Age-related macular degeneration (AMD) can be classified as either a nonexudative (dry) or exudative disease.1 Typical drusen, which are extracellular deposits within Bruch’s membrane and under the retinal pigment epithelium (RPE), are the hallmark of nonexudative AMD.2,3 Geographic atrophy (GA), which represents the late form of nonexudative AMD and corresponds to the loss of photoreceptors, RPE, and choriocapillaris, can be found in exudative AMD as well.4 Although several treatment options are available for exudative AMD, there is no proven treatment capable of slowing the progression of GA.5
Reticular pseudodrusen (RPD) are best identified using multimodal imaging techniques, and they often are associated with subretinal drusenoid deposits, which are common in the presence of typical drusen and GA.6–11 Unlike typical drusen, subretinal drusenoid deposits are located above the RPE. These RPD are found primarily around the superior or superotemporal vascular arcade.7,10,12 Although the etiology and prevalence of RPD are unknown,13 current evidence suggests that RPD are associated with a high risk of progression to both forms of late AMD known as the neovascular and atrophic forms.7,14–20
Although standard optical coherence tomography (OCT) imaging has become an essential tool for visualizing the retina-RPE complex and managing AMD, a modification of this standard technique known as enhanced depth imaging OCT (EDI-OCT) has proven useful for visualizing the choroid and reproducibly measuring its thickness.21,22 Studies using EDI-OCT have reported that CT measurements decrease with age and increasing axial length,23 and are thinner in AMD eyes compared with healthy eyes.24–27 In addition, AMD eyes with GA showed even thinner subfoveal CT measurements.28 However, these authors failed to take into account the presence or absence of RPD in eyes with AMD. Ueda-Arakawa et al29 investigated AMD eyes with RPD and compared these eyes with normal eyes using a swept-source OCT (SS-OCT) prototype. The CT was thinner in the RPD group, regardless of the presence of choroidal neovascularization or GA. In addition, the RPD group was divided into three groups (ie, eyes without late AMD, eyes with neovascular AMD, and eyes with GA), and no differences in CT measurements were observed between these groups. Although this study showed thinner CT in AMD eyes with RPD compared with normal eyes, AMD eyes with and without RPD were not compared. In this study, we compare the subfoveal CT measurements from normal age-distributed eyes with eyes diagnosed with nonexudative AMD with and without RPD.
Patients and Methods
Before the initiation of this study, approval was obtained from the Institutional Review Board at the University of Miami Miller School of Medicine. Informed consent was obtained from all patients before determination of full eligibility, and the study was performed in accordance with the Health Insurance Portability and Accountability Act (HIPAA). The COMPLETE study is registered at www.clinicaltrials.gov, and the clinical trial accession number is NTC 00935883.
Patients with nonexudative AMD were enrolled in the COMPLETE study at the Bascom Palmer Eye Institute.5,30 An age-distributed control group, which comprised individuals with no known ocular disease, was recruited at the Bascom Palmer Eye Institute and used to determine how CT measurements change with respect to age and axial length.31
At baseline visits, all patients in the study and control groups underwent a complete ophthalmologic examination, axial length measurement (IOLMaster; Carl Zeiss Meditec, Dublin, CA), and spectral-domain OCT (SD-OCT) imaging. SD-OCT was performed using two different instruments (Cirrus; Carl Zeiss Meditec; and Spectralis; Heidelberg Engineering, Heidelberg, Germany). Patients in the COMPLETE study group also underwent color fundus photography (Topcon Medical, Tokyo, Japan), fundus autofluorescence (Topcon and Heidelberg Engineering), and infrared reflectance (Heidelberg Engineering) imaging.
To investigate the impact of RPD on the thickness of the choroid, the multimodal images of all of the patients in the study group were evaluated and divided into subgroups depending on the presence of RPD. The diagnosis of RPD was based on three distinct imaging modalities: color fundus photography, fundus autofluorescence, and infrared reflectance (Figure 1). Three graders (MRT, RG, and RPN) were masked to CT measurements and independently evaluated the presence or absence of RPD. Any disagreement among the graders was adjudicated by a senior retina specialist (PJR). For purposes of this study, RPD were defined by a yellowish reticular pattern on color fundus photography, most commonly temporal or superotemporal to the macula, and/or by autofluorescence or reflectance patterns seen on fundus autofluorescence or infrared reflectance images. SD-OCT B-scan images were used to confirm the presence of subretinal drusenoid deposits in areas suspicious for RPD.
