March 2012
Volume 53, Issue 3
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Retina  |   March 2012
Choroidal Changes Associated with Reticular Pseudodrusen
Author Affiliations & Notes
  • Giuseppe Querques
    From the Department of Ophthalmology, Centre Hospitalier Intercommunal de Creteil, University Paris Est Creteil, Creteil, France; and
    the Department of Ophthalmology, Hospital San Raffaele, University Vita Salute San Raffaele, Milan, Italy.
  • Lea Querques
    From the Department of Ophthalmology, Centre Hospitalier Intercommunal de Creteil, University Paris Est Creteil, Creteil, France; and
    the Department of Ophthalmology, Hospital San Raffaele, University Vita Salute San Raffaele, Milan, Italy.
  • Raimondo Forte
    From the Department of Ophthalmology, Centre Hospitalier Intercommunal de Creteil, University Paris Est Creteil, Creteil, France; and
  • Nathalie Massamba
    From the Department of Ophthalmology, Centre Hospitalier Intercommunal de Creteil, University Paris Est Creteil, Creteil, France; and
  • Florence Coscas
    From the Department of Ophthalmology, Centre Hospitalier Intercommunal de Creteil, University Paris Est Creteil, Creteil, France; and
  • Eric H. Souied
    From the Department of Ophthalmology, Centre Hospitalier Intercommunal de Creteil, University Paris Est Creteil, Creteil, France; and
  • Corresponding author: Giuseppe Querques, Department of Ophthalmology, Centre Hospitalier Intercommunal de Creteil, 40 Avenue de Verdun, 94000 Creteil, France; giuseppe.querques@hotmail.it
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 1258-1263. doi:10.1167/iovs.11-8907
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      Giuseppe Querques, Lea Querques, Raimondo Forte, Nathalie Massamba, Florence Coscas, Eric H. Souied; Choroidal Changes Associated with Reticular Pseudodrusen. Invest. Ophthalmol. Vis. Sci. 2012;53(3):1258-1263. doi: 10.1167/iovs.11-8907.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To analyze choroidal changes associated with reticular pseudodrusen by indocyanine green angiography (ICGA) and enhanced depth imaging spectral-domain optical coherence tomography (EDI SD-OCT).

Methods.: Twenty-two consecutive patients (22 eyes) with reticular pseudodrusen, and without medium/large drusen, underwent ICGA and EDI OCT. Twenty-one age- and sex-matched subjects (21 eyes) with early age-related macular degeneration (AMD), and without pseudodrusen, also underwent EDI OCT.

Results.: Mean age of patients with reticular pseudodrusen and with early AMD was 82.5 ± 0.9 and 79.3 ± 4.4 years of age, respectively (P = 0.9), and 59.0% and 76.2% were females, respectively (P = 0.7). On ICGA, reticular patterns appeared as hypofluorescent, not overlying the large choroidal vessels. Areas of iso/hyperfluorescence on ICGA, occurring adjacently to reticular patterns, appeared on OCT as subretinal deposits. The mean subfoveal choroidal thickness was significantly reduced in the group with reticular pseudodrusen compared with that in the control group (174.6 ± 10.1 and +241.4 ± 16.5, respectively; P < 0.001). At all measurement points, but the 3000 μm superior to the fovea, the choroidal thickness of eyes with reticular pseudodrusen appeared thinner than that of the control group. Interestingly, the choroid of eyes with reticular pseudodrusen appeared thicker at 3000 μm superior to the fovea compared with that at all other measurement points.

Conclusions.: It was shown that the reticular patterns appeared as hypofluorescent lesions on ICGA, closely abutting, but not overlying the large choroidal vessels. In eyes with reticular pseudodrusen, EDI OCT revealed an overall thinned choroid.

