SUBFOVEAL CHOROIDAL THICKNESS IN RETINAL ANGIOMATOUS PROLIFERATION TAIZO YAMAZAKI, MD, HIDEKI KOIZUMI, MD, PHD, TETSUYA YAMAGISHI, MD, SHIGERU KINOSHITA, MD, PHD Purpose: To investigate the subfoveal choroidal thickness in patients with retinal angiomatous proliferation (RAP). Methods: In consecutive patients with RAP, subfoveal choroidal thickness was retrospectively measured by the use of enhanced depth imaging spectral domain optical coherence tomography in comparison with age-matched control subjects. Results: Nineteen eyes of 19 patients with RAP and 32 eyes of 32 control subjects were included in this study. No significant differences were found between the eyes with RAP and the control eyes regarding age, gender, spherical equivalent, and axial length. Mean subfoveal choroidal thickness in 19 eyes with RAP was significantly less than that in the control eyes (129.5 ± 35.8 mm vs. 201.3 ± 55.0 mm, P , 0.0001). The difference in mean subfoveal choroidal thickness between eyes with Stage 2 RAP (132.8 ± 38.2 mm) and eyes with Stage 3 RAP (126.4 ± 36.6 mm) was not significant, though each measurement was significantly less than that in the control eyes (P , 0.001 and P = 0.002, respectively). Conclusion: Eyes with RAP had a significantly thinner subfoveal choroid compared with normal eyes. Such morphologic features may be related to the pathologic mechanism of RAP. RETINA 34:1316–1322, 2014
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patients with unilateral RAP increases over time with high percentages varying from 36.3% to 100% within 3 years.7,8 We previously reported that choroidal circulatory disturbances seemed to play a role in the development of RAP.9 In that report, the incidence of persistent, decreased choroidal filling in the macula was observed not only in 81.8% of eyes with RAP, but also in 50% of fellow eyes of patients with unilateral RAP on indocyanine green angiography.9 However, even though the development of concurrent choroidal neovascularization is reportedly observed in the advanced stage of RAP, little is known about morphologic features of the choroid under the RAP lesions and choroidal neovascularization. If the choroidal circulation in patients with RAP is disturbed, the choroidal thickness also may be altered. The imaging method known as enhanced depth imaging optical coherence tomography (EDI-OCT) has been developed.10 Enhanced depth imaging optical coherence tomography enables visualization of the cross-sectional structure of the choroid and measurement of the choroidal thickness. Several previous studies demonstrated that choroidal thickness in normal
etinal angiomatous proliferation (RAP) is a clinical entity generally categorized as a subtype of neovascular age-related macular degeneration (AMD), and represents a peculiar form of neovascularization.1 Yannuzzi et al1 proposed that the neovascular membranes originate from the retinal capillaries and extend toward the subretinal space, eventually forming retinochoroidal anastomoses with concurrent choroidal neovascularization, though the origin of the neovascular process is still a subject of discussion.1–3 Several hospital-based studies demonstrated that the prevalence of RAP in newly diagnosed neovascular AMD was 15.1% in whites and 4.5% in Asians.4–6 Several studies have reported that although RAP is a relatively rare subtype of neovascular AMD, bilateral severe loss of vision frequently occurs in patients with RAP, and the risk of fellow-eye involvement in From the Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Hideki Koizumi, MD, PhD, Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602–0841, Japan; e-mail: hidekoiz@ koto.kpu-m.ac.jp
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eyes could be measured using the EDI-OCT technique, and the results indicated that there were significant correlations between choroidal thickness and age, spherical equivalent, and the axial length.11–14 Several previous studies reported successful measurements of choroidal thickness in eyes with neovascular AMD, that is, in typical neovascular AMD and polypoidal choroidal vasculopathy.15–19 In addition, we recently demonstrated that subfoveal choroidal thickness in eyes with neovascular AMD including RAP decreased after the intravitreal injections of ranibizumab.20 In that study, one eye with RAP appeared to have a markedly thin choroid at baseline compared with eyes with typical neovascular AMD or polypoidal choroidal vasculopathy.20 However, the thin choroid in eyes with RAP might be attributed to age-related changes or the influence of previous treatments, and the pathologic relationship between the thin choroid and RAP still remains unclear. In this study, in an attempt to assess the morphologic feature of the choroid in RAP, we investigated subfoveal choroidal thickness in eyes of patients with RAP using EDI-OCT and compared the data with that obtained from control eyes.
Patients and Methods For this cross-sectional study, we retrospectively evaluated 48 eyes of 24 consecutive patients with symptomatic RAP who were initially seen at the Macula Service of Kyoto Prefectural University of Medicine between April 2009 and May 2012. At the time of initial diagnosis, each patient underwent comprehensive ophthalmic examinations including refraction, best-corrected visual acuity testing with a Landort C chart, measurement of the axial length using an interferometer (IOL Master; Carl Zeiss Meditec, Inc, La Jolla, CA), slit-lamp biomicroscopy with contact or noncontact lenses, color fundus photography, fluorescein angiography, and indocyanine green angiography using a confocal scanning laser ophthalmoscopy (HRA-2; Heidelberg Engineering Inc, Dossenheim, Germany), and spectral domain OCT (3D-OCT 2000; Topcon Corp, Tokyo, Japan). The diagnosis of RAP was then made by an experienced ophthalmologist (H.K.) based on the funduscopic and angiographic findings, and was classified into one of three vasogenic stages according to the established grading system.1 Stage 1 RAP involved proliferation of intraretinal capillaries originating from the deep retinal complex and confined within the neurosensory retina. Stage 2 RAP was determined by extension of the proliferating intraretinal membranes into the
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subretinal space, with or without pigment epithelial detachment. Stage 3 RAP had retinal angiomatous neovascular membranes coexisting with choroidal neovascularization. The exclusion criteria for eyes of patients with RAP were 1) treatment histories of RAP; 2) a disciform scar formation resulting from the neovascular process; 3) concurrent diabetic retinopathy because of possibly altered choroidal thickness21; 4) intraocular surgery within the previous 6 months; 5) additional chorioretinal disorders impairing vision; and 6) no available spherical equivalent or axial length data. When the patient had bilateral RAP lesion, the right eye was included in this study to prevent a selection bias. To measure the subfoveal choroidal thickness, the EDI-OCT method was applied by using the choroidal mode within the OCT.10,15,20 In all examined eyes, 6-mm horizontal and vertical scans, each consisting of a maximum of 50 averaged scans, were obtained through the center of the fovea. The one of two scans in which the choroid–scleral interface was more clearly visualized was selected. Subfoveal choroidal thickness was measured as the vertical distance from the hyperreflective line corresponding to the Bruch membrane beneath the retinal pigment epithelium (RPE) under the fovea to the inner scleral border using the caliper function within the OCT. The average value of the measurements by two independent observers (T.Y. and T.Y.), who were masked to the patients’ information, was defined as the subfoveal choroidal thickness. The correlation of choroidal thickness measurements between the observers was assessed using the Spearman’s correlation test. For the comparative study, 32 control eyes of 32 subjects in which EDI-OCT images were available were randomly selected as age-matched control subjects from the database of patients who complained of visual impairment because of senile cataract without another disorder, such as retinal disease, glaucoma, and uveitis, etc. All patients in the database underwent comprehensive ophthalmic examinations including refraction, best-corrected visual acuity testing with a Landort C chart, measurement of the axial length using the interferometer, slit-lamp biomicroscopy with contact or noncontact lenses, color fundus photography, and spectral domain OCT. Patients who did not have spherical equivalent within ± 6.00 diopters (D) or an axial length between 22.0 mm and 26.0 mm were excluded from the control group. To construct the age-matched control group, the age groups were truncated to match those of the patients with RAP. The control subjects were then selected at random from the truncated lists. The right eyes of the control subjects were included in the control eyes to prevent a selection bias, and in the eyes with RAP.
