Peripheral retinal degenerations are increasingly recognized as an important manifestation in age-related macular degeneration (AMD) patients.
AMD is classified into two categories, dry and wet, or atrophic and neovascular, respectively, and is the leading cause of irreversible vision loss in developed countries.1 The prevalence of the disease is expected to reach 288 million affected individuals by the year 2040 as the population continues to age.2
This article will highlight key points regarding viewing, diagnosing, and managing peripheral retinal lesions and their relationship with AMD.
Viewing peripheral retinal lesions
Funduscopy is a crucial way of examining the peripheral retina and can be done so in a number of ways. Binocular indirect ophthalmoscopy (BIO) with the use of scleral depression to delineate certain retinal lesions can allow for 360° of peripheral and mid-peripheral retinal evaluation.
In addition, biomicroscopy at the slit lamp using a 90D lens, or the mirrors of a Goldmann 3-mirror lens, can allow for a more detailed and magnified view of peripheral retinal lesions, but with a smaller field of view.
Advanced fundus imaging has also become a mainstay in peripheral retinal evaluation, as technological advancements have continued to improve. Widefield and ultra-widefield (UWF) imaging help to capture peripheral retinal lesions and offer additional information.
The combination of UWF imaging with fundus autofluorescence (FAF), optical coherence tomography/angiography (OCT/OCTA), fluorescein angiography (FA), and indocyanine green angiography (ICGA) has been a game-changer for myriad conditions.
To note, widefield images encompass the area between the posterior pole and the vortex vein ampullae in all four quadrants, while UWF images include the area between the vortex vein ampullae and the pars plana.3
Various UWF camera options exist:
- The Optos UWF system is capable of viewing 200° of the fundus and up to 220° when using the auto-montage feature.3
- UWF images, however, can present with color discrepancies as well as eyelash interference, limiting the visualization of the superior and/or inferior fundus.
- The Clarus 500 camera from ZEISS has a slightly narrower range with the ability to capture 133° in one image and up to 200° with multiple images.3
Other modalities are available but offer a less extensive view of the peripheral retina, and some require a contact lens to obtain the image. The Heidelberg Spectralis has a more limited field but has the ability to be used in conjunction with OCT to provide wide field OCT/OCTA functionality. All devices mentioned can also perform FAF, FA, and ICGA.4
The photos included in this article were obtained via the Optos California UWF camera.
AMD: An overview
Dry or atrophic AMD is characterized by the formation of drusen which is composed of insoluble extracellular aggregates, appearing as focal yellow lesions that accumulate between the pigment epithelium and Bruch membrane.
The late stage of this form of AMD can progress to geographic atrophy (GA), a confluent degeneration of the retinal pigment epithelium (RPE), causing damage to the photoreceptors in that area as they lack sustenance from the underlying RPE.
Treatment is centered around monitoring for conversion to the wet form plus lifestyle modifications like smoking cessation as well as diet and specific nutrient supplementation. Low vision rehabilitation is also an option to provide magnification and maximize functional vision.
More recently, the FDA approved medications such as avacincaptad pegol (IZERVAY, Astellas Pharma) and pegcetacoplan (SYFOVRE, Apellis Pharma) that can inhibit complement activity.5 These drugs are injected intravitreally to try and limit the progression of GA.
Wet AMD
Wet or neovascular AMD (nAMD) is characterized by macular neovascularization (MNV), in which abnormal blood vessels typically grow from the choroid into the outer retinal layers and begin to leak due to their fragility.
Treatment of nAMD is centered around inhibiting vascular endothelial growth factor (VEGF) with intravitreal injection of such drugs as ranibizumab (LUCENTIS, Genentech), bevacizumab (AVASTIN, Genentech), aflibercept (EYLEA, Regeneron), and faricimab (VABYSMO, Genentech). Low vision rehabilitation is also a good management option for these patients.
Test your knowledge on peripheral retinal disease in AMD with our quiz!
