Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Reticular Pseudodrusen and Thin Choroid Are Associated With Angioid Streaks

Vinod Kumar, MS, DNB, MNAMS, FRCS (Glasg)

Abstract

BACKGROUND AND OBJECTIVE:

To report the association of angioid streaks in patients with Pseudoxanthoma elasticum (PXE) with reticular pseudodrusen (RPD), thin choroid, and retinal pigment epithelium (RPE) atrophy using swept-source optical coherence tomography (SS-OCT) and short-wave autofluorescence (SWAF).

PATIENTS AND METHODS:

Retrospective cross-sectional study. Records of consecutive patients with angioid streaks due to PXE, who presented with a decrease of vision due to choroidal neovascularization (CNV), were reviewed for best-corrected visual acuity, color fundus photographs, SS-OCT, SWAF, and red-free images with special emphasis on presence or absence of RPD, subfoveal choroidal thickness (SFCT), and RPE atrophy.

RESULTS:

Sixteen eyes of eight patients with a mean age of 45.5 years ± 9.4 years were enrolled in the study. RPD were seen in 10 of the 16 eyes and were seen commonly along the superotemporal quadrant. Mean subfoveal thickness in study eyes (175.7 μm ± 37.2 μm) was significantly reduced when compared to controls (286.4 μm ± 40.8 μm). The mean SFCT was similar between the eyes with and without CNV. Four eyes had RPE atrophy in the macular area, whereas four eyes had peripapillary RPE atrophy.

CONCLUSIONS:

Angioid streaks in PXE are associated with RPD, thin choroid, and RPE atrophy. These features occur at a younger age as compared to age-related macular degeneration and appear to be interrelated because of single pathophysiological mechanism.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:402–408.]

Abstract

BACKGROUND AND OBJECTIVE:

To report the association of angioid streaks in patients with Pseudoxanthoma elasticum (PXE) with reticular pseudodrusen (RPD), thin choroid, and retinal pigment epithelium (RPE) atrophy using swept-source optical coherence tomography (SS-OCT) and short-wave autofluorescence (SWAF).

PATIENTS AND METHODS:

Retrospective cross-sectional study. Records of consecutive patients with angioid streaks due to PXE, who presented with a decrease of vision due to choroidal neovascularization (CNV), were reviewed for best-corrected visual acuity, color fundus photographs, SS-OCT, SWAF, and red-free images with special emphasis on presence or absence of RPD, subfoveal choroidal thickness (SFCT), and RPE atrophy.

RESULTS:

Sixteen eyes of eight patients with a mean age of 45.5 years ± 9.4 years were enrolled in the study. RPD were seen in 10 of the 16 eyes and were seen commonly along the superotemporal quadrant. Mean subfoveal thickness in study eyes (175.7 μm ± 37.2 μm) was significantly reduced when compared to controls (286.4 μm ± 40.8 μm). The mean SFCT was similar between the eyes with and without CNV. Four eyes had RPE atrophy in the macular area, whereas four eyes had peripapillary RPE atrophy.

CONCLUSIONS:

Angioid streaks in PXE are associated with RPD, thin choroid, and RPE atrophy. These features occur at a younger age as compared to age-related macular degeneration and appear to be interrelated because of single pathophysiological mechanism.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:402–408.]

Introduction

Pseudoxanthoma elasticum (PXE) is genetic disorder affecting multiple organs including skin, eyes, and cardiovascular system. It is an autosomal recessive disorder caused by mutations in ABCA6 gene1 and is characterized by fragmentation and mineralization of elastin fibers that affects the connective tissues. The reported incidence of PXE varies from one in 25,000 to one in 100,000.2

Characteristic ophthalmic features of PXE include angioid streaks, peau d'orange, optic disc drusen, and comet lesions.3,4 Angioid streaks are irregular disruptions in the Bruch's membrane that are frequently associated with choroidal neovascularization (CNV).3 Other uncommonly reported features in patients with PXE include pattern dystrophy-like appearance,5 reticular pseudodrusen (RPD)-like deposits,6,7 and geographic atrophy.8 All of these features have been studied independently; however, no attempt has been made to correlate them. Although RPD are typically associated with thinner choroid9 and increased incidence of geographic atrophy of retinal pigment epithelium (RPE),10 the choroid has been variably reported to be thin to normal in eyes with PXE.11–13 Thus, the presence of RPD and choroidal thickness in patients with PXE is not clear in the available literature. This study aims to assess the presence or absence of RPD and choroidal thickness along with RPE atrophy in patients with angioid streaks due to PXE using multimodal imaging.