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The obtained data were analyzed with frequency and descriptive statistics. The Mann–Whitney U test was used for the analyses of age, spherical equivalent, axial length, and subfoveal choroidal thickness and the chi-square test for the analysis of sex between the 2 groups. The Spearman’s correlation test was performed to assess the variation in subfoveal choroidal thickness in relation to age, spherical equivalent, and axial length. Best-corrected visual acuity was converted to logarithm of the minimum angle of resolution units before the calculations. All values were expressed as mean ± standard deviation. A P , 0.05 was considered statistically significant. All statistical analyses were performed with Statcell software version 3.0 (OMS Publishing Inc, Saitama, Japan). This retrospective study followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Kyoto Prefectural University of Medicine.
Results Forty-eight eyes of 24 patients with RAP were initially evaluated. Of the 48 eyes, 24 eyes were excluded, including 7 unaffected fellow eyes, 8 eyes with various treatment histories for RAP, 6 eyes with a disciform scar in the macula, 2 eyes with concurrent diabetic retinopathy, and 1 pseudophakic eye with missing data of the axial length. Because 5 patients (26%) had bilateral RAP lesion, the left eyes were excluded. Nineteen eyes of 19 patients were subsequently included in this study. All of the 19 included eyes had spherical equivalent within ± 6.00 D or an axial length between 22.00 mm and 26.00 mm. Of the 19 treatment-naive eyes with RAP, 1 eye (5%) was diagnosed as Stage 1, 11 eyes (58%) were diagnosed as Stage 2, and 7 eyes (37%) were diagnosed as Stage 3. The clinical profile of the 19 included patients with RAP is summarized in Table 1. Characteristics of the RAP group (19 eyes) and the age-matched control group (32 eyes) are summarized in Table 2. There were no significant differences not only between the patients with RAP and the control subjects regarding age and gender (P = 0.38 and P = 0.08, respectively), but also between the eyes with RAP and the control eyes regarding spherical equivalent and axial length (P = 0.79 and P = 0.20, respectively). The logarithm of the minimum angle of resolution bestcorrected visual acuity of the control eyes was significantly lower than that of the eyes with RAP (P , 0.001). There was a highly significant correlation of choroidal thickness measurements between the 2 independent observers (rs = 0.95, P , 0.001). Mean
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subfoveal choroidal thickness in all 19 eyes with RAP was significantly less than that in the 32 control eyes (129.5 ± 35.8 mm vs. 201.3 ± 55.0 mm, P , 0.0001) (Figure 1). Regarding the stages of RAP, the subfoveal choroidal thickness in eye with Stage 1 RAP was 115 mm. After that eye was excluded because of the small sample size, the difference in mean subfoveal choroidal thickness between eyes with Stage 2 RAP (132.8 ± 38.2 mm) and eyes with Stage 3 RAP (126.4 ± 36.6 mm) was evaluated (Figure 2). Although mean subfoveal choroidal thickness in each of the 2 groups of eyes with RAP was significantly less than that in the control eyes (P , 0.001 and P = 0.002, respectively), there was no significant difference between the 2 groups (P = 0.75). Interestingly, mean subfoveal choroidal thickness in the 7 unaffected fellow eyes of the 7 patients with unilateral RAP (149.6 ± 50.7 mm) was significantly less than that in the control eyes (P = 0.03). Subfoveal choroidal thickness in all 19 included eyes with RAP was found to be not correlated with age, spherical equivalent, and axial length (rs = 0.15, P = 0.52, rs = 0.09, P = 0.76, and rs = 0.06, P = 0.81, respectively), whereas that in the control eyes was correlated with age (rs = 0.45, P = 0.01) but was not correlated with spherical equivalent and axial length (rs = 0.19, P = 0.30 and rs = 0.20, P = 0.27, respectively). The representative case is shown in Figure 3. Discussion In this study, EDI-OCT measurements of subfoveal choroidal thickness demonstrated that eyes with RAP had a significantly thinner choroid compared with the age-matched control eyes. Although mean subfoveal choroidal thickness in each of the eyes with Stage 2 RAP and Stage 3 RAP was significantly less than that in the control eyes, there was no significant difference between the 2 groups. Mean subfoveal choroidal thickness was less even in the unaffected fellow eyes of patients with unilateral RAP than in the control eyes. These results suggest that the thin choroid would have already presented in the unaffected fellow eyes of patients with unilateral RAP and might not be caused by the development or progression of the neovascular lesions of RAP. Therefore, it may be possible that the thin choroid has a certain relationship with the pathologic mechanism of RAP. In our previous report, choroidal circulatory disturbances on indocyanine green angiography were commonly seen not only in eyes with RAP, but also in the contralateral fellow eyes of patients with unilateral RAP.9 Therefore, the results shown in this study might be consistent with such angiographic abnormalities.
