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Clinical Characteristics of Exudative Age-related Macular Degeneration in Japanese Patients
Clinical Characteristics of Exudative Age-related Macular Degeneration in Japanese Patients ICHIRO MARUKO, TOMOHIRO IIDA, MASAAKI SAITO, DAI NAGAYAMA, AND KUNIHARU SAITO ● PURPOSE:
To clarify the clinical characteristics of exudative age-related macular degeneration (AMD) in Japanese patients. ● DESIGN: Retrospective, observational, consecutive case series. ● METHODS: Two hundred and eighty-nine patients with neovascular AMD were examined. ● RESULTS: The authors classified the patients into three subtypes of neovascular AMD: polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and typical AMD. One hundred and fifty-eight patients (54.7%) were diagnosed with PCV and 102 patients (35.3%) with typical AMD. RAP was observed in 13 patients (4.5%). In 16 patients (5.5%), one eye had PCV and the other eye had typical AMD. Most patients with PCV and typical AMD had unilateral disease (81.6% and 94.1%, respectively) with a male preponderance (77.8% and 71.6%, respectively). Nine of 13 patients with RAP were female (69.2%). Patients with RAP were older (mean, 80.3 years for men and 75.3 years for women) than patients with other subtypes. Serous and hemorrhagic pigment epithelial detachment developed in 69 patients (43.7%) with PCV, 22 patients (21.6%) with typical AMD, and nine patients (69.2%) with RAP. In the patients with unilateral disease in each subtype, large drusen in the unaffected eye were seen in 24.0% with PCV, 30.2% with typical AMD, and 77.8% with RAP. ● CONCLUSIONS: Neovascular AMD in Japanese patients has different demographic features compared with that in White patients. In Japanese patients, there is a preponderance of PCV, male gender, unilaterality, and absence of drusen in the second eye, with the exception of RAP. (Am J Ophthalmol 2007;144:15–22. © 2007 by Elsevier Inc. All rights reserved.)
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EOVASCULAR EXUDATIVE AGE-RELATED MACU-
lar degeneration (AMD) is a leading cause of legal blindness in elderly patients in developed countries. In Japan, the number of patients with neovascular AMD is not as great as in Western countries. The Beaver Dam Eye Study reported that the prevalence of
Accepted for publication Mar 29, 2007. From the Department of Ophthalmology, Fukushima Medical University School of Medicine, Fukushima, Japan. Inquiries to Tomohiro Iida, Department of Ophthalmology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Japan; e-mail: [email protected] 0002-9394/07/$32.00 doi:10.1016/j.ajo.2007.03.047
©
2007 BY
AMD was 1.6% in United States,1,2 the Blue Mountains Eye Study reported a prevalence of 1.9% in Australia,3 and the Rotterdam Eye Study reported a prevalence of 1.7% in The Netherlands4; whereas the Hisayama study, a Japanese only population-based study, reported a prevalence of 0.87%.5,6 However, the prevalence of AMD in Japan is increasing rapidly.7 Neovascular AMD is characterized by classic and occult choroidal neovascularization (CNV), which is classified by fluorescein angiography. Recently, indocyanine green (ICG) angiography has provided more information about the choroidal circulation and its abnormalities. New findings of retinal angiomatous proliferation (RAP)8 and polypoidal choroidal vasculopathy (PCV)9 –11 have emerged. Neovascularization in eyes with RAP originates in the retina and expands posteriorly into the subretinal space, in some cases communicating with choroidal new vessels.8 ICG angiography has documented that PCV, often manifesting as polypoidal AMD,12 has polypoidal lesions and a choroidal vascular network. At present, these subtypes of neovascular AMD include mixed classic and occult CNV, RAP, and PCV.12 Although these are descriptive terms that have been interpreted in different ways by different clinicians, this terminology is used to identify characteristics relevant to patient care. Some studies also have reported that the incidence of these subtypes of neovascular AMD in Japanese patients differs from that in White patients13–15; for example, the incidence of PCV in Japanese patients is higher and the incidence of RAP is lower. The Hisayama Study showed the prevalence of drusen to be 9.8% in Japanese people.5 This is a very small percentage compared with that of reports from Western countries; for example, the Beaver Dam Eye Study16 reported a prevalence of 86% and the Barbados Eye Study17 reported a prevalence of 66.2%. Although Japanese patients do not have much drusen, basal laminar deposits, which are recognized as one of the lesions of age-related maculopathy, were observed in elderly Japanese patients as well as in White patients.18 In addition, one of the genes, HTRA1, of neovascular AMD has been identified not only in White but also in Chinese persons, considerably similar to Japanese patients.19,20 Thus, CNV in elderly Japanese patients may be considered similar to AMD in White patients. Each subtype is characterized by differences in clinical behavior, examination findings, and pathologic deductions. Accurate diagnoses of these subtypes are important for appropriate patient management.8,21,22 To
ELSEVIER INC. ALL
RIGHTS RESERVED.
15
FIGURE 1. Images from a 72-year-old man with polypoidal choroidal vasculopathy (PCV) in the right eye at presentation. (Top left) Red-free fundus photograph showing the elevated orange-red lesions in the macular area surrounded by exudation. (Top right) Late-phase fluorescein angiography results showing occult with no classic choroidal neovascularization (CNV) in the macular area and serous and hemorrhagic pigment epithelial detachment (PED) in the upper area of macula. (Bottom left) Early-phase indocyanine green (ICG) angiography shows clusters of grape-like polypoidal lesions in the macular area (arrows).
our knowledge, no study has clarified the clinical characteristics of neovascular AMD including typical AMD, PCV, and RAP in Japanese patients. We report the clinical features of neovascular AMD in Japanese patients.
was provided, each patient with suspected neovascular AMD signed a written consent form that described the importance of fundus angiography. All participants were examined by digital fluorescein angiography and ICG angiography. We used a digital imaging system with an infrared camera and standard fundus camera (TRC-50 IA/ IMAGEnet H1024 system; Topcon, Tokyo, Japan). Imaging procedures were performed successfully for all patients. We classified the patients as having one of three subtypes of neovascular AMD: PCV, RAP, and typical AMD. All angiograms were evaluated by three retina specialists (I.M., D.N., and M.S.) masked to the clinical findings. Fourteen (4.8%) of 289 patients could not be classified into one of the three subtypes by the three reviewers. In these cases, a fourth reviewer (T.I.) determined the subtype classification. The following definitions were used to describe the related clinical and angiographic abnormalities evaluated in the study.
