Management Of Age-related Macular Degeneration Research Articles

Early persistent retinal fluid during treatment of neovascular AMD with ranibizumab and aflibercept

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in subjects aged >65 years living in economically developed countries (1,2). As birthrates drop and life expectancy rises, the prevalence of AMD is expected to increase, along with the social and economical burden associated with the disease and its treatment. Anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the management of neovascular AMD (nAMD) and are now considered the mainstay of therapy (1,3). Although monthly injections seem to produce the best functional results according to clinical trials (4-7), the increasing patient numbers and exponentially growing costs made it clear that alternatives should be sought for a clinical practice setting. To this day, plentiful controversies still exist over the best available drug and treatment regimen for the management of nAMD. Variations in patient response to anti-VEGF therapy have been identified in clinical trials, regardless of the drug or regimen used. Understanding the reasons (epidemiological, genetic, functional, anatomical, etc.) behind these variations could help predict the injection requirements of individual patients, thus reducing unnecessary visits and preventing over- or undertreatment (8). Although most patients respond rapidly to anti-VEGF treatment, residual fluid on OCT persists in a subgroup of eyes across clinical trials of different drugs and regimens. Since treatment decisions are often driven by the presence of fluid on OCT, the quest for imaging biomarkers capable of predicting the functional and anatomical prognosis became the goal of several investigators.

Dietary fatty acids and lipoproteins on progression of age-related macular degeneration

Age-related macular degeneration (AMD) is a medical condition of central loss vision and blindness. Numerous studies have revealed that changes on certain dietary fatty acids (FAs) could have useful for AMD management. This review summarizes the effects of dietary omega-3 long-chain PUFAs, MUFAs, and SFAs, and lipoproteins on AMD. Findings are consistent with the beneficial role of dietary omega-3 long-chain PUFAs, while the effects of dietary MUFAs and SFAs appeared to be ambiguous with respect to the possible protection from MUFAs and to the possible adverse impact from SFAs on AMD. Some of the pathological mechanisms associated with lipoproteins on AMD share those observed previously in cardiovascular diseases. It was also noticed that the effects of FAs in the diet and lipoprotein on AMD could be modulated by genetic variants. From a population health perspective, the findings of this review are in favour of omega-3 long-chain FAs recommendations in a preventive and therapeutic regimen to attain lower AMD occurrence and progression rates. Additional long-term and short-term nutrigenomic studies are required to clearly establish the role and the relevance of interaction of dietary FAs, lipoproteins, and genes in the genesis and progression of AMD.

Recent advances in the management and understanding of macular degeneration.

Current management of age-related macular degeneration (AMD) is directed at intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors for the treatment of wet AMD and supplementation with oral antioxidants for the treatment of dry AMD. In this article, we will review recent clinical trials for the treatment of dry and wet AMD.

Targeting modifiable risk factors in age-related macular degeneration in optometric practice in Sweden.

PurposeThe purpose of this study was to investigate the extent to which ophthalmologists and optometrists in Sweden recommend the use of nutritional supplements, changes in diet, or smoking cessation to patients who are at risk of or with signs of age-related macular degeneration (AMD). In addition, this study also examined how these practitioners rate the strength of evidence for nutritional supplements in AMD management and which sources of information they consult to determine supplement recommendations for the prevention or treatment of AMD.MethodsThis study implemented a cross-sectional design using data from a questionnaire. All Swedish optometrists and ophthalmologists who were registered in the membership databases of their respective professional organizations were invited to participate. The questionnaire contained 18 forced choice questions and one free text question and was organized into the following four sections: use of nutritional supplements, dietary advice, smoking and eye diseases, and strength of evidence and the sources of information regarding nutritional supplement interventions.ResultsThe response rate was 40.3% for optometrists and 5% for ophthalmologists. Optometrists were more likely than ophthalmologists to recommend nutritional supplements in AMD and provided significantly more advice about diet than did the ophthalmologists for both patients at risk for AMD and those with established disease. The ophthalmologists were more likely than the optometrists to rely on the findings from the age-related eye disease studies of AMD regarding treatment with and selection of supplements and to recommend smoking cessation.ConclusionCommon evidence-based strategies for AMD management among eye care professionals would presumably be beneficial for AMD patients. Targeted education and implementation strategies may be needed.