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SUBFOVEAL CHOROIDAL THICKNESS IN RAP YAMAZAKI ET AL Table 1. Clinical Profiles of the Patients With RAP
Case
Age, years/ Gender
1
65/M
2
68/M
3
71/F
4
79/F
5
85/M
6
90/M
7
79/M
8
82/M
9
82/M
10
87/M
11
88/F
12
89/M
13
85/F
14
82/F
15
85/F
16
85/M
17
76/M
18
91/M
19
92/F
Eye
Disorder
Previous Treatment
OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS
Stage 2 RAP Drusen Drusen Stage 2 RAP Stage 2 RAP Drusen Drusen Stage 2 RAP Stage 2 RAP Drusen Drusen Stage 3 RAP Stage 3 RAP Stage 1 RAP/excluded Stage 2 RAP Stage 3 RAP/excluded Stage 2 RAP Stage 3 RAP/excluded Stage 2 RAP Stage 3 RAP/excluded Stage 3 RAP Stage 3 RAP/excluded Stage 3 RAP Stage 3 RAP/excluded Stage 1 RAP Disciform/excluded Disciform/excluded Stage 2 RAP Disciform/excluded Stage 2 RAP Stage 2 RAP Disciform/excluded Disciform/excluded Stage 3 RAP Stage 3 RAP Disciform/excluded Stage 3 RAP Disciform/excluded
− − − − − − − − − − − − − − − − − − − − − − − + − − + − − − − − + − − − − −
BCVA, logMAR 0.52 0.00 0.05 0.70 1.16 −0.08 0.30 0.52 0.82 0.22 0.52 1.52 1.10 0.30 0.40 1.22 0.52 1.10 0.70 1.70 2.00 0.82 0.70 1.70 0.30 2.00 2.00 0.40 2.00 0.82 0.52 2.00 1.52 1.00 1.22 0.05 1.52 2.00
Lens
Spherical Equivalent, D
Axial Length, mm
SCT, mm
Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic IOL IOL IOL IOL IOL IOL Phakic Phakic IOL IOL IOL Phakic Phakic Phakic IOL Phakic IOL Phakic Phakic IOL Phakic Phakic
−4.250 −4.250 1.125 −1.750 −1.000 −0.625 −5.75 −5.750 −0.375 1.000 0.750 −0.500 −1.500 −2.875 1.250 1.125 −1.000* −1.750* −2.250* 2.000* −1.500* −2.250* 1.250 0.250 −0.500* −1.000* −1.500* 0.375 −0.375 0.375 −1.625* −1.500 −1.750* −0.125 2.250 −0.125* 0.125 1.125
NA NA 23.91 24.01 24.00 24.29 25.06 25.00 23.93 23.68 23.67 23.42 24.15 24.97 23.47 22.99 23.36 23.07 22.72 22.44 22.40 22.46 NA NA 22.41 22.22 22.76 23.30 23.33 23.37 24.80 NA 23.57 23.71 25.09 NA NA NA
110.0 105.0 148.0 159.0 128.0 120.5 169.5 135.0 168.0 180.5 88.0 122.0 86.0 79.0 128.5 142.0 73.0 73.5 197.0 193.5 101.5 181.5 161.5 NA 115.0 NA NA 76.0 NA 165.5 121.0 NA NA 149.5 88.0 NA 176.5 NA
*Data were obtained after the insertion of IOL. BCVA, best-corrected visual acuity; F, female; IOL, intraocular lens; M, male; NA, not available; OD, right eye; OS, left eye; SCT, subfoveal choroidal thickness.
By means of EDI-OCT, subfoveal choroidal thickness was measured in normal eyes and was shown to be inversely proportional to age and axial length.11–14 In this study, although subfoveal choroidal thickness in normal eyes was negatively correlated with increasing age, it was not related to age, spherical equivalent, or axial length in eyes with RAP. These findings indicate that other unknown factors may be involved primarily in the pathophysiology of RAP and may greatly affect choroidal thickness as compared with the expected reduction induced by aging or myopia. The cause of the thin choroid and its relationship to the development of RAP remain unknown. It has been suggested that vascular endothelial growth factor
(VEGF)-A secretion from RPE cells toward choriocapillaris is disturbed by age-related thickening of the Bruch membrane with lipophilic material.22 Thus, VEGF-A from the RPE cells might not be able to regulate the integrity of choriocapillaris or be able to maintain the fenestrated permeable phenotype of its endothelium,23 which results in choriocapillaris atrophy as disclosed histologically in aged eyes.24 Retinal angiomatous proliferation is more prevalent in older patients, and large and multiple drusen were frequently seen in eyes with RAP and even in the unaffected fellow eyes.5 Accordingly, a high degree of diffusional disturbances of VEGF-A in eyes of patients with RAP may induce atrophic changes of choriocapillaris
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Table 2. Characteristics of the Patients With RAP and the Age-Matched Control Subjects
Age, years, mean ± SD Female, n (%) Spherical equivalent, mean ± SD, D Axial length, mean ± SD, mm BCVA, mean ± SD, logMAR
RAP Group (19 Eyes)
Control Group (32 Eyes)
P
82.2 ± 7.6 (65 to 91) 7 (37) −0.69 ± 2.14‡ (−5.75 to 2.25) 23.7 ± 0.8§ (22.4 to 25.1) 0.87 ± 0.46 (0.30 to 2.00)
81.2 ± 6.6 (68 to 96) 20 (63) −0.71 ± 1.69 (−4.56 to 1.88) 23.4 ± 0.7 (22.3 to 25.0) 0.38 ± 0.28 (−0.08 to 0.82)
0.38* 0.08† 0.79* 0.20* ,0.001*
*Mann–Whitney U test. †Chi-square test. ‡Data of 14 eyes except for 5 pseudophakic eyes. §Data of 16 eyes having the available data. BCVA, best-corrected visual acuity; SD, standard deviation.
compared with normal eyes. The reason why the thin choroid was seen in eyes of patients with RAP including the unaffected fellow eyes might be, at least partially, attributed to choriocapillaris atrophy, although the precise cause of the thin choroid remains unexplained. Another possibility is that the choroidal thinning seen in patients with RAP might be destined by a certain factor, for example, by the genetic background.25,26 Holz et al27 hypothesized that an imbalance between VEGF and pigment epithelial-derived factors arising from the apical side of the RPE cells may induce the growth of neovascular membranes outward from the retinal capillaries in RAP. Indeed, it has been recently reported that in eyes with untreated neovascular AMD, aqueous humor levels of VEGF are significantly higher in Type 3 neovascularization (so-called “RAP”) than in Type 1 or Type 2 neovascularization.28 The cause for such differences in cytokine levels is unknown, but there might be a decrease in the metabolic supply from the choroid as a result of reduced diffusion of substances through the thickened Bruch membrane, or there might be a reduced oxygen supply resulting from
changes in choriocapillaries.29 Our results showing that the thin choroid had already presented in the unaffected fellow eyes of patients with unilateral RAP may support the hypothesis by Holz et al27 in terms of the possibility that the thin choroid induces hypoxic conditions in the RPE cells. We previously reported that mean subfoveal choroidal thickness was greater in eyes with polypoidal choroidal vasculopathy (293.4 mm) than in those with typical AMD (244.6 mm).15 Mean subfoveal choroidal thickness in eyes with RAP, which was 129.5 mm, appeared to be the thinnest among these 3 subtypes of neovascular AMD measured in the previous and present studies. Therefore, although RAP is now generally classified as one subtype of neovascular AMD, morphologic differences in the choroid may be engaged in great variation in clinical characteristics of neovascular AMD. Further studies are needed to elucidate the differences in pathophysiology among the subtypes of neovascular AMD. It should be noted that there were several limitations in this study, such as few subjects included and its
Fig. 1. Subfoveal choroidal thickness comparison between eyes with RAP (19 eyes) and control eyes (32 eyes). Mean subfoveal choroidal thickness was significantly less in the eyes with RAP (129.5 ± 35.8 mm) than in the control eyes (201.3 ± 55.0 mm) (P , 0.0001).
Fig. 2. The differences in subfoveal choroidal thickness among Stage 2 RAP eyes, Stage 3 RAP eyes, and control eyes. One eye with Stage 1 RAP was excluded from this comparison because of the small sample size. Mean subfoveal choroidal thickness was 132.8 ± 38.2 mm, 126.4 ± 36.6 mm, and 201.3 ± 55.0 mm, respectively. Each of the mean subfoveal choroidal thickness findings in the two groups of eyes with RAP was significantly less than that in the normal eyes (P , 0.001 and P = 0.002, respectively), although there was no significant difference in mean subfoveal choroidal thickness between the 2 groups (P = 0.75).
