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Development of Typical Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy in Fellow Eyes of Japanese Patients with Exudative Age-related Macular Degeneration
Development of Typical Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy in Fellow Eyes of Japanese Patients with Exudative Agerelated Macular Degeneration TAKASHI UETA, AYA IRIYAMA, JASMINE FRANCIS, HIDENORI TAKAHASHI, TOMOKO ADACHI, RYO OBATA, YUJI INOUE, YASUHIRO TAMAKI, AND YASUO YANAGI ● PURPOSE:
To investigate the development of typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) in fellow eyes of Japanese patients with exudative AMD. ● DESIGN: Retrospective observational consecutive case series. ● METHODS: Two hundred and sixteen Japanese patients were enrolled in this study from the outpatient clinic of the University of Tokyo Hospital. Ninety-one patients had typical AMD and one hundred and twenty-five patients had PCV. The average follow-up period was 33.6 and 25.1 months for typical AMD and PCV patients. ● RESULTS: The cumulative incidence of involvement in fellow eyes with overall exudative AMD, including both typical AMD and PCV, was 3.4% in one year, 9.3% in three years, and 11.3% in five years. It was 3.6%, 7.3%, and 11.2% in typical AMD, and 3.2%, 11.1%, and 11.1% in PCV in one, three, and five years, respectively. Before the development of exudative AMD, patients with typical AMD had a variety of funduscopic findings including retinal pigment epithelium (RPE) atrophy, drusen, drusenoid pigment epithelial detachments (PED), and normal macula. PCV patients, on the other hand, had funduscopic findings of RPE atrophy. Inner choroidal vascular abnormality of vascular network and polypoidal formation was observed in several eyes before the clinical manifestation of exudative changes. ● CONCLUSIONS: Typical AMD and PCV had similar probabilities of involving the fellow eye in unilaterally affected Japanese patients. RPE atrophy was a prevailing finding in fellow eyes of patients who developed PCV. In PCV, choroidal vascular network and polypoidal formation gradually grow before exudative changes. (Am J Ophthalmol 2008;146:96 –101. © 2008 by Elsevier Inc. All rights reserved.) Accepted for publication Mar 3, 2008. From the Department of Ophthalmology, University of Tokyo School of Medicine, Bunkyo-ku, Tokyo, Japan (T.U., A.I., H.T., T.A., R.O., Y.I., Y.T., Y.Y.); and the New York Eye and Ear Infirmary, New York, New York (J.F.). Inquiries to Yasuo Yanagi, Department of Ophthalmology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 1138655, Japan; e-mail: [email protected]
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(AMD) is a leading cause of legal blindness in developed countries.1– 4 It is considered that exudative AMD in Japanese patients is classified into three subtypes:5 1) typical AMD characterized by choroidal neovascularization (CNV), 2) polypoidal choroidal vasculopathy (PCV) characterized by orange-red lesions found by fundus examination or characteristic polypoidal lesions on an indocyanine green angiography (ICGA), and 3) retinal angiomatous proliferation (RAP). With the advent of ICGA,6 PCV is generally recognized as a condition mimicking the clinical manifestation of AMD and has generally become considered a subtype of exudative AMD.7–9 Although PCV was originally described in Black women with multiple recurrent serosanguineous pigment epithelial detachments (PED),10 this condition is now considered to be more common in all ethnic groups, especially in Asian and Black populations.7–9,11,12 In Japanese patients, PCV occupies a substantial proportion of exudative AMD.5,13 On the other hand, the proportion of RAP is considerably lower than in White populations.5,13 Regarding the risk of bilateral involvement of exudative AMD, prospective studies from White populations have documented that unilaterally affected patients have around a 6% to 9% annual risk of the fellow eye becoming affected.1,14,15 Japanese patients, on the other hand, were reported to have a relatively low risk of being bilaterally affected. For example, Uyama and associates16 and Yuzawa and associates17 reported a cumulative incidence of about 12% of the fellow eye becoming affected by exudative AMD over a five-year period. However, to the best of the authors’ knowledge, the difference of the fellow eye involvement between the two major subtypes of Japanese AMD, typical AMD and PCV, has not been investigated to date. The primary goal of this study was to assess the cumulative incidence of typical AMD and PCV in fellow eyes of unilaterally affected patients. The secondary objective was to assess the funduscopic, fluorescein angiography (FA), and ICGA findings of the fellow eyes just before the onset of the exudative changes. Data on funduscopic features of those who did not develop AMD in fellow eyes were also
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TABLE 1. Demographic Features of Patients with Typical Exudative Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy
Number of patients Fellow eyes involved Male Age at first visit (years)
Typical AMD
PCV
P value
91 8 (8.8%) 71 (78.1%) 70.4
125 7 (5.6%) 91 (72.8%) 70.2
.383 .823
FIGURE 1. Kaplan-Meier survival curve of overall patients with age-related macular degeneration (AMD).