In 1990 our group first described reticular pseudodrusen as a peculiar yellowish pattern in the macula of patients with age-related macular degeneration (AMD). 1 A few years later, Arnold et al., 2 on the histopathologic study of one eye showing the peculiar reticular pattern, reported no evidence of drusen and speculated that the condition represented the loss of choroidal vessels accompanied by fibrous replacement of the choroidal stroma in a reticular pattern. Interestingly, Zweifel et al., 3 by using spectral-domain optical coherence tomography (SD-OCT), demonstrated that discrete collections of hyperreflective material located not under (as typical drusen of AMD do) but above the retinal pigment epithelium (RPE), were consistent with the original description of pseudodrusen. 
Recently, the analysis of integrated imaging allowed our group to show that only the center of reticular pseudodrusen appeared on SD-OCT as well-defined round or triangular hyperreflective deposits localized between, externally, the RPE layer, and, internally, the external limiting membrane or the outer plexiform layer. 4 Interestingly, the periphery of pseudodrusen deposits, appearing on infrared reflectance (IR) as hyporeflective halos (target aspect) adjacent to hyperreflective areas (responsible for the peculiar reticular pattern), were characterized on SD-OCT by the loss of both outer segment (OS)/RPE interface and inner segment (IS)/OS. 
Based on integrated imaging 4 and histopathologic study 2 we recently proposed that, in reticular pseudodrusen, fibrosis of the choroid could lead to the derangement of the RPE and secondary accumulation of photoreceptor outer segments above the RPE. However, in our previous series, no specific sub-RPE alterations were detected on SD-OCT scans corresponding to reticular pseudodrusen, probably because of the limited capability to image the choroid. 2 In fact, conventional SD-OCT is not sensitive enough to detect sub-RPE alterations and any possible fibrotic replacement of the choroid. 5  
Recently, a new approach to improve depth imaging by OCT, termed enhanced depth imaging (EDI) OCT, has been shown to be able to reliably image the full thickness of the choroid. 5 EDI OCT uses the SD-OCT (Spectralis SD-OCT; Heidelberg Engineering, Heidelberg, Germany) positioned closer to the eye than ordinary, such that a stable inverted image is produced. The net effect of this practice is that the sensitivity of the imaging in deeper layers of tissue is increased. 5 In this fashion, EDI OCT may represent a useful approach to investigate, in vivo, the choroidal changes in eyes with reticular pseudodrusen. 
Indocyanine green angiography (ICGA) represents another useful method to analyze, in vivo, the choroidal changes associated with the peculiar reticular pattern of pseudodrusen. It was introduced in the 1970s for imaging the choroidal circulation because of the particular optical properties of the dye. 6 ICG absorbs and reflects in the near-infrared portion of the spectrum (805 and 835 nm, respectively) and, thus, the RPE is essentially rendered invisible. 
In this study, our aim was to investigate in vivo the choroidal changes associated with reticular pseudodrusen. With this aim, using ICGA, we analyzed a homogeneous population of eyes showing the peculiar reticular pattern without other macular changes. Moreover, using EDI OCT we compared the choroidal measures of this population with those of a homogeneous population of eyes with early AMD without reticular pseudodrusen. 
Methods
All patients were recruited from the AMD outpatient clinic at the University Eye Clinic of Creteil between June 2011 and September 2011, and underwent a complete ophthalmologic examination, including ICGA and EDI OCT, as part of their routine clinical work-up. To be included for analysis, reticular pseudodrusen were defined by the peculiar yellowish reticular pattern at the macula, whose visibility was enhanced by IR reflectance 2 4 with or without blue light fundus photography. 1 Noninclusion criteria were refractive error > 5 diopters, diagnosis of early AMD (the presence of 5 or more medium drusen [63–124 μm] or any large drusen [>125 μm] within the macula in the study eye), the presence of choroidal neovascularization (CNV) or geographic atrophy in the study eye, signs of any other active retinal disease in the study eye such as retinal vascular (i.e., diabetic retinopathy and retinal vein occlusion) or vitreoretinal diseases (i.e., vitreomacular traction syndrome and epiretinal membrane). Informed consent was obtained, as required by the French bioethical legislation, in agreement with the Declaration of Helsinki for research involving human subjects. Institutional Review Board approval was obtained for this study. 
Age- and sex-matched control subjects (control group) presenting at least one eye with early AMD (the presence of 5 or more medium drusen [63–124 μm] or any large drusen [>125 μm] within the macula) without pseudodrusen were also included in the current analysis. All these control patients also underwent a complete ophthalmologic examination, including EDI OCT, as part of their routine clinical work-up. 
Study Protocol
Monocular best-corrected visual acuity (BCVA) was determined in all subjects with Early Treatment Diabetic Retinopathy Study charts. Retinal status was evaluated by fundus biomicroscopy, after pupil dilation by two experienced retinal physicians (GQ, EHS), and fluorescein angiography. Automated central macular thickness measurements were generated by the integrated SD-OCT device (Spectralis HRA+OCT; Heidelberg Engineering), using a 19 horizontal lines protocol (6 × 6 mm area), each consisting of 1024 A scans per line (Spectralis Acquisition and Viewing Modules, version 5.3.2; Heidelberg Engineering). All subjects underwent choroidal imaging by ICGA and thickness measurements by EDI OCT. EDI OCT scans were performed by two retinal physicians (GA, NM), experienced at performing scans using the integrated device (Spectralis SD-OCT). 
ICGA Analysis
A standardized imaging protocol was performed in all patients, which included acquisition of early-, mean-, and late-phase ICGA frames (excitation λ = 787 nm; emission λ > 800 nm; field of view, 30° × 30°; image resolution, 768 × 768 pixels). With confocal image acquisition, light from a conjugate plane of interest is detected by the image sensor, permitting suppression of light from planes anterior and posterior to the plane of interest and resulting in high-contrast fundus images. Using automated eye tracking and image alignment based on confocal scanning laser ophthalmoscopic images, the software allows averaging a variable number of single images in real time (Automatic Real Time [ART] Module; Heidelberg Engineering). 
For each study eye, one late ICGA ART image (up to 100 single images) was selected for further analysis and exported as a bitmap to image-analysis software (ImageJ; developed by Wayne Rasband, National Institutes of Health, Bethesda, MD; available at http://rsb.info.nih.gov/ij/index.html). Brightness and contrast settings were optimized for each file. The optimization process consisted of improving image brightness by stretching the pixel histogram using the entire range of available pixel values (0–255). Image contrast was manually adjusted, so that the visualization of the details was subjectively maximally enhanced. Using image-analysis software (ImageJ) the IR reflectance images were then overlaid onto the ICGA images as a separate layer to align the vascular patterns. By changing transparency of the layer, images were aligned with each other. Retinal vessel crossing points were used as invariant landmarks to allow manual registration of the IR reflectance images image with the ICGA images and to evaluate correspondence between the reticular pseudodrusen lesions at the macula on IR reflectance images and the reticular pattern on ICGA images. By switching on and off each layer, the location and size of lesion were compared with those of other layers. In every eye, the number of individual reticular pseudodrusen lesions was assessed in a standardized area (a predefined 1 × 1 mm square, along the vertical axis, just beneath the superior arcades). Analysis was performed by a single observer (GQ). 
EDI OCT Analysis
The method of obtaining EDI OCT images has been previously reported. 5 The choroid was imaged by positioning the integrated device (Spectralis SD-OCT) close enough to the eye to obtain an inverted image. Two 9-mm high-quality line scans through the fovea (one horizontal and one vertical) were obtained for each eye. The line scans were saved for analysis after 100 frames were averaged using the automatic averaging and eye-tracking features of the proprietary device. The resultant images were viewed and measured with the contained software package (Heidelberg Eye Explorer software, version 1.7.0.0; Heidelberg Engineering). The choroid was measured by two retinal physicians (GQ, LQ) from the outer portion of the hyperreflective line corresponding to the RPE to the inner surface of the sclera. These measurements were made of the subfoveal choroid and at 1500-μm intervals from the fovea to 3 mm nasal, 3 mm temporal, 3 mm superior, and 3 mm inferior from the center of the fovea (Figs. 1 and 2). Values of the measurements were compared for each observer and then the values were averaged to compare with those from another observer (EHS) who was blinded to the measurements of the first observer. 
Figure 1.
 