SUBFOVEAL CHOROIDAL THICKNESS IN RAP YAMAZAKI ET AL
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Fig. 3. Case 2: The left eye of a 68-year-old man with Stage 2 RAP. A. Color fundus photograph shows a reddish neovascular membrane (arrow) and multiple soft drusen. B. Fluorescein angiography reveals dye leakage from the neovascular lesion. C. Enhanced depth imaging optical coherence tomography through the center of the fovea horizontally demonstrates cystic spaces in the neurosensory retina and the crosssectional choroidal structure. The subfoveal choroidal thickness was 159 mm (double-headed arrow). Arrowheads indicate the inner surface of the sclera. D. Indocyanine green angiography shows a hyperfluorescent spot (arrow) corresponding to the retinal neovascular lesion, but there is no evident concurrent choroidal neovascularization.
retrospective cross-sectional design. The measurement of subfoveal choroidal thickness was obtained manually because currently there is no automated software available. In addition, a comparison with an agematched non-RAP neovascular AMD group could not be performed. More importantly, the decrease in choroidal thickness might not be necessarily correlated with reduced choroidal blood flow.30 However, and to the best of our knowledge, this is the first report concerning choroidal thickness in RAP. In conclusion, this study demonstrated that subfoveal choroidal thickness in eyes with RAP appeared to be significantly thinner than that in control eyes. The thin choroid had already presented in the unaffected fellow eyes of patients with unilateral RAP. Such morphologic features in the choroid might be involved in the pathologic mechanism of RAP. The EDI-OCT imaging used in this study was a noninvasive method to enable to obtain the images of the choroid unavailable by other means. Additional studies are warranted to investigate the relationship between choroidal circulation and choroidal thickness on EDI-OCT images, which might provide a further understanding of the pathophysiology of RAP.
Key words: age-related macular degeneration, retinal angiomatous proliferation, subfoveal choroidal thickness, enhanced depth imaging optical coherence tomography. References 1. Yannuzzi LA, Negrao S, Iida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 2001;21:416–434. 2. Freund KB, Ho IV, Barbazetto IA, et al. Type 3 neovascularization: the expanded spectrum of retinal angiomatous proliferation. Retina 2008;28:201–211. 3. Gass JD, Agarwal A, Lavina AM, Tawansy KA. Focal inner retinal hemorrhages in patients with drusen: an early sign of occult choroidal neovascularization and chorioretinal anastomosis. Retina 2003;23:741–751. 4. Cohen SY, Creuzot-Garcher C, Darmon J, et al. Types of choroidal neovascularisation in newly diagnosed exudative age-related macular degeneration. Br J Ophthalmol 2007;91: 1173–1176. 5. Maruko I, Iida T, Saito M, et al. Clinical characteristics of exudative age-related macular degeneration in Japanese patients. Am J Ophthalmol 2007;144:15–22. 6. Liu Y, Wen F, Huang S, et al. Subtype lesions of neovascular age-related macular degeneration in Chinese patients. Graefes Arch Clin Exp Ophthalmol 2007;245:1441–1445.
1322 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 7. Campa C, Harding SP, Pearce IA, et al. Incidence of neovascularization in the fellow eye of patients with unilateral retinal angiomatous proliferation. Eye (Lond) 2010;24:1585–1589. 8. Gross NE, Aizman A, Brucker A, et al. Nature and risk of neovascularization in the fellow eye of patients with unilateral retinal angiomatous proliferation. Retina 2005;25:713–718. 9. Koizumi H, Iida T, Saito M, et al. Choroidal circulatory disturbances associated with retinal angiomatous proliferation on indocyanine green angiography. Graefes Arch Clin Exp Ophthalmol 2008;246:515–520. 10. Spaide RF. Enhanced depth imaging optical coherence tomography of retinal pigment epithelial detachment in age-related macular degeneration. Am J Ophthalmol 2009;147:644–652. 11. Margolis R, Spaide RF. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am J Ophthalmol 2009;147:811–815. 12. Li XQ, Larsen M, Munch IC. Subfoveal choroidal thickness in relation to sex and axial length in 93 Danish university students. Invest Ophthalmol Vis Sci 2011;52:8438–8441. 13. Ding X, Li J, Zeng J, et al. Choroidal thickness in healthy Chinese subjects. Invest Ophthalmol Vis Sci 2011;52:9555–9560. 14. Tan CS, Ouyang Y, Ruiz H, Sadda SR. Diurnal variation of choroidal thickness in normal, healthy subjects measured by spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci 2012;53:261–266. 15. Koizumi H, Yamagishi T, Yamazaki T, et al. Subfoveal choroidal thickness in typical age-related macular degeneration and polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2011;249:1123–1128. 16. Chung SE, Kang SW, Lee JH, Kim YT. Choroidal thickness in polypoidal choroidal vasculopathy and exudative age-related macular degeneration. Ophthalmology 2011;118:840–845. 17. Maruko I, Iida T, Sugano Y, et al. Subfoveal retinal and choroidal thickness after verteporfin photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol 2011; 151:594–603.e1. 18. Kim SW, Oh J, Kwon SS, et al. Comparison of choroidal thickness among patients with healthy eyes, early age-related maculopathy, neovascular age-related macular degeneration, central serous chorioretinopathy, and polypoidal choroidal vasculopathy. Retina 2011;31:1904–1911.
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19. Jirarattanasopa P, Ooto S, Nakata I, et al. Choroidal thickness, vascular hyperpermeability, and complement factor H in agerelated macular degeneration and polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 2012;53:3663–3672. 20. Yamazaki T, Koizumi H, Yamagishi T, Kinoshita S. Subfoveal choroidal thickness after ranibizumab therapy for neovascular age-related macular degeneration: 12-month results. Ophthalmology 2012;119:1621–1627. 21. Regatieri CV, Branchini L, Carmody J, et al. Choroidal thickness in patients with diabetic retinopathy analyzed by spectral-domain optical coherence tomography. Retina 2012;32:563–568. 22. Holz FG, Sheraidah G, Pauleikhoff D, Bird AC. Analysis of lipid deposits extracted from human macular and peripheral Bruch’s membrane. Arch Ophthalmol 1994;112:402–406. 23. Esser S, Wolburg K, Wolburg H, et al. Vascular endothelial growth factor induces endothelial fenestrations in vitro. J Cell Biol 1998;140:947–959. 24. Ramrattan RS, van der Schaft TL, Mooy CM, et al. Morphometric analysis of Bruch’s membrane, the choriocapillaris, and the choroid in aging. Invest Ophthalmol Vis Sci 1994;35:2857–2864. 25. Hayashi H, Yamashiro K, Gotoh N, et al. CFH and ARMS2 variations in age-related macular degeneration, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation. Invest Ophthalmol Vis Sci 2010;51:5914–5919. 26. Tanaka K, Nakayama T, Yuzawa M, et al. Analysis of candidate genes for age-related macular degeneration subtypes in the Japanese population. Mol Vis 2011;17:2751–2758. 27. Holz FG, Pauleikhoff D, Klein R, Bird AC. Pathogenesis of lesions in late age-related macular disease. Am J Ophthalmol 2004;137:504–510. 28. dell’Omo R, Cassetta M, dell’Omo E, et al. Aqueous humor levels of vascular endothelial growth factor before and after intravitreal bevacizumab in type 3 versus type 1 and 2 neovascularization. A prospective, case-control study. Am J Ophthalmol 2012;153:155–161. 29. Moore DJ, Hussain AA, Marshall J. Age-related variation in the hydraulic conductivity of Bruch’s membrane. Invest Ophthalmol Vis Sci 1995;36:1290–1297. 30. Sogawa K, Nagaoka T, Takahashi A, et al. Relationship between choroidal thickness and choroidal circulation in healthy young subjects. Am J Ophthalmol 2012;153:1129–1132.
