Genetics of reticular pseudodrusen in age-related macular degeneration.

Reticular pseudodrusen (RPD) are subretinal deposits that, when observed with age-related macular degeneration (AMD), form a distinct phenotype, often associated with late-stage disease. To date, RPD genetic risk associations overlap six well-established AMD-risk regions. Determining RPD-specific underlying genetic causes by using adequate imaging methods should improve our understanding of the pathophysiology of RPD.

Electrophysiological findings in extensive macular atrophy with pseudodrusen.

PURPOSE: To present electroretinogram findings in extensive macular atrophy with pseudodrusen (EMAP) and describe associated systemic factors. DESIGN: Retrospective case series. METHODS: Data on medical history, visual symptoms, multimodal imaging findings, and visual field were collected from the medical records of patients with extensive macular atrophy with pseudodrusen who attended a visual electrophysiology laboratory. Electrophysiological tests, including full-field electroretinogram, multifocal electroretinogram and photopic negative response, were performed. RESULTS: Eighteen patients (10 [56%] females, age 49-66 years) were included. Of these, 17 (94%) had a history of rheumatic fever in childhood and/or adolescence, 7 (39%) had cardiovascular disease, 4 (22%) had autoimmune disease, and 10 (56%) had inflammatory conditions. The primary visual complaints were nyctalopia (95%), followed by visual field loss (67%) and dyschromatopsia (67%). The key retinal findings included retinal pigmented epithelium atrophy in the macular region and subretinal drusenoid deposits. Regarding electrophysiological results, 100% of patients had abnormalities on multifocal electroretinogram, 94% displayed alterations in photopic negative response, and 78% showed changes in the full-field electroretinogram. CONCLUSIONS: In this cohort, electrophysiologic evaluation demonstrated diffuse retinal dysfunction affecting all layers of the retina in patients with EMAP. The disease is associated with immune-mediated systemic conditions, chiefly rheumatic fever.

PHOTOBIOMODULATION THERAPY FOR LARGE SOFT DRUSEN AND DRUSENOID PIGMENT EPITHELIAL DETACHMENT IN AGE-RELATED MACULAR DEGENERATION: A Single-Center Prospective Pilot Study.

PURPOSE: To evaluate visual acuity and morphologic changes after photobiomodulation (PBM) for patients affected with large soft drusen and/or drusenoid pigment epithelial detachment associated with dry age-related macular degeneration. METHOD: Twenty eyes with large soft drusen and/or drusenoid pigment epithelial detachment age-related macular degeneration were included and treated using the LumiThera Valeda Light Delivery System. All patients underwent two treatments per week for 5 weeks. Outcome measures included best-corrected visual acuity, microperimetry-scotopic testing, drusen volume, central drusen thickness, and quality of life score at baseline and month 6 (M6) follow-up. Data of best-corrected visual acuity, drusen volume, and central drusen thickness were also recorded at week 5 (W5). RESULTS: Best-corrected visual acuity significantly improved at M6 with a mean score gain of 5.5 letters ( P = 0.007). Retinal sensitivity decreased by 0.1 dB ( P = 0.17). The mean fixation stability increased by 0.45% ( P = 0.72). Drusen volume decreased by 0.11 mm 3 ( P = 0.03). Central drusen thickness was reduced by a mean of 17.05 µ m ( P = 0.01). Geographic atrophy area increased by 0.06 mm 2 ( P = 0.01) over a 6-month follow-up, and quality of life score increased by 3,07 points on average ( P = 0.05). One patient presented a drusenoid pigment epithelial detachment rupture at M6 after PBM treatment. CONCLUSION: The visual and anatomical improvements in our patients support previous reports on PBM. PBM may provide a valid therapeutic option for large soft drusen and drusenoid pigment epithelial detachment age-related macular degeneration and may potentially slow the natural course of the disease.

N-Glycosylation Patterns across the Age-Related Macular Degeneration Spectrum.