Patients and Methods

Subjects

This was a retrospective study of consecutive patients undergoing treatment for CNV associated with angioid streaks at a tertiary eye care center in north India. The study period ranged from January 2015 to May 2017. It adhered to the tenets set forth in the Declaration of Helsinki as well as all institutional guidelines. Informed consent was obtained from all of the patients.

Inclusion and Exclusion Criteria

All patients with angioid streaks who presented with decrease of vision due to CNV in one or both the eyes were included in the study. Only patients with clinical features of PXE (confirmed during systemic work-up) were included in the study. The diagnosis of PXE was made based on skin findings (characteristic pseudoxanthomatous papules and plaques on the neck or flexural creases) along with the presence of retinal features (angioid streaks, peau d'orange, and comet tail lesions).

Exclusion criteria included media haze enough to preclude fundus imaging, myopia (> 4 diopters), and previous treatment with intravitreal anti-vascular endothelial growth factor (VEGF) injections or photodynamic therapy. Sixteen eyes of eight patients met these criteria and were included in the study.

Parameters Assessed/Outcome Measures

Patient medical records were reviewed and the detailed demographic data, Snellen best-corrected visual acuities (BCVAs), anterior segment, and fundus examination were noted. The presence of fundus findings such as angioid streaks, peau d'orange, CNV (active or inactive), comet lesions, and especially presence of RPD were noted. All patients underwent color fundus photographs and swept-source optical coherence tomography (SS-OCT) (DRI OCT Triton; Topcon, Tokyo, Japan). Short-wave fundus autofluorescence (SWAF) was done using the Triton and fundus fluorescein angiography (FFA) was done in selected patients. RPD were identified on SS-OCT by typical appearance of granular hyperreflective lesions with triangular shape localizing between the RPE layer and the ellipsoid zone. Subfoveal choroidal thickness (SFCT) was measured manually from the outer boundary of hyperreflective RPE band to the sclerochoroidal junction through the foveal center. The primary outcome measure was to assess the presence of RPD and to measure SFCT. SFCT of 10 eyes of five healthy (no ocular or systemic disease) age-matched controls was measured and served as control. The patients with active CNV were treated with intravitreal anti-VEGF injections (loading dose followed by pro re nata basis). Visual acuities were converted to Snellen fraction for statistical analysis. The data were entered in to Microsoft Excel (Microsoft, Redmond, WA) and values were expressed as mean ± standard deviation. The various groups were compared using Mann-Whitney U test. A P value of less than .05 was considered significant.

Results

Sixteen eyes of eight patients with a mean age of 45.5 years ± 9.4 years met the criteria and were recruited in to the study. Five patients were male, and three were female. The mean presenting BCVA (Snellen fraction) was 0.40 ± 0.39. All 16 eyes had prominent angioid streaks. Five patients had CNV in only one eye, out of which one did not show signs of activity. Three patients had CNV in both the eyes; one of these patients had inactive CNV in one eye. Peau d'orange appearance was noted in 10 eyes (62.5%), whereas comet lesions were seen in 50% of the eyes. The detailed demographic details and clinical features are described in the Table.

