Journal of Clinical Medicine

Editorial

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4 pages, 165 KiB

Open AccessEditorial

Age-Related Macular Degeneration (AMD): A View to the Future

by Joan W. Miller, Lily L. D’Anieri, Deeba Husain, John B. Miller and Demetrios G. Vavvas

J. Clin. Med. 2021, 10(5), 1124; https://doi.org/10.3390/jcm10051124 - 8 Mar 2021

Cited by 10 | Viewed by 3199

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in people over age 50 worldwide, and the third leading cause of blindness overall [...] Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

Research

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8 pages, 1152 KiB

Open AccessArticle

Systemic Complement Activation Profiles in Nonexudative Age-Related Macular Degeneration: A Meta-Analysis

by Jonathan B. Lin, Stylianos Serghiou, Joan W. Miller and Demetrios G. Vavvas

J. Clin. Med. 2022, 11(9), 2371; https://doi.org/10.3390/jcm11092371 - 23 Apr 2022

Cited by 2 | Viewed by 2219

Abstract

Although complement inhibition has emerged as a possible therapeutic strategy for age-related macular degeneration (AMD), there is not a clear consensus regarding what aspects of the complement pathway are dysregulated in AMD and when this occurs relative to disease stage. We recently published [...] Read more.

Although complement inhibition has emerged as a possible therapeutic strategy for age-related macular degeneration (AMD), there is not a clear consensus regarding what aspects of the complement pathway are dysregulated in AMD and when this occurs relative to disease stage. We recently published a systematic review describing systemic complement activation profiles in patients with early/intermediate AMD or geographic atrophy (GA) compared to non-AMD controls. Here, we sought to meta-analyze these results to estimate the magnitude of complement dysregulation in AMD using restricted maximum likelihood estimation. The seven meta-analyzed studies included 710 independent participants with 23 effect sizes. Compared with non-AMD controls, patients with early/intermediate nonexudative AMD (N = 246) had significantly higher systemic complement activation, as quantified by the levels of complement proteins generated by common final pathway activation, and significantly lower systemic complement inhibition. In contrast, there were no statistically significant differences in the systemic levels of complement common final pathway activation products or complement inhibition in patients with GA (N = 178) versus non-AMD controls. We provide evidence that systemic complement over-activation is a feature of early/intermediate nonexudative AMD; no such evidence was identified for patients with GA. These findings provide mechanistic insights and inform future clinical trials. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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16 pages, 2340 KiB

Open AccessArticle

Short- and Long-Term Visual Outcomes in Patients Receiving Intravitreal Injections: The Impact of the Coronavirus 2019 Disease (COVID-19)—Related Lockdown

by Vivian Paraskevi Douglas, Konstantinos A. A. Douglas, Demetrios G. Vavvas, Joan W. Miller and John B. Miller

J. Clin. Med. 2022, 11(8), 2097; https://doi.org/10.3390/jcm11082097 - 8 Apr 2022

Cited by 7 | Viewed by 2096

Abstract

Purpose: To investigate the short- and long-term impact of COVID-19—related lockdown on the vision of patients requiring intravitreal injections (IVI) for neovascular Age-related Macular degeneration (nvAMD), diabetic retinopathy (DR), central retinal vein occlusion (CRVO), or branch retinal vein occlusion (BRVO). Methods: [...] Read more.

Purpose: To investigate the short- and long-term impact of COVID-19—related lockdown on the vision of patients requiring intravitreal injections (IVI) for neovascular Age-related Macular degeneration (nvAMD), diabetic retinopathy (DR), central retinal vein occlusion (CRVO), or branch retinal vein occlusion (BRVO). Methods: This is a retrospective study from the Retina department of three Mass Eye and Ear centers. Charts of patients age of ≥ 18 years with any of the abovementioned diagnoses who had a scheduled appointment anytime between 17 March 2020 until 18 May 2020 (lockdown period in Boston, Massachusetts) were reviewed at baseline (up to 12 weeks before the lockdown), at first available follow-up (=actual f/u) during or after the lockdown period, at 3 months, 6 months, and at last available completed appointment of 2020. Results: A total of 1001 patients met the inclusion criteria. Of those patients, 479 (47.9%) completed their intended f/u appointment, while 522 missed it (canceled and “no show”). The delay in care of those who missed it was 59.15 days [standard deviation (SD) ± 49.6]. In these patients, significant loss of vision was noted at actual f/u [Best corrected visual acuity (BCVA) in LogMAR (Logarithm of the Minimum Angle of Resolution)—mean (±SD)—completed: 0.45 (±0.46), missed: 0.53 (±0.55); p = 0.01], which was more prominent in the DR group [Visual acuity (VA) change in LogMAR—mean (±SD); completed: 0.04 (±0.28), missed: 0.18 (±0.44); p = 0.02] and CRVO [completed: −0.06 (±0.27), missed: 0.11 (±0.35); p = <0.001] groups followed by nvAMD [completed: 0.006 (±0.16), missed: 0.06 (±0.27); p = 0.004] and BRVO [completed: −0.02 (±0.1), missed: 0.03 (±0.14); p = 0.02] ones. Overall, a higher percent of people who missed their intended f/u experienced vision loss of more than 15 letters at last f/u compared to those who completed it [missed vs. completed; 13.4% vs. 7.4% in nvAMD (p = 0.72), 7.8% vs. 6.3% in DR (0.84), 15.5% vs. 9.9% in CRVO (p < 0.001) and 9.6% vs. 2% in BRVO (p = 0.48)]. Conclusions: Delay in care of about 8.45 weeks can lead to loss of vision in patients who receive IVI with DR and CRVO patients being more vulnerable in the short-term, whereas in the long-term, CRVO patients followed by the nvAMD patients demonstrating the least vision recovery. BRVO patients were less likely to be affected by the delay in care. Adherence to treatment is key for maintaining and improving visual outcomes in patients who require IVI. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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10 pages, 1711 KiB

