Late Stages Of Age-related Macular Degeneration Research Articles

Dynamics of clinical and immunological parameters in retinal pigment epithelium transplantation in the context of combined immunosuppressive therapy in the rabbit model of retinal degeneration

Progressive damage of the retinal pigment epithelium (RPE) underlies the pathogenesis of degenerative retinal diseases such as: age-related macular degeneration (AMD), Stargardt’s disease, retinitis pigmentosa, Best’s disease and others. This group of diseases led by AMD leads to irreversible loss of visual functions, blindness and disability. The possibilities of therapy of late stages of AMD are extremely limited. The most promising approach to replace the damaged retinal pigment epithelium appears to be transplantation of RPE cells derived from induced pluripotent stem cells (iPSC-RPE) into the subretinal space (SRS). Despite immune privilege in the SRS, transplantation of xenogeneic cellular material causes severe inflammation in the posterior segment of the eye and leads to graft rejection in an in vivo experiment in the absence of immunosuppression. The solution to the problem of tissue incompatibility in this case can be the use of combined immunosuppressive therapy (CIT), aimed, on the one hand, at suppression of local inflammation (in the eye) and, on the other hand, at suppression of the systemic transplantation immune response. The aim of the study: clinical and immunological analysis of the results of transplantation of IPSC-RPE suspension on the background of CIT, including single intravitreal intraoperative administration of kenalog and further systemic application of mycophenolate mofetil (MMF), in the model of RPE atrophy in rabbits. Standard and specialized ophthalmological examination was performed at early and distant terms after the intervention in order to clinically assess the posttransplantation process. To analyze the immune status, vitreous humor (VH) and blood serum (BS) of rabbits of the experimental groups were collected. The concentrations of TGF-β1, TGF-β2, and IL-2 were determined in the biomaterial using solid-phase enzyme immunoassay. According to the results of the study, subretinal transplantation of IPSC-RPE, performed against the background of combination of single intravitreal intraoperative administration of kenalog and systemic application of MMF, is a safe method, which provides preservation of the retina and other adjacent structures of the eye and allows to prevent rejection of xenogenic material during its transplantation both in a healthy eye and with pre-formed RPE atrophy, which opens perspectives for full testing of biological effects realized by IPSC-RPE.

Deep Neural Networks for Automated Outer Plexiform Layer Subsidence Detection on Retinal OCT of Patients With Intermediate AMD.

The subsidence of the outer plexiform layer (OPL) is an important imaging biomarker on optical coherence tomography (OCT) associated with early outer retinal atrophy and a risk factor for progression to geographic atrophy in patients with intermediate age-related macular degeneration (AMD). Deep neural networks (DNNs) for OCT can support automated detection and localization of this biomarker. The method predicts potential OPL subsidence locations on retinal OCTs. A detection module (DM) infers bounding boxes around subsidences with a likelihood score, and a classification module (CM) assesses subsidence presence at the B-scan level. Overlapping boxes between B-scans are combined and scored by the product of the DM and CM predictions. The volume-wise score is the maximum prediction across all B-scans. One development and one independent external data set were used with 140 and 26 patients with AMD, respectively. The system detected more than 85% of OPL subsidences with less than one false-positive (FP)/scan. The average area under the curve was 0.94 ± 0.03 for volume-level detection. Similar or better performance was achieved on the independent external data set. DNN systems can efficiently perform automated retinal layer subsidence detection in retinal OCT images. In particular, the proposed DNN system detects OPL subsidence with high sensitivity and a very limited number of FP detections. DNNs enable objective identification of early signs associated with high risk of progression to the atrophic late stage of AMD, ideally suited for screening and assessing the efficacy of the interventions aiming to slow disease progression.