R
patients with unilateral RAP increases over time with high percentages varying from 36.3% to 100% within 3 years.7,8 We previously reported that choroidal circulatory disturbances seemed to play a role in the development of RAP.9 In that report, the incidence of persistent, decreased choroidal filling in the macula was observed not only in 81.8% of eyes with RAP, but also in 50% of fellow eyes of patients with unilateral RAP on indocyanine green angiography.9 However, even though the development of concurrent choroidal neovascularization is reportedly observed in the advanced stage of RAP, little is known about morphologic features of the choroid under the RAP lesions and choroidal neovascularization. If the choroidal circulation in patients with RAP is disturbed, the choroidal thickness also may be altered. The imaging method known as enhanced depth imaging optical coherence tomography (EDI-OCT) has been developed.10 Enhanced depth imaging optical coherence tomography enables visualization of the cross-sectional structure of the choroid and measurement of the choroidal thickness. Several previous studies demonstrated that choroidal thickness in normal
etinal angiomatous proliferation (RAP) is a clinical entity generally categorized as a subtype of neovascular age-related macular degeneration (AMD), and represents a peculiar form of neovascularization.1 Yannuzzi et al1 proposed that the neovascular membranes originate from the retinal capillaries and extend toward the subretinal space, eventually forming retinochoroidal anastomoses with concurrent choroidal neovascularization, though the origin of the neovascular process is still a subject of discussion.1–3 Several hospital-based studies demonstrated that the prevalence of RAP in newly diagnosed neovascular AMD was 15.1% in whites and 4.5% in Asians.4–6 Several studies have reported that although RAP is a relatively rare subtype of neovascular AMD, bilateral severe loss of vision frequently occurs in patients with RAP, and the risk of fellow-eye involvement in From the Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Hideki Koizumi, MD, PhD, Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602–0841, Japan; e-mail: hidekoiz@ koto.kpu-m.ac.jp
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SUBFOVEAL CHOROIDAL THICKNESS IN RAP YAMAZAKI ET AL
eyes could be measured using the EDI-OCT technique, and the results indicated that there were significant correlations between choroidal thickness and age, spherical equivalent, and the axial length.11–14 Several previous studies reported successful measurements of choroidal thickness in eyes with neovascular AMD, that is, in typical neovascular AMD and polypoidal choroidal vasculopathy.15–19 In addition, we recently demonstrated that subfoveal choroidal thickness in eyes with neovascular AMD including RAP decreased after the intravitreal injections of ranibizumab.20 In that study, one eye with RAP appeared to have a markedly thin choroid at baseline compared with eyes with typical neovascular AMD or polypoidal choroidal vasculopathy.20 However, the thin choroid in eyes with RAP might be attributed to age-related changes or the influence of previous treatments, and the pathologic relationship between the thin choroid and RAP still remains unclear. In this study, in an attempt to assess the morphologic feature of the choroid in RAP, we investigated subfoveal choroidal thickness in eyes of patients with RAP using EDI-OCT and compared the data with that obtained from control eyes.
Patients and Methods For this cross-sectional study, we retrospectively evaluated 48 eyes of 24 consecutive patients with symptomatic RAP who were initially seen at the Macula Service of Kyoto Prefectural University of Medicine between April 2009 and May 2012. At the time of initial diagnosis, each patient underwent comprehensive ophthalmic examinations including refraction, best-corrected visual acuity testing with a Landort C chart, measurement of the axial length using an interferometer (IOL Master; Carl Zeiss Meditec, Inc, La Jolla, CA), slit-lamp biomicroscopy with contact or noncontact lenses, color fundus photography, fluorescein angiography, and indocyanine green angiography using a confocal scanning laser ophthalmoscopy (HRA-2; Heidelberg Engineering Inc, Dossenheim, Germany), and spectral domain OCT (3D-OCT 2000; Topcon Corp, Tokyo, Japan). The diagnosis of RAP was then made by an experienced ophthalmologist (H.K.) based on the funduscopic and angiographic findings, and was classified into one of three vasogenic stages according to the established grading system.1 Stage 1 RAP involved proliferation of intraretinal capillaries originating from the deep retinal complex and confined within the neurosensory retina. Stage 2 RAP was determined by extension of the proliferating intraretinal membranes into the
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subretinal space, with or without pigment epithelial detachment. Stage 3 RAP had retinal angiomatous neovascular membranes coexisting with choroidal neovascularization. The exclusion criteria for eyes of patients with RAP were 1) treatment histories of RAP; 2) a disciform scar formation resulting from the neovascular process; 3) concurrent diabetic retinopathy because of possibly altered choroidal thickness21; 4) intraocular surgery within the previous 6 months; 5) additional chorioretinal disorders impairing vision; and 6) no available spherical equivalent or axial length data. When the patient had bilateral RAP lesion, the right eye was included in this study to prevent a selection bias. To measure the subfoveal choroidal thickness, the EDI-OCT method was applied by using the choroidal mode within the OCT.10,15,20 In all examined eyes, 6-mm horizontal and vertical scans, each consisting of a maximum of 50 averaged scans, were obtained through the center of the fovea. The one of two scans in which the choroid–scleral interface was more clearly visualized was selected. Subfoveal choroidal thickness was measured as the vertical distance from the hyperreflective line corresponding to the Bruch membrane beneath the retinal pigment epithelium (RPE) under the fovea to the inner scleral border using the caliper function within the OCT. The average value of the measurements by two independent observers (T.Y. and T.Y.), who were masked to the patients’ information, was defined as the subfoveal choroidal thickness. The correlation of choroidal thickness measurements between the observers was assessed using the Spearman’s correlation test. For the comparative study, 32 control eyes of 32 subjects in which EDI-OCT images were available were randomly selected as age-matched control subjects from the database of patients who complained of visual impairment because of senile cataract without another disorder, such as retinal disease, glaucoma, and uveitis, etc. All patients in the database underwent comprehensive ophthalmic examinations including refraction, best-corrected visual acuity testing with a Landort C chart, measurement of the axial length using the interferometer, slit-lamp biomicroscopy with contact or noncontact lenses, color fundus photography, and spectral domain OCT. Patients who did not have spherical equivalent within ± 6.00 diopters (D) or an axial length between 22.0 mm and 26.0 mm were excluded from the control group. To construct the age-matched control group, the age groups were truncated to match those of the patients with RAP. The control subjects were then selected at random from the truncated lists. The right eyes of the control subjects were included in the control eyes to prevent a selection bias, and in the eyes with RAP.