Open AccessArticle

Monthly Alternating Injections of Aflibercept and Bevacizumab for Neovascular Age-Related Macular Degeneration

by Junyeop Lee, You Na Kim and June-Gone Kim

J. Clin. Med. 2022, 11(6), 1543; https://doi.org/10.3390/jcm11061543 - 11 Mar 2022

Cited by 2 | Viewed by 2073

Abstract

We investigated the efficacy of monthly alternating injections of aflibercept and bevacizumab (MAAB) for maintenance treatment in patients with neovascular age-related macular degeneration (AMD) who showed improvement with the initial monthly injections but presented with rapid worsening after conversion to bimonthly injections. We [...] Read more.

We investigated the efficacy of monthly alternating injections of aflibercept and bevacizumab (MAAB) for maintenance treatment in patients with neovascular age-related macular degeneration (AMD) who showed improvement with the initial monthly injections but presented with rapid worsening after conversion to bimonthly injections. We included 72 patients with neovascular AMD who showed improvement with loading injections of aflibercept. For maintenance treatment, bevacizumab was administered every alternate month between the bimonthly aflibercept injections in 24 (33.3%) eyes showing worsening (MAAB group). The other eyes were treated with aflibercept (BiA group) bimonthly. Baseline low retinal thickness, thick choroid, and presence of intraretinal fluid were associated with worsening after extending the injection intervals. Visual improvement was lower in the MAAB group than in the BiA group, but the final visual outcomes were comparable. Additional bevacizumab stabilized the early fluctuation of retinal thickness, thus maintaining long-term visual stability without increasing the risk of geographic atrophy or disciform scar until the second year. Previously treated eyes or those with polypoidal choroidal vasculopathy responded less to the initial loading doses and showed worsening under the bimonthly regimen. MAAB was effective in preventing anatomical and functional deterioration when bimonthly aflibercept proved insufficient for the maintenance treatment of neovascular AMD. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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9 pages, 273 KiB

Open AccessArticle

Urinary Mass Spectrometry Profiles in Age-Related Macular Degeneration

by Ines Lains, Kevin M. Mendez, João Q. Gil, John B. Miller, Rachel S. Kelly, Patrícia Barreto, Ivana K. Kim, Demetrios G. Vavvas, Joaquim Neto Murta, Liming Liang, Rufino Silva, Joan W. Miller, Jessica Lasky-Su and Deeba Husain

J. Clin. Med. 2022, 11(4), 940; https://doi.org/10.3390/jcm11040940 - 11 Feb 2022

Cited by 3 | Viewed by 1918

Abstract

We and others have shown that patients with different severity stages of age-related macular degeneration (AMD) have distinct plasma metabolomic profiles compared to controls. Urine is a biofluid that can be obtained non-invasively and, in other fields, urine metabolomics has been proposed as [...] Read more.

We and others have shown that patients with different severity stages of age-related macular degeneration (AMD) have distinct plasma metabolomic profiles compared to controls. Urine is a biofluid that can be obtained non-invasively and, in other fields, urine metabolomics has been proposed as a feasible alternative to plasma biomarkers. However, no studies have applied urinary mass spectrometry (MS) metabolomics to AMD. This study aimed to assess urinary metabolomic profiles of patients with different stages of AMD and a control group. We included two prospectively designed, multicenter, cross-sectional study cohorts: Boston, US (n = 185) and Coimbra, Portugal (n = 299). We collected fasting urine samples, which were used for metabolomic profiling (Ultrahigh Performance Liquid chromatography—Mass Spectrometry). Multivariable logistic and ordinal logistic regression models were used for analysis, accounting for gender, age, body mass index and use of AREDS supplementation. Results from both cohorts were then meta-analyzed. No significant differences in urine metabolites were seen when comparing patients with AMD and controls. When disease severity was considered as an outcome, six urinary metabolites differed significantly (p < 0.01). In particular, two of the metabolites identified have been previously shown by our group to also differ in the plasma of patients of AMD compared to controls and across severity stages. While there are fewer urinary metabolites associated with AMD than plasma metabolites, this study identified some differences across stages of disease that support previous work performed with plasma, thus highlighting the potential of these metabolites as future biomarkers for AMD. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