The incidence of macular atrophy in patients with long-term use of anti-vascular endothelial growth factor (VEGF) in age-related macular degeneration (AMD): a systematic review and meta-analysis

Background: Age-related macular degeneration (AMD) is the chief factor in sightlessness in affluent nations. Visual symptoms at a late stage of AMD are frequently severe and irreversible and might include drastically reduced center vision in both eyes. Patients with nAMD are mostly preserved with anti-vascular endothelial growth factor (VEGF) medications. Chronic anti-VEGF treatment, however, has also been connected to the emergence of macular atrophy (MA). This study aims to determine the prevalence of MA in AMD patients who have been on anti-VEGF medications for a long time. Methods: The literature research was performed by systematically searching PubMed, Cochrane, ScienceDirect, and Google Scholar using the search terms “macular atrophy”, “Anti-VEGF”, “age-related macular degeneration”, and “trial”. The Review Manager v.5.4 and R statistical software v.3.3 are used in this study. Results: The study includes 2094 individuals from 7 clinical trial trials. Anti-VEGF therapy had an overall proportion of MA episodes in MDA patients of 0.29 (95% CI 0.24 - 0.34). Between the anti-VEGF and control groups, there is no discernible difference in the risk of MA (OR 1.44; 95% CI 0.34 - 6.04; p=0.39). Additionally, there is no discernible difference between the comparison group and anti-VEGF regarding mean MA area scores (MD 0.03; 95% CI -0.28 - 0.34; p=0.85). Conclusion: The incidence of MA in long-term anti-VEGF use with other comparators in AMD was not significantly different.

P2X7-mediated alteration of membrane fluidity is associated with the late stages of age-related macular degeneration.

We have shown deficits in monocyte phagocytosis from patients with age-related macular degeneration (AMD). Cell membrane fluidity is known to affect phagocytic capacity and leucocyte functionality more generally. Therefore, we examined membrane fluidity of peripheral blood leucocytes in human patients with AMD and in the P2X7 null mouse model of AMD using flow cytometry with a fluorescent probe for fluidity, TMA-DPH. The results showed that membrane fluidity was decreased in all leucocyte types of late AMD relative to healthy controls (HC) including monocytes, neutrophils and lymphocytes but this was not apparent in earlier stages of AMD. Further analysis of factors contributing to membrane fluidity indicated that pre-treatment of monocytes and lymphocytes with ATP greatly increased membrane fluidity in humans and mice. Evidence from P2X7 null mice and P2X7 antagonists confirmed that these ATP-driven increases in membrane fluidity were mediated by P2X7 but were not associated with the classic P2X7 functions of pore formation or phagocytosis. Analysis of P2X7 expression indicated that receptor levels were elevated in classic monocytes of late AMD patients, further suggesting the P2X7 may contribute to altered plasma membrane properties. Our findings identified a novel biological function of P2X7 in modulating membrane fluidity of leucocytes and demonstrated reduced membrane fluidity in cellular changes associated with the late stage of AMD.

A multimodal deep learning system to distinguish late stages of AMD and to compare expert vs. AI ocular biomarkers

Within the next 1.5 decades, 1 in 7 U.S. adults is anticipated to suffer from age-related macular degeneration (AMD), a degenerative retinal disease which leads to blindness if untreated. Optical coherence tomography angiography (OCTA) has become a prime technique for AMD diagnosis, specifically for late-stage neovascular (NV) AMD. Such technologies generate massive amounts of data, challenging to parse by experts alone, transforming artificial intelligence into a valuable partner. We describe a deep learning (DL) approach which achieves multi-class detection of non-AMD vs. non-neovascular (NNV) AMD vs. NV AMD from a combination of OCTA, OCT structure, 2D b-scan flow images, and high definition (HD) 5-line b-scan cubes; DL also detects ocular biomarkers indicative of AMD risk. Multimodal data were used as input to 2D-3D Convolutional Neural Networks (CNNs). Both for CNNs and experts, choroidal neovascularization and geographic atrophy were found to be important biomarkers for AMD. CNNs predict biomarkers with accuracy up to 90.2% (positive-predictive-value up to 75.8%). Just as experts rely on multimodal data to diagnose AMD, CNNs also performed best when trained on multiple inputs combined. Detection of AMD and its biomarkers from OCTA data via CNNs has tremendous potential to expedite screening of early and late-stage AMD patients.