Early (top left), mean (top middle), and late phase (top right) ICGA frames show, in a patient with reticular pseudodrusen and without medium/large drusen, the hypofluorescent reticular patterns (top, arrows) overlying choroidal stroma (closely abutting, but not overlying the large choroidal vessels) (top, enlarged view). Enlarged view shows the predefined 1 × 1 mm square (a standardized area along the vertical axis, just beneath the superior arcades) in which the number of individual reticular pseudodrusen lesions was assessed in every eye. EDI OCT reveals an overall thinned choroid in both horizontal (middle) and vertical (bottom) axes, with a slight thickening in the upper vertical axis compared with the subfoveal choroid. Hypereflective deposits localized between the retinal pigment epithelium layer and the external limiting membrane/outer plexiform layer (middle and bottom, arrows) colocalize to intervascular choroidal stroma as visualized on EDI OCT.
Figure 1.
 
Early (top left), mean (top middle), and late phase (top right) ICGA frames show, in a patient with reticular pseudodrusen and without medium/large drusen, the hypofluorescent reticular patterns (top, arrows) overlying choroidal stroma (closely abutting, but not overlying the large choroidal vessels) (top, enlarged view). Enlarged view shows the predefined 1 × 1 mm square (a standardized area along the vertical axis, just beneath the superior arcades) in which the number of individual reticular pseudodrusen lesions was assessed in every eye. EDI OCT reveals an overall thinned choroid in both horizontal (middle) and vertical (bottom) axes, with a slight thickening in the upper vertical axis compared with the subfoveal choroid. Hypereflective deposits localized between the retinal pigment epithelium layer and the external limiting membrane/outer plexiform layer (middle and bottom, arrows) colocalize to intervascular choroidal stroma as visualized on EDI OCT.
Figure 2.
 
Early (top left), mean (top middle), and late phase (top right) ICGA frames show, in a patient with medium/large drusen (early age-related macular degeneration) and without reticular pseudodrusen, the absence of reticular patterns. EDI OCT reveals an overall normal thickness of the choroid in both horizontal (middle) and vertical (bottom) axes.
Figure 2.
 
Early (top left), mean (top middle), and late phase (top right) ICGA frames show, in a patient with medium/large drusen (early age-related macular degeneration) and without reticular pseudodrusen, the absence of reticular patterns. EDI OCT reveals an overall normal thickness of the choroid in both horizontal (middle) and vertical (bottom) axes.
Statistical Analysis
Statistical calculations were performed using a commercial package (Statistical Package for Social Sciences, version 17.0; SPSS Inc., Chicago, IL). The difference between early AMD subjects (control group) and patients with reticular pseudodrusen was generated by conducting t-tests for each individual axial choroidal thickness over the horizontal and vertical line scans (at 1500-μm intervals from the fovea to 3 mm nasal, 3 mm temporal, 3 mm superior, and 3 mm inferior from the center of the fovea). The concordance correlation coefficient (Pearson correlation) was calculated for interobserver correlations and considered to be strong if the correlation coefficient was >0.8. Univariate linear regression analyses were performed to evaluate the relationships between choroidal thickness and age in each group (control group and reticular pseudodrusen group). Analysis of covariance tests were performed to evaluate the effects of diagnoses (early AMD and reticular pseudodrusen) on choroidal thickness after removal of variance (covariates = sex, age). For both early AMD subjects (control group) and patients with reticular pseudodrusen, the coefficient of variation was mapped for each individual axial choroidal thickness over the horizontal and vertical line scans. The chosen level of statistical significance was P < 0.05. 
Results
Patients Demographics and Clinical Characteristics
A total of 22 eyes of 22 consecutive patients with reticular pseudodrusen (13 female [59.0%]; mean age, 82.5 ± 0.9 years; range, 80.4–84.5 years) were included in the analysis (Table 1). In all included eyes, reticular pseudodrusen were defined by the peculiar yellowish reticular pattern at the macula, whose visibility was enhanced using blue light and IR reflectance. Mean BCVA was 0.21 ± 0.02 logMAR (range, 0–0.4) (Table 1). 
Table 1.
 