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Peripheral Retinal Disease in AMD Quiz
This quiz features questions based on this article to test your understanding of peripheral retinal changes in AMD.
Peripheral retinal findings in AMD patients
Early studies of AMD recognized several clinical findings located beyond the macula and into the retinal periphery.6,7 New evidence has emerged to show that clinical features associated with AMD are not exclusive to the macula. In a meta-analysis of 12 studies that included 3,261 eyes, Foreshaw et al. reviewed peripheral retinal lesions in eyes with AMD.7
The peripheral lesions most commonly observed were drusen, atrophy, and changes to the RPE. In eyes with AMD, peripheral lesions were found in 82.7% of eyes (95% confidence interval [CI] 78.4 to 86.7%) compared with 33.3% of healthy eyes (95% CI 28.3 to 38.5%).7
Below, UWF color images reveal nAMD in both eyes with subtle mid-peripheral and peripheral findings. Note the pigmentary changes of the right eye in Figure 1 and drusen in the left in Figure 2.
Figure 1: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
Figure 2: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
Drusen and reticular pigmentary changes on UWF imaging
Drusen and reticular pigmentary changes in the peripheral retina are more commonly seen in AMD patients than in patients without AMD. The OPERA study reported peripheral drusen in 97% of AMD patients and only 48% of healthy controls.7
Similarly, reticular pigmentary changes, granular circumferential areas of pigmentation usually presenting bilaterally, were also found at a higher rate in AMD patients (48%) versus those without the disease (16%).7
UWF color images of the right (Figure 3) and left (Figure 4) eyes in a patient with intermediate dry AMD and peripheral reticular degeneration.
Figure 3: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
Figure 4: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
Findings on UWF FAF imaging
It has also been noted that FAF abnormalities consistent with chorioretinal atrophy, as seen in pavingstone/cobblestone degeneration, are more prevalent in eyes with more advanced diseases—like nAMD.8 Morphologic changes in AMD are characterized by inflammatory and oxidative stress. FAF works by using the fluorescent component of lipofuscin to highlight areas of altered metabolic activity and disease.
Lipofuscin is released secondary to incomplete degradation of lipids in phagocytosed photoreceptor outer segments within the cells in the RPE. The buildup of lipofuscin in RPE cells is consistent with aging and the accumulation of these molecules contributes to RPE cell death.3,9
Hyperautofluorescence is present in areas where RPE cells possess excess lipofuscin but have yet to result in cell death and thus exemplify increased metabolic stress. Hypoautofluorescence is present in areas where RPE cells are lost, such as cases of GA.
UWF FAF images in Figures 5 and 6 show the hypoautofluorescent and hyperautofluorescent pattern of the lesions both in the macula and retinal periphery.
Figure 5: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
Figure 6: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
The UWF color photographs below reveal a patient with nAMD of the right eye (Figure 7), dry AMD of the left eye (Figure 8), and multiple diffuse areas of peripheral chorioretinal atrophy OU.
Figure 7: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
Figure 8: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
In Figures 9 and 10, UWF FAF images show the hypoautofluorescent pattern of the peripheral chorioretinal atrophy secondary to lost RPE cells.
Figure 9: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
Figure 10: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
Peripheral exudative hemorrhagic chorioretinopathy (PEHCR)
Wide field OCT/OCTA, FA, and ICGA can also be useful in identifying areas of concern and reveal neovascularization outside of the macula, such as in peripheral exudative hemorrhagic chorioretinopathy (PEHCR), a condition that causes peripheral hemorrhages and exudation.
PEHCR has been found to have associations with macular drusenoid deposits and has been noted to exist in 5% of cases which may suggest comparable pathophysiological components as those found in AMD.6,7
In Figures 11 and 12, UWF images demonstrate bilateral early dry AMD, bilateral PEHCR, and peripheral degenerative pigmentary changes. Clinical findings include intraretinal hemes OS > OD, subretinal heme OD superior-temporally, and inferior/temporally. In the OS, note superior-nasal multi-lobed elevated hemorrhagic masses with surrounding intraretinal heme.