Different imaging modalities showing reticular pseudrodrusen (RPD) presentation in a 93-year-old woman with geographic atrophy (GA). (A) Color fundus image. (B) Fundus autofluorescence image. (C) Infrared reflectance image. (D) Spectral-domain (SD) OCT horizontal B-scan. (E) Magnified SD-OCT horizontal B-scan showing RPD (white arrows). The yellow line in A, B, and C represents the scanned area on SD-OCT.
Central macular EDI-OCT scans obtained for the purpose of measuring subfoveal CT were acquired by a single experienced operator. For comparison between groups, CT was measured from scans obtained using the EDI mode of the Spectralis OCT. A rectangular scan measuring 30° × 5° was centered on the fovea, and seven cross-sectional B-scans were obtained. Each B-scan comprised an average of 51 individual scans. Images were reviewed and manual measurements were performed using the proprietary Heidelberg Explorer software (version 18.104.22.168). Measurements of subfoveal CT from the outer limit of the RPE to the inner surface of the sclera were performed on the same scan by two independent investigators using the built-in calipers. The software automatically provided the result in microns. The mean of the two measurements was calculated, and the mean results were used for statistical analyses. In all of the groups (nonexudative AMD and normal controls), one eye of each participant was selected for analysis. If both eyes equally met inclusion criteria, then the eye that was included in the study was randomly selected.
Statistical calculations were performed using SPSS software version 21. Post hoc least significant difference tests were used to compare CT measurements after age and axial length adjustment. A previous study31 describes the relationship of CT to age and axial length in normal controls. In the current analyses, we used those multiple regression relationships to adjust CT measurements to the normal control mean age, 53.5 years, and axial length, 23.6 mm. A P value less than .05 was considered statistically significant.
A total of 60 eyes with nonexudative AMD were included in the study group, 30 drusen-only eyes and 30 eyes with GA.5,30 The control group included 155 normal eyes.31 The mean ± standard deviation age was 70.7 ± 7.0 years (range: 58.4 to 81.3 years) in the drusen group, 79.9 ± 6.6 years (range: 65.8 to 93.6 years) in the GA group, and 53.5 ± 20.0 years (range: 22.0 to 89.0 years) in the normal control cohort. Mean axial length showed no difference between the groups, and the measurements were 23.5 ± 1.1 mm in the drusen group, 23.3 ± 1.0 mm in the GA group, and 23.6 ± 1.0 mm in the control group (P = .281). The mean subfoveal CT was 276.4 ± 86.8 µm in the drusen group, 195.5 ± 109.5 µm in the GA group, and 286.0 ± 97.3 µm in the control group. After adjusting CT for age and axial length, the mean subfoveal CT was 315.6 ± 86.2 µm in the drusen group, 254.3 ± 99.8 µm in the GA group, and 286.1 ± 84.5 µm in the normal group. The differences between the drusen, GA, and normal groups were statistically significant (P = .026). The post hoc least significant difference tests demonstrated that the GA group had thinner CT measurements than the drusen group (P = .007). However, the difference in mean CT between the drusen and normal groups was not statistically significant (P = .090), and the difference between the GA and normal group was not statistically significant (P = .068) (Figure 2)
Box and whisker plots comparing choroidal thickness (CT) measurements of normal control eyes (n = 155; median CT = 276.1 µm), age-related macular degeneration (AMD) eyes with typical drusen without geographic atrophy (GA) (n = 30; median CT = 300.0 µm), and AMD eyes with GA (n = 30; median CT = 233.0 µm) after adjusting for age and axial length. Horizontal lines of the boxes represent lower quartile (below), median, and upper quartile (above) for each group. Whiskers denote the range from the minimum to maximum measurements that fall within one and a half times the interquartile range. Outliers are represented as black points separated from the box and whisker plots.