1318 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
The obtained data were analyzed with frequency and descriptive statistics. The Mann–Whitney U test was used for the analyses of age, spherical equivalent, axial length, and subfoveal choroidal thickness and the chi-square test for the analysis of sex between the 2 groups. The Spearman’s correlation test was performed to assess the variation in subfoveal choroidal thickness in relation to age, spherical equivalent, and axial length. Best-corrected visual acuity was converted to logarithm of the minimum angle of resolution units before the calculations. All values were expressed as mean ± standard deviation. A P , 0.05 was considered statistically significant. All statistical analyses were performed with Statcell software version 3.0 (OMS Publishing Inc, Saitama, Japan). This retrospective study followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Kyoto Prefectural University of Medicine.
Results Forty-eight eyes of 24 patients with RAP were initially evaluated. Of the 48 eyes, 24 eyes were excluded, including 7 unaffected fellow eyes, 8 eyes with various treatment histories for RAP, 6 eyes with a disciform scar in the macula, 2 eyes with concurrent diabetic retinopathy, and 1 pseudophakic eye with missing data of the axial length. Because 5 patients (26%) had bilateral RAP lesion, the left eyes were excluded. Nineteen eyes of 19 patients were subsequently included in this study. All of the 19 included eyes had spherical equivalent within ± 6.00 D or an axial length between 22.00 mm and 26.00 mm. Of the 19 treatment-naive eyes with RAP, 1 eye (5%) was diagnosed as Stage 1, 11 eyes (58%) were diagnosed as Stage 2, and 7 eyes (37%) were diagnosed as Stage 3. The clinical profile of the 19 included patients with RAP is summarized in Table 1. Characteristics of the RAP group (19 eyes) and the age-matched control group (32 eyes) are summarized in Table 2. There were no significant differences not only between the patients with RAP and the control subjects regarding age and gender (P = 0.38 and P = 0.08, respectively), but also between the eyes with RAP and the control eyes regarding spherical equivalent and axial length (P = 0.79 and P = 0.20, respectively). The logarithm of the minimum angle of resolution bestcorrected visual acuity of the control eyes was significantly lower than that of the eyes with RAP (P , 0.001). There was a highly significant correlation of choroidal thickness measurements between the 2 independent observers (rs = 0.95, P , 0.001). Mean
2014 VOLUME 34 NUMBER 7
subfoveal choroidal thickness in all 19 eyes with RAP was significantly less than that in the 32 control eyes (129.5 ± 35.8 mm vs. 201.3 ± 55.0 mm, P , 0.0001) (Figure 1). Regarding the stages of RAP, the subfoveal choroidal thickness in eye with Stage 1 RAP was 115 mm. After that eye was excluded because of the small sample size, the difference in mean subfoveal choroidal thickness between eyes with Stage 2 RAP (132.8 ± 38.2 mm) and eyes with Stage 3 RAP (126.4 ± 36.6 mm) was evaluated (Figure 2). Although mean subfoveal choroidal thickness in each of the 2 groups of eyes with RAP was significantly less than that in the control eyes (P , 0.001 and P = 0.002, respectively), there was no significant difference between the 2 groups (P = 0.75). Interestingly, mean subfoveal choroidal thickness in the 7 unaffected fellow eyes of the 7 patients with unilateral RAP (149.6 ± 50.7 mm) was significantly less than that in the control eyes (P = 0.03). Subfoveal choroidal thickness in all 19 included eyes with RAP was found to be not correlated with age, spherical equivalent, and axial length (rs = 0.15, P = 0.52, rs = 0.09, P = 0.76, and rs = 0.06, P = 0.81, respectively), whereas that in the control eyes was correlated with age (rs = 0.45, P = 0.01) but was not correlated with spherical equivalent and axial length (rs = 0.19, P = 0.30 and rs = 0.20, P = 0.27, respectively). The representative case is shown in Figure 3. Discussion In this study, EDI-OCT measurements of subfoveal choroidal thickness demonstrated that eyes with RAP had a significantly thinner choroid compared with the age-matched control eyes. Although mean subfoveal choroidal thickness in each of the eyes with Stage 2 RAP and Stage 3 RAP was significantly less than that in the control eyes, there was no significant difference between the 2 groups. Mean subfoveal choroidal thickness was less even in the unaffected fellow eyes of patients with unilateral RAP than in the control eyes. These results suggest that the thin choroid would have already presented in the unaffected fellow eyes of patients with unilateral RAP and might not be caused by the development or progression of the neovascular lesions of RAP. Therefore, it may be possible that the thin choroid has a certain relationship with the pathologic mechanism of RAP. In our previous report, choroidal circulatory disturbances on indocyanine green angiography were commonly seen not only in eyes with RAP, but also in the contralateral fellow eyes of patients with unilateral RAP.9 Therefore, the results shown in this study might be consistent with such angiographic abnormalities.
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SUBFOVEAL CHOROIDAL THICKNESS IN RAP YAMAZAKI ET AL Table 1. Clinical Profiles of the Patients With RAP
Case
Age, years/ Gender
1
65/M
2
68/M
3
71/F
4
79/F
5
85/M
6
90/M
7
79/M
8
82/M
9
82/M
10
87/M
11
88/F
12
89/M
13
85/F
14
82/F
15
85/F
16
85/M
17
76/M
18
91/M
19
92/F
Eye
Disorder
Previous Treatment
OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS OD OS
Stage 2 RAP Drusen Drusen Stage 2 RAP Stage 2 RAP Drusen Drusen Stage 2 RAP Stage 2 RAP Drusen Drusen Stage 3 RAP Stage 3 RAP Stage 1 RAP/excluded Stage 2 RAP Stage 3 RAP/excluded Stage 2 RAP Stage 3 RAP/excluded Stage 2 RAP Stage 3 RAP/excluded Stage 3 RAP Stage 3 RAP/excluded Stage 3 RAP Stage 3 RAP/excluded Stage 1 RAP Disciform/excluded Disciform/excluded Stage 2 RAP Disciform/excluded Stage 2 RAP Stage 2 RAP Disciform/excluded Disciform/excluded Stage 3 RAP Stage 3 RAP Disciform/excluded Stage 3 RAP Disciform/excluded
− − − − − − − − − − − − − − − − − − − − − − − + − − + − − − − − + − − − − −
BCVA, logMAR 0.52 0.00 0.05 0.70 1.16 −0.08 0.30 0.52 0.82 0.22 0.52 1.52 1.10 0.30 0.40 1.22 0.52 1.10 0.70 1.70 2.00 0.82 0.70 1.70 0.30 2.00 2.00 0.40 2.00 0.82 0.52 2.00 1.52 1.00 1.22 0.05 1.52 2.00
Lens
Spherical Equivalent, D
Axial Length, mm
SCT, mm
Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic Phakic IOL IOL IOL IOL IOL IOL Phakic Phakic IOL IOL IOL Phakic Phakic Phakic IOL Phakic IOL Phakic Phakic IOL Phakic Phakic
−4.250 −4.250 1.125 −1.750 −1.000 −0.625 −5.75 −5.750 −0.375 1.000 0.750 −0.500 −1.500 −2.875 1.250 1.125 −1.000* −1.750* −2.250* 2.000* −1.500* −2.250* 1.250 0.250 −0.500* −1.000* −1.500* 0.375 −0.375 0.375 −1.625* −1.500 −1.750* −0.125 2.250 −0.125* 0.125 1.125
NA NA 23.91 24.01 24.00 24.29 25.06 25.00 23.93 23.68 23.67 23.42 24.15 24.97 23.47 22.99 23.36 23.07 22.72 22.44 22.40 22.46 NA NA 22.41 22.22 22.76 23.30 23.33 23.37 24.80 NA 23.57 23.71 25.09 NA NA NA
110.0 105.0 148.0 159.0 128.0 120.5 169.5 135.0 168.0 180.5 88.0 122.0 86.0 79.0 128.5 142.0 73.0 73.5 197.0 193.5 101.5 181.5 161.5 NA 115.0 NA NA 76.0 NA 165.5 121.0 NA NA 149.5 88.0 NA 176.5 NA
*Data were obtained after the insertion of IOL. BCVA, best-corrected visual acuity; F, female; IOL, intraocular lens; M, male; NA, not available; OD, right eye; OS, left eye; SCT, subfoveal choroidal thickness.