METHODS TWO HUNDRED EIGHTY-NINE CONSECUTIVE JAPANESE PA-
tients newly diagnosed with neovascular AMD were examined at Fukushima Medical University Hospital, Fukushima, Japan. All patients were older than 50 years of age and were examined first in our clinic between March 2003 and February 2005. The patients were evaluated based on age, gender, and best-corrected visual acuity (BCVA). The BCVA was measured with a Japanese standard decimal visual acuity (VA) chart, and the mean BCVA was calculated using the logarithm of the minimum angle of resolution (logMAR) scale. The clinical examination included indirect ophthalmoscopy, slit-lamp biomicroscopy with a contact lens or noncontact lens (e.g., 60 diopters), and color and red-free fundus photography. Biomicroscopy and color and red-free photography are useful for evaluating the disease; however, it is well known that these can undergrade the presence of early and subtle age-related maculopathy lesions. After informed consent 16
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● POLYPOIDAL CHOROIDAL VASCULOPATHY: The diagnostic criteria for PCV were proposed on the basis of the fundus examination results, ICG angiographic findings, or both. Definite cases met at least one of the following criteria23: elevated orange-red lesions (excluding pigment epithelial detachment [PED], choroidal hemangioma, and OF
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FIGURE 2. Images from a 82-year-old woman with stage 2 retinal angiomatous proliferation (RAP) in the right eye. (Top left) Red-free fundus photograph showing pigment epithelial detachment (PED), cystoid macular edema, and hard exudates. (Top right) Early-phase fluorescein angiography results showing retinal–retinal anastomosis and sudden termination of retinal vessels. (Bottom left) Late-phase fluorescein angiography results showing occult with no classic choroidal neovascularization (CNV) and cystoid macular edema. (Bottom right) Early-phase indocyanine green (ICG) angiography showing a hot spot at the area of retinal–retinal anastomosis (arrow).
subretinal blood) observed by fundus examination or characteristic polypoidal lesions on ICG angiography. We also evaluated PCV on fluorescein angiography images. We recorded the number of eyes with components of classic CNV over the polypoidal lesions. Figure 1 shows a representative case of PCV.
than 50% of the total lesion size; minimally classic CNV, lesions in which the classic CNV components were less than 50% of the total lesion size; occult with no classic CNV, lesions in which there was no classic CNV component.21,24 Figure 3 shows a representative case of typical AMD. ● OTHER FUNDUS FINDINGS:
● RETINAL ANGIOMATOUS PROLIFERATION:
The diagnostic criteria for RAP were based on the fundus examination with a contact lens, fluorescein angiography, and ICG angiography. Definite cases had subretinal, intraretinal, or preretinal hemorrhages or retinal edema, dilated retinal vessels, retinal–retinal anastomosis, sudden termination of retinal vessels, a ring of lipid exudates and PED, and retinal– choroidal anastomosis. We determined the vasogenic stage of RAP according to the classification of Yannuzzi and associates8: stage 1, intraretinal neovascularization; stage 2, subretinal neovascularization; and stage 3, CNV. Figure 2 shows a representative case of RAP.
We recorded the number of eyes with serous and hemorrhagic PEDs. According to the Age-Related Eye Disease Study reports, we counted the large drusen (size, ⱖ125 m) in the fellow eyes of patients with unilateral neovascular AMD.25–28
● EXCLUSION CRITERIA:
Patients with other macular diseases such as high myopia, angioid streaks, and central serous chorioretinopathy were excluded.
RESULTS TABLE 1 SHOWS THE CHARACTERISTICS OF NEOVASCULAR
● TYPICAL AGE-RELATED MACULAR DEGENERATION:
The area of the lesion of typical AMD was composed of classic CNV on fluorescein angiography and was evaluated as follows: predominantly classic CNV, a neovascular lesion in which the classic CNV component was greater VOL. 144, NO. 1
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AMD in the current study. Two hundred and eighty-nine patients (212 men [73.4%] and 77 women [26.6%]) had neovascular AMD. Among them, 158 patients (54.7%) were diagnosed with PCV and 102 patients (35.3%) were diagnosed with typical AMD; RAP was observed in 13 IN JAPANESE
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FIGURE 3. Images from a 70-year-old man with typical age-related macular degeneration (AMD) in the right eye. (Top left) Red-free fundus photograph showing a grayish lesion and subretinal hemorrhages. (Top right) Early-phase and (Bottom left) late-phase fluorescein angiography results showing predominantly classic choroidal neovascularization (CNV) with cystoid macular edema at the center of the CNV. (Bottom right) Late-phase indocyanine green (ICG) angiography results showing staining of the hyperfluorescent CNV, including the macular area.
with no classic CNV (Table 2). In the 17 eyes of 13 patients with RAP, one eye had stage 1, 13 eyes stage 2, and three eyes stage 3 disease. Most patients had purely occult CNV or minimally classic CNV on fluorescein angiography (Table 2). Regarding the clinical fundus features in Table 3, serous and hemorrhagic PEDs were seen in 69 patients (43.7%) with PCV, 22 patients (21.6%) with typical AMD, and nine patients (69.2%) with RAP. In patients with typical AMD with serous and hemorrhagic PEDs, seven patients had minimally classic CNV, and 15 patients had purely occult CNV. In the cases with unilateral disease in each subtype, large drusen (size ⱖ125 m) in the unaffected eye were observed in 31 patients (24.0%) with PCV, in 29 patients (30.2%) with typical AMD, and in seven patients (77.8%) with RAP. The fellow eyes in cases of unilateral RAP had a high percentage of large drusen (Table 1).