Figure 11: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
Figure 12: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
In Figures 13 and 14, UWF IVFA OD in the same patient shows cystoid macular edema (CME) due to epimacular membrane, late hyperfluorescence of the inferior temporal lesion, and a mild degree of focal vasculitis. In the OS, note similar CME and late hyperfluorescence of superior nasal and temporal lesions.
Figure 13: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
As illustrated in Figures 15 and 16, PEHCR resolved 3 months later without intervention (observation only). The patient eventually received an initial injection of anti-VEGF treatment OU 10 months after onset.
Figure 15: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
Figure 16: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
The corresponding UWF FAF images, Figures 17 and 18, show hypoautofluorescence of residual subretinal hemorrhage and hypo/hyperautofluorescence of RPE pigmentary changes OD/OS.
Figure 17: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
Figure 18: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
Another example of PEHCR seen in the right eye of a patient with bilateral peripheral and dominant drusen can be seen in Figure 19.
Figure 19: Courtesy of Joseph J. Pizzimenti, OD, FAAO, FORS.
Genetic factors of AMD
Genetic components have been discussed at length in relation to AMD and have also been applied to peripheral retinal changes in AMD patients.10 Variants of complement factor H (CFH) polymorphisms like the CFHY402H gene have shown an increased risk of AMD and have also been linked to peripheral drusen as well as reticular pigmentary changes.11,12
This risk variant has been seen to impair the regulation of complement activation due to reduced binding of CFH to specific molecules like C-reactive protein. Dysregulation occurs, leading to chronic inflammation sparking the development and progression of AMD changes in the macula and retinal periphery.
This has also been seen in the case of other complement gene variants.11 Deviations in C3 specifically have shown a connection between AMD and peripheral drusen as well as reticular pseudodrusen.12,13
Risk variants and genes linked with AMD
Risk variants of the ARMS2/HTRA1 gene were shown to have a significant impact on the presence of large soft drusen and reticular pseudodrusen in comparison to those without the gene variant, as seen in the EYE-RISK study.14 No significant difference was observed in hard or soft drusen <125 microns in size when comparing those with the risk haplotype to those without.
Development of late-stage AMD in genetic carriers of ARMS2/HTRA1 variants was greater, 9.4% for heterozygous and 26.8% for homozygous carriers, than for non-carriers, 4.4%. These findings propose a higher predisposition of more advanced subtypes of drusen, like reticular pseudodrusen and soft drusen, in patients with the ARMS2/HTRA1 variant.13,14,15
Other gene variations have shown an increased risk of AMD, such as the T280M variant of the CX3CR1 gene, variations near the TIMP3 gene, variants in the CFI gene encoding complement factor I, LIPC, and variants in the VEGFA gene encoding vascular endothelial growth factor A for example.11,16
However, there is not strong evidence to directly correlate these variants, especially alone, with increased risks of AMD or peripheral retinal manifestations, and more research must be conducted in this arena.11
Conclusions
Overall, associations between AMD and peripheral retinal degenerations have been shown to possess a link that can support more advanced disease and increased risks of disease.
This topic warrants further exploration to determine how significant the relationship between macular and peripheral findings may be, especially when determining the link between potential contributory genetic factors.
AMD patients may be better managed when taking into consideration the entirety of the retina and documenting appropriately with use of current imaging technologies.
Article takeaways:
- Although macular findings are the hallmark of AMD, there has been a renewed interest in peripheral retinal associations.
- Peripheral findings have a higher prevalence in AMD patients compared to the general population. This has led to an increased focus on exploring their significance.
- The emergence of UWF imaging, with and without FAF, OCT/OCT-A, FA, and ICGA, has led to a better understanding of peripheral retinal changes that may occur in AMD patients.
- The presence of peripheral lesions may contribute to impaired visual function in AMD patients.
