Age-related macular degeneration (AMD) is a complex disorder triggered by a wide range of environmental and genetic risk factors.1-3 Numerous common variants are known markers of AMD including several complement pathway genes: complement factor H (CFH),4-8 complement factor I,9 complement component 2, complement factor B,7,10 and complement 3.11
We previously reported the association of a rare CFH variant with AMD, R1210C, which is the strongest genetic risk factor to date, with an odds ratio (OR) of 20.12,13 The R1210C variant is also known to be associated with inherited forms of atypical hemolytic uremic syndrome and primary glomerulonephritis.14-21 In addition to linking 2 clinically unrelated conditions, such as AMD and atypical hemolytic uremic syndrome,the R1210C finding suggests that compromised function of the factorH protein is involved in AMD pathogenesis as a causal factor and not merely as an associated factor.12
In that initial report, the R1210C rare variant was associated with an earlier age at diagnosis of advanced AMD.12 This variant is also significantly associated with progression from early or intermediate AMD to advanced stages in a multigene prediction model.22,23 However, the fundus phenotype typically related to the variant is still to be determined. This knowledge is needed to better understand the manifestations of this rare CFH mutation and to help detect and characterize this phenotype in clinical practice. Identification of such high-risk individuals will be important for screening, potential new therapeutic strategies, and personalized medicine. Therefore, the objective of this study, conducted from 2012 to 2014, was to determine specific fundus features of a white population carrying the CFH R1210C rare variant.
Full Paper: Phenotypic Characterization of Complement Factor H R1210C Rare Genetic Variant in Age-Related Macular Degeneration
(461K PDF)
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Anti-VEGF therapies in many patients with wet age-related macular degeneration go on to develop atrophy. The speculation for causes of this are:
- Natural progression of underlying age-related macular degeneration driving the atrophy.
- Atrophy is associated with choroidal neovascularization.
- Atrophy is associated with anti-VEGF therapy independent of choroidal neovascularization.
No answers to these theories are yet available, so we should not change how we treat patients. We should, however, advise patients that treating wet age-related macular degeneration may not stop the progression of their underlying dry age-related macular degeneration.
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Findings From the 15-Year Follow-up of an Australian Cohort
Early age-related macular degeneration (AMD) is characterized by the presence of drusen and retinal pigmentary abnormalities.1,2 Drusen vary in size (diameter range, ≤63 to ≥250 μm) and type (hard, soft, distinct, and indistinct). Pigmentary abnormalities include clusters of pigment granules within the sensory retina (increased pigmentation) and sharply demarcated areas of retinal pigment epithelium (RPE) depigmentation.
The international classification and grading system for AMD categorizes medium drusen as intermediate soft drusen, defined as drusen with a maximum diameter of 63 to less than 125 μm, larger than the maximum diameter of hard drusen (‹63 μm) but smaller than the minimum diameter of large soft drusen (≥ 125 μm).1 A similar definition of this drusen type was used by the Age-Related Eye Disease Study2 and clinical classification system,3 categorized as medium drusen. urthermore, the Wisconsin Age-Related Maculopathy Grading System4 defines medium drusen by the maximum diameter, although the categorization of medium drusen is not used. In this study, we describe this type of drusen as medium drusen.
Despite recent interest in medium drusen and their inclusion in AMD incidence studies,5,6 knowledge of the associated risk factors and the progression of medium drusen is limited. Medium drusen have been underrepresented in studies3,7-9 compared with large drusen, soft drusen, and pigmentary lesions. In this study, we aimed to assess the 15-year incidence and progression of medium drusen in an older Australian cohort, as well as associations between common AMD risk factors and the development and progression of medium drusen.
Full Paper: Incidence, Progression, and Associated Risk Factors of Medium Drusen in Age-Related Macular Degeneration
(200K PDF)
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The role of the vitreomacular interface (VMI) in the pathophysiologic features and treatment of neovascular age-related macular degeneration (AMD) has generated much recent interest. In retrospective and prospective observational case series, a higher prevalence of vitreomacular adhesion (VMA) has been reported in eyes with neovascular AMD compared with eyes with nonneovascular AMD.1-3 In a paired eye study, VMA was observed more frequently in eyes with neovascular AMD compared with the fellow nonneovascular AMD eye that served as a control.4 Some investigators also have observed that VMA occurs at the vitreoretinal interface overlying the choroidal neovascularization (CNV).1,2,4 Vitreomacular adhesion also influences treatment and outcomes in neovascular AMD; the absence of VMA has been associated with slightly better visual acuity (VA),5,6 and eyes with VMA may require more frequent dosing compared with neovascular AMD eyes without VMA.5,6 This combined body of evidence suggests thatVMA may have a role in the pathogenesis and management of CNV.
