are effective in human and murine RPE cells. • Promising compounds for pharmaceutical intervention in atrophic AMD.

RANIBIZUMAB IN PIGMENT EPITHELIAL TEARS SECONDARY TO AGE-RELATED MACULAR DEGENERATION: A Prospective Study.

PURPOSE: To assess efficacy of intravitreal ranibizumab in retinal pigment epithelium tears secondary to neovascular age-related macular degeneration. METHODS: The Ranibizumab In Pigment epithelial tears secondary to age-related macular degeneration (RIP) study is a prospective, single-arm, multicenter, investigator-initiated trial. Twenty four eyes of 24 patients with a retinal pigment epithelium tear secondary to age-related macular degeneration received monthly intravitreal injection of 0.5mg ranibizumab for 12 months, together with monthly assessments of morphologic and functional efficacy parameters. Primary outcome measure was mean best-corrected visual acuity at final visit compared with baseline. RESULTS: Mean best-corrected visual acuity remained stable over the 12-month study period with 50.3 Early Treatment of Diabetic Retinopathy Study letters (±18.7; Snellen equivalent 20/100) at baseline and 52.9 letters (±19.7; Snellen equivalent 20/100) at final visit (P = 0.39). One eye (4%) experienced a vision loss of ≥15 letters, and 2 eyes (8%) gained ≥15 letters. Mean central retinal thickness decreased from 571 µm (±185 µm) to 436 µm (±171 µm; P = 0.0001). Vision-related quality of life was stable with a mean VFQ-25 score of 79.0 (±10.8) at baseline and 74.3 (±13.9) at final visit (P = 0.12). CONCLUSION: In retinal pigment epithelium tears secondary to age-related macular degeneration, monthly intravitreal ranibizumab therapy results in stabilization of visual acuity over 12 months.

Visual impairment and blindness in institutionalized elderly in Germany.

PURPOSE: To determine the prevalence of and identify factors associated with visual impairment and blindness in institutionalized elderly in Germany. METHODS: In this prospective multicenter cross-sectional study, ophthalmic health care need and provision were investigated in institutionalized elderly in 32 nursing homes in Germany. All participants underwent a standardized examination including medical and ocular history, refraction, visual acuity testing, tonometry, biomicroscopy, and dilated funduscopy. A standardized questionnaire was used to identify factors associated with eye healthcare utilization, visual impairment and/or blindness. RESULTS: Visual acuity of 566 (94.3%; 413 women and 153 men) of a total of 600 institutionalized elderly was determined. Mean age of the included patients was 82.9 years (± 9.8). Of all participants, 30 (5.3%; 95% CI 3.4-7.2%) were blind and 106 (18.7%; 95% CI 15.5-21.9%) were moderately or severely visually impaired according to the World Health Organization definition. The 136 blind and moderately or severely visually impaired participants were older (OR, Odds Ratio = 1.1, 95% CI 1.0-1.1; p < 0.001), and more likely to have reduced mobility (OR = 12.6, 95% CI 2.8-57.6; p = 0.001). CONCLUSION: A high proportion of blindness and visual impairment was found amongst nursing home residents. Age and reduced mobility were factors associated with an increased likelihood of blindness and visual impairment. Any surveys of blindness and visual impairment excluding nursing homes may considerably underestimate the prevalence of visual impairment and blindness.

Multimodal Imaging Patterns for Development of Central Atrophy Secondary to Age-Related Macular Degeneration.

Purpose: To evaluate the development of central atrophy in eyes with age-related macular degeneration (AMD). Methods: Six-year longitudinal multimodal retinal imaging data (MODIAMD study) from 98 eyes of 98 subjects with non-late-stage AMD in the study eye at baseline were analyzed for the presence of central atrophy at each annual follow-up visit. Development, manifestation, and further progression of complete retinal pigment epithelium and outer retinal atrophy (cRORA) by multimodal imaging data were compared with atrophy detection based on color fundus photography only. Results: Seventeen study eyes with development of central cRORA within 6 years (cumulative rate: 17.4%) were identified based on multimodal imaging. In 10 (60%) of these eyes, presence of central manifest atrophy was initially not detectable by color fundus photography. In six (35%) eyes, central cRORA occurred by the spread of existing paracentral atrophy toward the fovea. Drusen-associated atrophy development was noted in eight eyes. In two eyes, atrophy development was associated with refractile deposits, while only pigmentary changes in absence of large drusen or refractile deposits were detectable before atrophy occurrence in one eye. Conclusions: The earlier and more precise detection of central cRORA by multimodal imaging as compared to atrophy detection solely based on color fundus photography allows for more accurate detection and identification of different pathways for atrophy development. In accordance with previous clinical and histopathologic reports, the results confirm that different precursor lesions may independently proceed to central cRORA in AMD.