14 pages, 738 KiB

Open AccessArticle

Factors of Anti-Vascular Endothelial Growth Factor Therapy Withdrawal in Patients with Neovascular Age-Related Macular Degeneration: Implications for Improving Patient Adherence

by Fumi Gomi, Reiko Toyoda, Annabelle Hein Yoon and Kota Imai

J. Clin. Med. 2021, 10(14), 3106; https://doi.org/10.3390/jcm10143106 - 14 Jul 2021

Cited by 14 | Viewed by 3294

Abstract

We investigated the factors associated with the discontinuation of anti-vascular endothelial growth factor (VEGF) therapies in patients with neovascular age-related macular degeneration (AMD). Japanese patients with AMD aged ≥50 years, reporting at least one prior injection of an anti-VEGF drug, completed an online [...] Read more.

We investigated the factors associated with the discontinuation of anti-vascular endothelial growth factor (VEGF) therapies in patients with neovascular age-related macular degeneration (AMD). Japanese patients with AMD aged ≥50 years, reporting at least one prior injection of an anti-VEGF drug, completed an online survey covering reasons for discontinuation or dissatisfaction with therapy, quality of life (EQ-5D-5L) and patient activation (PAM-13). The respondents were divided into two cohorts: Cohort 1—patients who discontinued anti-VEGF therapy (n = 207); Cohort 2—patients continuing anti-VEGF therapy (n = 65). The most common reason for discontinuing therapy was the “doctor’s decision” in 89.4% (Cohort 1-1). In the other 22 (10.6%) patients in Cohort 1 (Cohort 1-2), reasons included “no deterioration in vision”, “financial burden” and “ineffective treatment”. Patients in Cohort 2 were dissatisfied with “long waiting times” (77%), “financial burden” and “ineffective treatment”. Pain/discomfort posed the greatest impact on quality of life. Only 5% of patients in Cohorts 1-1 and 2 and none in Cohort 1-2 were considered advocates for their own health. In conclusion, most patients who discontinued anti-VEGF therapy did so at their doctor’s decision. Addressing the reasons associated with discontinuation or dissatisfaction with anti-VEGF therapies might help improve their continuation. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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12 pages, 671 KiB

Open AccessArticle

Exploratory Study on Visual Acuity and Patient-Perceived Visual Function in Patients with Subretinal Drusenoid Deposits

by Manjot K. Grewal, Shruti Chandra, Sarega Gurudas, Alan Bird, Glen Jeffery and Sobha Sivaprasad

J. Clin. Med. 2020, 9(9), 2832; https://doi.org/10.3390/jcm9092832 - 1 Sep 2020

Cited by 4 | Viewed by 2188

Abstract

Purpose: To investigate the value of visual acuity and patient-perceived visual function test when subretinal drusenoid deposits (SDD) are incorporated into the classification of age-related macular degeneration (AMD). A total of 50 participants were recruited into the study in these groups: healthy ageing [...] Read more.

Purpose: To investigate the value of visual acuity and patient-perceived visual function test when subretinal drusenoid deposits (SDD) are incorporated into the classification of age-related macular degeneration (AMD). A total of 50 participants were recruited into the study in these groups: healthy ageing (n = 11), intermediate AMD (iAMD) with no SDD (n = 17), iAMD with SDD (n = 11) and non-foveal atrophic AMD (n = 11) confirmed by two retinal imaging modalities. Best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) were measured and low luminance deficit (LLD) was calculated. Participants were also interviewed with the low luminance questionnaire (LLQ). Linear regression was used to assess function–function relations. Compared with healthy participants, BCVA and LLVA scores were significantly reduced in the atrophic AMD group (p < 0.0001 and p = 0.00016, respectively) and in patients with SDD (p = 0.028 and p = 0.045, respectively). Participants with atrophy also had reduced BCVA (p = 0.001) and LLVA (p = 0.009) compared with the iAMD no SDD group. However, there were no differences in visual function tests between healthy aging and iAMD without SDD and between iAMD with SDD and atrophic AMD groups. The LLD score did not differ between groups. BCVA and LLVA correlated well. The LLQ did not correlate with visual function tests. This study shows that LLD is not a marker of disease severity as assessed clinically. Although LLQ is a good marker for disease severity using the current AMD classification, it does not differentiate between eyes with and without SDD. Eyes with non-macular geographic atrophy and SDD had lower function than eyes with no SDD and healthy controls. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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Review