An integrated analysis of clinical and morphometric indications of atrophic forms of age-related macular degeneration

The atrophic form of late age-related macular degeneration (AMD) is a common cause of severe vision loss. Recently, a new classification system has been proposed, which identifies two types of atrophy in the late stage of AMD that require a more detailed study: (1) drusenassociated geographic atrophy (GA), which is the final stage of progression of dry AMD, and (2) macular atrophy (MA), which occurs in wet AMD, including the period of AMD treatment with angiogenesis inhibitors. Purpose: an integrated analysis of clinical and morphometric signs of atrophic AMD forms. Material and methods. 48 people (61eyes) aged 48–84 with GA (group 1) and MA (group 2) and a control group, recruited from age-matching 25 healthy volunteers (35 eyes), underwent standard ophthalmological examinations, fundus autofluorescence (FAF) with lesion area measurement, fundus photography, optical coherence tomography (OCT) in the standard mode and Enhanced Depth Imagine Mode, Multicolor, and OCT angiography. Results. The comparative analysis of two atrophic AMD forms showed that in GA eyes, foci of atrophy capturing the fovea were significantly more common, while, contrariwise in MA eyes atrophic foci not capturing the fovea were more frequent (p < 0.05). Photoreceptor tubulation was diagnosed mainly in eyes with GA (p < 0.05). The morphometric analysis showed a significant decrease in the subfoveal thickness of the choroid in the groups with GA and MA as compared to the control (p < 0.05), whilst no significant differences between two groups were noted. The assessment of the frequency of occurrence of types of fundus AF patterns in groups 1 and 2 followed by a comparative analysis, showed the presence of all types of patterns in GA patients, including the heterogeneous and the bordering pattern (p < 0.05). In the MA group, diffuse and focal types of patterns were revealed, while the frequency of the diffuse pattern turned out to be significantly more frequent (p < 0.05). Conclusion. The integrated analysis revealed the main semiological signs and morphometric parameters, their features and prevalence in GA and MA, which may have diagnostic and prognostic importance for the management and treatment of patients with AMD.

Nucleoside reverse transcriptase inhibitors and Kamuvudines inhibit amyloid-\u03b2 induced retinal pigmented epithelium degeneration

Nonfibrillar amyloid-β oligomers (AβOs) are a major component of drusen, the sub-retinal pigmented epithelium (RPE) extracellular deposits characteristic of age-related macular degeneration (AMD), a common cause of global blindness. We report that AβOs induce RPE degeneration, a clinical hallmark of geographic atrophy (GA), a vision-threatening late stage of AMD that is currently untreatable. We demonstrate that AβOs induce activation of the NLRP3 inflammasome in the mouse RPE in vivo and that RPE expression of the purinergic ATP receptor P2RX7, an upstream mediator of NLRP3 inflammasome activation, is required for AβO-induced RPE degeneration. Two classes of small molecule inflammasome inhibitors—nucleoside reverse transcriptase inhibitors (NRTIs) and their antiretrovirally inert modified analog Kamuvudines—both inhibit AβOs-induced RPE degeneration. These findings crystallize the importance of P2RX7 and NLRP3 in a disease-relevant model of AMD and identify inflammasome inhibitors as potential treatments for GA.

Deficits in Monocyte Function in Age Related Macular Degeneration: A Novel Systemic Change Associated With the Disease.

Age-related macular degeneration (AMD) is characterized by the accumulation of debris in the posterior eye. In this study we evaluated peripheral blood monocyte phagocytic function at various stages of AMD and in aged matched control participants. Real-time tri-color flow cytometry was used to quantify phagocytic function of peripheral blood monocyte subsets (non-classic, intermediate and classic) isolated from subjects with intermediate or late AMD and compared with age matched healthy controls. Assessment of phagocytic function of monocytes isolated from those with and without reticular pseudodrusen was also made, and the effect of glatiramer acetate on phagocytic function assessed. Phagocytic function was reduced in all subjects with AMD, irrespective of stage of disease. However, there was no correlation between phagocytic function and drusen load, nor any difference between the level of phagocytosis in those with or without reticular pseudodrusen. Treatment with glatiramer acetate increased phagocytosis of classical and non-classical monocytes, normalizing the reduction in phagocytosis observed in those with AMD. These findings suggest that defective systemic phagocytosis is associated with both intermediate and late stages of AMD, highlighting a potential role in the accumulation of debris that occurs early in the disease process. Assessing peripheral monocyte phagocytic function provides further insights into the etiology of this disease and offer a novel therapeutic target.