Demographics and Clinical Features of the Study Subjects
Table 1.
 
Demographics and Clinical Features of the Study Subjects
Factor Subjects with Reticular Pseudodrusen Subjects with Early AMD (Control Group) P
Number 22 21
Female/Male 13/9 16/5 0.7
Age, y 82.5 ± 0.9 79.3 ± 4.4 0.9
Refractive error, diopters +0.12 ± 1.4 +0.41 ± 1.9 0.05
BCVA 0.21 ± 0.02 0.18 ± 0.08 0.6
CT at Fovea (CV) 176.4 ± 10.1 (0.27) 241.5 ± 16.5 (0.31) <0.001
CT at 1500-μm nasal (CV) 126.7 ± 10.2 (0.38) 185.8 ± 15.1 (0.37) 0.001
CT at 3000-μm nasal (CV) 90.0 ± 8.9 (0.46) 120.9 ± 12.3 (0.46) 0.02
CT at 1500-μm temporal (CV) 175.8 ± 8.1 (0.21) 228.9 ± 15.3 (0.30) 0.001
CT at 3000-μm temporal (CV) 171.7 ± 9.0 (0.24) 213.1 ± 17.1 (0.36) 0.01
CT at 1500-μm inferior (CV) 150.5 ± 9.5 (0.29) 196.3 ± 14.0 (0.32) 0.004
CT at 3000-μm inferior (CV) 144.7 ± 7.9 (0.25) 174.4 ± 12.8 (0.33) 0.02
CT at 1500-μm superior (CV) 175.7 ± 9.6 (0.25) 230.0 ± 14.9 (0.29) 0.001
CT at 3000-μm superior (CV) 187.2 ± 9.5 (0.23) 210.5 ± 11.8 (0.25) 0.06
Twenty-one eyes of 21 consecutive subjects with early AMD (16 female [76.2%]; mean age, 79.3 ± 4.4 years; range, 77.2–81.3 years) were also included in the analysis (control group) (Table 1). Mean BCVA was 0.18 ± 0.08 logMAR (range, 0–0.4) (Table 1). None of the eyes included in the control group showed the peculiar reticular pattern at the macula on blue light and/or IR reflectance. 
Two eyes of two patients with reticular pseudodrusen showed coincident pseudovitelliform material within the macular area (Querques G, et al. IOVS 2010;51:ARVO E-Abstract 2265). 4,7  
ICGA Overlapping IR Reflectance
Reticular patterns were localized mainly in the superior macular area and appeared as areas of hypofluorescence on ICGA (Figs. 1, 3, and 4). Registered IR and ICGA images displayed overlapping areas of reticular involvement. Both IR and ICGA imaging also revealed reticular patterns in the central macular area, which were not visible on fundus biomicroscopy. 
Figure 3.
 
IR image (top left) shows iso/hypereflective areas between hyporeflective reticular patterns, which colocalize to large choroidal vessels, as visualized on ICGA (bottom left, enlarged view). Most of the individual reticular pseudodrusen lesions (the center of reticular pseudodrusen, appearing as hyporeflective/“target” on IR reflectance) appear as closely abutting, but not overlying the large choroidal vessels (arrows). EDI OCT (right) shows hypereflective deposits localized between the retinal pigment epithelium layer and the external limiting membrane/outer plexiform layer. The hypereflective deposits lie immediately adjacent to the reticular patterns (see the corresponding IR image, top left), and appear to colocalize to intervascular choroidal stroma as visualized on ICGA.
Figure 3.
 
IR image (top left) shows iso/hypereflective areas between hyporeflective reticular patterns, which colocalize to large choroidal vessels, as visualized on ICGA (bottom left, enlarged view). Most of the individual reticular pseudodrusen lesions (the center of reticular pseudodrusen, appearing as hyporeflective/“target” on IR reflectance) appear as closely abutting, but not overlying the large choroidal vessels (arrows). EDI OCT (right) shows hypereflective deposits localized between the retinal pigment epithelium layer and the external limiting membrane/outer plexiform layer. The hypereflective deposits lie immediately adjacent to the reticular patterns (see the corresponding IR image, top left), and appear to colocalize to intervascular choroidal stroma as visualized on ICGA.
Figure 4.
 
IR image (top left) shows iso/hypereflective areas between hyporeflective reticular patterns, which colocalize to large choroidal vessels, as visualized on ICGA (bottom left, enlarged view). Most of the individual reticular pseudodrusen lesions (the center of reticular pseudodrusen, appearing as hyporeflective/“target” on IR reflectance) appear as closely abutting, but not overlying the large choroidal vessels (arrows). EDI OCT (right) shows hypereflective deposits localized between the retinal pigment epithelium layer and the external limiting membrane/outer plexiform layer. The hypereflective deposits lie immediately adjacent to the reticular patterns (see the corresponding IR image, top left), and appear to colocalize to intervascular choroidal stroma as visualized on ICGA.
Figure 4.
 