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10 pages, 754 KiB

Open AccessReview

Subthreshold Exudative Choroidal Neovascularization (CNV): Presentation of This Uncommon Subtype and Other CNVs in Age-Related Macular Degeneration (AMD)

by Vivian Paraskevi Douglas, Itika Garg, Konstantinos A. A. Douglas and John B. Miller

J. Clin. Med. 2022, 11(8), 2083; https://doi.org/10.3390/jcm11082083 - 7 Apr 2022

Cited by 3 | Viewed by 3938

Abstract

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in people over the age of 50 worldwide. Exudative or neovascular AMD is a more severe subset of AMD which is characterized by the presence of choroidal neovascularization (CNV). Recent advancements [...] Read more.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in people over the age of 50 worldwide. Exudative or neovascular AMD is a more severe subset of AMD which is characterized by the presence of choroidal neovascularization (CNV). Recent advancements in multimodal ophthalmic imaging, including optical coherence tomography (OCT) and OCT-angiography (OCT-A), have facilitated the detection and characterization of previously undetectable neovascular lesions and have enabled a more refined classification of CNV in exudative as well as nonexudative AMD patients. Subthreshold exudative CNV is a novel subtype of exudative AMD that typically presents asymptomatically with good visual acuity and is characterized by stable persistent or intermittent subretinal fluid (SRF). This review aims to provide an overview of the clinical as well as multimodal imaging characteristics of CNV in AMD, including this new clinical phenotype, and propose effective approaches for management. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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21 pages, 869 KiB

Open AccessReview

AMD Genomics: Non-Coding RNAs as Biomarkers and Therapeutic Targets

by Charles Zhang, Leah A. Owen, John H. Lillvis, Sarah X. Zhang, Ivana K. Kim and Margaret M. DeAngelis

J. Clin. Med. 2022, 11(6), 1484; https://doi.org/10.3390/jcm11061484 - 9 Mar 2022

Cited by 9 | Viewed by 2877

Abstract

Age-related macular degeneration (AMD) is a progressive neurodegenerative disease that is the world’s leading cause of blindness in the aging population. Although the clinical stages and forms of AMD have been elucidated, more specific prognostic tools are required to determine when patients with [...] Read more.

Age-related macular degeneration (AMD) is a progressive neurodegenerative disease that is the world’s leading cause of blindness in the aging population. Although the clinical stages and forms of AMD have been elucidated, more specific prognostic tools are required to determine when patients with early and intermediate AMD will progress into the advanced stages of AMD. Another challenge in the field has been the appropriate development of therapies for intermediate AMD and advanced atrophic AMD. After numerous negative clinical trials, an anti-C5 agent and anti-C3 agent have recently shown promising results in phase 3 clinical trials, in terms of slowing the growth of geographic atrophy, an advanced form of AMD. Interestingly, both drugs appear to be associated with an increased incidence of wet AMD, another advanced form of the disease, and will require frequent intravitreal injections. Certainly, there remains a need for other therapeutic agents with the potential to prevent progression to advanced stages of the disease. Investigation of the role and clinical utility of non-coding RNAs (ncRNAs) is a major advancement in biology that has only been minimally applied to AMD. In the following review, we discuss the clinical relevance of ncRNAs in AMD as both biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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24 pages, 1575 KiB

Open AccessReview

Dark Adaptation and Its Role in Age-Related Macular Degeneration

by Archana K. Nigalye, Kristina Hess, Shrinivas J. Pundlik, Brett G. Jeffrey, Catherine A. Cukras and Deeba Husain

J. Clin. Med. 2022, 11(5), 1358; https://doi.org/10.3390/jcm11051358 - 1 Mar 2022

Cited by 17 | Viewed by 5567

Abstract

Dark adaptation (DA) refers to the slow recovery of visual sensitivity in darkness following exposure to intense or prolonged illumination, which bleaches a significant amount of the rhodopsin. This natural process also offers an opportunity to understand cellular function in the outer retina [...] Read more.