The pathogenesis of age-related macular degeneration (AMD) remains elusive, despite numerous research studies. Therefore, we aimed to investigate the changes of plasma and IgG-specific N-glycosylation across the disease severity spectrum. We examined 2835 subjects from the 10.001 Dalmatians project, originating from the isolated Croatian islands of Vis and Korcula. All subjects were classified into four groups, namely (i) bilateral AMD, (ii) unilateral AMD, (iii) early-onset drusen, and (iv) controls. We analysed plasma and IgG N-glycans measured by HPLC and their association with retinal fundus photographs. There were 106 (3.7%) detected cases of AMD; 66 of them were bilateral. In addition, 45 (0.9%) subjects were recorded as having early-onset retinal drusen. We detected several interesting differences across the analysed groups, suggesting that N-glycans can be used as a biomarker for AMD. Multivariate analysis suggested a significant decrease in the immunomodulatory bi-antennary glycan structures in unilateral AMD (adjusted odds ratio 0.43 (95% confidence interval 0.22-0.79)). We also detected a substantial increase in the pro-inflammatory tetra-antennary plasma glycans in bilateral AMD (7.90 (2.94-20.95)). Notably, some of these associations were not identified in the aggregated analysis, where all three disease stages were collapsed into a single category, suggesting the need for better-refined phenotypes and the use of disease severity stages in the analysis of more complex diseases. Age-related macular degeneration progression is characterised by the complex interplay of various mechanisms, some of which can be detected by measuring plasma and IgG N-glycans. As opposed to a simple case-control study, more advanced and refined study designs are needed to understand the pathogenesis of complex diseases.

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.

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.

EYES WITH SUBRETINAL DRUSENOID DEPOSITS AND NO DRUSEN: Progression of Macular Findings.

PURPOSE: To investigate the macular changes over time in eyes containing subretinal drusenoid deposits (also known as pseudodrusen) with no drusen >63 µm. METHODS: A consecutive series of patients were examined with color fundus photography, optical coherence tomography, and autofluorescence imaging with fluorescein angiography used as necessary. Exclusionary criteria included macular neovascularization, history of retinal surgery, pseudoxanthoma elasticum, and drusen >63 µm. RESULTS: There were 85 eyes of 54 patients. The mean age at baseline was 83.6 (±7.8) years, and there were 17 men. The mean follow-up was 5.0 (±2.9) years. At initial optical coherence tomography examination, 12 eyes had extrafoveal atrophy and 17 eyes had vitelliform deposits, which were yellowish white subretinal collections that showed intense hyperautofluorescence. During follow-up, 11 eyes lost vitelliform material. After the disappearance of small deposits, focal hyperpigmentation remained. Loss of larger deposits was associated with noteworthy sequela; six developed subfoveal atrophy and one macular neovascularization close to regressing vitelliform material. Subfoveal geographic atrophy developed in four other eyes without vitelliform material by extension from areas of extrafoveal atrophy. Macular neovascularization developed in seven eyes over follow-up. The CFH Y402H and ARMS2 A69S allele frequencies were 57% and 48.9%, respectively, which is similar to a group of age-related macular degeneration controls. One patient had a novel PRPH2 mutation, but did not have a vitelliform deposit; the remainder had a normal PRPH2 and BEST1 coding sequences. CONCLUSION: Eyes with subretinal drusenoid deposits and no drusen >63 mm have significant risk for the development of both neovascularization and geographic atrophy, the fundamental components of late age-related macular degeneration. An intermediate step in some eyes was the development of a vitelliform deposit, an entity not traditionally associated with age-related macular degeneration, but in these patients, the material seemed to be an important component of the disease pathophysiology. This vitelliform deposit was not associated with genetic markers for pattern dystrophy or Best disease.

Retinal vascular flow and choroidal thickness in eyes with early age-related macular degeneration with reticular pseudodrusen.