Beyond AREDS Formulations, What Is Next for Intermediate Age-Related Macular Degeneration (iAMD) Treatment? Potential Benefits of Antioxidant and Anti-inflammatory Apocarotenoids as Neuroprotectors.

Age-related macular degeneration (AMD) is the commonest cause of severe visual loss and blindness in developed countries among individuals aged 60 and older. AMD slowly progresses from early AMD to intermediate AMD (iAMD) and ultimately late-stage AMD. Late AMD encompasses either neovascular AMD (nAMD) or geographic atrophy (GA). nAMD is defined by choroidal neovascularization (CNV) and hemorrhage in the subretinal space at the level of the macula. This induces a rapid visual impairment caused by the death of photoreceptor cells. Intravitreal injection of anti-vascular endothelial growth factor (VEGF) antibodies is the standard treatment of nAMD but adds to the burden of patient care. GA is characterized by slowly expanding photoreceptor, and retinal pigment epithelium (RPE) degeneration patches progressively leading to blindness. There is currently no therapy to cure GA. Late AMD continues to be an unmet medical need representing a major health problem with millions of patients worldwide. Oxidative stress and inflammation are recognized as some of the main risk factors to developing late AMD. The antioxidant formulation AREDS (Age-Related Eye Disease Studies), contains β-carotene, which has been replaced by lutein and zeaxanthin in AREDS2, are given to patients with iAMD but have a limited effect on the incidence of nAMD and GA. Thus, to avoid or slowdown the development of late stages of AMD (nAMD or GA), new therapies targeting iAMD are needed such as crocetin obtained through hydrolysis of crocin, an important component of saffron (Crocus sativus L.), and norbixin derived from bixin extracted from Bixa orellana seeds. We have shown that these apocarotenoids preserved more effectively RPE cells against apoptosis following blue light exposure in the presence of A2E than lutein and zeaxanthin. In this review, we will discuss the potential use of apocarotenoids to slowdown the progression of iAMD, to reduce the incidence of both forms of late AMD.

The flicker response of venous oxygen saturation is significantly reduced in the early and late stages of age-related macular degeneration.

Retinal oxygen saturation (SO2) during flicker light stimulation was measured non-invasively in humans with age-related macular degeneration (AMD). Furthermore, the differences between early and late stages of AMD were evaluated. In 60 eyes of 45 AMD patients (74 ± 8.3 years) and 23 eyes of 23 healthy controls (73.4 ± 7.4 years), the SO2 of arterioles and venules was measured with the oximetry module of the Retinal Vessel Analyzer. Arterial SO2, venous SO2 and arteriovenous SO2 difference at baseline and with the flicker were assessed and compared with controls. From the difference between the arteriovenous SO2 under flicker stimulation and at baseline, the parameter delta av. Diff was calculated. Subgroup analyses of non-exudative (dry) AMD, exudative (wet) AMD and their end stages, geographic atrophy (GA) and disciform scar (DS) were performed. In comparison with healthy subjects (mean - 4.90, CI [- 6.32, - 3.43]), the parameter delta av. Diff was significantly reduced in all AMD patients (mean - 2.20, CI - 3.15, -1.23, p = 0.003), dry AMD (mean - 1.97, CI - 3.31, -0.63, p = 0.013) and wet AMD (mean - 2.35, CI - 3.50, - 1.19, p = 0.025). The comparison between wet and dry AMD revealed no significant results (p = 1). The comparison between AMD subgroups and healthy controls (median (IQR) - 4.29 (- 8.32; - 2.42) %) showed significant differences in non-neovascular (early dry AMD) (median (IQR) - 2.43 (- 4.59; - 0.74) %, p = 0.038), GA (median (IQR) 0.10 (- 4.02; 3.15) %, p = 0.019) and DS (median (IQR) - 1.67 (- 3.52; - 0.12) %, p = 0.03). A nearly significant reduction was observed in exudative (early wet) AMD (median (IQR) - 2.71 (- 5.84; - 0.2) %, p = 0.055). Minimal, not statistically significant differences of delta av. Diff were found between AMD subgroups. None of the baseline parameters was significantly different between patients and healthy controls, even after flicker light stimulation. Non-invasive retinal oximetry with flicker light stimulation seems to be a suitable method to study the pathogenetic mechanisms of AMD. The mathematically derived parameter delta av. Diff appears to be more sensitive than arteriovenous SO2 difference. Results suggest that the regulation of retinal oxygen supply, oxygen consumption or both is impaired in AMD.