Dark adaptation (DA) refers to the slow recovery of visual sensitivity in darkness following exposure to intense or prolonged illumination, which bleaches a significant amount of the rhodopsin. This natural process also offers an opportunity to understand cellular function in the outer retina and evaluate for presence of disease. How our eyes adapt to darkness can be a key indicator of retinal health, which can be altered in the presence of certain diseases, such as age-related macular degeneration (AMD). A specific focus on clinical aspects of DA measurement and its significance to furthering our understanding of AMD has revealed essential findings underlying the pathobiology of the disease. The process of dark adaptation involves phototransduction taking place mainly between the photoreceptor outer segments and the retinal pigment epithelial (RPE) layer. DA occurs over a large range of luminance and is modulated by both cone and rod photoreceptors. In the photopic ranges, rods are saturated and cone cells adapt to the high luminance levels. However, under scotopic ranges, cones are unable to respond to the dim luminance and rods modulate the responses to lower levels of light as they can respond to even a single photon. Since the cone visual cycle is also based on the Muller cells, measuring the impairment in rod-based dark adaptation is thought to be particularly relevant to diseases such as AMD, which involves both photoreceptors and RPE. Dark adaptation parameters are metrics derived from curve-fitting dark adaptation sensitivities over time and can represent specific cellular function. Parameters such as the cone-rod break (CRB) and rod intercept time (RIT) are particularly sensitive to changes in the outer retina. There is some structural and functional continuum between normal aging and the AMD pathology. Many studies have shown an increase of the rod intercept time (RIT), i.e., delays in rod-mediated DA in AMD patients with increasing disease severity determined by increased drusen grade, pigment changes and the presence of subretinal drusenoid deposits (SDD) and association with certain morphological features in the peripheral retina. Specifications of spatial testing location, repeatability of the testing, ease and availability of the testing device in clinical settings, and test duration in elderly population are also important. We provide a detailed overview in light of all these factors. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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9 pages, 225 KiB

Open AccessReview

Telemedicine for the Diagnosis and Management of Age-Related Macular Degeneration: A Review

by Grayson W. Armstrong and John B. Miller

J. Clin. Med. 2022, 11(3), 835; https://doi.org/10.3390/jcm11030835 - 5 Feb 2022

Cited by 9 | Viewed by 2758

Abstract

Use of ophthalmic telemedicine for patients with age-related macular degeneration (AMD) has shown remarkable advances over recent years. The recent COVID pandemic accelerated this transition since in-person evaluation of elderly patients at high risk for advanced AMD and severe vision loss were also [...] Read more.

Use of ophthalmic telemedicine for patients with age-related macular degeneration (AMD) has shown remarkable advances over recent years. The recent COVID pandemic accelerated this transition since in-person evaluation of elderly patients at high risk for advanced AMD and severe vision loss were also at higher risk for complications from COVID infection. To date, ophthalmic telemedicine has been successfully used in remote retinal consultation by general ophthalmologists for AMD management, hybrid testing visits with both in-office testing and remote evaluation, as well as early successes in home-based remote monitoring of patients with high-risk AMD. We therefore review the current literature and evidence base related to ophthalmic telemedicine for AMD. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

14 pages, 4492 KiB

Open AccessReview

Cell Death in AMD: The Rationale for Targeting Fas

by David N. Zacks, Andrew J. Kocab, Joanne J. Choi, Meredith S. Gregory-Ksander, Marisol Cano and James T. Handa

J. Clin. Med. 2022, 11(3), 592; https://doi.org/10.3390/jcm11030592 - 25 Jan 2022

Cited by 13 | Viewed by 5293

Abstract

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the developed world. While great advances have been made in the treatment of the neovascular (“wet”) form of the disease, there is still a significant need for therapies that prevent the [...] Read more.

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the developed world. While great advances have been made in the treatment of the neovascular (“wet”) form of the disease, there is still a significant need for therapies that prevent the vision loss associated with the advanced forms of dry, atrophic AMD. In this atrophic form, retinal pigment epithelial (RPE) and photoreceptor cell death is the ultimate cause of vision loss. In this review, we summarize the cell death pathways and their relation to RPE and retinal cell death in AMD. We review the data that support targeting programmed cell death through inhibition of the Fas receptor as a novel approach to preserve these structures and that this effect results from inhibiting both canonical death pathway activation and reducing the associated inflammatory response. These data lay the groundwork for current clinical strategies targeting the Fas pathway in this devastating disease. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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12 pages, 5907 KiB

Open AccessReview

Peripheral Manifestations in Age Related Macular Degeneration: A Review of Imaging and Findings

by Andrew Pivovar and Patrick Oellers

J. Clin. Med. 2021, 10(17), 3993; https://doi.org/10.3390/jcm10173993 - 3 Sep 2021

Cited by 4 | Viewed by 2719

Abstract

Purpose: To review novel findings in research with ultra-widefield imaging for analysis of peripheral manifestations in macular degeneration (AMD). We introduce the evolving widefield imaging modalities while summarizing the analytical techniques used in data collection of peripheral retinal findings thus far. Our review [...] Read more.