Detailed Demographic and Clinical Features of all Study Eyes

Table:

Detailed Demographic and Clinical Features of all Study Eyes

RPD could be identified in 10 eyes (62.5%). These were seen predominantly along the vascular arcades especially along the superotemporal vascular arcade (Figure 1). Although RPD could also be localized on red-free (Figures 2a and 2b) and color fundus photographs, they were best identified with SS-OCT (Figures 2c and 2d). In one patient, RPD were seen to be present nasal to the optic disc, as well (Figure 3). The choroid was visibly thin in all of the eyes (Figure 4) with angioid streaks, and mean SFCT was 175.7 μm ± 37.2 μm. Mean SFCT in age-matched controls was 286.4 μm ± 40.8 μm. The difference between the two groups was statistically significant (P < .0001). The choroidal thickness was compared between the eyes with CNV (active or inactive) and eyes without CNV. The mean SFCT in eyes with CNV was 175.4 μm ± 41.9 μm, whereas in eyes without CNV, the mean SFCT was 176.4 μm ± 28.1 μm. The difference between the two groups was not statistically different (P = .95). The BCVA and choroidal thickness had a weak positive relationship, but the relationship was not statistically significant (r = 0.21; P = .43). The presence or absence of RPD, however, did not affect BCVA (P = .33).

Color fundus photographs of the right eye (a) and the left eye (c) showing reticular pseudodrusen along superior arcade (blue arrows). Disc-centered color photographs of the right eye (b) and the left eye (d) showing angioid streaks. Note choroidal neovascularization at macula of the left eye (c, d)

Figure 1.

Color fundus photographs of the right eye (a) and the left eye (c) showing reticular pseudodrusen along superior arcade (blue arrows). Disc-centered color photographs of the right eye (b) and the left eye (d) showing angioid streaks. Note choroidal neovascularization at macula of the left eye (c, d)

Red-free photographs of the same patient of the right (a) and the left (b) eyes showing reticular pseudodrusen (RPD) as bright dots (small arrows). Large arrows indicate position of optical coherence tomography (OCT) scans. Swept-source OCT scans of the right (c) and the left (d) eyes show RPD (arrows) as triangular depositions above the retinal pigment epithelium. The left eye has a choroidal neovascularization at the fovea.

Figure 2.

Red-free photographs of the same patient of the right (a) and the left (b) eyes showing reticular pseudodrusen (RPD) as bright dots (small arrows). Large arrows indicate position of optical coherence tomography (OCT) scans. Swept-source OCT scans of the right (c) and the left (d) eyes show RPD (arrows) as triangular depositions above the retinal pigment epithelium. The left eye has a choroidal neovascularization at the fovea.

Disc-centered color photographs of the right (a) and left eyes (d) show angioid streaks and peripapillary retinal pigment epithelium atrophy. Reticular pseudodrusen (RPD) are better seen on red-free photographs (b, d). Swept-source optical coherence tomography scans (arrows in a, d) show RPD nasal to the optic disc (c, e).

Figure 3.

Disc-centered color photographs of the right (a) and left eyes (d) show angioid streaks and peripapillary retinal pigment epithelium atrophy. Reticular pseudodrusen (RPD) are better seen on red-free photographs (b, d). Swept-source optical coherence tomography scans (arrows in a, d) show RPD nasal to the optic disc (c, e).

Color fundus photograph of the right eye of a patient with angioid streaks (a); there was no choroidal neovascularization in this eye. Vertical swept-source optical coherence tomography scan (b); position marked by arrow in (a) shows thin choroid (subfoveal choroidal thickness was 160 μm).

Figure 4.

Color fundus photograph of the right eye of a patient with angioid streaks (a); there was no choroidal neovascularization in this eye. Vertical swept-source optical coherence tomography scan (b); position marked by arrow in (a) shows thin choroid (subfoveal choroidal thickness was 160 μm).

Four eyes (25%) showed evidence of RPE atrophy (geographic atrophy) in the macular area and nasal to the optic disc (Figures 5a–5d and Figure 6). In addition, four eyes (25%) showed RPE atrophy in the peripapillary area (Figure 4a). This was confirmed on SS-OCT and SWAF images. One patient had prominent subretinal yellow deposits, which appeared hyperautofluorescent on SWAF images (Figures 5c–5e). Though these deposits were similar to those seen in pattern dystrophy, these were more on the nasal side of the optic disc.