By means of EDI-OCT, subfoveal choroidal thickness was measured in normal eyes and was shown to be inversely proportional to age and axial length.11–14 In this study, although subfoveal choroidal thickness in normal eyes was negatively correlated with increasing age, it was not related to age, spherical equivalent, or axial length in eyes with RAP. These findings indicate that other unknown factors may be involved primarily in the pathophysiology of RAP and may greatly affect choroidal thickness as compared with the expected reduction induced by aging or myopia. The cause of the thin choroid and its relationship to the development of RAP remain unknown. It has been suggested that vascular endothelial growth factor
(VEGF)-A secretion from RPE cells toward choriocapillaris is disturbed by age-related thickening of the Bruch membrane with lipophilic material.22 Thus, VEGF-A from the RPE cells might not be able to regulate the integrity of choriocapillaris or be able to maintain the fenestrated permeable phenotype of its endothelium,23 which results in choriocapillaris atrophy as disclosed histologically in aged eyes.24 Retinal angiomatous proliferation is more prevalent in older patients, and large and multiple drusen were frequently seen in eyes with RAP and even in the unaffected fellow eyes.5 Accordingly, a high degree of diffusional disturbances of VEGF-A in eyes of patients with RAP may induce atrophic changes of choriocapillaris
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2014 VOLUME 34 NUMBER 7
Table 2. Characteristics of the Patients With RAP and the Age-Matched Control Subjects
Age, years, mean ± SD Female, n (%) Spherical equivalent, mean ± SD, D Axial length, mean ± SD, mm BCVA, mean ± SD, logMAR
RAP Group (19 Eyes)
Control Group (32 Eyes)
P
82.2 ± 7.6 (65 to 91) 7 (37) −0.69 ± 2.14‡ (−5.75 to 2.25) 23.7 ± 0.8§ (22.4 to 25.1) 0.87 ± 0.46 (0.30 to 2.00)
81.2 ± 6.6 (68 to 96) 20 (63) −0.71 ± 1.69 (−4.56 to 1.88) 23.4 ± 0.7 (22.3 to 25.0) 0.38 ± 0.28 (−0.08 to 0.82)
0.38* 0.08† 0.79* 0.20* ,0.001*
*Mann–Whitney U test. †Chi-square test. ‡Data of 14 eyes except for 5 pseudophakic eyes. §Data of 16 eyes having the available data. BCVA, best-corrected visual acuity; SD, standard deviation.
compared with normal eyes. The reason why the thin choroid was seen in eyes of patients with RAP including the unaffected fellow eyes might be, at least partially, attributed to choriocapillaris atrophy, although the precise cause of the thin choroid remains unexplained. Another possibility is that the choroidal thinning seen in patients with RAP might be destined by a certain factor, for example, by the genetic background.25,26 Holz et al27 hypothesized that an imbalance between VEGF and pigment epithelial-derived factors arising from the apical side of the RPE cells may induce the growth of neovascular membranes outward from the retinal capillaries in RAP. Indeed, it has been recently reported that in eyes with untreated neovascular AMD, aqueous humor levels of VEGF are significantly higher in Type 3 neovascularization (so-called “RAP”) than in Type 1 or Type 2 neovascularization.28 The cause for such differences in cytokine levels is unknown, but there might be a decrease in the metabolic supply from the choroid as a result of reduced diffusion of substances through the thickened Bruch membrane, or there might be a reduced oxygen supply resulting from
changes in choriocapillaries.29 Our results showing that the thin choroid had already presented in the unaffected fellow eyes of patients with unilateral RAP may support the hypothesis by Holz et al27 in terms of the possibility that the thin choroid induces hypoxic conditions in the RPE cells. We previously reported that mean subfoveal choroidal thickness was greater in eyes with polypoidal choroidal vasculopathy (293.4 mm) than in those with typical AMD (244.6 mm).15 Mean subfoveal choroidal thickness in eyes with RAP, which was 129.5 mm, appeared to be the thinnest among these 3 subtypes of neovascular AMD measured in the previous and present studies. Therefore, although RAP is now generally classified as one subtype of neovascular AMD, morphologic differences in the choroid may be engaged in great variation in clinical characteristics of neovascular AMD. Further studies are needed to elucidate the differences in pathophysiology among the subtypes of neovascular AMD. It should be noted that there were several limitations in this study, such as few subjects included and its
Fig. 1. Subfoveal choroidal thickness comparison between eyes with RAP (19 eyes) and control eyes (32 eyes). Mean subfoveal choroidal thickness was significantly less in the eyes with RAP (129.5 ± 35.8 mm) than in the control eyes (201.3 ± 55.0 mm) (P , 0.0001).
Fig. 2. The differences in subfoveal choroidal thickness among Stage 2 RAP eyes, Stage 3 RAP eyes, and control eyes. One eye with Stage 1 RAP was excluded from this comparison because of the small sample size. Mean subfoveal choroidal thickness was 132.8 ± 38.2 mm, 126.4 ± 36.6 mm, and 201.3 ± 55.0 mm, respectively. Each of the mean subfoveal choroidal thickness findings in the two groups of eyes with RAP was significantly less than that in the normal eyes (P , 0.001 and P = 0.002, respectively), although there was no significant difference in mean subfoveal choroidal thickness between the 2 groups (P = 0.75).