In a subgroup analysis, patients with nonexudative AMD were divided into subgroups with and without RPD. Only three drusen eyes (10%) were diagnosed with RPD. In the GA group, 20 eyes (66.7%) were diagnosed with RPD. When adjusting CT for age and axial length, the mean adjusted CT was 293.1 ± 74.7 µm in drusen eyes with RPD and 318.1 ± 88.3 µm in drusen eyes without RPD. This difference was not statistically significant (P = .64), but the number of drusen eyes with RPD was small. In GA eyes with RPD, the mean adjusted CT was 213.7 ± 53.1 µm, and in GA eyes without RPD, the mean adjusted CT was 335.3 ± 123.2 µm. This difference was statistically significant (P < .001). Figure 3 shows the representative box-and-whisker plots demonstrating mean CT measurements of the different adjusted groups.
Box and whisker plots comparing choroidal thickness (CT) measurements of normal control eyes (n = 155; median CT = 276.1 µm), age-related macular degeneration (AMD) eyes with typical drusen without reticular pseudodrusen (RPD) (n = 27; median CT = 300.0 µm), AMD eyes with typical drusen and RPD (n = 3; median CT = 269.1 µm), AMD eyes with geographic atrophy (GA) without RPD (n = 10; median CT = 310.8 µm), and AMD eyes with GA and RPD (n = 20; median CT = 211.0 µm) after adjusting for age and axial length. Horizontal lines of the boxes represent lower quartile (below), median, and upper quartile (above) for each group. Whiskers denote the range from minimum to maximum measurements that fall within one and a half times the interquartile range. The difference in CT measurements between the GA eyes with and without RPD was statistically significant (P = .001).
Although there was a difference in mean age between the two groups with GA, the axial lengths were similar. On average, axial lengths of the GA group with and without RPD were 23.5 ± 1.0 mm and 23.1 ± 0.9 mm, respectively, and there was no significant difference between the groups (P = .259). The mean age of GA patients with RPD was 82.9 ± 4.7 years (range: 72.8 to 93.6 years), and the mean age of GA patients without RPD was 73.7 ± 5.4 (range: 65.8 to 81.5 years); the mean age of drusen patients with RPD was 72.0 ± 4.5 (range: 66.8 to 74.8) and the mean age of drusen patients without RPD was 70.6 ± 7.3 (range: 58.4 to 81.3). Although the difference in ages for the four AMD groups was statistically significant (P < .001), this difference was due to the fact that patients with GA and RPD were older than each of the other three groups (P < .01 for all). Figures 4 and 5 show representative examples of AMD eyes with GA in the presence and absence of RPD, respectively.
Choroidal thickness (CT) measurement of age-related macular degeneration eye with geographic atrophy in the presence of reticular pseudodrusen in the right eye of an 83-year-old woman. (A) Color fundus image. (B) Fundus autofluorescence image. (C) Infrared reflectance image. (D) Spectral-domain OCT horizontal B-scan with subfoveal CT measurement corresponding to 175 µm.
Choroidal thickness (CT) measurement of age-related macular degeneration eye with geographic atrophy in the absence of reticular pseudodrusen in the right eye of a 74-year-old woman. (A) Color fundus image. (B) Fundus autofluorescence image. (C) Infrared reflectance image. (D) Spectral-domain OCT horizontal B-scan with subfoveal CT measurement corresponding to 424 µm.
A post hoc least significant difference test showed that after adjusting for age and axial length, the GA group with RPD had a mean subfoveal CT that was thinner than all of the other groups (P < .001 for all), except for the small group of eyes with typical drusen and RPD (P = .131). The GA group without RPD had a mean CT that was not statistically different from the normal control group (P = .076) or the drusen group without RPD (P = .45). Figure 6 shows that eyes of patients with GA in the presence of RPD had thinner subfoveal CT measurements than eyes of similarly aged normal control patients without RPD.
Choroidal thickness (CT) versus age by patient group. This comparison of eyes with geographic atrophy (GA) in the presence or absence of reticular pseudodrusen (RPD) demonstrates that eyes in patients of a similar age (75 to 85 years) show markedly different CT measurements depending on the presence of RPD.