IR image (top left) shows iso/hypereflective areas between hyporeflective reticular patterns, which colocalize to large choroidal vessels, as visualized on ICGA (bottom left, enlarged view). Most of the individual reticular pseudodrusen lesions (the center of reticular pseudodrusen, appearing as hyporeflective/“target” on IR reflectance) appear as closely abutting, but not overlying the large choroidal vessels (arrows). EDI OCT (right) shows hypereflective deposits localized between the retinal pigment epithelium layer and the external limiting membrane/outer plexiform layer. The hypereflective deposits lie immediately adjacent to the reticular patterns (see the corresponding IR image, top left), and appear to colocalize to intervascular choroidal stroma as visualized on ICGA.
On ICGA, individual reticular lesions appeared to overly choroidal stroma (closely abutting, but generally not overlying the large choroidal vessels) (Figs. 1, 3, and 4). A mean of 18.1 ± 5.2 individual reticular pseudodrusen lesions were quantified in a predefined 1 × 1 mm square area (along the vertical axis, just beneath the superior arcades). 
Areas of iso/hyperfluorescence on ICGA, as well as the corresponding areas of iso/hypereflectance on IR reflectance, which occurred directly adjacently to reticular (hyporeflective) pseudodrusen lesions, 4 appeared on OCT as subretinal deposits with IS/OS disruption. 
EDI OCT
The mean refractive error was +0.12 ± 1.4 D for eyes with reticular pseudodrusen, and +0.41 ± 1.9 D eyes with early AMD (control group) (P = 0.05). The mean subfoveal choroidal thickness was significantly reduced in the group with reticular pseudodrusen compared with the control group (176.4 ± 10.1 and +241.4 ± 16.5 μm, respectively; P < 0.001) (Table 1). Similarly, the mean choroidal thickness was significantly reduced in the group with reticular pseudodrusen compared with the control group, at 1500-μm nasal to the fovea (126.7 ± 10.2 and 185.8 ± 15.1 μm, respectively; P = 0.001), at 3000-μm nasal to the fovea (90.0 ± 8.9 and 120.9 ± 12.3 μm, respectively, P = 0.02), at 1500-μm temporal to the fovea (175.8 ± 8.1 and 228.9 ± 15.3 μm, respectively; P = 0.001), at 3000-μm temporal to the fovea (171.7 ± 9.0 and 213.1 ± 17.1 μm, respectively; P = 0.01), at 1500-μm inferior to the fovea (150.5 ± 9.5 and 196.3 ± 14.0 μm, respectively; P = 0.004), at 3000-μm inferior to the fovea (144.7 ± 7.9 and 174.4 ± 12.8 μm, respectively; P = 0.02), and at 1500-μm superior to the fovea (175.7 ± 9.6 and 230.0 ± 14.9 μm, respectively; P = 0.001) (Table 1). No significant differences of choroidal thickness between the two groups were present at 3000-μm superior to the fovea (187.2 ± 9.5 and 210.5 ± 11.8 μm, respectively; P = 0.06). Surprisingly, the choroid of eyes with reticular pseudodrusen appeared to be slightly thicker at 3000-μm superior to the fovea compared with all other measurement points (including the subfoveal point) (Table 1). The coefficient of variation for each individual axial choroidal thickness was greater in the control group (Table 1). 
Computed tomography measurements were significantly correlated between the two observers at each location (Pearson's coefficient in all evaluated points: r = 0.98, P = 0.01) (Table 2). 
Table 2.
 
Concordance Correlation Coefficients of Computed Tomography Measurements between Two Observers at Each Location
Table 2.
 
Concordance Correlation Coefficients of Computed Tomography Measurements between Two Observers at Each Location
Location Concordance Correlation Coefficient (Pearson) 95% Confidence Interval P
Fovea 0.9838 0.9815–0.9926 0.01
Nasal 1500 μm 0.9845 0.9821–0.9932 0.01
Nasal 3000 μm 0.9852 0.9829–0.9912 0.001
Temporal 1500 μm 0.9850 0.9763–0.9897 0.01
Temporal 3000 μm 0.9840 0.9781–0.9898 0.02
Superior 1500 μm 0.9855 0.9841–0.9895 0.01
Superior 3000 μm 0.9870 0.9852–0.9891 0.001
Inferior 1500 μm 0.9841 0.9821–0.9898 0.001
Inferior 3000 μm 0.9850 0.9830–0.9891 0.01
Total 0.9878 0.9847–0.9897 0.01
Age was the factor most strongly associated with choroidal thickness (fovea: F = 12.067, P = 0.001) at all measurement points (group with reticular pseudodrusen: F = 13.526, P = 0.001; control group: F = 10.224, P = 0.001) (Table 3). Sex and refractive error were not significantly correlated with choroidal thickness. 
Table 3.
 
Results of Analysis of Covariance Tests at All Measurement Points in the Study Subjects
Table 3.
 