patients (4.5%). In 16 patients (5.5%), one eye had PCV and the other eye had typical AMD. Four men (30.8%) and nine women (69.2%) had RAP. The mean ages ⫾ standard deviation of the men and women, respectively, were 73.6 ⫾ 8.0 years and 71.9 ⫾ 9.9 years. The cases were bilateral in 29 (18.4%) of 158 patients with PCV, six (5.9%) of 102 patients with typical AMD, and four (30.8%) of 13 patients with RAP. The mean BCVAs were 0.24 in patients with PCV, 0.16 in patients with typical AMD, and 0.18 in patients with RAP (calculated in logMAR units; Table 1). In 203 eyes with PCV, we found not only polypoidal CNV but also classic CNV lesions in 23 eyes (11.3%). When we evaluated PCV using only fluorescein angiography, we classified predominantly classic CNV in three eyes (1.5%), minimally classic CNV in 20 eyes (9.8%), and occult with no classic CNV in 180 eyes (88.7%; Table 2). Polypoidal vascular abnormalities in 174 patients with PCV (including patients with one eye with PCV and the other eye with typical AMD) were in the macula in 163 patients (93.7%) and in the peripapillary region in 11 patients (6.3%). Among 124 eyes with typical AMD, 27 eyes (21.8%) had predominantly classic CNV, 46 eyes (37.1%) had minimally classic CNV, and 51 eyes (41.1%) had occult 18
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DISCUSSION THE CURRENT STUDY SHOWED THAT THE PROPORTION OF
PCV was more than 50% and that RAP occurred in approximately 5% of Japanese patients with neovascular OF
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TABLE 1. Characteristics of Neovascular Age-Related Macular Degeneration in this Study Characteristic
PCV
Typical AMD
Combined*
RAP
No. patients (n ⫽ 289) % Gender (%) Male Female Affected eye (%) Bilateral‡ Unilateral§ Mean age (yrs ⫾ SD) Total Male Female Mean BCVA† Drusen in unaffected fellow eye (%)¶
158 54.7%
102 35.3%
16 5.5%
13 4.5%
123 (77.8%) 35 (22.2%)
73 (71.6%) 29 (28.4%)
12 (75%) 4 (25%)
4 (30.8%) 9 (69.2%)
29 (18.4%) 129 (81.6%)
6 (5.9%) 96 (94.1%)
72.8 ⫾ 7.9 73.1 ⫾ 7.5 71.8 ⫾ 9.4 0.24 31/129 (24.0%)
73.0 ⫾ 9.4 73.6 ⫾ 9.2 71.6 ⫾ 9.9 0.16 29/96 (30.2%)
16 — 73.5 ⫾ 8.6 75.8 ⫾ 6.5 66.6 ⫾ 11.2 0.20 —
4 (30.8%) 9 (69.2%) 76.8 ⫾ 9.7 80.3 ⫾ 3.6 75.3 ⫾ 11.2 0.18 7/9 (77.8%)
AMD ⫽ age-related macular degeneration; BCVA ⫽ best-corrected visual acuity; PCV ⫽ polypoidal choroidal vasculopathy; RAP ⫽ retinal angiomatous proliferation; SD ⫽ standard deviation. *Patients with one eye with PCV and the other eye had typical AMD. † BCVA at the diagnostic visit based on each eye with AMD. Decimal visual acuity was calculated in logarithm of the minimum angle of resolution units. ‡ Bilateral patients with the same subtype. § Unilateral patients with each subtype. ¶ Large drusen (ⱖ125 m) in the second eyes of unilaterally affected patients with neovascular AMD.
TABLE 2. Evaluation of Eyes with Each Subtype of AgeRelated Macular Degeneration Using Fluorescein Angiography
Subgroup* on FA
Predominantly classic CNV Minimally classic CNV Occult with no classic CNV
PCV (203 eyes)†
Typical AMD (124 eyes)†
RAP (17 eyes)†
3 (1.5%) 20 (9.8%)
27 (21.8%) 46 (37.1%)
0 3 (17.6%)
180 (88.7%)
51 (41.1%)
14 (82.4%)
AMD ⫽ age-related macular degeneration; CNV ⫽ choroidal neovascularization; FA ⫽ fluorescein angiography; PCV ⫽ polypoidal choroidal vasculopathy; RAP ⫽ retinal angiomatous proliferation. *A neovascular lesion in which the classic CNV component is more than 50% of the total lesion size was defined as predominantly classic CNV; lesions in which the classic CNV components were less than 50% of the total lesion size were defined as minimally classic CNV; lesions in which there was no classic CNV component were referred to as occult with no classic CNV. † A total of 344 eyes (289 patients) were evaluated by fluorescein angiography.
AMD. Although this study was not population based, these proportions are higher compared with the results from other American, Asian, and even previous Japanese reports8,11,13–15,29 –32 (Tables 4 and 5). VOL. 144, NO. 1
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PCV previously was thought to be rare and bilateral and to affect women exclusively. Recently, PCV seems to occur more often in pigmented individuals such as Blacks and Asians, and the clinical features differ from those in White patients.10,11,13 The current study also showed that the proportion of PCV in Japanese patients is very high: PCV was diagnosed in 54.7% with neovascular AMD. There was a male preponderance (77.8%) and unilateral involvement (82.9%) in the current study. In Japanese patients, Sho and associates reported that 100 (24%) of 418 patients with neovascular AMD had PCV,14 and Yoshimura reported 42% (Table 4).31 The discrepancies might be because PCV recently has become well recognized and the resolution of ICG angiography devices has improved. PCV previously was thought to be a peripapillary disease10; however, it was mostly in the macula (93.7%) in the current study. Sho and associates also reported that in 93 (85%) of 110 eyes, the PCV was in the macula.14 It is noteworthy that a PED was observed in more than 40% of eyes. Lim and associates also reported 13 eyes (50%) with PED among the 26 eyes of Asian patients with neovascular AMD.33 This may indicate that PCV is more common in Asian individuals than previously thought. We observed drusen in approximately 20% of the fellow eyes with unilateral PCV. In the current study, typical AMD had a male preponderance (71.6%) and was unilateral (94.1%). Among eyes with typical AMD (124 eyes), 21.8% had predominantly IN JAPANESE
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TABLE 3. Clinical Features of Patients with Pigment Epithelial Detachment in Each Subtype of Age-Related Macular Degeneration Characteristic
PCV (n ⫽ 158)
Typical AMD (n ⫽ 102)
Combined* (n ⫽ 16)
RAP (n ⫽ 13)
Patients with PED (%) Gender (%) Male Female Affected eye (%) Bilateral† Unilateral‡ Mean age (yrs ⫾ SD) Total Male Female
69 (43.7%)
22 (21.6%)
10 (62.5%)
9 (69.2%)
57 (82.6%) 12 (17.4%)
15 (68.2%) 7 (31.8%)
8 (80%) 2 (20%)
4 (44.4%) 5 (55.6%)
7 (10.1%) 62 (89.9%)
0 (0%) 22 (100%)
3 (30%) 7 (70%)
1 (11.1%) 8 (88.9%)
72.4 ⫾ 7.8 72.9 ⫾ 7.5 70.1 ⫾ 9.2
74.6 ⫾ 9.1 74.0 ⫾ 8.8 75.9 ⫾ 10.3
74.1 ⫾ 10.0 75.9 ⫾ 7.5 66.9 ⫾ 19.4
78.8 ⫾ 8.0 80.3 ⫾ 3.6 77.6 ⫾ 10.7
AMD ⫽ age-related macular degeneration; PCV ⫽ polypoidal choroidal vasculopathy; PED ⫽ serous and hemorrhagic pigment epithelial detachment; RAP ⫽ retinal angiomatous proliferation. *Patients with one eye with PCV and the other eye with typical AMD. † Patients with PED in both eyes. ‡ Unilateral patients with PED.