The purpose of our study was to assess the relationship of the VMI to treatment frequency in neovascular AMD, as well as to VA and anatomic outcomes in the Comparison of AMD Treatments Trials (CATT),7 one of the largest prospective treatment trials for neovascular AMD conducted to date.
Full Paper: Influence of the Vitreomacular Interface on Treatment Outcomes in the Comparison of Age-Related Macular Degeneration Treatments Trials
(319K PDF)
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AGE-RELATED MACULAR DEGENERATION (AMD) IS the leading cause of late-onset visual impairment and blindness in persons over 65 years of age.1,2 Age-related macular degeneration is staged as early, intermediate, or late. Small drusen are the hallmark of earlystage AMD; intermediate-stage AMD consists of extensive medium-size drusen or any large drusen, with or without pigment changes. Late-stage AMD is defined by either choroidal neovascularization or geographic atrophy.3–6 In the United States, it is estimated that ~1.2 million persons have neovascular AMD; 970,000 have geographic atrophy; and 8 million have intermediate-stage AMD.1
Antiretroviral-treated, immune-restored, human immunodeficiency virus (HIV)-infected persons have a marked reduction in opportunistic infections and a substantially increased lifespan compared to those from the era before modern combination antiretroviral therapy.7–10 However, despite the improved immune function and increased lifespan, antiretroviral therapy does not fully restore health. Compared to similarly-aged, non-HIV-infected peers, antiretroviral-treated, immune-restored, HIV-infected persons have a substantially shortened lifespan, largely owing to an increased risk of non–acquired immunodeficiency syndrome (AIDS) diseases associated with aging.11–14 These diseases include cardiovascular disease, non-AIDS cancers, metabolic diseases, and neurocognitive decline, and collectively suggest that antiretroviral-treated, immune-restored HIV infection is associated with an “accelerated/accentuated aging” phenotype.11 Therefore, we undertook to evaluate whether persons with AIDS had an increased prevalence of AMD, using retinal photographs taken at enrollment in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) cohort.
Full Paper: Prevalence of Intermediate-Stage Age-Related Macular Degeneration in Patients With Acquired Immunodeficiency Syndrome
(340K PDF)
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Age-related macular degeneration is a very common condition that is caused by a complex interplay of genetic and environmental factors. It is likely that, in the future, genetic testing will allow physicians to achieve better clinical outcomes by administering specific treatments to patients based on their genotypes. However, improved outcomes for genotyped patients have not yet been demonstrated in a prospective clinical trial, and as a result, the costs and risks of routine genetic testing currently outweigh the benefits for patients with age-related macular degeneration.
Full Paper: Genetic Testing for Age-Related Macular Degeneration Not Indicated Now
(197K PDF)
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Importance
For the management of retinal disease, the use of intravitreous injections of anti–vascular endothelial growth factor has increased. Recent reports have suggested that this therapymay cause sustained elevation of intraocular pressure (IOP) and may potentially increase the risk of glaucoma for patients with retinal disease. OBJECTIVE To assess the risk of sustained IOP elevation or the need for IOP-lowering treatments for eyes with diabetic macular edema following repeated intravitreous injections of ranibizumab.
Design, Setting, and Participants
An exploratory analysiswas conducted within a Diabetic Retinopathy Clinical Research Network randomized clinical trial. Study enrollment dates were from March 20, 2007, to December 17, 2008. Of 582 eyes (of 486 participants) with center-involved diabetic macular edema and no preexisting open-angle glaucoma, 260 were randomly assigned to receive a sham injection plus focal/grid laser treatment, and 322 were randomly assigned to receive ranibizumab plus deferred or prompt focal/grid laser treatment.
Main Outcomes and Measures
The cumulative probability of sustained IOP elevation, defined as IOP of at least 22mmHg and an increase of at least 6mmHg from baseline at 2 consecutive visits, or the initiation or augmentation of ocular hypotensive therapy, through 3 years of follow-up.
Results
The mean (SD) baseline IOP in both treatment groups was 16 (3)mmHg (range, 5-24mmHg). The cumulative probability of sustained IOP elevation or of initiation or augmentation of ocular hypotensive therapy by 3 years, after repeated ranibizumab injections, was 9.5%for the participants who received ranibizumab plus prompt or deferred focal/grid laser treatment vs 3.4%for the participants who received a sham injection plus focal/grid laser treatment (difference, 6.1%[99%CI, −0.2%to 12.3%]; hazard ratio, 2.9 [99% CI, 1.0-7.9]; P = .01). The distribution of IOP and the change in IOP from baseline at each visit through 3 years were similar in each group.