Results of Analysis of Covariance Tests at All Measurement Points in the Study Subjects
Factor Subjects with Reticular Pseudodrusen Subjects with Early AMD (Control Group)
F P F P
Sex 0.423 0.622 0.381 0.321
Age 13.526 0.001 10.224 0.001
Refractive error 1.281 0.201 1.116 0.323
Diagnosis 5.187 0.001 5.623 0.001
Discussion
In the present study we analyzed the choroidal changes associated with pseudodrusen to investigate whether the reticular patterns could be explained by choroidal alterations, as originally proposed. 2  
First, we found that large choroidal vessels, as visualized on ICGA, colocalized to iso/hypereflective (IR reflectance) areas between hyporeflective reticular patterns. Individual reticular pseudodrusen lesions (the center of reticular pseudodrusen, appearing as hyporeflective/“target” on IR reflectance) 4 were closely abutting, but not overlying the large choroidal vessels. Therefore, hypereflective deposits localized between the RPE layer and the external limiting membrane/outer plexiform layer 4 (also known as subretinal drusendoid deposits) 3 lie immediately adjacent to the reticular patterns, and colocalize to intervascular choroidal stroma as visualized on ICGA. These findings are consistent with the impaired choroidal filling reported in eyes with reticular pseudodrusen, 1,2,8 and explain why the extent of subretinal drusendoid deposits on SD-OCT cannot account for the extent of the reticular patterns. 
Second, we found that the subfoveal choroidal thickness was reduced in eyes with only reticular pseudodrusen (without medium/large drusen), compared with eyes with early AMD (defined as the presence of 5 or more medium drusen [63–124 μm] or any large drusen [>125 μm] within the macula) without pseudodrusen. Similarly, the choroidal thickness of eyes with reticular pseudodrusen appeared thinner than that of eyes with early AMD, at all measurement points except for the measurements at 3000-μm superior to the fovea. Interestingly, reticular pseudodrusen were localized mainly in the superior macula, thus matching with the area of (slight) choroidal thickening. Arnold et al., 2 in their histopathologic report, showed a loss of the small choroidal vessels and increased spacing between the large choroidal veins, and proposed that a loss of vascularity and fibrotic replacement (and thus a slight thickening) of the choroidal stroma may be responsible for reticular pseudodrusen. Taken together, our in vivo findings and histopathologic data suggest that, in reticular pseudodrusen development and progression, there may be first a diffuse loss of small choroidal vessels (and thus a diffuse choroidal thinning), and, later, a fibrotic replacement (and thus a slight thickening) mainly in the area of higher concentration of pseudodrusen (i.e., the superior macula). 
The current analysis is in agreement with the findings recently reported by Sohrab et al. 9 The authors, by analyzing en face sections of the choroid from SD-OCT scans, localized the reticular pattern to the intervascular choroidal stroma, 9 and suggested that subretinal deposits (which did not colocalize with the reticular pattern), may represent secondary mechanical or biological disturbances in the overlying RPE and outer retina. 
In this study, we found that, in the horizontal axis, in both the reticular pseudodrusen group and the control group, the choroid is thickest in the fovea and progressively thins toward the periphery. These findings are very similar to findings reported previously using the EDI OCT. 5,10 Moreover, in the current series, we also found that in the vertical axis, in both the reticular pseudodrusen group and the control group, the choroid is thickest in the fovea and progressively thins toward the periphery, except for the measurements at 3000-μm superior to the fovea in the reticular pseudodrusen group. To the best of our knowledge, there are no published series showing the choroidal thickness in the vertical axis as evaluated by EDI OCT. 
Using EDI SD-OCT Margolis and Spaide 10 found that normal subfoveal choroidal thickness was 287.6 ± 76 μm, in patients with a mean age of 50.4 years. Given that subfoveal choroidal thickness has been reported to decrease 1.56 μm for each year of age (15 years) these values can be considered similar to those of our control group (241.4 ± 16.5 μm, mean age 79.3 ± 4.4 years). 
Our study has several limitations. The series presented here is relatively small. However, one should look at the current series in consideration of the strict inclusion criteria for both reticular pseudodrusen and control group: eyes with only reticular pseudodrusen, without medium/large drusen, versus eyes with medium/large drusen (early AMD) without pseudodrusen. On this regard, one could object that it would make more sense to compare AMD eyes showing medium/large drusen with and without pseudodrusen, rather than comparing eyes showing only reticular pseudodrusen with eyes showing only medium/large drusen. However, this study was designed to investigate the choroidal changes in eyes presenting the peculiar reticular pattern without other macular changes, and to assess whether the reticular pseudodrusen could be explained by choroidal alterations. In other words, we compared eyes with only reticular pseudodrusen versus eyes with early AMD because, here, our hypothesis was that pseudodrusen and medium/large drusen may represent different conditions with different characteristics. Moreover, choosing eyes with association of reticular pseudodrusen with medium/large drusen might not have allowed understanding whether a choroidal thinning was due to the association of both medium/large drusen and pseudodrusen, or to reticular pseudodrusen itself. A further limitation may be explained by the fact that the two graders were not masked to the presence of reticular pseudodrusen because the software (Heidelberg Engineering) displays the IR image alongside the B scans. However, the excellent reproducibility between graders may have limited this inevitable measurement bias, due to the knowledge of the objective of the study. Another limitation may be represented by the age difference and the difference in refraction between patients with reticular pseudodrusen and control group (82.5 ± 0.9 vs. 79.3 ± 4.4 years, and +0.12 ± 1.4 vs. +0.41 ± 1.9, respectively). Both age and refraction have shown, in previous studies, to influence choroidal thickness. 10,11 However, the absence of definite statistical significance may have limited the impact of such bias in the current series. Finally, the method of image analysis we used may not have accounted for exact pixel-to-pixel registration, and we had no examples of histopathology to correlate to the changes noted on ICGA and SD-OCT. 
Our study cannot answer the question of cause–effect relationship. In other words, we cannot conclude whether the decrease in choroidal thickness causes the development of reticular pseudodrusen or whether the presence of pseudodrusen may represent a barrier to the free distribution of trophic substances that are needed to maintain a normal viable choroid. Further studies are needed to clarify this question. 
In conclusion, we showed that hyporeflective reticular patterns (IR reflectance) appeared as areas of hypofluorescence on ICGA, closely abutting, but not overlying the large choroidal vessels, which suggests that the pattern of reticular pseudodrusen is related to the choroidal stroma. EDI OCT revealed an overall thinned choroid, favoring the idea that the derangement of the RPE because of underlying atrophy and fibrosis of the choroid could lead to the accumulation of photoreceptor outer segments above the RPE (subretinal deposits). These results aim to a better understanding of the reticular pattern and give insights on the pathophysiology of reticular pseudodrusen. 
Footnotes
 Disclosure: G. Querques, None; L. Querques, None; R. Forte, None; N. Massamba, None; F. Coscas, None; E.H. Souied, None
References
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Figure 1.
 