BACKGROUND: To investigate the characteristics of retinal vessels and retinal thickness in eyes with early age-related macular degeneration (AMD) with or without reticular pseudodrusen. METHODS: We retrospectively evaluated the clinical history and optical coherence tomography (OCT) and OCT angiography images of consecutive patients with early AMD. We calculated the retinal vessel densities of the superficial and deep capillary plexus with the ImageJ software (National Institutes of Health, Bethesda, MD, USA) and investigated the relationship with mean retinal thickness and subfoveal choroidal thickness. RESULTS: We included 135 early AMD eyes and classified 60 of them into a reticular pseudodrusen group and 75 into a non-reticular pseudodrusen group. The vascular densities of the superficial and deep capillary plexus in the reticular pseudodrusen group (32.35% ± 3.67 and 26.71% ± 2.88%) were not different from those of the non-reticular pseudodrusen group (33.18% ± 2.2% and % 27.43 ± 1.79%; P = 0.546 and P = 0.318, respectively). The retinal thickness of the reticular pseudodrusen group (287.31 µm ± 24.36 µm) did not differ from that of the non-reticular pseudodrusen group (294.27 µm ± 20.71 µm; P = 0.493), while subfoveal choroidal thickness in the reticular pseudodrusen group (158.13 µm ± 42.53 µm) was lower than that in the non-reticular pseudodrusen group (237.89 µm ± 60.94 µm; P <  0.001). Multivariate analysis revealed that lower vascular density of the superficial capillary plexus and subfoveal choroidal thickness were associated with retinal thinning in reticular pseudodrusen group (P = 0.003 and P = 0.036) and older age was associated with retinal thickness in the non-reticular pseudodrusen group (P = 0.005). CONCLUSIONS: Retinal thinning in early AMD patients with reticular pseudodrusen was accompanied by choroidal and retinal vascular loss, which suggests a possible linkage of retinal thinning with vascular alterations.

Peripapillary choroidal thickness in patients with early age-related macular degeneration and reticular pseudodrusen.

PURPOSE: The purpose of this study was to investigate peripapillary and macular choroidal thickness (CT) in patients with early age-related macular degeneration (AMD) with or without reticular pseudodrusen (RPD). METHODS: We investigated the medical records of 89 patients (89 eyes) with early AMD. The eyes were grouped into three categories according to the extent of RPD: no RPD, localized RPD, and diffuse RPD. Peripapillary and macular CT were measured with images obtained by spectral domain optical coherence tomography. CT in the peripapillary and macular areas was compared among groups. RESULTS: Both RPD groups exhibited an older subject age and a greater female predominance compared to the non-RPD group (P = 0.007 and P = 0.030, respectively). Macular and peripapillary CT were different among the three groups (all, P < 0.001), and both RPD groups showed a thinner choroid in all areas compared to the non-RPD group after adjusting for age and sex (all, P ≤ 0.016). Temporal peripapillary and nasal macular CT at 500 µm and 1500 µm, respectively, from the fovea in eyes with diffuse RPD were significantly thinner than that in eyes with localized RPD (P = 0.008, P = 0.016 and P < 0.001, respectively). CONCLUSIONS: In addition to the macular area, the peripapillary CT, including the area outside the macula, was thinner in eyes with RPD than in those without RPD. Significant differences in the papillomacular choroid were observed based on RPD distribution type, which suggests that variation in CT is based on the extent of RPD.

TYPE 2 (SUBRETINAL) NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION ASSOCIATED WITH PURE RETICULAR PSEUDODRUSEN PHENOTYPE.

PURPOSE: To report the association of pure type 2 neovascularization (NV) in age-related macular degeneration occurring almost exclusively in patients with reticular pseudodrusen. METHODS: An observational retrospective cohort study of all eyes receiving antivascular endothelial growth factor therapy for newly diagnosed neovascular age-related macular degeneration by a single practitioner over a 6-year period. Only patients with treatment-naive, pure type 2 NV who also had either pre-neovascular imaging of the study eye or imaging of a nonneovascular fellow eye available to determine baseline characteristics including drusen type and choroidal thickness were incuded. RESULTS: Of 694 patients treated for neovascular age-related macular degeneration, only 8 met the inclusion criteria with pure type 2 NV. Of these, 7 (88%) had exclusively reticular pseudodrusen (5 in the nonneovascular fellow eye, 2 in the study eye before developing NV). Six (75%) patients in the affected neovascular eye and 6 (75%) in the fellow nonneovascular eye had choroidal thickness <120 µm. Mean follow-up was 46 months (range, 3.0-63.3). Best-corrected vision improved from 20/89 (range, 20/30-20/796) at baseline to 20/60 (range, 20/20-20/399) at last follow-up. CONCLUSION: Pure type 2 NV is rare in age-related macular degeneration, occurring almost exclusively in patients with reticular pseudodrusen and thin choroids.