Conclusions and Relevance
In eyes with center-involved diabetic macular edema and no prior open-angle glaucoma, repeated intravitreous injections of ranibizumab may increase the risk of sustained IOP elevation or the need for ocular hypotensive treatment. Clinicians should be aware of this risk and should consider this information when following up with patients who have received intravitreous injections of anti–vascular endothelial growth factor for the treatment of diabetic macular edema.
Full Paper: Repeated Intravitreous Ranibizumab Injections
(231K PDF)
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AUTOSOMAL RECESSIVE STARGARDT DISEASE (STGD1) is the most common inherited juvenile macular degeneration.1 Most patients develop bilateral loss of vision in childhood or early adulthood. This subtype of Stargardt disease is caused by mutations in the ABCA4 gene, which encodes a retina-specific transporter protein (ABCR) in the rims of rod and cone photoreceptor outer segment discs.2–4 Retinal degeneration in ABCA4-linked Stargardt disease is believed to result from the toxic effects of lipofuscin that accumulates in the retinal pigment epithelium (RPE) and the subsequent degeneration of photoreceptors.5
Light can induce photochemical injury at the ocular fundus. Depending on the level and duration of the irradiance, the primary site of damage can be either the photoreceptors or the RPE.6 In ABCA4-linked retinopathies, products generated by the visual cycle accumulate and contribute to retinal damage via both direct toxic effects and increased photosensitivity. A major fluorophore of lipofuscin, bis-retinoid N-retinylidene-N-retinyl-ethanolamine (A2E), accumulates with other, currently unidentified lipofuscin constituents within the RPE.7–9 Thus, an excessive accumulation of A2E has been observed in both Abca4-/- mice and patients with Stargardt disease.5,10 Lipofuscins (and A2E in particular) are potent photosensitizers11–14 that can induce oxidative damage, thereby accelerating light-induced retinal damage and RPE atrophy.14–16 This oxidative damage may affect the rate of disease progression in patients with Stargardt disease…
Full Paper: The Effect of Light Deprivation in Patients With Stargardt Disease
(1.33M PDF)
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It is the intent of this Update to provide you with information that is practical and useful in answering your patient’s questions in your clinical practice. To that end, we present new and emerging data regarding the studies being done with antiangiogenic agents, combination therapies, pharmacological and surgical management of age-related macular degeneration. We will also include review of gene testing and gene therapy, vitamin therapy for age-related macular degeneration, emerging developments in ocular imaging, artificial vision, diabetic retinopathy update, and an induced pluripotent stem cell update.
In addition to cutting edge research information, clinical findings that are important signs to recognize when following up on patients who have had retinal detachment surgery, treatments for age-related macular degeneration, retinal vein occlusions, and other retinal diseases will be discussed. Emphasis will be placed on clinical signs that are important for re-referral to a retina subspecialist.
Practical application to your daily practices will be our focus so we can all provide the most up-to-date information and care to our patients. Additionally, distilling the research frontiers with the greatest potential for clinical applicability will enable us to give hope to our patients with severe debilitating diseases.
We encourage feedback on ways we can improve our effort to meet your educational and practice needs.
Update [March 2014]
Dr. Radtke’s current newsletter to patients and colleagues.
(729K PDF)
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Two recent articles published in the Archives of Ophthalmology expose the risks of Ocriplasmin injection into the vitreous:
1. Acute Panretinal Structural and Functional Abnormalities After Intravitreous Ocriplasmin Injection — JAMA Ophthalmol. 2014;132(4):484-486.
Conclusion: Retinal dysfunction associated with intravitreous ocriplasmin injection is not limited to the macular region and seems to involve the entire retina. Enzymatic cleavage of intraretinal laminin is a biologically plausible mechanism for acute ocriplasmin retinal toxic effects.
2. Vision Loss After Intravitreal Ocriplasmin: Correlation of Spectral-Domain Optical Coherence Tomography and Electroretinography — JAMA Ophthalmol. 2014;132(4):487-490.
Conclusion: On the basis of these findings, it is possible that ocriplasmin may have a diffuse enzymatic effect on photoreceptors or the retinal pigment epithelium that is not limited to areas of vitreomacular adhesion. The rod photoreceptors may be more susceptible than cone photoreceptors to the effects of ocriplasmin. Further work is needed to understand mechanisms of visual impairment after ocriplasmin.
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