Is age-related macular degeneration a local manifestation of systemic disorder? Changes in nailfold capillaries at age-related macular degeneration.

Determining whether nailfold capillary involvement is present in patients with Age-related macular degeneration (AMD) and whether there are different nailfold capillaroscopy findings between wet and dry types. From January 2016 to December 2017, with an initial diagnosis of AMD, 53 consecutive adult patients (AMD group) and 91 age- and sex-matched healthy individuals were studied prospectively. There was no history of any other ocular disease and other disease affecting nailfold capillaries. All subjects underwent a complete ophthalmic examination. The classified and advanced stages of wet and dry types were not included. All nailfold capillaroscopy examinations were performed by the same rheumatologist. It was found that the frequency of major capillaroscopic findings such as capillary ectasia, micro-hemorrhage, tortuosity, neo-formation, bizarre capillary, and bushy capillaries increased in the AMD group according to the normal group, but no significant relationship was found for capillary aneurysm. In dry or wet type of AMD in terms of ectasia, micro-hemorrhage, tortuosity, neo-formation, bizarre structure, bushy structure, or aneurism of nailfold capillaries, no significant correlation was found. Nailfold capillaroscopy can detect microvascular changes in the nailfold capillary, in early and late stages of AMD. There were morphological changes in the nailfold capillaries of AMD patients, suggesting that there are systemic superficial microvascular changes that may be due to the systemic nature of the disease.

Imbalances in tissue inhibitors of metalloproteinases differentiate choroidal neovascularization from geographic atrophy.

Tissue inhibitor of metalloproteinase (TIMP) is known to play a role in age-related macular degeneration (AMD). We wished to investigate alterations in different late stages of AMD: neovascular AMD and geographic atrophy (GA). This was a prospective case-control study. A total of 125 participants were included consecutively during a period of 18months. We included 46 patients with neovascular AMD, 46 patients with GA without any sign of choroidal neovascularization in either eye, and 33 healthy aged controls. Patients with immune-affecting disorders were not included. Commercial immunoassay kits were used to quantify levels of TIMP-1, TIMP-3, MMP-2 and MMP-9 in blood plasma. We found that patients with neovascular AMD had lower plasma concentration of TIMP-3 (p=0.028) than healthy controls. Patients with GA had higher plasma levels of TIMP-1 (p<0.001) and MMP-9 (p=0.022) compared to healthy controls. Also, we found that TIMP-1 levels in patients with GA increased with age (Spearman's rho=0.04, p=0.006). Matrix metalloproteinases (MMPs) and TIMPs, which are known to be involved in age-related changes in Bruch's membrane, are significantly altered systemically, suggesting the presence of an imbalance in the homeostasis of the extracellular matrix. These imbalances may explain differences in the clinical manifestation of late AMD.