Early (top left), mean (top middle), and late phase (top right) ICGA frames show, in a patient with reticular pseudodrusen and without medium/large drusen, the hypofluorescent reticular patterns (top, arrows) overlying choroidal stroma (closely abutting, but not overlying the large choroidal vessels) (top, enlarged view). Enlarged view shows the predefined 1 × 1 mm square (a standardized area along the vertical axis, just beneath the superior arcades) in which the number of individual reticular pseudodrusen lesions was assessed in every eye. EDI OCT reveals an overall thinned choroid in both horizontal (middle) and vertical (bottom) axes, with a slight thickening in the upper vertical axis compared with the subfoveal choroid. Hypereflective deposits localized between the retinal pigment epithelium layer and the external limiting membrane/outer plexiform layer (middle and bottom, arrows) colocalize to intervascular choroidal stroma as visualized on EDI OCT.
Figure 1.
 
Early (top left), mean (top middle), and late phase (top right) ICGA frames show, in a patient with reticular pseudodrusen and without medium/large drusen, the hypofluorescent reticular patterns (top, arrows) overlying choroidal stroma (closely abutting, but not overlying the large choroidal vessels) (top, enlarged view). Enlarged view shows the predefined 1 × 1 mm square (a standardized area along the vertical axis, just beneath the superior arcades) in which the number of individual reticular pseudodrusen lesions was assessed in every eye. EDI OCT reveals an overall thinned choroid in both horizontal (middle) and vertical (bottom) axes, with a slight thickening in the upper vertical axis compared with the subfoveal choroid. Hypereflective deposits localized between the retinal pigment epithelium layer and the external limiting membrane/outer plexiform layer (middle and bottom, arrows) colocalize to intervascular choroidal stroma as visualized on EDI OCT.
Figure 2.
 
Early (top left), mean (top middle), and late phase (top right) ICGA frames show, in a patient with medium/large drusen (early age-related macular degeneration) and without reticular pseudodrusen, the absence of reticular patterns. EDI OCT reveals an overall normal thickness of the choroid in both horizontal (middle) and vertical (bottom) axes.
Figure 2.
 
Early (top left), mean (top middle), and late phase (top right) ICGA frames show, in a patient with medium/large drusen (early age-related macular degeneration) and without reticular pseudodrusen, the absence of reticular patterns. EDI OCT reveals an overall normal thickness of the choroid in both horizontal (middle) and vertical (bottom) axes.
Figure 3.
 
IR image (top left) shows iso/hypereflective areas between hyporeflective reticular patterns, which colocalize to large choroidal vessels, as visualized on ICGA (bottom left, enlarged view). Most of the individual reticular pseudodrusen lesions (the center of reticular pseudodrusen, appearing as hyporeflective/“target” on IR reflectance) appear as closely abutting, but not overlying the large choroidal vessels (arrows). EDI OCT (right) shows hypereflective deposits localized between the retinal pigment epithelium layer and the external limiting membrane/outer plexiform layer. The hypereflective deposits lie immediately adjacent to the reticular patterns (see the corresponding IR image, top left), and appear to colocalize to intervascular choroidal stroma as visualized on ICGA.
Figure 3.
 