Color photograph of the right eye (a) showing angioid streaks, retinal pigment epithelium (RPE) atrophy (arrow), and yellow subretinal deposits along the superotemporal vascular arcade. Short-wave autofluorescence of right eye (c) shows hypoautofluorescence corresponding to the RPE atrophy and multiple hyperautofluorescent spots corresponding to the deposits, which were more on the nasal side (e). Apart from the presence of fibrotic choroidal neovascularization, similar findings were seen in the left eye (b, d, f).

Figure 5.

Color photograph of the right eye (a) showing angioid streaks, retinal pigment epithelium (RPE) atrophy (arrow), and yellow subretinal deposits along the superotemporal vascular arcade. Short-wave autofluorescence of right eye (c) shows hypoautofluorescence corresponding to the RPE atrophy and multiple hyperautofluorescent spots corresponding to the deposits, which were more on the nasal side (e). Apart from the presence of fibrotic choroidal neovascularization, similar findings were seen in the left eye (b, d, f).

Color fundus photographs of the right eye (a) showing angioid streaks, peripapillary atrophy, and reticular pseudodrusen along superior arcade (arrows). Color fundus photographs of the left (b) eye showing angioid streaks, fibrotic choroidal neovascularization, and large area of retinal pigment epithelium atrophy at the macula.

Figure 6.

Color fundus photographs of the right eye (a) showing angioid streaks, peripapillary atrophy, and reticular pseudodrusen along superior arcade (arrows). Color fundus photographs of the left (b) eye showing angioid streaks, fibrotic choroidal neovascularization, and large area of retinal pigment epithelium atrophy at the macula.

Discussion

This study highlights the presence of RPD in patients with angioid streaks associated with PXE. This was also associated with thin choroid and RPE atrophy in these patients. Although these observations have been made in selected studies, these findings have not been reported to occur together. Zweifel et al. and Gleim et al. have described RPD in PXE.7,14 Zweifel et al. first reported subretinal drusenoid deposits in PXE in 15 out of the 42 eyes (35.7%) studied. They concluded that subretinal drusenoid deposits seen in PXE were similar to those seen in age-related macular degeneration (AMD) but occurred at a younger age than that of AMD. Gleim et al. noted RPD in 52% of their patients. They found that prevalence of RPD was highest in the fifth decade and along the superior arcade and least common in the central macula. This is similar to that seen in the present study, though prevalence was little higher in our study (62.5%). This may be due to use of SS-OCT that provides higher-resolution images as compared to spectral-domain OCT (SD-OCT), which was used in previous studies.

Choroidal thickness has been studied in patients with angioid streaks and PXE.11–13 Ellabban et al. showed with SS-OCT that choroid in eyes with angioid streaks without CNV was as thick as that in normal controls but was significantly thinner in eyes with angioid streaks that had developed CNV.11 Gleim et al. demonstrated with SD-OCT that compared to controls, mean SFCT in eyes of patients with PXE was significantly reduced irrespective of the presence of CNV. In the present study, choroidal thickness was also reduced significantly in all eyes. The difference between the eyes with or without the CNV was not significant. Atrophy of RPE and outer retina has also been found to be a common finding in patients with PXE and characteristically has an early onset and fast progression with subsequent visual loss independent from CNV.15

All these features are likely to have a common pathogenesis, which, in the case of PXE, is expected to be in the Bruch's membrane. Bruch's membrane serves the important functions of regulating the diffusion of biomolecules between the choroid and RPE and providing support for RPE cell adhesion and migration.16 With aging, Bruch's membrane undergoes several changes including increased deposition of lipids, increased collagen cross-linking, thickening, and calcification of elastic lamina.16 These changes, along with environmental and genetic factors, play an important part in the causation of AMD. In PXE, calcification of elastic lamina of Bruch's membrane occurs at a younger age, thereby accentuating and hastening the aging changes in the Bruch's membrane. This leads to increased depositions on the retinal side of Bruch's membrane (subretinal drusenoid deposits and yellow material similar to that seen in pattern dystrophy) and loss of RPE cells. On the other hand, due to lack of various regulating biomolecules, which are secreted by the RPE and are required for the maintenance of choroidal vasculature, the choroidal thickness is decreased.12 This also explains the earlier occurrence of RPD and RPE atrophy in eyes with PEX as compared to those with AMD. Similar features have been described in other disorders that affect the Bruch's membrane, such as Sorsby's fundus dystrophy.17 Alternatively, RPD have been associated with thinner choroid, though cause and consequence status are not clear in the literature.18 RPD have also been associated with increased risk of geographic atrophy in studies.19