TABLE 4. Comparison of Proportions of Patients with PCV in Other Age-Related Macular Degeneration Studies No. of Patients
Author(s), Year
Yannuzzi and associates, 1999
11
Ahuja and associates,32 2000
Sho and associates,14 2003 Wen and associates,30 2004 Yoshimura,31 2004 Current study
167
34
418 166 — 289
Ethnicity
White, 20% Black, 50% Asian, 30% White, 74% Black, 20% Asian, 6% Japanese Chinese Japanese Japanese
TABLE 5. Comparison of Proportions of Patients with RAP in Other Age-Related Macular Degeneration Studies
PCV (%)
Authors, Year
Yannuzzi and associates, 2001 Arai and associates,15 2003 Current study
7.8
8
Ethnicity
RAP (%)
— 530 289
— Japanese Japanese
10–15 1.1 4.5
47 RAP ⫽ retinal angiomatous proliferation. 24 22.3 42 54.7
ratio, 3:7), which is substantially different from other subtypes (male-to-female ratio, 7:3). The mean patient age was older (80.3 years in men, 75.3 years in women) than in the other subtypes. RAP more often was bilateral, but even in the unilateral cases, large drusen were observed in 77.8% of the fellow eyes. RAP has a higher risk of bilaterality in Japanese patients. Gross and associates reported a higher risk of neovascularization in the fellow eyes of patients with unilateral RAP.34 We also found a high percentage of PEDs. RAP has different features from other subtypes of Japanese neovascular AMD; the vasogenic potential and the clinical course should be recognized. It is important to examine patients carefully using biomicroscopy with a contact lens, fluorescein angiography, and ICG angiography. In the fellow eye with unilateral neovascular AMD, the higher risk of developing neovascularization is a concern; this characteristic early finding most often predicts that the future visual loss is drusen related.27,28 Drusen did not
PCV ⫽ polypoidal choroidal vasculopathy.
classic CNV, 37.1% minimally classic CNV, and 41.1% occult with no classic CNV (Table 2). Yannuzzi and associates reported that the prevalence of RAP is between 10% and 15% (Table 5), with a preponderance of women and White patients.8 In Japan, there have been few reports on the demographic features of RAP. In a retrospective study, Arai and associates reported that six (1.1%) of 530 patients with neovascular AMD had RAP.15 We observed RAP in 4.5% of patients with neovascular AMD. This difference in proportion reveals the importance of the fundus examination with a contact lens and ICG angiography for diagnosing RAP. In addition, there was a female preponderance (male-to-female 20
No. of Patients
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develop as frequently in Japanese patients. Uyama and associates reported that the prevalence of large drusen was only 18% in the second eye with unilateral neovascular AMD, and the current study also supported that.27 Japanese patients do not have a great deal of drusen. However, the incidence of large drusen in the fellow eyes of Japanese patients with RAP was high and similar to that of White patients.
In conclusion, there is a predominance of PCV, male gender, and unilaterality and an absence of large drusen in the fellow eyes, with the exception of RAP, in Japanese patients with neovascular AMD. Because this was a clinicbased sample study, we should not consider this a population-based study. However, neovascular AMD in Japanese patients has different demographic features from those in White patients.
THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. INVOLVED IN DESIGN AND conduct of study (I.M., T.I.); collection (I.M., T.I., M.S., D.N.); management, analysis, and interpretation of data (I.M., T.I., M.S., K.S.); and preparation, review, and approval of the manuscript (T.I.). For this retrospective study, the approval of the institutional review board was not required.
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14. Sho K, Takahashi K, Yamada H, et al. Polypoidal choroidal vasculopathy: incidence, demographic features, and clinical characteristics. Arch Ophthalmol 2003;121:1392–1396. 15. Arai K, Kawamura A, Yuzawa M. Retinal angiomatous proliferation in age-related macular degeneration [in Japanese]. Folia Ophthalmol Jpn 2003;54:513–518. 16. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1992;99:933–943. 17. Schachat AP, Hyman L, Leske MC, Connell AM, Wu SY. Features of age-related macular degeneration in a black population: the Barbados Eye Study Group. Arch Ophthalmol 1995;113:728 –735. 18. Ishibashi T, Patterson R, Ohnishi Y, Inomata H, Ryan SJ. Formation of drusen in the human eye. Am J Ophthalmol 1986;101:342–353. 19. Dewan A, Liu M, Hartman S, et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 2006;314:989 –992. 20. Yang Z, Camp NJ, Sun H, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 2006;314:992–993. 21. Barbazetto I, Burdan A, Bressler NM, et al., Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study Group, Verteporfin in Photodynamic Therapy Study Group. Photodynamic therapy of subfoveal choroidal neovascularization with verteporfin: fluorescein angiographic guidelines for evaluation and treatment— TAP and VIP report No. 2. Arch Ophthalmol 2003;121: 1253–1268. 22. Uyama M, Wada M, Nagai Y, et al. Polypoidal choroidal vasculopathy: natural history. Am J Ophthalmol 2002;133: 639 – 648. 23. Japanese study group of polypoidal choroidal vasculopathy. Criteria for diagnosis of polypoidal choroidal vasculopathy [in Japanese]. Nippon Gannka Gakkai Zasshi 2005;109:417– 427. 24. Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in agerelated macular degeneration with Verteporfin: one-year results of 2 randomized clinical trials—TAP report. Arch Ophthalmol 1999;117:1329 –1345. 25. Bird AC, Bressler NM, Bressler SB, et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration: the International IN JAPANESE
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Biosketch Ichiro Maruko, MD, graduated from the Fukushima Medical University School of Medicine, Fukushima, Japan in 1999. He worked at College of Optometry, University of Houston, Houston, Texas, USA from 2002 to 2004. Dr Maruko is currently a Research Associate of the Department of Ophthalmology, Fukushima Medical University School of Medicine, Fukushima, Japan.