Purpose: To review novel findings in research with ultra-widefield imaging for analysis of peripheral manifestations in macular degeneration (AMD). We introduce the evolving widefield imaging modalities while summarizing the analytical techniques used in data collection of peripheral retinal findings thus far. Our review provides a summary of advancements to date and a commentary on future direction for AMD research. Methods: This is a literature review of all significant publications focused on the relationship between AMD and the retinal periphery conducted within the last two decades. Results and Conclusion: Promising research has been undertaken to elucidate peripheral retinal manifestations in macular degeneration using novel methodology. Advancements in ultra-widefield imaging and fundus autofluorescence have allowed us to elucidate peripheral retinal pigmentary changes, drusen deposition, and much more. Novel grid overlay techniques have been introduced to aid in analyzing these changes for pattern recognition and grouping of findings. This review discusses these findings in detail, providing evidence for the pan-retinal manifestations of AMD. Inter-study discordance in analytical approach highlights a need for more systematic future study. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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14 pages, 1479 KiB

Open AccessReview

Measuring the Contrast Sensitivity Function in Non-Neovascular and Neovascular Age-Related Macular Degeneration: The Quantitative Contrast Sensitivity Function Test

by Filippos Vingopoulos, Karen M. Wai, Raviv Katz, Demetrios G. Vavvas, Leo A. Kim and John B. Miller

J. Clin. Med. 2021, 10(13), 2768; https://doi.org/10.3390/jcm10132768 - 24 Jun 2021

Cited by 31 | Viewed by 4867

Abstract

Age-related macular degeneration (AMD) affects various aspects of visual function compromising patients’ functional vision and quality of life. Compared to visual acuity, contrast sensitivity correlates better with vision-related quality of life and subjectively perceived visual impairment. It may also be affected earlier in [...] Read more.

Age-related macular degeneration (AMD) affects various aspects of visual function compromising patients’ functional vision and quality of life. Compared to visual acuity, contrast sensitivity correlates better with vision-related quality of life and subjectively perceived visual impairment. It may also be affected earlier in the course of AMD than visual acuity. However, lengthy testing times, coarse sampling and resolution, and poor test–retest reliability of the existing contrast testing methods have limited its widespread adoption into routine clinical practice. Using active learning principles, the qCSF can efficiently measure contrast sensitivity across multiple spatial frequencies with both high sensitivity in detecting subtle changes in visual function and robust test–retest reliability, emerging as a promising visual function endpoint in AMD both in clinical practice and future clinical trials. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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12 pages, 713 KiB

Open AccessReview

A Review of Completed and Ongoing Complement Inhibitor Trials for Geographic Atrophy Secondary to Age-Related Macular Degeneration

by Omar A. Halawa, Jonathan B. Lin, Joan W. Miller and Demetrios G. Vavvas

J. Clin. Med. 2021, 10(12), 2580; https://doi.org/10.3390/jcm10122580 - 11 Jun 2021

Cited by 37 | Viewed by 5475

Abstract

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness among older adults in the Western world. While therapies exist for patients with exudative AMD, there are currently no approved therapies for non-exudative AMD and its advanced form of geographic atrophy (GA). [...] Read more.

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness among older adults in the Western world. While therapies exist for patients with exudative AMD, there are currently no approved therapies for non-exudative AMD and its advanced form of geographic atrophy (GA). The discovery of genetic variants in complement protein loci with increased susceptibility to AMD has led to the investigation of the role of complement inhibition in AMD with a focus on GA. Here, we review completed and ongoing clinical trials evaluating the safety and efficacy of these studies. Overall, complement inhibition in GA has yielded mixed results. The inhibition of complement factor D has failed pivotal phase 3 trials. Studies of C3 and C5 inhibition meeting their primary endpoint are limited by high rates of discontinuation and withdrawal in the treatment arm and higher risks of conversion to exudative AMD. Studies evaluating other complement members (CFB, CFH, CFI and inhibitors of membrane attack complex—CD59) are ongoing and could offer other viable strategies. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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10 pages, 618 KiB

Open AccessReview

A Review of the Role of the Intestinal Microbiota in Age-Related Macular Degeneration

by Phoebe Lin, Scott M. McClintic, Urooba Nadeem and Dimitra Skondra

J. Clin. Med. 2021, 10(10), 2072; https://doi.org/10.3390/jcm10102072 - 12 May 2021

Cited by 25 | Viewed by 4796

Abstract

Blindness from age-related macular degeneration (AMD) is an escalating problem, yet AMD pathogenesis is incompletely understood and treatments are limited. The intestinal microbiota is highly influential in ocular and extraocular diseases with inflammatory components, such as AMD. This article reviews data supporting the [...] Read more.