CHOROIDAL THICKENING IN PATIENTS WITH CUTICULAR DRUSEN COMBINED WITH VITELLIFORM MACULAR DETACHMENT.

PURPOSE: To analyze the subfoveal choroidal thickness (SFCT) in patients with cuticular drusen. METHODS: Retrospective, monocentric, study of consecutive patients examined with enhanced depth imaging spectral domain optical coherence tomography (EDI SD-OCT, Cirrus, Zeiss) between 2009 and 2014 in a tertiary care center. Measurements of the height of the subfoveal vitelliform detachment and SFCT were manually performed. RESULTS: Thirteen patients, 3 men and 10 women, aged from 35 to 73 (mean: 53.6 years) were selected. For the 24 eyes without macular atrophy at first visit, SFCT ranged from 195 to 559 µm (mean ± SD = 317.5 ± 93). The SFCT was significantly thicker in 12 eyes with vitelliform macular detachment at presentation (369 ± 96, median = 368.5) than in 12 eyes without (266 ± 58, median = 257.5) (P = 0.007), whereas the 2 groups did not differ in age (P = 0.35) or refractive error (P = 0.56). No correlation was observed between SFCT and the height of the foveal detachment. For 10 eyes followed up longer than 24 months (mean: 38.9 months), the SFCT significantly decreased over time, from 375 ± 96 (median = 368.5) to 303 ± 138 (median = 319) µm (P = 0.022). CONCLUSION: Eyes with cuticular drusen combined with vitelliform macular detachment present with choroidal thickening, suggesting that the choroidal vasculature may play a role in the occurrence of macular detachments in patients with cuticular drusen. The life cycle of these vitelliform lesions evolves from translucent subretinal fluid to the accumulation of yellowish material eventually resolving and leading to atrophy with marked and rapid thinning of the choroid.

Laser treatment of drusen to prevent progression to advanced age-related macular degeneration.

BACKGROUND: Drusen are amorphous yellowish deposits beneath the sensory retina. People with drusen, particularly large drusen, are at higher risk of developing age-related macular degeneration (AMD). The most common complication in AMD is choroidal neovascularisation (CNV), the growth of new blood vessels in the centre of the macula. The risk of CNV is higher among people who are already affected by CNV in one eye.It has been observed clinically that laser photocoagulation of drusen leads to their disappearance and may prevent the occurrence of advanced disease (CNV or geographic atrophy) associated with visual loss. OBJECTIVES: To examine the effectiveness and adverse effects of laser photocoagulation of drusen in AMD. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2015), EMBASE (January 1980 to August 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to August 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 3 August 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) of laser treatment of drusen in AMD in which laser treatment had been compared with no intervention or sham treatment. Two types of trials were included. Some trials studied one eye of each participant (unilateral studies); other studies recruited participants with bilateral drusen and randomised one eye to photocoagulation or control and the fellow eye to the other group. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data. We pooled data from unilateral and bilateral studies using a random-effects model. For the bilateral studies, we estimated the within-person correlation coefficient from one study and assumed it was valid for the others. MAIN RESULTS: The update of this review found two additional studies, totaling 11 studies that randomised 2159 participants (3580 eyes) and followed them up to two years, of which six studies (1454 participants) included people with one eye randomised to treatment and one to control. Studies were conducted in Australia, Europe and North America.Overall, the risk of bias in the included studies was low, particularly for the larger studies and for the primary outcome development of CNV. Photocoagulation did not reduce the development of CNV at two years' follow-up (odds ratio (OR) 1.07, 95% confidence interval (CI) 0.79 to 1.46, 11 studies, 2159 participants (3580 eyes), high quality evidence). This estimate means that, given an overall occurrence of CNV of 8.3% in the control group, we estimated an absolute risk reduction by no more than 1.4% in the laser group, according to the lower CI limit. Only two studies investigated the effect on the development of geographic atrophy and could not show a difference, but estimates were imprecise (OR 1.30, 95% CI 0.38 to 4.51, two studies, 148 participants (148 eyes), low quality evidence).Among secondary outcomes, photocoagulation led to drusen reduction (OR 9.16, 95% CI 6.28 to 13.4, three studies, 570 participants (944 eyes), high quality evidence) but was not shown to limit loss of 3 or more lines of visual acuity (OR 0.99, 95% CI 0.81 to 1.22, nine studies, 2002 participants (2386 eyes), moderate quality evidence).In a subgroup analysis, no difference could be shown for conventional visible (eight studies) versus subthreshold invisible (four studies) photocoagulation for the primary outcomes (P value = 0.29). The effect in the subthreshold group did not suggest a relevant benefit (OR 1.27, 95% CI 0.82 to 1.98). No study used micropulse subthreshold photocoagulation.No other adverse effects (apart from development of CNV, geographic atrophy or visual loss) were reported. AUTHORS' CONCLUSIONS: The trials included in this review confirm the clinical observation that laser photocoagulation of drusen leads to their disappearance. However, treatment does not result in a reduction in the risk of developing CNV, and was not shown to limit the occurrence of geographic atrophy or visual acuity loss.Ongoing studies are being conducted to assess whether the use of extremely short laser pulses (i.e. nanosecond laser treatment) cannot only lead to drusen regression but also prevent neovascular AMD.