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Biosketch Tomohiro Iida, MD, is a retina specialist at Department of Ophthalmology, Gunma University Hospital, Maebashi, Japan and LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital, New York, New York. Dr Iida is currently a Professor and Chairman of the Department of Ophthalmology, Fukushima Medical University School of Medicine, Fukushima, Japan.
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To clarify the clinical characteristics of exudative age-related macular degeneration (AMD) in Japanese patients. ● DESIGN: Retrospective, observational, consecutive case series. ● METHODS: Two hundred and eighty-nine patients with neovascular AMD were examined. ● RESULTS: The authors classified the patients into three subtypes of neovascular AMD: polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and typical AMD. One hundred and fifty-eight patients (54.7%) were diagnosed with PCV and 102 patients (35.3%) with typical AMD. RAP was observed in 13 patients (4.5%). In 16 patients (5.5%), one eye had PCV and the other eye had typical AMD. Most patients with PCV and typical AMD had unilateral disease (81.6% and 94.1%, respectively) with a male preponderance (77.8% and 71.6%, respectively). Nine of 13 patients with RAP were female (69.2%). Patients with RAP were older (mean, 80.3 years for men and 75.3 years for women) than patients with other subtypes. Serous and hemorrhagic pigment epithelial detachment developed in 69 patients (43.7%) with PCV, 22 patients (21.6%) with typical AMD, and nine patients (69.2%) with RAP. In the patients with unilateral disease in each subtype, large drusen in the unaffected eye were seen in 24.0% with PCV, 30.2% with typical AMD, and 77.8% with RAP. ● CONCLUSIONS: Neovascular AMD in Japanese patients has different demographic features compared with that in White patients. In Japanese patients, there is a preponderance of PCV, male gender, unilaterality, and absence of drusen in the second eye, with the exception of RAP. (Am J Ophthalmol 2007;144:15–22. © 2007 by Elsevier Inc. All rights reserved.)
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EOVASCULAR EXUDATIVE AGE-RELATED MACU-
lar degeneration (AMD) is a leading cause of legal blindness in elderly patients in developed countries. In Japan, the number of patients with neovascular AMD is not as great as in Western countries. The Beaver Dam Eye Study reported that the prevalence of
Accepted for publication Mar 29, 2007. From the Department of Ophthalmology, Fukushima Medical University School of Medicine, Fukushima, Japan. Inquiries to Tomohiro Iida, Department of Ophthalmology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Japan; e-mail: [email protected] 0002-9394/07/$32.00 doi:10.1016/j.ajo.2007.03.047
©
2007 BY
AMD was 1.6% in United States,1,2 the Blue Mountains Eye Study reported a prevalence of 1.9% in Australia,3 and the Rotterdam Eye Study reported a prevalence of 1.7% in The Netherlands4; whereas the Hisayama study, a Japanese only population-based study, reported a prevalence of 0.87%.5,6 However, the prevalence of AMD in Japan is increasing rapidly.7 Neovascular AMD is characterized by classic and occult choroidal neovascularization (CNV), which is classified by fluorescein angiography. Recently, indocyanine green (ICG) angiography has provided more information about the choroidal circulation and its abnormalities. New findings of retinal angiomatous proliferation (RAP)8 and polypoidal choroidal vasculopathy (PCV)9 –11 have emerged. Neovascularization in eyes with RAP originates in the retina and expands posteriorly into the subretinal space, in some cases communicating with choroidal new vessels.8 ICG angiography has documented that PCV, often manifesting as polypoidal AMD,12 has polypoidal lesions and a choroidal vascular network. At present, these subtypes of neovascular AMD include mixed classic and occult CNV, RAP, and PCV.12 Although these are descriptive terms that have been interpreted in different ways by different clinicians, this terminology is used to identify characteristics relevant to patient care. Some studies also have reported that the incidence of these subtypes of neovascular AMD in Japanese patients differs from that in White patients13–15; for example, the incidence of PCV in Japanese patients is higher and the incidence of RAP is lower. The Hisayama Study showed the prevalence of drusen to be 9.8% in Japanese people.5 This is a very small percentage compared with that of reports from Western countries; for example, the Beaver Dam Eye Study16 reported a prevalence of 86% and the Barbados Eye Study17 reported a prevalence of 66.2%. Although Japanese patients do not have much drusen, basal laminar deposits, which are recognized as one of the lesions of age-related maculopathy, were observed in elderly Japanese patients as well as in White patients.18 In addition, one of the genes, HTRA1, of neovascular AMD has been identified not only in White but also in Chinese persons, considerably similar to Japanese patients.19,20 Thus, CNV in elderly Japanese patients may be considered similar to AMD in White patients. Each subtype is characterized by differences in clinical behavior, examination findings, and pathologic deductions. Accurate diagnoses of these subtypes are important for appropriate patient management.8,21,22 To
ELSEVIER INC. ALL
RIGHTS RESERVED.
15
FIGURE 1. Images from a 72-year-old man with polypoidal choroidal vasculopathy (PCV) in the right eye at presentation. (Top left) Red-free fundus photograph showing the elevated orange-red lesions in the macular area surrounded by exudation. (Top right) Late-phase fluorescein angiography results showing occult with no classic choroidal neovascularization (CNV) in the macular area and serous and hemorrhagic pigment epithelial detachment (PED) in the upper area of macula. (Bottom left) Early-phase indocyanine green (ICG) angiography shows clusters of grape-like polypoidal lesions in the macular area (arrows).
our knowledge, no study has clarified the clinical characteristics of neovascular AMD including typical AMD, PCV, and RAP in Japanese patients. We report the clinical features of neovascular AMD in Japanese patients.
was provided, each patient with suspected neovascular AMD signed a written consent form that described the importance of fundus angiography. All participants were examined by digital fluorescein angiography and ICG angiography. We used a digital imaging system with an infrared camera and standard fundus camera (TRC-50 IA/ IMAGEnet H1024 system; Topcon, Tokyo, Japan). Imaging procedures were performed successfully for all patients. We classified the patients as having one of three subtypes of neovascular AMD: PCV, RAP, and typical AMD. All angiograms were evaluated by three retina specialists (I.M., D.N., and M.S.) masked to the clinical findings. Fourteen (4.8%) of 289 patients could not be classified into one of the three subtypes by the three reviewers. In these cases, a fourth reviewer (T.I.) determined the subtype classification. The following definitions were used to describe the related clinical and angiographic abnormalities evaluated in the study.