Recognizing age-related macular degeneration in primary care.

Age-related macular degeneration (AMD) is a disabling condition that results in central vision loss and significantly affects the quality of life for the growing population of older adults. Primary care providers play a vital role in early recognition of disease. This article reviews the risk factors, symptoms, physical examination findings, and management of AMD. Although there is no cure at this time, early referral and treatment may prevent some patients from progressing to complete vision loss.

Randomized Trial of Treat-and-Extend versus Monthly Dosing for Neovascular Age-Related Macular Degeneration: 2-Year Results of the TREX-AMD Study

To evaluate a prospective treat-and-extend (TREX) management strategy compared with monthly dosing with intravitreal ranibizumab (Lucentis) in neovascular age-related macular degeneration (AMD). Prospective, randomized, multicenter clinical trial. Sixty patients with treatment-naïve neovascular AMD randomized 1:2 to monthly or TREX cohorts. Patients with Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) of 20/32 to 20/500 (Snellen equivalent) were randomized to receive intravitreal 0.5 mg ranibizumab monthly or, according to a TREX protocol, no less frequently than every 12 weeks. After interval extension, if recurrent exudative disease was identified, this maximum interval between treatments was rechallenged according to a strict prospective protocol. Change in ETDRS BCVA from baseline. Sixty patients were enrolled and 50 completed month 24, at which point mean ETDRS BCVA letter gains were similar: 10.5 and 8.7 for the monthly and TREX cohorts, respectively (P= 0.64). At month 24, 4 patients (20%) and 12 patients (30%) in the monthly and TREX cohorts, respectively, gained at least 15 letters (P= 0.41). No monthly cohort patient lost more than 2 letters, whereas 5 TREX cohort patients (13%) lost at least 15 letters. Anatomic improvements were similar between the cohorts. Through month 24, the mean number of injections administered was 25.5 (range, 22-27) and 18.6 (range, 10-25) for the monthly and TREX cohorts, respectively (P< 0.001). Among TREX patients completing month 24, 14 (47%) were at an extension interval of 8 weeks or more, and the mean maximum tolerated extension was 8.5 weeks over the course of 2 years. Of the 26 TREX patients (65%) who demonstrated recurrent exudation upon interval extension, the first maximum extension interval was consistent in most eyes (n= 19 [73%]). The TREX neovascular AMD management protocol used with ranibizumab in the Treat-and-Extend Protocol in Patients with Wet Age-Related Macular Degeneration (TREX-AMD) study resulted in visual and anatomic gains comparable with those obtained with monthly dosing, and most patients randomized to TREX therapy demonstrated a relatively consistent maximum extension interval.

Short-term effects of intravitreal ranibizumab and bevacizumab administration on 24-h ambulatory blood pressure monitoring recordings in normotensive patients with age-related macular degeneration.

PurposeTo evaluate effects of intravitreal ranibizumab and bevacizumab administration on ambulatory blood pressure monitoring (ABPM) recordings in normotensive patients with age-related macular degeneration (AMD).Patients and methodsA total of 72 patients (mean age: 61.8(6.2) years, 52.8% were females) diagnosed with AMD were included in this study as divided into ranibizumab (n=34) and bevacizumab (n=38) treatment groups. Twenty-four hour, nighttime, and daytime ABMP values for systolic and diastolic BP were recorded in study groups before and after the third intravitreal injection of ranibizumab or bevacizumab.ResultsRanibizumab injection had no impact on ABPM recordings and dipping status. In the bevacizumab group, increased daytime (129.0(6.6) vs 127.7(6.6) mm Hg, P=0.002) and nighttime systolic (116.9(7.5) vs 112.6(7.1) mmHg, p<0.001) BP and decreased daytime diastolic (80.1(6.5) vs 82.4(6.1)mm Hg, P=0.001) BP were noted in the post-injection period. Also, percentage of non-dippers was significantly increased from 5.3% at pre-injection to 28.9% (P=0.004) at the post-injection period.ConclusionIn conclusion, given that it has no significant impact on ABPM recordings and dipping status, in our study, intravitreal ranibizumab injection may be the better choice in the management of AMD.