Disappearance of soft drusen and subsequent development of choroidal neovascularization following macular hole surgery: a case report.

BACKGROUND: Drusen are important risk factor for neovascular age-related macular degeneration (AMD) and have a dynamic nature as they can enlarge, newly form, or disappear over time. There have been few reports on drusen regression or choroidal neovascularization (CNV) development after macular hole surgery. We report, to our knowledge, the first case of both drusen regression and subsequent CNV development within 7 months of successful macular hole surgery. CASE PRESENTATION: A 73-year-old woman presented with a stage 3 full-thickness macular hole and large, confluent soft macular drusen in the right eye and a neovascular age-related macular degeneration (AMD) in the fellow eye. Four months after the successful macular hole surgery, significant regression of drusen was seen, especially in the temporal area to the fovea. Three months later, the patient developed CNV and her best-corrected visual acuity decreased to 20/100, despite further regression of macular drusen. CONCLUSIONS: Macular hole patients with macular soft drusen need to be carefully followed up after surgery for possible drusen regression and CNV development.

Choroidal neovascularization associated with extensive macular atrophy and pseudodrusen.

PURPOSE: To describe a case of extensive macular atrophy and pseudodrusen complicated by bilateral choroidal neovascularization (CNV). METHODS: A 53-year-old woman showed extensive macular atrophy at the posterior pole associated with disciform scar in the right eye and fibrotic juxtafoveal CNV in the left eye. RESULTS: The patient underwent a complete ophthalmological examination including fundus autofluorescence, fluorescein angiography, and spectral-domain optical coherence tomography, showing a disciform scar at the posterior pole of the right eye and an extensive macular atrophy associated with a fibrotic juxtafoveal CNV. The patient was previously treated with four and seven intravitreal bevacizumab injections, respectively, in the right eye and in the left eye. Molecular analyses of the ABCA4 gene revealed the variant c.1268A

Reticular pseudodrusen: a risk factor for geographic atrophy in fellow eyes of individuals with unilateral choroidal neovascularization.