Systemic inflammation and eye diseases. The Beijing Eye Study

PurposeSystemic inflammation is potentially associated with ocular diseases such as late age-related macular degeneration (AMD). Using the serum concentration of high-sensitive C-reactive protein (hs-CRP) as surrogate of systemic inflammation, we examined potential associations between the serum hs-CRP concentration and the presence and degree of eye diseases.MethodsThe population-based Beijing Eye Study included 3468 Chinese individuals. The study participants underwent a standardized interview and a detailed ophthalmic examination. The serum concentration of hs-CRP was determined.ResultsOut of 3468 participants, 2452 (70.7%) individuals (mean age:63.4±9.4 year; range:50–91 years) had hs-CRP measurements (mean:1.96±4.07mg/L). In multivariate analysis, higher serum concentration of hs-CRP was significantly (regression coefficient r: 0.21) associated with a higher level of diabetic retinopathy (P = 0.007; standardized regression coefficient beta:0.06; non-standardized regression coefficient B:1.35; 95% confidence interval (CI):0.37,2.22) and polypoidal choroidal vasculopathy (P = 0.002;beta:0.06;B:6.22;95%CI:2.24,10.2) after adjusting for higher serum concentration of high-density lipoproteins (P<0.001;beta:-0.12;B:-1.31;95%CI:-1.77,-0.85), higher body mass index (P = 0.01;beta:0.06;B:0.06;95%CI:0.01, 0.11), lower level of education (P = 0.04;beta:-0.06;B:-0.22;95%CI:-0.42,-0.02), lower cognitive function score (P = 0.01;beta:-0.07;B:-0.08;95%CI:-0.13,-0.02). If the presences of other ocular diseases were added to the model, the presence of glaucoma (P = 0.99), open-angle glaucoma (P = 0.80), angle-closure glaucoma (P = 0.67), pseudoexfoliation (P = 0.18), nuclear cataract (P = 0.30), cortical cataract (P = 0.15), subcapsular cataract (P = 0.59), retinal vein occlusions (P = 0.33), central serous choroidopathy (P = 0.44), early stage of age-related macular degeneration (AMD) (P = 0.46), intermediate stage of AMD (P = 0.20) and late stage of AMD (P = 0.91) including geographic atrophy (P = 0.60) or neovascular AMD (P = 0.68) were not significantly associated with the serum concentration of hs-CRP.ConclusionsIn Chinese aged 50+ years, higher serum concentration of hs-CRP was significantly associated with a higher level of diabetic retinopathy and higher frequency of polypoidal choroidal vasculopathy. Other major ocular disorders, namely glaucoma including open-angle glaucoma and angle-closure glaucoma, pseudoexfoliation, nuclear, cortical or subcapsular cataract, retinal vein occlusions, central serous choroidopathy, early, intermediate or late stage of AMD including geographic atrophy, were not significantly associated with hs-CRP serum concentrations. It suggests that these diseases, in contrast to diabetic retinopathy and polypoidal choroidal vasculopathy, were not associated with a major systemic inflammatory component.

A Deep Learning Algorithm for Prediction of Age-Related Eye Disease Study Severity Scale for Age-Related Macular Degeneration from Color Fundus Photography

Age-related macular degeneration (AMD) is a common threat to vision. While classification of disease stages is critical to understanding disease risk and progression, several systems based on color fundus photographs are known. Most of these require in-depth and time-consuming analysis of fundus images. Herein, we present an automated computer-based classification algorithm. Algorithm development for AMD classification based on a large collection of color fundus images. Validation is performed on a cross-sectional, population-based study. We included 120 656 manually graded color fundus images from 3654 Age-Related Eye Disease Study (AREDS) participants. AREDS participants were >55 years of age, and non-AMD sight-threatening diseases were excluded at recruitment. In addition, performance of our algorithm was evaluated in 5555 fundus images from the population-based Kooperative Gesundheitsforschung in der Region Augsburg (KORA; Cooperative Health Research in the Region of Augsburg) study. We defined 13 classes (9 AREDS steps, 3 late AMD stages, and 1 for ungradable images) and trained several convolution deep learning architectures. An ensemble of network architectures improved prediction accuracy. An independent dataset was used to evaluate the performance of our algorithm in a population-based study. κ Statistics and accuracy to evaluate the concordance between predicted and expert human grader classification. A network ensemble of 6 different neural net architectures predicted the 13 classes in the AREDS test set with a quadratic weighted κ of 92% (95% confidence interval, 89%-92%) and an overall accuracy of 63.3%. In the independent KORA dataset, images wrongly classified as AMD were mainly the result of a macular reflex observed in young individuals. By restricting the KORA analysis to individuals >55 years of age and prior exclusion of other retinopathies, the weighted and unweighted κ increased to 50% and 63%, respectively. Importantly, the algorithm detected 84.2% of all fundus images with definite signs of early or late AMD. Overall, 94.3% of healthy fundus images were classified correctly. Our deep learning algoritm revealed a weighted κ outperforming human graders in the AREDS study and is suitable to classify AMD fundus images in other datasets using individuals >55 years of age.