When we attempted to correlate the area of GA with CT measurements, we found that eyes with GA and RPD had thin CT measurements that were not correlated with the area of GA (P = .499), whereas GA eyes without RPD showed an unambiguous correlation between decreasing CT measurements and increasing area of GA (P = .004; Figure 7). The difference in slopes between the groups with respect to their relationship between CT and the area of GA was significant (P = .001; Figure 7). For the entire group of GA eyes without RPD at baseline, the age and axial length adjusted CT became thinner by −89.5 (SE: 22.4) µm for each increase of 1 mm in the square root of the GA area at baseline. In an additional analysis, the growth of GA lesions for a period of 52 weeks was correlated with CT changes during the same period. In eyes without RPD, there was a statistically significant correlation between increasing GA area and choroidal thinning (r = .76, P = .010), whereas there was no such correlation evident in eyes with RPD (r = .02, P = .92). When the increase in GA was compared with the change in CT, the CT became thinner by −89.4 (SE: 26.8) µm for each 1 mm increase in the square root of the GA area.
Choroidal thickness (CT) adjusted for age and axial length versus square root area of geographic atrophy (GA). Comparison of GA with (n = 20) and without (n = 10) reticular pseudodrusen (RPD) revealed a negative correlation of CT and GA area in eyes without RPD (P = .004), but no correlation was found in eyes with RPD (P = .499). The difference in slopes between the groups was significant (P = .001).
In eyes with nonexudative AMD stratified based on the presence or absence of RPD, eyes with GA and RPD had thinner CT measurements compared with GA and drusen eyes without RPD, and these differences were statistically significant. This association between late AMD and RPD3,14,15,32–34 and the observation of thinner CT measurements in AMD eyes35 has been reported previously. In particular, Fleckenstein et al36 found that all eyes with GA and the diffuse-trickling autofluorescence phenotype exhibited RPD and presented with thin CT measurements. However, our study takes these observations further and shows that the thinner CT measurements in eyes with GA group were primarily driven by the presence of RPD, and in the absence of RPD, eyes with GA did not have abnormally thin CT measurements compared with controls after correcting for age and axial length. However, in these eyes, the CT measurements decreased as the area of GA increased. This suggests that the classic features of drusen and early GA are not associated with a significant thinning of the subfoveal choroid, but rather, subfoveal choroidal thinning is primarily associated with the presence of RPD in AMD eyes regardless of the size of GA. In AMD eyes without RPD, the subfoveal choroid gets thinner only as the area of GA enlarges. This finding suggests that the presence of RPD is likely related to an underlying abnormality of the choroidal circulation, and the thin choroid precedes the formation and growth of GA.
Whether RPD is a manifestation of AMD or aging has yet to be determined. In a retrospective study of 200 patients with AMD, Finger et al20 demonstrated that those patients with RPD developed late-stage AMD more often than those without RPD. Although there is a known relationship between RPD and late AMD, it appears as though RPD is independently associated with an unusually thin choroid and either represents a variation of typical AMD or a manifestation of aging that is independent of AMD but capable of exacerbating the appearance of late AMD. However, once late AMD is present, it is unclear whether the presence of RPD causes a more rapid progression of disease. Although a previous study on the progression of GA in the presence of RPD showed a high correlation between these two factors, with GA progressing more rapidly in areas with previous RPD compared with areas that did not manifest RPD,37 we found in the COMPLETE study that there was no association between the presence of RPD and the growth rate of GA (P = .808 at 26 weeks; P = .863 at 52 weeks).5
One important difference between our study and the study by Marsiglia et al37 is that we chose patients with GA no more than seven disc areas and visual acuity of 20/63 or better. We also measured the growth rates using the difference in the square root of the area measurements, which allowed us to measure growth rates that were independent of the baseline lesion size. We used this strategy because our previous research showed that larger areas of GA at baseline appeared to grow faster when the growth rate was calculated by just taking the difference in area measurements.5 If Marsiglia et al37 chose eyes with large areas of GA in the presence of RPD, then that might explain why they detected an accelerated growth rate. However, even if the presence of RPD influences the enlargement rate of GA, then it still is not clear whether RPD are a manifestation of AMD and precede the formation of GA or whether RPD are an age-related phenomenon that is an independent risk factor contributing to disease progression due to impairment of the choroidal circulation. The key to understanding the cause-and-effect relationship between RPD and AMD will depend on whether we can identify changes at the level of the RPE and photoreceptors that cause thinning of the choroid or whether we can identify a mechanism that primarily affects choroidal perfusion leading to a thinning of the choroid and subsequent RPE and photoreceptor abnormalities.