A view of the current and future role of optical coherence tomography in the management of age-related macular degeneration.

Optical coherence tomography (OCT) has become an established diagnostic technology in the clinical management of age-related macular degeneration (AMD). OCT is being used for primary diagnosis, evaluation of therapeutic efficacy, and long-term monitoring. Computer-based advances in image analysis provide complementary imaging tools such as OCT angiography, further novel automated analysis methods as well as feature detection and prediction of prognosis in disease and therapy by machine learning. In early AMD, pathognomonic features such as drusen, pseudodrusen, and abnormalities of the retinal pigment epithelium (RPE) can be imaged in a qualitative and quantitative way to identify early signs of disease activity and define the risk of progression. In advanced AMD, disease activity can be monitored clearly by qualitative and quantified analyses of fluid pooling, such as intraretinal cystoid fluid, subretinal fluid, and pigment epithelial detachment (PED). Moreover, machine learning methods detect a large spectrum of new biomarkers. Evaluation of treatment efficacy and definition of optimal therapeutic regimens are an important aim in managing neovascular AMD. In atrophic AMD hallmarked by geographic atrophy (GA), advanced spectral domain (SD)-OCT imaging largely replaces conventional fundus autofluorescence (FAF) as it adds insight into the condition of the neurosensory layers and associated alterations at the level of the RPE and choroid. Exploration of imaging features by computerized methods has just begun but has already opened relevant and reliable horizons for the optimal use of OCT imaging for individualized and population-based management of AMD-the leading retinal epidemic of modern times.

Optical coherence tomography angiography in age-related macular degeneration: persistence of vascular network in quiescent choroidal neovascularization.

Optical coherence tomography angiography in age-related macular degeneration: persistence of vascular network in quiescent choroidal neovascularization.

Vascular endothelial growth factor gene polymorphisms and association with age related macular degeneration in Indian patients

BackgroundAge-related macular degeneration (AMD) is an important cause of visual impairment in elderly people. AMD is a multifactorial disease in which both environmental and genetic factors have been implicated. Various single nucleotide polymorphisms (SNPs) have been found to be associated with AMD. AimThis study was aimed to investigate the association of polymorphisms in VEGF genes with age related macular degeneration (AMD) in Indian patients. MethodGenotyping for the VEGF −1154 (G>A), −2578 (C>A), +405 (G>C) and −460 (C>T) SNPs was performed in 100 AMD patients and 100 controls by polymerase chain reaction (PCR), restriction fragment length polymorphism (PCR-RFLP) and sequencing method. ResultsOut of the four SNPs, heterozygous genotypes of VEGF −1154G>A (OR=2.58, p=0.0035), +460C>T (OR=2.90, p=0.0046), and +405G>C (OR=2.02, p=0.02) have shown susceptible association with AMD. However, VEGF −2578C>A did not show any statistical significance. Further A-A-G-T haplotype comprising of three mutant alleles revealed risk association (OR=12.7, p=0.0030) with AMD. ConclusionThe present study suggests significant genetic associations for VEGF −1154G>A, +460C>T, and +405G>C polymorphisms with AMD. Early detection of individuals with risk to these SNPs could lead to strategies for prevention, early diagnosis, and management of AMD.

Infrared reflectance imaging in age-related macular degeneration.