SUBFOVEAL CHOROIDAL THICKNESS IN RAP YAMAZAKI ET AL
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Fig. 3. Case 2: The left eye of a 68-year-old man with Stage 2 RAP. A. Color fundus photograph shows a reddish neovascular membrane (arrow) and multiple soft drusen. B. Fluorescein angiography reveals dye leakage from the neovascular lesion. C. Enhanced depth imaging optical coherence tomography through the center of the fovea horizontally demonstrates cystic spaces in the neurosensory retina and the crosssectional choroidal structure. The subfoveal choroidal thickness was 159 mm (double-headed arrow). Arrowheads indicate the inner surface of the sclera. D. Indocyanine green angiography shows a hyperfluorescent spot (arrow) corresponding to the retinal neovascular lesion, but there is no evident concurrent choroidal neovascularization.
retrospective cross-sectional design. The measurement of subfoveal choroidal thickness was obtained manually because currently there is no automated software available. In addition, a comparison with an agematched non-RAP neovascular AMD group could not be performed. More importantly, the decrease in choroidal thickness might not be necessarily correlated with reduced choroidal blood flow.30 However, and to the best of our knowledge, this is the first report concerning choroidal thickness in RAP. In conclusion, this study demonstrated that subfoveal choroidal thickness in eyes with RAP appeared to be significantly thinner than that in control eyes. The thin choroid had already presented in the unaffected fellow eyes of patients with unilateral RAP. Such morphologic features in the choroid might be involved in the pathologic mechanism of RAP. The EDI-OCT imaging used in this study was a noninvasive method to enable to obtain the images of the choroid unavailable by other means. Additional studies are warranted to investigate the relationship between choroidal circulation and choroidal thickness on EDI-OCT images, which might provide a further understanding of the pathophysiology of RAP.
Key words: age-related macular degeneration, retinal angiomatous proliferation, subfoveal choroidal thickness, enhanced depth imaging optical coherence tomography. References 1. Yannuzzi LA, Negrao S, Iida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 2001;21:416–434. 2. Freund KB, Ho IV, Barbazetto IA, et al. Type 3 neovascularization: the expanded spectrum of retinal angiomatous proliferation. Retina 2008;28:201–211. 3. Gass JD, Agarwal A, Lavina AM, Tawansy KA. Focal inner retinal hemorrhages in patients with drusen: an early sign of occult choroidal neovascularization and chorioretinal anastomosis. Retina 2003;23:741–751. 4. Cohen SY, Creuzot-Garcher C, Darmon J, et al. Types of choroidal neovascularisation in newly diagnosed exudative age-related macular degeneration. Br J Ophthalmol 2007;91: 1173–1176. 5. Maruko I, Iida T, Saito M, et al. Clinical characteristics of exudative age-related macular degeneration in Japanese patients. Am J Ophthalmol 2007;144:15–22. 6. Liu Y, Wen F, Huang S, et al. Subtype lesions of neovascular age-related macular degeneration in Chinese patients. Graefes Arch Clin Exp Ophthalmol 2007;245:1441–1445.
1322 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 7. Campa C, Harding SP, Pearce IA, et al. Incidence of neovascularization in the fellow eye of patients with unilateral retinal angiomatous proliferation. Eye (Lond) 2010;24:1585–1589. 8. Gross NE, Aizman A, Brucker A, et al. Nature and risk of neovascularization in the fellow eye of patients with unilateral retinal angiomatous proliferation. Retina 2005;25:713–718. 9. Koizumi H, Iida T, Saito M, et al. Choroidal circulatory disturbances associated with retinal angiomatous proliferation on indocyanine green angiography. Graefes Arch Clin Exp Ophthalmol 2008;246:515–520. 10. Spaide RF. Enhanced depth imaging optical coherence tomography of retinal pigment epithelial detachment in age-related macular degeneration. Am J Ophthalmol 2009;147:644–652. 11. Margolis R, Spaide RF. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am J Ophthalmol 2009;147:811–815. 12. Li XQ, Larsen M, Munch IC. Subfoveal choroidal thickness in relation to sex and axial length in 93 Danish university students. Invest Ophthalmol Vis Sci 2011;52:8438–8441. 13. Ding X, Li J, Zeng J, et al. Choroidal thickness in healthy Chinese subjects. Invest Ophthalmol Vis Sci 2011;52:9555–9560. 14. Tan CS, Ouyang Y, Ruiz H, Sadda SR. Diurnal variation of choroidal thickness in normal, healthy subjects measured by spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci 2012;53:261–266. 15. Koizumi H, Yamagishi T, Yamazaki T, et al. Subfoveal choroidal thickness in typical age-related macular degeneration and polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2011;249:1123–1128. 16. Chung SE, Kang SW, Lee JH, Kim YT. Choroidal thickness in polypoidal choroidal vasculopathy and exudative age-related macular degeneration. Ophthalmology 2011;118:840–845. 17. Maruko I, Iida T, Sugano Y, et al. Subfoveal retinal and choroidal thickness after verteporfin photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol 2011; 151:594–603.e1. 18. Kim SW, Oh J, Kwon SS, et al. Comparison of choroidal thickness among patients with healthy eyes, early age-related maculopathy, neovascular age-related macular degeneration, central serous chorioretinopathy, and polypoidal choroidal vasculopathy. Retina 2011;31:1904–1911.
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19. Jirarattanasopa P, Ooto S, Nakata I, et al. Choroidal thickness, vascular hyperpermeability, and complement factor H in agerelated macular degeneration and polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 2012;53:3663–3672. 20. Yamazaki T, Koizumi H, Yamagishi T, Kinoshita S. Subfoveal choroidal thickness after ranibizumab therapy for neovascular age-related macular degeneration: 12-month results. Ophthalmology 2012;119:1621–1627. 21. Regatieri CV, Branchini L, Carmody J, et al. Choroidal thickness in patients with diabetic retinopathy analyzed by spectral-domain optical coherence tomography. Retina 2012;32:563–568. 22. Holz FG, Sheraidah G, Pauleikhoff D, Bird AC. Analysis of lipid deposits extracted from human macular and peripheral Bruch’s membrane. Arch Ophthalmol 1994;112:402–406. 23. Esser S, Wolburg K, Wolburg H, et al. Vascular endothelial growth factor induces endothelial fenestrations in vitro. J Cell Biol 1998;140:947–959. 24. Ramrattan RS, van der Schaft TL, Mooy CM, et al. Morphometric analysis of Bruch’s membrane, the choriocapillaris, and the choroid in aging. Invest Ophthalmol Vis Sci 1994;35:2857–2864. 25. Hayashi H, Yamashiro K, Gotoh N, et al. CFH and ARMS2 variations in age-related macular degeneration, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation. Invest Ophthalmol Vis Sci 2010;51:5914–5919. 26. Tanaka K, Nakayama T, Yuzawa M, et al. Analysis of candidate genes for age-related macular degeneration subtypes in the Japanese population. Mol Vis 2011;17:2751–2758. 27. Holz FG, Pauleikhoff D, Klein R, Bird AC. Pathogenesis of lesions in late age-related macular disease. Am J Ophthalmol 2004;137:504–510. 28. dell’Omo R, Cassetta M, dell’Omo E, et al. Aqueous humor levels of vascular endothelial growth factor before and after intravitreal bevacizumab in type 3 versus type 1 and 2 neovascularization. A prospective, case-control study. Am J Ophthalmol 2012;153:155–161. 29. Moore DJ, Hussain AA, Marshall J. Age-related variation in the hydraulic conductivity of Bruch’s membrane. Invest Ophthalmol Vis Sci 1995;36:1290–1297. 30. Sogawa K, Nagaoka T, Takahashi A, et al. Relationship between choroidal thickness and choroidal circulation in healthy young subjects. Am J Ophthalmol 2012;153:1129–1132.