PURPOSE: To determine whether reticular pseudodrusen (RPD) confer an increased risk of progression to late-stage age-related macular degeneration (AMD) in fellow eyes of those recently diagnosed with unilateral choroidal neovascularization (CNV). DESIGN: Retrospective study. PARTICIPANTS: Two hundred consecutive participants with CNV secondary to AMD in 1 eye and no signs of late-stage AMD in the fellow eye. METHODS: Clinical examination and comprehensive retinal imaging, including spectral-domain optical coherence tomography, near-infrared reflectance (NIR), and color fundus photography, at baseline and every follow-up visit. MAIN OUTCOME MEASURES: Incidence of geographic atrophy (GA) and CNV in the fellow eye. RESULTS: Mean age ± standard deviation was 77±7 years, and 61% of the cohort were female. Fifty-eight percent (n = 116) had RPD, 68% had drusen of 125 µm or more, 36% had pigmentary changes, 10% had both drusen of 125 µm or more and pigmentary changes, and 17% had only RPD in their fellow eyes. After a mean follow-up of 2.3 years, CNV developed in 36% of patients and GA developed in 14% of patients. Those with RPD demonstrated late-stage AMD (61% vs. 33.4%; P <0.001) and GA (22.4% with RPD vs. 2.4% without RPD; P <0.001) more often. The presence of reticular pseudodrusen was an independent risk factor for the development of GA (hazard ratio [HR], 4.93; P = 0.042), but not for CNV (HR, 1.19; P = 0.500), at least within the follow-up of this study. Both drusen of 125 µm or more and pigmentary changes at baseline were significant risk factors for the development of CNV and GA (HR, 1.96-11.73; P ≤0.020). CONCLUSIONS: Reticular pseudodrusen seem to confer an increased risk of progression to GA, in addition to drusen and pigmentary changes. The presence of RPD needs to be taken into account when discussing a patient's prognosis and planning management.

Reticular macular lesions: a review of the phenotypic hallmarks and their clinical significance.

Reticular macular lesions, also known as 'reticular macular disease', 'reticular drusen', 'reticular pseudodrusen', or 'subretinal drusenoid deposits', are a pattern of lesions commonly found in age-related macular degeneration and best visualized using at least two imaging techniques in combination. Reticular lesions have four stages of progression observable on spectral domain optical coherence tomography, but they do not show the usual signs of regression of soft drusen (calcification and pigment changes). Furthermore, reticular lesions correlate histologically with subretinal drusenoid deposits localized between the retinal pigment epithelium and the inner segment ellipsoid band. Reticular lesions are most commonly seen in older age groups of female patients with age-related macular degeneration and are usually bilateral. They are not clearly associated with known age-related macular degeneration genes and are highly associated with late-stage age-related macular degeneration and an increased mortality rate. They are also associated with alterations in the neural retina and choroid.

Subretinal drusenoid deposits, age-related macular degeneration, and cardiovascular disease.

Decades of studies on age-related macular degeneration (AMD), cardiovascular disease and stroke have not found consistent associations between AMD and systemic vascular disease. This study suggests that there is in fact no general relationship, but instead a strong, specific association between only the subretinal drusenoid deposit (SDD) phenotype of AMD on retinal imaging and certain co-existent vascular diseases that are high risk for compromised cardiac output or internal carotid artery stenosis. Future screening initiatives for these high -risk vascular diseases (HRVDs) with fast, inexpensive retinal imaging could make a significant contribution to public health and save lives. Likewise, screening patients with known HRVDs for unrecognized AMD of the SDD form could enable needed treatment and save vision.

Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: implications for age-related degenerative diseases of the eye.