PurposeThe purpose of this article is to describe the appearance of age‐related macular degeneration (AMD) phenotypes using infrared (IR) reflectance imaging. IR reflectance imaging of the retina has the potential to highlight specific sub‐retinal features and pathology. However, its role in macular disease, specifically AMD, is often underestimated and requires clarification.Recent findingsRecent advances in clinical methods, imaging and scientific knowledge may be integrated to improve the accuracy of disease stratification in AMD. In particular, IR imaging holds an underutilised sensitivity to detect reticular pseudodrusen, which have been repeatedly described as a high‐risk sign for late AMD.SummaryThis article provides clinically relevant descriptions of AMD phenotypes using IR reflectance imaging. The findings are integrated with images from cases seen at the Centre for Eye Health. As primary eye‐care providers assume a critical role in the detection, diagnosis and management of AMD, we also provide a chair‐side reference to assist clinicians in interpreting IR images in AMD.

Age-related macular degeneration and polypoidal choroidal vasculopathy in Asians.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly people globally. It is estimated that there will be more Asians with AMD than the rest of the world combined by 2050. In Asian populations, polypoidal choroidal vasculopathy (PCV) is a common subtype of exudative AMD, while choroidal neovascularization secondary to AMD (CNV-AMD) is the typical subtype in Western populations. The two subtypes share many common clinical features and risk factors, but also have different epidemiological and clinical characteristics, natural history and treatment outcomes that point to distinct pathophysiological processes. Recent research in the fields of genetics, proteomics and imaging has provided further clarification of differences between PCV and CNV-AMD. Importantly, these differences have manifested as disparity in response to intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) treatment between PCV and CNV-AMD, emphasizing the need for accurate diagnosis of PCV and in distinguishing PCV from CNV-AMD, particularly in Asian patients. Current clinical trials of intravitreal anti-VEGF therapy and photodynamic therapy will provide clearer perspectives of evidence-based management of PCV and may lead to paradigm shifts in therapeutic strategies away from those currently employed in the treatment of CNV-AMD. Further research is needed to clarify the relative contribution of specific pathways in inflammation, complement activation, extracellular matrix dysregulation, lipid metabolism and angiogenesis to the pathogenesis of PCV. Findings from this research, together with improved diagnostic technology and new therapeutics, will facilitate more optimal management of Asian AMD.

The role of Aflibercept in the management of age-related macular degeneration

ABSTRACTIntroduction: During the past decade, significant advances have occurred in the management of neovascular age-related macular degeneration (NV-AMD). The advent of anti-vascular endothelial growth factor (anti-VEGF) therapy has shifted the treatment goal of NV-AMD from merely salvaging vision to improving visual acuity and maintaining a good quality of life. Aflibercept (AFL) is a significant addition to the arsenal of anti-VEGF therapies against the NV-AMD. In the index review, pharmacology and efficacy of AFL has been reviewed.Areas Covered: An extensive literature search was performed to identify preclinical and clinical studies performed to illustrate the role of AFL in NV-AMD. Randomized clinical trials evaluating other anti-VEGF agents were also included for comparison. Additionally, studies where AFL was employed to treat anti-VEGF-resistant cases agents have been reviewed.Expert Opinion: AFL is an effective agent in the management of NV-AMD and its efficacy has been found to be comparable to ranibizumab (RBZ). Additionally, AFL is a good alternative agent in patients with NV-AMD resistant to RBZ and bevacizumab (BVZ), and can potentially lessen the treatment burden. As more research is conducted, the role of AFL in varying dosing regimens, as monotherapy and in combination with other agents, will become further defined.

Management of Neovascular Age-related Macular Degeneration: A Review on Landmark Randomized Controlled Trials.

In the last decade, a number of prospective clinical trials with carefully designed study protocols have been conducted for the treatment of neovascular age-related macular degeneration (AMD). These landmark clinical trials such as ANCHOR and MARINA and, more recently, the Comparison of AMD Treatment Trials and VIEW studies have revolutionized the management of neovascular AMD. While AMD continues to remain a leading cause of severe visual loss worldwide, advances in pharmacotherapeutics have led to substantial improvements in the outcome of these patients. The introduction of anti-vascular endothelial growth factor agents has resulted in improvement of visual outcomes and has had a positive impact on the quality of life among elderly population. While the contemporary management of neovascular AMD has been successful in tremendously reducing the visual morbidity, the financial burden of therapy has increased exponentially. To overcome these challenges, newer pharmacologic agents are evaluated for their efficacy and safety in AMD. Ground-breaking advances in bench to bedside research have led to discovery of new pathways that appear to be viable targets for preventing visual loss in AMD. In this review, study designs and results of landmark clinical trials in AMD from the past decade have been summarized.