Blindness from age-related macular degeneration (AMD) is an escalating problem, yet AMD pathogenesis is incompletely understood and treatments are limited. The intestinal microbiota is highly influential in ocular and extraocular diseases with inflammatory components, such as AMD. This article reviews data supporting the role of the intestinal microbiota in AMD pathogenesis. Multiple groups have found an intestinal dysbiosis in advanced AMD. There is growing evidence that environmental factors associated with AMD progression potentially work through the intestinal microbiota. A high-fat diet in apo-E-/- mice exacerbated wet and dry AMD features, presumably through changes in the intestinal microbiome, though other independent mechanisms related to lipid metabolism are also likely at play. AREDS supplementation reversed some adverse intestinal microbial changes in AMD patients. Part of the mechanism of intestinal microbial effects on retinal disease progression is via microbiota-induced microglial activation. The microbiota are at the intersection of genetics and AMD. Higher genetic risk was associated with lower intestinal bacterial diversity in AMD. Microbiota-induced metabolite production and gene expression occur in pathways important in AMD pathogenesis. These studies suggest a crucial link between the intestinal microbiota and AMD pathogenesis, thus providing a novel potential therapeutic target. Thus, the need for large longitudinal studies in patients and germ-free or gnotobiotic animal models has never been more pressing. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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20 pages, 2286 KiB

Open AccessReview

Trends of Stem Cell Therapies in Age-Related Macular Degeneration

by Tadao Maeda, Sunao Sugita, Yasuo Kurimoto and Masayo Takahashi

J. Clin. Med. 2021, 10(8), 1785; https://doi.org/10.3390/jcm10081785 - 20 Apr 2021

Cited by 28 | Viewed by 7508

Abstract

Age-related macular degeneration (AMD) is a highly prevalent irreversible impairment in the elderly population worldwide. Stem cell therapies have been considered potentially viable for treating AMD through the direct replacement of degenerated cells or secretion of trophic factors that facilitate the survival of [...] Read more.

Age-related macular degeneration (AMD) is a highly prevalent irreversible impairment in the elderly population worldwide. Stem cell therapies have been considered potentially viable for treating AMD through the direct replacement of degenerated cells or secretion of trophic factors that facilitate the survival of existing cells. Among them, the safety of pluripotent stem cell-derived retinal pigment epithelial (RPE) cell transplantation against AMD, and some hereditary retinal degenerative diseases, has been discussed to a certain extent in clinical studies of RPE cell transplantation. Preparations are in progress for its clinical application. On the other hand, clinical trials using somatic stem cells are also being conducted, though these had controversial outcomes. Retinal regenerative medicine using stem cells is expected to make steady progress toward practical use while new technologies are incorporated from various fields, thereby making the role of ophthalmologists in this field increasingly important. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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16 pages, 336 KiB

Open AccessReview

Inflammatory Complications of Intravitreal Anti-VEGF Injections

by Jacob T. Cox, Dean Eliott and Lucia Sobrin

J. Clin. Med. 2021, 10(5), 981; https://doi.org/10.3390/jcm10050981 - 2 Mar 2021

Cited by 73 | Viewed by 4765

Abstract

Intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents is a commonly used therapy for numerous retinal diseases. The most commonly used of these medications are bevacizumab, ranibizumab, aflibercept, and brolucizumab. However, intravitreal administration of these agents is also associated with several inflammatory [...] Read more.

Intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents is a commonly used therapy for numerous retinal diseases. The most commonly used of these medications are bevacizumab, ranibizumab, aflibercept, and brolucizumab. However, intravitreal administration of these agents is also associated with several inflammatory and non-inflammatory adverse events. The three inflammatory adverse events are sterile intraocular inflammation, brolucizumab-associated retinal vasculitis, and post-injection endophthalmitis. This narrative review summarizes the current literature regarding these conditions, including their epidemiology, presentation, management, outcomes, and pathogenesis. The inflammatory adverse events also share a number of overlapping features, which can make them difficult to discern from one another in a clinical context. This review discusses certain distinguishing features of these conditions that may aid providers in discerning between them and establishing the correct diagnosis. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

16 pages, 4786 KiB

Open AccessReview

Optical Coherence Tomography Angiography of the Choriocapillaris in Age-Related Macular Degeneration

by Jackson Scharf, Giulia Corradetti, Federico Corvi, SriniVas Sadda and David Sarraf

J. Clin. Med. 2021, 10(4), 751; https://doi.org/10.3390/jcm10040751 - 13 Feb 2021

Cited by 22 | Viewed by 4111

Abstract

The advent of optical coherence tomography angiography (OCTA) has allowed for remarkable advancements in our understanding of the role of the choriocapillaris in age-related macular degeneration (AMD). As a relatively new imaging modality, techniques to analyze and quantify choriocapillaris images are still evolving. [...] Read more.