Age related macular degeneration (AMD) is one of the leading causes of blindness in Western society. A hallmark of early stage AMD are drusen, extracellular deposits that accumulate in the outer retina. Advanced glycation endproducts (AGE) accumulate with aging and are linked to several age-related diseases such as Alzheimer's disease, osteoarthritis, atherosclerosis and AMD. AGE deposits are found in drusen and in Bruch's membrane of the eye and several studies have suggested its role in promoting oxidative stress, apoptosis and lipofuscin accumulation. Recently, complement activation and chronic inflammation have been implicated in the pathogenesis of AMD. While AGEs have been shown to promote inflammation in other diseases, whether it plays a similar role in AMD is not known. This study investigates the effects of AGE stimulation on pro- and anti-inflammatory pathways in primary culture of human retinal pigment epithelial cells (RPE). Differential gene expression studies revealed a total of 41 up- and 18 down-regulated RPE genes in response to AGE stimulation. These genes fell into three categories as assessed by gene set enrichment analysis (GSEA). The main categories were inflammation (interferon-induced, immune response) and proteasome degradation, followed by caspase signaling. Using suspension array technology, protein levels of secreted cytokines and growth factors were also examined. Anti-inflammatory cytokines including IL10, IL1ra and IL9 were all overexpressed. Pro-inflammatory cytokines including IL4, IL15 and IFN-γ were overexpressed, while other pro-inflammatory cytokines including IL8, MCP1, IP10 were underexpressed after AGE stimulation, suggesting a para-inflammation state of the RPE under these conditions. Levels of mRNA of chemokine, CXCL11, and viperin, RSAD2, were up-regulated and may play a role in driving the inflammatory response via the NF-kB and JAK-STAT pathways. CXCL11 was strongly immunoreactive and associated with drusen in the AMD eye. The pathways and novel genes identified here highlight inflammation as a key response to AGE stimulation in primary culture of human RPE, and identify chemokine CXCL11 as putative novel agent associated with the pathogenesis of AMD.

Role of sleep-disordered breathing in age-related macular degeneration.

AIMS: To examine the association between obstructive sleep apnoea (OSA) and age-related macular degeneration (AMD), and the subphenotype of AMD with reticular pseudodrusen (RPD). METHODS: Case-control study with 351 participants (211 AMD and 140 controls) using the Epworth Sleepiness Scale (ESS) and the STOP-BANG Questionnaire (SBQ) validated sleep questionnaires. Participant risk of having moderate-to-severe OSA was determined using a binary risk scale based on the ESS and SBQ combined and an ordinal risk scale based on the SBQ. A prior diagnosis of OSA and whether receiving assisted breathing treatment was also ascertained. Retinal imaging allowed AMD and RPD determination. RESULTS: Higher risk of moderate-to-severe OSA according to the binary and ordinal scales was not associated with the presence of AMD (p≥0.519) nor AMD with RPD (p≥0.551). Per point increase in ESS or SBQ questionnaire score was also not associated with AMD nor AMD with RPD (p≥0.252). However, being on assisted breathing treatment for diagnosed OSA was significantly associated with a higher likelihood of having AMD with RPD, but not all AMD, (OR 3.70; p=0.042 and OR 2.70; p=0.149, respectively), when compared with those without diagnosed OSA on treatment. CONCLUSIONS: Formally diagnosed OSA undergoing treatment, increased the likelihood of having AMD with RPD, but not overall AMD compared with those who were not undergoing treatment. Risk-based OSA questionnaires showed no difference in risk for all AMD or AMD with RPD. Future research, using formal sleep studies could further explore the potential role of nocturnal hypoxia in AMD.

Choroidal vascularity index in leptochoroid: A comparative analysis between reticular pseudodrusen and high myopia.

PURPOSE: To investigate the choroidal vascularity index (CVI) in patients affected by leptochoroid. METHODS: Three distinct age-matched cohorts were collected: patients with reticular pseudodrusen (RPD) secondary to age-related macular degeneration, patients with high-myopia, and healthy controls. CVI was calculated in the subfoveal 6000 µm diameter area. RESULTS: 54 eyes (54 patients) were included (18 eyes in each cohort). No statistical differences were disclosed in terms of age between controls, RPD patients (p = 0.062), and myopic patients (p = 0.070). Total choroidal area showed a different distribution among the 3 cohorts (p < 0.001), due to the reduction of luminal and stromal choroidal area in both RPD and myopic groups in comparison to controls (p < 0.001). Interestingly, CVI showed a different distribution between the 3 cohorts (p < 0.001). In detail, RPD group showed no changes in CVI in comparison to controls (p = 1.000), whereas the myopic group showed a higher CVI in comparison to both RPD group and controls (p < 0.001 in both analyses). CONCLUSIONS: Different changes of the choroidal vascular and stromal components characterize the leptochoroid secondary to RPD eyes and high-myopic eyes. The relative greater impairment of the vascular area in RPD eyes in comparison to myopic eyes could be at the basis of the lower development of RPD in patients with high myopia.