There are several limitations of the study including small sample size, cross-sectional study design, and retrospective nature of the study. A longitudinal study with a larger sample size would provide further insights in to the pathophysiology in PXE. Multimodal imaging was not used for the diagnosis of RPD, the latter being a poorly understood entity. However, Ueda-Arakawa et al. reported high sensitivity (94.6%) and specificity (98.4%) of SD-OCT alone for the diagnosis of RPD.20 Lastly absence of genetic/histologic diagnosis of PXE could have led to selection bias.

To conclude, this study for the first time demonstrates the association of reticular pseudodrusen; thin choroid and RPE atrophy simultaneously in eyes with angioid streaks due to Pseudoxanthoma elasticum and proposes a common pathophysiological mechanism for the same.

References

  1. Bergen AA, Plomp AS, Schuurman EJ, et al. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet. 2000;25(2):228–231. doi:10.1038/76109 [CrossRef]
  2. Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A. Pseudoxanthoma elasticum: A clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations. J Med Genet. 2005;42(12):881–892. doi:10.1136/jmg.2004.030171 [CrossRef]
  3. Hu X, Plomp AS, van Soest S, Winjholds J, de Jong PT, Bergen AA. Pseudoxanthoma elasticum: A clinical, histopathological and molecular update. Surv Ophthalmol. 2003;48(4):424–438. doi:10.1016/S0039-6257(03)00053-5 [CrossRef]
  4. Gass JD. “Comet” lesion: An ocular sign of Pseudoxanthoma elasticum. Retina. 2003;23(5):729–730. doi:10.1097/00006982-200310000-00029 [CrossRef]
  5. Agarwal A, Patel P, Adkins T, Gass JD. Spectrum of pattern dystrophy in pseudoxanthoma elasticum. Arch Ophthalmol. 2005;123(7):923–928. doi:10.1001/archopht.123.7.923 [CrossRef]
  6. McDonald HR, Schatz H, Aaberg TM. Reticular-like pigmentary patterns in pseudoxanthoma elasticum. Ophthalmology. 1988;95(3):306–311. doi:10.1016/S0161-6420(88)33182-9 [CrossRef]
  7. Zweifel SA, Imamura Y, Freund KB, Spaide RF. Multimodal fundus imaging of pseudoxanthoma elasticum. Retina. 2011;31(3):482–491. doi:10.1097/IAE.0b013e3181f056ce [CrossRef]
  8. Sawa M, Ober MD, Freund KB, Spaide RF. Fundus autofluorescence in patients with pseudoxanthoma elasticum. Ophthalmology. 2006;113(5):814–820. doi:10.1016/j.ophtha.2006.01.037 [CrossRef]
  9. Querques G, Querques L, Forte R, Massamba N, Coscas F, Souied EH. Choroidal changes associated with reticular pseudodrusen. Invest Ophthalmol Vis Sci. 2012;53(3):1258–1263. doi:10.1167/iovs.11-8907 [CrossRef]
  10. Finger RP, Wu Z, Luu CD, et al. Reticular pseudodrusen: A risk factor for geographic atrophy in fellow eyes of individuals with unilateral choroidal neovascularization. Ophthalmology. 2014;121(6):1252–1256. doi:10.1016/j.ophtha.2013.12.034 [CrossRef]
  11. Ellabban AA, Tsujikawa A, Matsumoto A, et al. Macular choroidal thickness and volume in eyes with angioid streaks measured by swept source optical coherence tomography. Am J Ophthalmol. 2012;153(6):1133–1143. doi:10.1016/j.ajo.2011.12.013 [CrossRef]
  12. Gliem M, Fimmers R, Müller PL, et al. Choroidal changes associated with Bruch membrane pathology in pseudoxanthoma elasticum. Am J Ophthalmol. 2014;158(1):198–207. doi:10.1016/j.ajo.2014.04.005 [CrossRef]
  13. Dolz-Marco R, Andreu-Fenoll M, Hernández-Martínez P, Pinazo-Durán MD, Gallego-Pinazo R. Automated macular choroidal thickness measurement by swept-source optical coherence tomography in pseudoxanthoma elasticum. Int J Retina Vitreous. 2016;2:15. doi:10.1186/s40942-016-0040-0 [CrossRef]
  14. Gliem M, Hendig D, Finger RP, Holz FG, Issa PC. Reticular pseudodrusen associated with a diseased Bruch membrane in pseudoxanthoma elasticum. JAMA Ophthalmol. 2015;133(5):581–588. doi:10.1001/jamaophthalmol.2015.117 [CrossRef]
  15. Gliem M, Müller PL, Birtel J, Hendig D, Holz FG, Issa PC. Frequency, phenotypic characteristics and progression of atrophy associated with a diseased Bruch's membrane in pseudoxanthoma elasticumatrophy in pseudoxanthoma elasticum. Invest Ophthalmol Vis Sci. 2016;57(7):3323–3330. doi:10.1167/iovs.16-19388 [CrossRef]
  16. Booij JC, Baas DC, Beisekeeva J, Gorgels TG, Bergen AA. The dynamic nature of Bruch's membrane. Prog Retin Eye Res. 2010;29:1–8. doi:10.1016/j.preteyeres.2009.08.003 [CrossRef]
  17. Gliem M, Müller PL, Mangold E, Bolz HJ, Stöhr H, Weber BH, Holz FG, Issa PC. Reticular pseudodrusen in Sorsby fundus dystrophy. Ophthalmology. 2015;122(8):1555–1562. doi:10.1016/j.ophtha.2015.04.035 [CrossRef]
  18. Mrejen S, Spaide RF. The relationship between pseudodrusen and choroidal thickness. Retina. 2014;34(8):1560–1566. doi:10.1097/IAE.0000000000000139 [CrossRef]
  19. Schmitz-Valckenberg S, Alten F, Steinberg JS, et al. Reticular drusen associated with geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011;52(9):5009–5015. doi:10.1167/iovs.11-7235 [CrossRef]
  20. Ueda-Arakawa N, Ooto S, Tsujikawa A, et al. Sensitivity and specificity of detecting reticular pseudodrusen in multimodal imaging in Japanese patients. Retina. 2013;33(3):490–497. doi:10.1097/IAE.0b013e318276e0ae [CrossRef]