Early and intermediate age-related macular degeneration: update and clinical review.

Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss in developed countries. With the aging of population, AMD will become globally an increasingly important and prevalent disease worldwide. It is a complex disease whose etiology is associated with both genetic and environmental risk factors. An extensive decline in the quality of life and progressive need of daily living assistance resulting from AMD among those most severely affected highlights the essential role of preventive strategies, particularly advising patients to quit smoking. In addition, maintaining a healthy diet, controlling other risk factors (such as hypertension, obesity, and atherosclerosis), and the use of nutritional supplements (antioxidants) are recommendable. Genetic testing may be especially important in patients with a family history of AMD. Recently, unifying criteria for the clinical classification of AMD, defining no apparent aging changes; normal aging changes; and early, intermediate, and late AMD stages, are of value in predicting AMD risk of progression and in establishing recommendations for the diagnosis, therapeutic approach, and follow-up of patients. The present review is focused on early and intermediate AMD and presents a description of the clinical characteristics and ophthalmological findings for these stages, together with algorithms for the diagnosis and management of patients, which are easily applicable in daily clinical practice.

GEOGRAPHIC ATROPHY: Semantic Considerations and Literature Review.

There is a lack of agreement regarding the types of lesions and clinical conditions that should be included in the term "geographic atrophy." Varied and conflicting views prevail throughout the literature and are currently used by retinal experts and other health care professionals. We reviewed the nominal definition of the term "geographic atrophy" and conducted a search of the ophthalmologic literature focusing on preceding terminologies and the first citations of the term "geographic atrophy" secondary to age-related macular degeneration. According to the nominal definition, the term "geography" stands for a detailed description of the surface features of a specific region, indicating its relative position. However, it does not necessarily imply that the borders of the region must be sharply demarcated or related to any anatomical structures. The term "geographical areas of atrophy" was initially cited in the 1960s in the ophthalmologic literature in the context of uveitic eye disease and shortly thereafter also for the description of variants of "senile macular degeneration." However, no direct explanation could be found in the literature as to why the terms "geographical" and "geographic" were chosen. Presumably the terms were used as the atrophic regions resembled the map of a continent or well-defined country borders on thematic geographical maps. With the evolution of the terminology, the commonly used adjunct "of the retinal pigment epithelium" was frequently omitted and solely the term "geographic atrophy" prevailed for the nonexudative late-stage of age-related macular degeneration itself. Along with the quantification of atrophic areas, based on different imaging modalities and the use of both manual and semiautomated approaches, various and inconsistent definitions for the minimal lesion diameter or size of atrophic lesions have also emerged. Reconsideration of the application of the term "geographic atrophy" in the context of age-related macular degeneration seems to be prudent given ongoing advances in multimodal retinal imaging technology with identification of various phenotypic characteristics, and the observation of atrophy development in eyes under antiangiogenic therapy.

Genetics of Unilateral and Bilateral Age-Related Macular Degeneration Severity Stages.

BackgroundAge-related macular degeneration (AMD) is a common disease causing visual impairment and blindness. Various gene variants are strongly associated with late stage AMD, but little is known about the genetics of early forms of the disease. This study evaluated associations of genetic factors and different AMD stages depending on unilateral and bilateral disease severity.MethodsIn this case-control study, participants were assigned to nine AMD severity stages based on the characteristics of each eye. 18 single nucleotide polymorphisms (SNPs) were genotyped and attempted to correlate with AMD severity stages by uni- and multivariate logistic regression analyses and trend analyses. Area under the receiver operating characteristic curves (AUC) were calculated.ResultsOf 3444 individuals 1673 were controls, 379 had early AMD, 333 had intermediate AMD and 989 showed late AMD stages. With increasing severity of disease and bilateralism more SNPs with significant associations were found. Odds ratios, especially for the main risk polymorphisms in ARMS2 (rs10490924) and CFH (rs1061170), gained with increasing disease severity and bilateralism (exemplarily: rs1061170: unilateral early AMD: OR = 1.18; bilateral early AMD: OR = 1.20; unilateral intermediate AMD: OR = 1.28; bilateral intermediate AMD: OR = 1.39, unilateral geographic atrophy (GA): OR = 1.50; bilateral GA: OR = 1.71). Trend analyses showed p<0.0001 for ARMS2 (rs10490924) and for CFH (rs1061170), respectively. AUC of risk models for various AMD severity stages was lowest for unilateral early AMD (AUC = 0.629) and showed higher values in more severely and bilaterally affected individuals being highest for late AMD with GA in one eye and neovascular AMD in the other eye (AUC = 0.957).ConclusionThe association of known genetic risk factors with AMD became stronger with increasing disease severity, which also led to an increasing discriminative ability of AMD cases and controls. Genetic predisposition was also associated with the disease severity of the fellow-eye, highlighting the importance of both eyes in AMD patients.