The advent of optical coherence tomography angiography (OCTA) has allowed for remarkable advancements in our understanding of the role of the choriocapillaris in age-related macular degeneration (AMD). As a relatively new imaging modality, techniques to analyze and quantify choriocapillaris images are still evolving. Quantification of the choriocapillaris requires careful consideration of many factors, including the type of OCTA device, segmentation of the choriocapillaris slab, image processing techniques, and thresholding method. OCTA imaging shows that the choriocapillaris is impaired in intermediate non-neovascular AMD, and the severity of impairment may predict the advancement of disease. In advanced atrophic AMD, the choriocapillaris is severely impaired underneath the area of geographic atrophy, and the level of impairment surrounding the lesion predicts the rate of atrophy enlargement. Macular neovascularization can be readily identified and classified using OCTA, but it is still unclear if neovascularization features with OCTA can predict the lesion’s level of activity. The choriocapillaris surrounding macular neovascularization is impaired while the more peripheral choriocapillaris is spared, implying that choriocapillaris disruption may drive neovascularization growth. With continued innovation in OCTA image acquisition and analysis methods, advancement in clinical applications and pathophysiologic discoveries in AMD are set to follow. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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14 pages, 9641 KiB

Open AccessReview

Subthreshold Nano-Second Laser Treatment and Age-Related Macular Degeneration

by Amy C. Cohn, Zhichao Wu, Andrew I. Jobling, Erica L. Fletcher and Robyn H. Guymer

J. Clin. Med. 2021, 10(3), 484; https://doi.org/10.3390/jcm10030484 - 28 Jan 2021

Cited by 11 | Viewed by 3750

Abstract

The presence of drusen is an important hallmark of age-related macular degeneration (AMD). Laser-induced regression of drusen, first observed over four decades ago, has led to much interest in the potential role of lasers in slowing the progression of the disease. In this [...] Read more.

The presence of drusen is an important hallmark of age-related macular degeneration (AMD). Laser-induced regression of drusen, first observed over four decades ago, has led to much interest in the potential role of lasers in slowing the progression of the disease. In this article, we summarise the key insights from pre-clinical studies into the possible mechanisms of action of various laser interventions that result in beneficial changes in the retinal pigment epithelium/Bruch’s membrane/choriocapillaris interface. Key learnings from clinical trials of laser treatment in AMD are also summarised, concentrating on the evolution of laser technology towards short pulse, non-thermal delivery such as the nanosecond laser. The evolution in our understanding of AMD, through advances in multimodal imaging and functional testing, as well as ongoing investigation of key pathological mechanisms, have all helped to set the scene for further well-conducted randomised trials to further explore potential utility of the nanosecond and other subthreshold short pulse lasers in AMD. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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Other

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6 pages, 2181 KiB

Open AccessCase Report

Complete Resolution of Central Soft Drusen without Geographic Atrophy or Choroidal Neovascularization

by Rebecca Zeng, Itika Garg and John B. Miller

J. Clin. Med. 2022, 11(6), 1637; https://doi.org/10.3390/jcm11061637 - 16 Mar 2022

Cited by 2 | Viewed by 5199

Abstract

The treatment and prevention of dry age-related macular degeneration (AMD) traditionally involve lifestyle modifications and antioxidant supplementation, including the AREDS2 formula. We present a case of a woman with dry AMD in her right eye with several large, confluent central drusen on her [...] Read more.

The treatment and prevention of dry age-related macular degeneration (AMD) traditionally involve lifestyle modifications and antioxidant supplementation, including the AREDS2 formula. We present a case of a woman with dry AMD in her right eye with several large, confluent central drusen on her exam and optical coherence tomography B-scan. Over the course of a year, the drusen almost completely disappeared, but the retinal layers were preserved without the development of geographic atrophy or choroidal neovascularization. While the exact cause of this phenomenon is unclear, it was thought to be associated with this patient’s strict daily use of numerous dietary supplements. This case highlights the potential in exploring alternative medicine supplements in the treatment of AMD. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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10 pages, 1292 KiB

Open AccessOpinion

Complement Inhibition for Geographic Atrophy: A Tempting Target with Mixed Results

by Jonathan B. Lin, Omar A. Halawa, Joan W. Miller and Demetrios G. Vavvas

J. Clin. Med. 2021, 10(13), 2890; https://doi.org/10.3390/jcm10132890 - 29 Jun 2021

Cited by 8 | Viewed by 2759

Abstract

Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. One of the strongest genetic risk factors for AMD is a complement factor H (CFH) gene polymorphism characterized by a tyrosine-histidine change at amino acid position 402 (Y402H). The magnitude [...] Read more.

Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. One of the strongest genetic risk factors for AMD is a complement factor H (CFH) gene polymorphism characterized by a tyrosine-histidine change at amino acid position 402 (Y402H). The magnitude of this association between the Y402H variant and AMD is among the strongest that has been identified for any complex, multifactorial human disease. This strong association has motivated researchers to investigate a potential link between various elements of the complement pathway and AMD pathogenesis. Given the possible contribution of complement dysregulation to AMD, complement inhibition has emerged as a therapeutic strategy for slowing geographic atrophy (GA). Randomized clinical trials thus far have yielded mixed results. In this article, we provide the historical context for complement inhibition as a strategy for treating GA, discuss potential advantages and disadvantages of complement inhibition, and highlight the questions that must be addressed before complement inhibition can take center stage as a therapy for AMD. Full article

(This article belongs to the Special Issue Age-Related Macular Degeneration: Advances in Management and Diagnosis)

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