Detailed Demographic and Clinical Features of all Study Eyes

Age (Years) Sex Eye BCVA SFCT (μm) CNV RPD RPE Atrophy Comet Lesions Peau d' Orange Appearance
43 M R 1 163 No Yes No No Yes
L 0.25 154 Yes Yes No No Yes
40 F R 1 160 No No Yes (P) No Yes
L 0.1 170 Yes No Yes (P) No Yes
34 M R 0.16 236 Yes Yes Yes (P) Yes Yes
L 0.67 228 Yes Yes Yes (P) Yes Yes
43 M R 0.5 142 No Yes Yes Yes Yes
L 0.05 120 Yes (F) Yes Yes Yes Yes
63 M R 0.1 137 Yes Yes No No No
L 1 217 No Yes No No No
44 M R 0.1 122 Yes No No Yes Yes
L 0.33 188 Yes No No Yes Yes
41 F R 1 179 No No No No No
L 0.16 230 Yes No No No No
56 F R 0.1 166 Yes Yes Yes Yes No
L 0.01 179 Yes (F) Yes Yes Yes No
Authors

From Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.

Dr. Kumar reports no relevant financial disclosures.

Address correspondent to Vinod Kumar, MS, DNB, MNAMS, FRCS (Glasg), 57 Sadar Apartments, Mayur Vihar Phase 1 Extension, New Delhi, India 110091; email: drvinod_agg@yahoo.com.

Received: July 04, 2017
Accepted: November 01, 2017

10.3928/23258160-20180601-04

Sign up to receive

Journal E-contents