METHODS TWO HUNDRED EIGHTY-NINE CONSECUTIVE JAPANESE PA-
tients newly diagnosed with neovascular AMD were examined at Fukushima Medical University Hospital, Fukushima, Japan. All patients were older than 50 years of age and were examined first in our clinic between March 2003 and February 2005. The patients were evaluated based on age, gender, and best-corrected visual acuity (BCVA). The BCVA was measured with a Japanese standard decimal visual acuity (VA) chart, and the mean BCVA was calculated using the logarithm of the minimum angle of resolution (logMAR) scale. The clinical examination included indirect ophthalmoscopy, slit-lamp biomicroscopy with a contact lens or noncontact lens (e.g., 60 diopters), and color and red-free fundus photography. Biomicroscopy and color and red-free photography are useful for evaluating the disease; however, it is well known that these can undergrade the presence of early and subtle age-related maculopathy lesions. After informed consent 16
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● POLYPOIDAL CHOROIDAL VASCULOPATHY: The diagnostic criteria for PCV were proposed on the basis of the fundus examination results, ICG angiographic findings, or both. Definite cases met at least one of the following criteria23: elevated orange-red lesions (excluding pigment epithelial detachment [PED], choroidal hemangioma, and OF
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FIGURE 2. Images from a 82-year-old woman with stage 2 retinal angiomatous proliferation (RAP) in the right eye. (Top left) Red-free fundus photograph showing pigment epithelial detachment (PED), cystoid macular edema, and hard exudates. (Top right) Early-phase fluorescein angiography results showing retinal–retinal anastomosis and sudden termination of retinal vessels. (Bottom left) Late-phase fluorescein angiography results showing occult with no classic choroidal neovascularization (CNV) and cystoid macular edema. (Bottom right) Early-phase indocyanine green (ICG) angiography showing a hot spot at the area of retinal–retinal anastomosis (arrow).
subretinal blood) observed by fundus examination or characteristic polypoidal lesions on ICG angiography. We also evaluated PCV on fluorescein angiography images. We recorded the number of eyes with components of classic CNV over the polypoidal lesions. Figure 1 shows a representative case of PCV.
than 50% of the total lesion size; minimally classic CNV, lesions in which the classic CNV components were less than 50% of the total lesion size; occult with no classic CNV, lesions in which there was no classic CNV component.21,24 Figure 3 shows a representative case of typical AMD. ● OTHER FUNDUS FINDINGS:
● RETINAL ANGIOMATOUS PROLIFERATION:
The diagnostic criteria for RAP were based on the fundus examination with a contact lens, fluorescein angiography, and ICG angiography. Definite cases had subretinal, intraretinal, or preretinal hemorrhages or retinal edema, dilated retinal vessels, retinal–retinal anastomosis, sudden termination of retinal vessels, a ring of lipid exudates and PED, and retinal– choroidal anastomosis. We determined the vasogenic stage of RAP according to the classification of Yannuzzi and associates8: stage 1, intraretinal neovascularization; stage 2, subretinal neovascularization; and stage 3, CNV. Figure 2 shows a representative case of RAP.
We recorded the number of eyes with serous and hemorrhagic PEDs. According to the Age-Related Eye Disease Study reports, we counted the large drusen (size, ⱖ125 m) in the fellow eyes of patients with unilateral neovascular AMD.25–28
● EXCLUSION CRITERIA:
Patients with other macular diseases such as high myopia, angioid streaks, and central serous chorioretinopathy were excluded.
RESULTS TABLE 1 SHOWS THE CHARACTERISTICS OF NEOVASCULAR
● TYPICAL AGE-RELATED MACULAR DEGENERATION:
The area of the lesion of typical AMD was composed of classic CNV on fluorescein angiography and was evaluated as follows: predominantly classic CNV, a neovascular lesion in which the classic CNV component was greater VOL. 144, NO. 1
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AMD in the current study. Two hundred and eighty-nine patients (212 men [73.4%] and 77 women [26.6%]) had neovascular AMD. Among them, 158 patients (54.7%) were diagnosed with PCV and 102 patients (35.3%) were diagnosed with typical AMD; RAP was observed in 13 IN JAPANESE
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FIGURE 3. Images from a 70-year-old man with typical age-related macular degeneration (AMD) in the right eye. (Top left) Red-free fundus photograph showing a grayish lesion and subretinal hemorrhages. (Top right) Early-phase and (Bottom left) late-phase fluorescein angiography results showing predominantly classic choroidal neovascularization (CNV) with cystoid macular edema at the center of the CNV. (Bottom right) Late-phase indocyanine green (ICG) angiography results showing staining of the hyperfluorescent CNV, including the macular area.
with no classic CNV (Table 2). In the 17 eyes of 13 patients with RAP, one eye had stage 1, 13 eyes stage 2, and three eyes stage 3 disease. Most patients had purely occult CNV or minimally classic CNV on fluorescein angiography (Table 2). Regarding the clinical fundus features in Table 3, serous and hemorrhagic PEDs were seen in 69 patients (43.7%) with PCV, 22 patients (21.6%) with typical AMD, and nine patients (69.2%) with RAP. In patients with typical AMD with serous and hemorrhagic PEDs, seven patients had minimally classic CNV, and 15 patients had purely occult CNV. In the cases with unilateral disease in each subtype, large drusen (size ⱖ125 m) in the unaffected eye were observed in 31 patients (24.0%) with PCV, in 29 patients (30.2%) with typical AMD, and in seven patients (77.8%) with RAP. The fellow eyes in cases of unilateral RAP had a high percentage of large drusen (Table 1).