Choroidal thickness changes in age-related macular degeneration different forms and stages

Choroidal thickness measurement results of 124 patients (210 eyes) with age-related macular degeneration (AMD) obtained by enhanced depth imaging of spectral domain optical coherence tomography (EDI-OCT) are presented. There were no significant differences in choroidal thickness between patients with dry and wet AMD forms and healthy people of the same age group (р = 0.67; р = 0.26). A statistically significant choroidal thinning in patients with late AMD stages as compared to each of healthy people and dry and wet AMD patients was found (р 0.0001).

The association between statin use and risk of age-related macular degeneration.

The aim of the present study was to evaluate the association between statin use and the risk of age-related macular degeneration (AMD). A systematic search of the PubMed, EMBASE and ISI web of science databases was used to identify eligible published literatures without language restrictions up to April 2015. Summary relative ratios (RRs) and 95% CIs were estimated using a fixed-effect or random-effects model. A total of 14 studies met the inclusion criteria and were included in this meta-analysis. No significant association was observed between statin use and the risk of any AMD (RR, 0.95; 95% CI, 0.74–1.15); and stratified analysis showed that statins had a significantly different effects on early and late stages of AMD. For early AMD, statin use significantly reduced the risk approximately 17% (RR, 0.83; 95% CI, 0.66–0.99). At the late stage, we observed a significant protective association of statin use with exudative AMD (RR, 0.90; 95% CI, 0.80–0.99), in contrast with the absent association between statins and geographic atrophy (RR, 1.16; 95% CI, 0.77–1.56). These results demonstrated that statin use was protective for early and exudative AMD. Additional large prospective cohort studies and RCTs are required to determine the potential effect of statins on AMD prevention.

Prevalence of age‐related macular diseases in an old French population (the MONTRACHET Study)

PurposeTo describe the prevalence of age‐related macular diseases in a French population‐based study (the Montrachet study) older than 74 years.MethodsThe Three City study (3C) was a prospective study including 9294 patients aged of 65 years or more from three French cities (Dijon, Bordeaux, and Montpellier) at enrolment in 1999. After 10 years of follow‐up, an eye examination was proposed to participants of the 3C cohort in Dijon and 1153 participants were included in the so‐called Montrachet study. All patients underwent a complete eye examination including nonmydriatic color retinal photographs. The photographs were classified according to the type of abnormality (intermediate soft drusen, large soft distinct or indistinct drusen, reticular drusen or large area of soft drusen reaching 500 µm in diameter, hyperpigmentation or hypopigmentation), and their location (central or pericentral) using the classification of the Multi‐ethnic Study of Atherosclerosis (MESA) and that used in the Rotterdam Study. Patients were then classified into 3 categories: early age‐related macular degeneration (AMD), late AMD (atrophic or neovascular).ResultsData were available for 1069 patients: 396 men (37.0%) and 673 women (63.0%). The mean age was 82.2 ± 3.8 years. The prevalence of healthy subjects was 56.0%. Stages 1, 2 and 3 accounted for 32.6%, 7.7% and 1.5%, respectively. The late AMD stages represented 2.2% (24 patients). Smoking was not significantly associated with AMD categories.ConclusionsThe prevalence of AMD grading in our population is consistent with the literature. The classification of participants according to different macular abnormalities may predict the populations at risk of developing an advanced grade and can help to adapt the management. The relationship with other risk factors will be the next step of this analysis.