In addition to finding a correlation between the presence of RPD and thinner CT measurements in AMD eyes with GA and RPD, we found that the choroid did not get any thinner as the area of GA increased. However, in AMD eyes with GA but no RPD, we found a negative correlation between the size of GA at baseline and the subfoveal choroidal thickness: the larger the area of GA at baseline, the thinner the subfoveal CT measurements. For a period of 1 year, in individual eyes, we observed that as the area of GA enlarged, the corresponding subfoveal CT measurements decreased. We believe we were able to observe this association between the growth of GA and decreasing subfoveal CT because we started with eyes having fewer than seven disc areas of GA and visual acuity of 20/63 or better.5 As a result, most of our eyes had preserved RPE under the foveal center at baseline, and as the GA enlarged and the foveal RPE was lost, we were able to detect the decrease in the subfoveal CT. If we had included eyes with more advanced disease and larger areas of GA, this correlation between CT and the area of GA may not have been as obvious and may explain why other groups have not reported this correlation.
Our results would suggest that eyes with nonexudative AMD in the absence of RPD have subfoveal CT measurements that are no different than normal control eyes after adjusting for age and axial length. However, as GA enlarges beyond seven disc areas, then compensatory subfoveal choroidal thinning results as the late stage disease advances. Therefore, it would appear that choroidal thinning associated with RPD and choroidal thinning due to GA represent two distinct disease processes. Further studies are needed to investigate the prevalence and genetics of RPD in the absence of typical AMD to better understand whether RPD are a manifestation of AMD or aging and to appreciate how these findings are associated with changes in the vascular layers of the choroid.38
The limitations of this study include its small sample size and the lack of longer follow-up to determine whether RPD appear during a longer period of time and how the appearance and disappearance of RPD influence the rate of choroidal thinning. However, even with these limitations, our findings are statistically significant and unlikely to be the result of chance alone. Our inability to draw any definitive conclusion about thinner CT measurements in drusen-only eyes with RPD is because of the small number of eyes with RPD, the younger age of these patients, and possibly the limited distribution of RPD in these eyes. However, our findings were consistent with RPD being associated with thinner than normal choroidal measurements. Moreover, systemic factors that could have influenced the results, such as cardiovascular status, were not evaluated in this study.
The advantages of this study include the fact that GA patients were enrolled as part of the COMPLETE study based solely on the size of GA and EDTRS visual acuity of 20/63 or better. As mentioned previously, this may explain why we were able to demonstrate that there was no association between nonexudative AMD and choroidal thinning in the absence of RPD, and that there was a clear association between the presence of RPD and a thin choroid in eyes with GA. Unlike our study, other studies did not separate AMD eyes with and without RPD, and they also did not compare their study eyes with a well characterized age-controlled normal population. These aspects of our study allowed us to adequately control for the changes in CT measurements that occur as a function of age rather than disease. The fact that we showed a statistical significance with such a small number of patients strongly suggests that our observations are valid.
When compared with a normal, age-appropriate control group, eyes with intermediate or late nonexudative AMD in the absence of RPD did not exhibit decreased CT measurements after adjusting for age and axial length. AMD eyes with GA and RPD had thinner than normal subfoveal CT measurements. It is unclear whether RPD represent an AMD-independent, age-related change in the eye or whether RPD and AMD are manifestations of the same disease process. Larger prospective studies incorporating choroidal imaging with staging of AMD should prove useful in further understanding the relationship between AMD, RPD, CT, and disease progression.
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