patients (4.5%). In 16 patients (5.5%), one eye had PCV and the other eye had typical AMD. Four men (30.8%) and nine women (69.2%) had RAP. The mean ages ⫾ standard deviation of the men and women, respectively, were 73.6 ⫾ 8.0 years and 71.9 ⫾ 9.9 years. The cases were bilateral in 29 (18.4%) of 158 patients with PCV, six (5.9%) of 102 patients with typical AMD, and four (30.8%) of 13 patients with RAP. The mean BCVAs were 0.24 in patients with PCV, 0.16 in patients with typical AMD, and 0.18 in patients with RAP (calculated in logMAR units; Table 1). In 203 eyes with PCV, we found not only polypoidal CNV but also classic CNV lesions in 23 eyes (11.3%). When we evaluated PCV using only fluorescein angiography, we classified predominantly classic CNV in three eyes (1.5%), minimally classic CNV in 20 eyes (9.8%), and occult with no classic CNV in 180 eyes (88.7%; Table 2). Polypoidal vascular abnormalities in 174 patients with PCV (including patients with one eye with PCV and the other eye with typical AMD) were in the macula in 163 patients (93.7%) and in the peripapillary region in 11 patients (6.3%). Among 124 eyes with typical AMD, 27 eyes (21.8%) had predominantly classic CNV, 46 eyes (37.1%) had minimally classic CNV, and 51 eyes (41.1%) had occult 18
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DISCUSSION THE CURRENT STUDY SHOWED THAT THE PROPORTION OF
PCV was more than 50% and that RAP occurred in approximately 5% of Japanese patients with neovascular OF
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TABLE 1. Characteristics of Neovascular Age-Related Macular Degeneration in this Study Characteristic
PCV
Typical AMD
Combined*
RAP
No. patients (n ⫽ 289) % Gender (%) Male Female Affected eye (%) Bilateral‡ Unilateral§ Mean age (yrs ⫾ SD) Total Male Female Mean BCVA† Drusen in unaffected fellow eye (%)¶
158 54.7%
102 35.3%
16 5.5%
13 4.5%
123 (77.8%) 35 (22.2%)
73 (71.6%) 29 (28.4%)
12 (75%) 4 (25%)
4 (30.8%) 9 (69.2%)
29 (18.4%) 129 (81.6%)
6 (5.9%) 96 (94.1%)
72.8 ⫾ 7.9 73.1 ⫾ 7.5 71.8 ⫾ 9.4 0.24 31/129 (24.0%)
73.0 ⫾ 9.4 73.6 ⫾ 9.2 71.6 ⫾ 9.9 0.16 29/96 (30.2%)
16 — 73.5 ⫾ 8.6 75.8 ⫾ 6.5 66.6 ⫾ 11.2 0.20 —
4 (30.8%) 9 (69.2%) 76.8 ⫾ 9.7 80.3 ⫾ 3.6 75.3 ⫾ 11.2 0.18 7/9 (77.8%)
AMD ⫽ age-related macular degeneration; BCVA ⫽ best-corrected visual acuity; PCV ⫽ polypoidal choroidal vasculopathy; RAP ⫽ retinal angiomatous proliferation; SD ⫽ standard deviation. *Patients with one eye with PCV and the other eye had typical AMD. † BCVA at the diagnostic visit based on each eye with AMD. Decimal visual acuity was calculated in logarithm of the minimum angle of resolution units. ‡ Bilateral patients with the same subtype. § Unilateral patients with each subtype. ¶ Large drusen (ⱖ125 m) in the second eyes of unilaterally affected patients with neovascular AMD.
TABLE 2. Evaluation of Eyes with Each Subtype of AgeRelated Macular Degeneration Using Fluorescein Angiography
Subgroup* on FA
Predominantly classic CNV Minimally classic CNV Occult with no classic CNV
PCV (203 eyes)†
Typical AMD (124 eyes)†
RAP (17 eyes)†
3 (1.5%) 20 (9.8%)
27 (21.8%) 46 (37.1%)
0 3 (17.6%)
180 (88.7%)
51 (41.1%)
14 (82.4%)
AMD ⫽ age-related macular degeneration; CNV ⫽ choroidal neovascularization; FA ⫽ fluorescein angiography; PCV ⫽ polypoidal choroidal vasculopathy; RAP ⫽ retinal angiomatous proliferation. *A neovascular lesion in which the classic CNV component is more than 50% of the total lesion size was defined as predominantly classic CNV; lesions in which the classic CNV components were less than 50% of the total lesion size were defined as minimally classic CNV; lesions in which there was no classic CNV component were referred to as occult with no classic CNV. † A total of 344 eyes (289 patients) were evaluated by fluorescein angiography.
AMD. Although this study was not population based, these proportions are higher compared with the results from other American, Asian, and even previous Japanese reports8,11,13–15,29 –32 (Tables 4 and 5). VOL. 144, NO. 1
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PCV previously was thought to be rare and bilateral and to affect women exclusively. Recently, PCV seems to occur more often in pigmented individuals such as Blacks and Asians, and the clinical features differ from those in White patients.10,11,13 The current study also showed that the proportion of PCV in Japanese patients is very high: PCV was diagnosed in 54.7% with neovascular AMD. There was a male preponderance (77.8%) and unilateral involvement (82.9%) in the current study. In Japanese patients, Sho and associates reported that 100 (24%) of 418 patients with neovascular AMD had PCV,14 and Yoshimura reported 42% (Table 4).31 The discrepancies might be because PCV recently has become well recognized and the resolution of ICG angiography devices has improved. PCV previously was thought to be a peripapillary disease10; however, it was mostly in the macula (93.7%) in the current study. Sho and associates also reported that in 93 (85%) of 110 eyes, the PCV was in the macula.14 It is noteworthy that a PED was observed in more than 40% of eyes. Lim and associates also reported 13 eyes (50%) with PED among the 26 eyes of Asian patients with neovascular AMD.33 This may indicate that PCV is more common in Asian individuals than previously thought. We observed drusen in approximately 20% of the fellow eyes with unilateral PCV. In the current study, typical AMD had a male preponderance (71.6%) and was unilateral (94.1%). Among eyes with typical AMD (124 eyes), 21.8% had predominantly IN JAPANESE
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TABLE 3. Clinical Features of Patients with Pigment Epithelial Detachment in Each Subtype of Age-Related Macular Degeneration Characteristic
PCV (n ⫽ 158)
Typical AMD (n ⫽ 102)
Combined* (n ⫽ 16)
RAP (n ⫽ 13)
Patients with PED (%) Gender (%) Male Female Affected eye (%) Bilateral† Unilateral‡ Mean age (yrs ⫾ SD) Total Male Female
69 (43.7%)
22 (21.6%)
10 (62.5%)
9 (69.2%)
57 (82.6%) 12 (17.4%)
15 (68.2%) 7 (31.8%)
8 (80%) 2 (20%)
4 (44.4%) 5 (55.6%)
7 (10.1%) 62 (89.9%)
0 (0%) 22 (100%)
3 (30%) 7 (70%)
1 (11.1%) 8 (88.9%)
72.4 ⫾ 7.8 72.9 ⫾ 7.5 70.1 ⫾ 9.2
74.6 ⫾ 9.1 74.0 ⫾ 8.8 75.9 ⫾ 10.3
74.1 ⫾ 10.0 75.9 ⫾ 7.5 66.9 ⫾ 19.4
78.8 ⫾ 8.0 80.3 ⫾ 3.6 77.6 ⫾ 10.7
AMD ⫽ age-related macular degeneration; PCV ⫽ polypoidal choroidal vasculopathy; PED ⫽ serous and hemorrhagic pigment epithelial detachment; RAP ⫽ retinal angiomatous proliferation. *Patients with one eye with PCV and the other eye with typical AMD. † Patients with PED in both eyes. ‡ Unilateral patients with PED.