Diabetic macular edema, retinopathy and age-related macular degeneration as inflammatory conditions.

Diabetic macular edema (DME) and diabetic retinopathy (DR) are complications affecting about 25% of all patients with long-standing type 1 and type 2 diabetes mellitus and are a major cause of significant decrease in vision and quality of life. Age-related macular degeneration (AMD) is not uncommon, and diabetes mellitus affects the incidence and progression of AMD through altering hemodynamics, increasing oxidative stress, accumulating advanced glycation end products, etc. Recent studies suggest that DME, DR and AMD are inflammatory conditions characterized by a breakdown of the blood-retinal barrier, inflammatory processes and an increase in vascular permeability. Key factors that seem to have a dominant role in DME, DR and AMD are angiotensin II, prostaglandins and the vascular endothelial growth factor and a deficiency of anti-inflammatory bioactive lipids. The imbalance between pro- and anti-inflammatory eicosanoids and enhanced production of pro-angiogenic factors may initiate the onset and progression of DME, DR and AMD. This implies that bioactive lipids that possess anti-inflammatory actions and suppress the production of angiogenic factors could be employed in the prevention and management of DME, DR and AMD.

Prospective Trial of Treat-and-Extend versus Monthly Dosing for Neovascular Age-Related Macular Degeneration: TREX-AMD 1-Year Results

To assess prospectively a treat-and-extend (TREX) management strategy compared with monthly dosing of intravitreal ranibizumab in treatment-naïve neovascular age-related macular degeneration (AMD) patients. Phase IIIb, multicenter, randomized, controlled clinical trial. Sixty patients with treatment-naïve neovascular AMD randomized 1:2 to monthly or TREX management. Patients with Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) from 20/32 to 20/500 (Snellen equivalent) were randomized to receive intravitreal 0.5 mg ranibizumab monthly or according to a TREX protocol. The TREX patients were treated monthly for at least 3 doses, until resolution of clinical and spectral-domain optical coherence tomography evidence of exudative disease activity; the interval between visits then was individualized according to a strict prospective protocol. Mean ETDRS BCVA change from baseline. At baseline, mean age was 77 years (range, 59-96 years), mean BCVA was 20/60 (Snellen equivalent), and mean central retinal thickness (CRT) was 511 μm. Fifty-seven eyes (95%) completed month 12, at which point mean BCVA improved by 9.2 and 10.5 letters in the monthly and TREX cohorts, respectively (P = 0.60). The mean number of injections administered through month 12 was 13.0 and 10.1 (range, 7-13) in the monthly and TREX cohorts, respectively (P < 0.0001). Among TREX patients, 7 (18%) were maximally extended, 4 (10%) demonstrated fluid at every visit, and at month 12, 18 (45%) had achieved an extension interval of 8 weeks or more; the mean maximum extension interval between injections after the first 3 monthly doses was 8.4 weeks (range, 4-12 weeks). Most TREX patients who demonstrated recurrent exudative disease activity (17/24 [71%]) were unable to extend beyond their initial maximum extension interval. The TREX neovascular AMD management strategy used in this prospective, randomized, controlled trial resulted in visual and anatomic gains comparable with those obtained with monthly dosing.

Recent advances in drug delivery to the retina

SummaryDrug delivery to the retina is presently one of the greatest challenges in ophthalmology due to the inherent limitations of ocular barriers. This therapeutic impediment affects many promising treatments including; anti‐VEGFs, which have revolutionised the management of age‐related macular degeneration, and have increasing indications for use as sight‐saving therapies in diabetes and retinal vascular disease. However, large molecular weight anti‐VEGF therapies such as ranibizumab and bevacizumab currently require invasive intravitreal (IVT) injections to bypass ocular barriers, and thus carry a risk of significant side effects. Despite this, the success of anti‐VEGF therapies has led to a dramatic increase in the number of IVT procedures, placing a high burden on healthcare resources. For these reasons, the development of non‐invasive ocular drug delivery systems has received considerable interest in recent years. This talk outlines the current understanding of anatomical barriers to ocular drug delivery and recent developments in overcoming these barriers for delivery of large drug cargo to posterior ocular tissues. Particular focus will be paid to the role of nanotechnology and annexin A5, which we recently reported to enhance the delivery of topically applied bevacizumab to the rabbit retina.