IR image (top left) shows iso/hypereflective areas between hyporeflective reticular patterns, which colocalize to large choroidal vessels, as visualized on ICGA (bottom left, enlarged view). Most of the individual reticular pseudodrusen lesions (the center of reticular pseudodrusen, appearing as hyporeflective/“target” on IR reflectance) appear as closely abutting, but not overlying the large choroidal vessels (arrows). EDI OCT (right) shows hypereflective deposits localized between the retinal pigment epithelium layer and the external limiting membrane/outer plexiform layer. The hypereflective deposits lie immediately adjacent to the reticular patterns (see the corresponding IR image, top left), and appear to colocalize to intervascular choroidal stroma as visualized on ICGA.
Figure 4.
 
IR image (top left) shows iso/hypereflective areas between hyporeflective reticular patterns, which colocalize to large choroidal vessels, as visualized on ICGA (bottom left, enlarged view). Most of the individual reticular pseudodrusen lesions (the center of reticular pseudodrusen, appearing as hyporeflective/“target” on IR reflectance) appear as closely abutting, but not overlying the large choroidal vessels (arrows). EDI OCT (right) shows hypereflective deposits localized between the retinal pigment epithelium layer and the external limiting membrane/outer plexiform layer. The hypereflective deposits lie immediately adjacent to the reticular patterns (see the corresponding IR image, top left), and appear to colocalize to intervascular choroidal stroma as visualized on ICGA.
Figure 4.
 
IR image (top left) shows iso/hypereflective areas between hyporeflective reticular patterns, which colocalize to large choroidal vessels, as visualized on ICGA (bottom left, enlarged view). Most of the individual reticular pseudodrusen lesions (the center of reticular pseudodrusen, appearing as hyporeflective/“target” on IR reflectance) appear as closely abutting, but not overlying the large choroidal vessels (arrows). EDI OCT (right) shows hypereflective deposits localized between the retinal pigment epithelium layer and the external limiting membrane/outer plexiform layer. The hypereflective deposits lie immediately adjacent to the reticular patterns (see the corresponding IR image, top left), and appear to colocalize to intervascular choroidal stroma as visualized on ICGA.
Table 1.
 
Demographics and Clinical Features of the Study Subjects
Table 1.
 
Demographics and Clinical Features of the Study Subjects
Factor Subjects with Reticular Pseudodrusen Subjects with Early AMD (Control Group) P
Number 22 21
Female/Male 13/9 16/5 0.7
Age, y 82.5 ± 0.9 79.3 ± 4.4 0.9
Refractive error, diopters +0.12 ± 1.4 +0.41 ± 1.9 0.05
BCVA 0.21 ± 0.02 0.18 ± 0.08 0.6
CT at Fovea (CV) 176.4 ± 10.1 (0.27) 241.5 ± 16.5 (0.31) <0.001
CT at 1500-μm nasal (CV) 126.7 ± 10.2 (0.38) 185.8 ± 15.1 (0.37) 0.001
CT at 3000-μm nasal (CV) 90.0 ± 8.9 (0.46) 120.9 ± 12.3 (0.46) 0.02
CT at 1500-μm temporal (CV) 175.8 ± 8.1 (0.21) 228.9 ± 15.3 (0.30) 0.001
CT at 3000-μm temporal (CV) 171.7 ± 9.0 (0.24) 213.1 ± 17.1 (0.36) 0.01
CT at 1500-μm inferior (CV) 150.5 ± 9.5 (0.29) 196.3 ± 14.0 (0.32) 0.004
CT at 3000-μm inferior (CV) 144.7 ± 7.9 (0.25) 174.4 ± 12.8 (0.33) 0.02
CT at 1500-μm superior (CV) 175.7 ± 9.6 (0.25) 230.0 ± 14.9 (0.29) 0.001
CT at 3000-μm superior (CV) 187.2 ± 9.5 (0.23) 210.5 ± 11.8 (0.25) 0.06
Table 2.
 
Concordance Correlation Coefficients of Computed Tomography Measurements between Two Observers at Each Location
Table 2.
 
Concordance Correlation Coefficients of Computed Tomography Measurements between Two Observers at Each Location
Location Concordance Correlation Coefficient (Pearson) 95% Confidence Interval P
Fovea 0.9838 0.9815–0.9926 0.01
Nasal 1500 μm 0.9845 0.9821–0.9932 0.01
Nasal 3000 μm 0.9852 0.9829–0.9912 0.001
Temporal 1500 μm 0.9850 0.9763–0.9897 0.01
Temporal 3000 μm 0.9840 0.9781–0.9898 0.02
Superior 1500 μm 0.9855 0.9841–0.9895 0.01
Superior 3000 μm 0.9870 0.9852–0.9891 0.001
Inferior 1500 μm 0.9841 0.9821–0.9898 0.001
Inferior 3000 μm 0.9850 0.9830–0.9891 0.01
Total 0.9878 0.9847–0.9897 0.01
Table 3.
 
Results of Analysis of Covariance Tests at All Measurement Points in the Study Subjects
Table 3.
 
Results of Analysis of Covariance Tests at All Measurement Points in the Study Subjects
Factor Subjects with Reticular Pseudodrusen Subjects with Early AMD (Control Group)
F P F P
Sex 0.423 0.622 0.381 0.321
Age 13.526 0.001 10.224 0.001
Refractive error 1.281 0.201 1.116 0.323
Diagnosis 5.187 0.001 5.623 0.001
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