TABLE 4. Comparison of Proportions of Patients with PCV in Other Age-Related Macular Degeneration Studies No. of Patients
Author(s), Year
Yannuzzi and associates, 1999
11
Ahuja and associates,32 2000
Sho and associates,14 2003 Wen and associates,30 2004 Yoshimura,31 2004 Current study
167
34
418 166 — 289
Ethnicity
White, 20% Black, 50% Asian, 30% White, 74% Black, 20% Asian, 6% Japanese Chinese Japanese Japanese
TABLE 5. Comparison of Proportions of Patients with RAP in Other Age-Related Macular Degeneration Studies
PCV (%)
Authors, Year
Yannuzzi and associates, 2001 Arai and associates,15 2003 Current study
7.8
8
Ethnicity
RAP (%)
— 530 289
— Japanese Japanese
10–15 1.1 4.5
47 RAP ⫽ retinal angiomatous proliferation. 24 22.3 42 54.7
ratio, 3:7), which is substantially different from other subtypes (male-to-female ratio, 7:3). The mean patient age was older (80.3 years in men, 75.3 years in women) than in the other subtypes. RAP more often was bilateral, but even in the unilateral cases, large drusen were observed in 77.8% of the fellow eyes. RAP has a higher risk of bilaterality in Japanese patients. Gross and associates reported a higher risk of neovascularization in the fellow eyes of patients with unilateral RAP.34 We also found a high percentage of PEDs. RAP has different features from other subtypes of Japanese neovascular AMD; the vasogenic potential and the clinical course should be recognized. It is important to examine patients carefully using biomicroscopy with a contact lens, fluorescein angiography, and ICG angiography. In the fellow eye with unilateral neovascular AMD, the higher risk of developing neovascularization is a concern; this characteristic early finding most often predicts that the future visual loss is drusen related.27,28 Drusen did not
PCV ⫽ polypoidal choroidal vasculopathy.
classic CNV, 37.1% minimally classic CNV, and 41.1% occult with no classic CNV (Table 2). Yannuzzi and associates reported that the prevalence of RAP is between 10% and 15% (Table 5), with a preponderance of women and White patients.8 In Japan, there have been few reports on the demographic features of RAP. In a retrospective study, Arai and associates reported that six (1.1%) of 530 patients with neovascular AMD had RAP.15 We observed RAP in 4.5% of patients with neovascular AMD. This difference in proportion reveals the importance of the fundus examination with a contact lens and ICG angiography for diagnosing RAP. In addition, there was a female preponderance (male-to-female 20
No. of Patients
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develop as frequently in Japanese patients. Uyama and associates reported that the prevalence of large drusen was only 18% in the second eye with unilateral neovascular AMD, and the current study also supported that.27 Japanese patients do not have a great deal of drusen. However, the incidence of large drusen in the fellow eyes of Japanese patients with RAP was high and similar to that of White patients.
In conclusion, there is a predominance of PCV, male gender, and unilaterality and an absence of large drusen in the fellow eyes, with the exception of RAP, in Japanese patients with neovascular AMD. Because this was a clinicbased sample study, we should not consider this a population-based study. However, neovascular AMD in Japanese patients has different demographic features from those in White patients.
THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. INVOLVED IN DESIGN AND conduct of study (I.M., T.I.); collection (I.M., T.I., M.S., D.N.); management, analysis, and interpretation of data (I.M., T.I., M.S., K.S.); and preparation, review, and approval of the manuscript (T.I.). For this retrospective study, the approval of the institutional review board was not required.
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14. Sho K, Takahashi K, Yamada H, et al. Polypoidal choroidal vasculopathy: incidence, demographic features, and clinical characteristics. Arch Ophthalmol 2003;121:1392–1396. 15. Arai K, Kawamura A, Yuzawa M. Retinal angiomatous proliferation in age-related macular degeneration [in Japanese]. Folia Ophthalmol Jpn 2003;54:513–518. 16. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1992;99:933–943. 17. Schachat AP, Hyman L, Leske MC, Connell AM, Wu SY. Features of age-related macular degeneration in a black population: the Barbados Eye Study Group. Arch Ophthalmol 1995;113:728 –735. 18. Ishibashi T, Patterson R, Ohnishi Y, Inomata H, Ryan SJ. Formation of drusen in the human eye. Am J Ophthalmol 1986;101:342–353. 19. Dewan A, Liu M, Hartman S, et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 2006;314:989 –992. 20. Yang Z, Camp NJ, Sun H, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 2006;314:992–993. 21. Barbazetto I, Burdan A, Bressler NM, et al., Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study Group, Verteporfin in Photodynamic Therapy Study Group. Photodynamic therapy of subfoveal choroidal neovascularization with verteporfin: fluorescein angiographic guidelines for evaluation and treatment— TAP and VIP report No. 2. Arch Ophthalmol 2003;121: 1253–1268. 22. Uyama M, Wada M, Nagai Y, et al. Polypoidal choroidal vasculopathy: natural history. Am J Ophthalmol 2002;133: 639 – 648. 23. Japanese study group of polypoidal choroidal vasculopathy. Criteria for diagnosis of polypoidal choroidal vasculopathy [in Japanese]. Nippon Gannka Gakkai Zasshi 2005;109:417– 427. 24. Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in agerelated macular degeneration with Verteporfin: one-year results of 2 randomized clinical trials—TAP report. Arch Ophthalmol 1999;117:1329 –1345. 25. Bird AC, Bressler NM, Bressler SB, et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration: the International IN JAPANESE
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Biosketch Ichiro Maruko, MD, graduated from the Fukushima Medical University School of Medicine, Fukushima, Japan in 1999. He worked at College of Optometry, University of Houston, Houston, Texas, USA from 2002 to 2004. Dr Maruko is currently a Research Associate of the Department of Ophthalmology, Fukushima Medical University School of Medicine, Fukushima, Japan.
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Biosketch Tomohiro Iida, MD, is a retina specialist at Department of Ophthalmology, Gunma University Hospital, Maebashi, Japan and LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital, New York, New York. Dr Iida is currently a Professor and Chairman of the Department of Ophthalmology, Fukushima Medical University School of Medicine, Fukushima, Japan.
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