Traitement de la dégénérescence maculaire liée à l’âge : avis d’experts et algorithme thérapeutique

Intravitreal injections (IVT) of aflibercept are indicated in France for the treatment of neovascular age-related macular degeneration (AMD). An induction phase consisting of 3 monthly IVTs followed by follow-up visits and IVTs every other month during the first year is recommended. However, it may be necessary to adjust this schedule for some patients who might benefit from a more tailored approach, namely a follow-up visit immediately after the induction phase. The goal was to develop a treatment algorithm that would reflect current clinical experience and the opinions of experts on neovascular AMD. A group of retinologists took positions on therapeutic questions regarding management of AMD using a nominal group technique (NGT). The results were combined to create a treatment algorithm. Seventy-nine percent of experts considered that the approved schedule was efficacious when fluid was completely resorbed after the induction phase. Ninety-four percent of experts recommended, after a successful induction phase, a monthly follow-up visit for 3 to 6 months in order to determine the rhythm of recurrence for each patient. Ninety-six percent of experts recommended that persistent fluid after the induction phase, even if visual acuity is improved satisfactorily, should be a criterion for systematic retreatment. The proposed algorithm (expert opinion) after the first year of use of aflibercept in France captures the complexity of the clinical cases that exist in daily practice and the necessity for regular follow-ups.

Disease Burden in the Treatment of Age-Related Macular Degeneration: Findings From a Time-and-Motion Study

To examine the time burden of managing neovascular age-related macular degeneration (AMD) imposed on physicians, staff, patients, and caregivers. Mixed-methods, prospective, observational time-and-motion study. The multicenter study was conducted from March 2011 through August 2012. Retina specialists administering ≥50 vascular endothelial growth factor (VEGF)-inhibitor injections monthly were surveyed and completed records for ≥5 patients scheduled for office visits within 3 weeks for anti-VEGF injection or monitoring. A survey was administered to 75 neovascular AMD patients aged ≥50 years who received ≥1 anti-VEGF injection in the past 6 months. Telephone interviews were conducted with 13 neovascular AMD patient caregivers. Fifty-six physicians provided data for 221 patients with neovascular AMD. Patients accounted for 20% of the health care staff's time per week, with an average of 23 staff members. An average patient visit for neovascular AMD was 90 minutes (range: 13 minutes to >4 hours). Patients reported an average time per visit of almost 12 hours, including preappointment preparation (16 minutes), travel (66 minutes), waiting time (37 minutes), treatment time (43 minutes), and postappointment recovery (9 hours). Patients stated that caregivers took time away from work (22%) and personal activities (28%) to provide transportation to appointments. Neovascular AMD management imposes a substantial time burden on physicians, staff, patients, and caregivers. There may be a need for additional support and/or reimbursement for services required by patients and caregivers and provided by physicians.

Management of neovascular age-related macular degeneration: current state-of-the-art care for optimizing visual outcomes and therapies in development.

Contemporary management of neovascular age-related macular degeneration (AMD) has evolved significantly over the last few years. The goal of treatment is shifting from merely salvaging vision to maintaining a high quality of life. There have been significant breakthroughs in the identification of viable drug targets and gene therapies. Imaging tools with near-histological precision have enhanced our knowledge about pathophysiological mechanisms that play a role in vision loss due to AMD. Visual, social, and vocational rehabilitation are all important treatment goals. In this review, evidence from landmark clinical trials is summarized to elucidate the optimum modern-day management of neovascular AMD. Therapeutic strategies currently under development, such as gene therapy and personalized medicine, are also described.