AMD ⫽ age-related macular degeneration; PCV ⫽ polypoidal choroidal vasculopathy.
collected for comparison. In order to elucidate very first angiographic change of typical AMD and PCV, the current study carefully investigates the findings before the first recognition of any exudative changes. FIGURE 2. Kaplan-Meier survival curve of typical exudative AMD and polypoidal choroidal vasculopathy (PCV). Red line: PCV; blue line: typical exudative AMD.
METHODS ● PATIENTS:
This is a retrospective observational consecutive case series. Patients equal to or older than 50 years with a definitive diagnosis of exudative AMD who visited the authors’ outpatient macular clinic from April 2006 to March 2007 were considered to be potential candidates and their charts were investigated retrospectively. Patients enrolled in this study had both FA and ICGA within the first several visits and were diagnosed as unilateral exudative AMD, with the fellow eyes free of exudative change or dry AMD. The patients were classified as having either typical AMD or PCV. Diagnostic decision was made by at least two of the experienced specialists (Y.Y., R.O., Y.I., and Y.T.) for each patient, on the basis of fundus examination, FA, and ICGA. Distinction between typical AMD and PCV was made based on the characteristic CNV or polypoidal lesions depicted on the angiography. Cases with inconsistent diagnosis between the specialists or typical AMD accompanied by PCV at first presentation were excluded from this study. Patients with other neovascularized maculopathies, such as pathologic myopia, angioid streaks, and RAP, were also excluded. No patient had presumed ocular histoplasmosis syndrome.
● PATIENT FOLLOW-UP: Most follow-up visits to the clinic were at one-month to six-month intervals, depending on the activity of the patient’s exudative AMD, and all patients returned within a year for regular examinations. Patients who had recently undergone interventions such as photodynamic therapy (PDT) or intravitreal bevacizumab injection were more closely followed up. At every visit patients underwent a best-corrected visual acuity test, a binocular ophthalmoscopy, and a slit-lamp biomicroscopy with contact lenses or noncontact lenses. Color fundus
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photography and optical coherence tomography (OCT) (OCT3; Carl Zeiss, Dublin, California, USA) were conducted when necessary from the therapeutic point of view. Both FA and ICGA were performed to diagnose the potential candidates of interventions such as PDT or intravitreal bevacizumab injection, and to evaluate the efficacy of these interventions. Bilateral fundus photography was routinely conducted with the angiography. FA/ ICGA and fundus photographs were taken in both eyes for each patient to detect possible subclinical angiographic changes. Patients were usually diagnosed as having the fellow eye involved when both exudative change on fundus and consistent neovascularization on the FA and ICGA were found. However, in some cases, before the onset of clinical symptoms, an abnormality in the choroidal vessels such as polypoidal lesions and/or abnormal inner choroidal vascular abnormalities were detected on ICGA without exudative changes; in such cases, the patients were diagnosed as having the fellow eye involved at the point when the choroidal abnormalities were first detected by the angiography. The follow-up period was defined from the first to the most recent visit at the time of writing. ● STATISTICAL ANALYSIS:
Statistical analysis was performed with SPSS software version 11.0 (SPSS Inc, Chicago, Illinois, USA). Mann–Whitney U test was used for numerical data and the Fisher exact test for categorical data. Log-rank test was used for the analysis of the difference between the cumulative incidences of typical AMD and PCV.
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TABLE 2. Findings of Typical Exudative Age-Related Macular Degeneration Just Before Exudative Changes No
CNV Type
FA/ICGA Findings (months before exudative change)
Funduscopic Findings
1 2 3 4 5 6 7 8
Occult Occult Occult Occult Classic Occult Occult Occult
RPE atrophy, CNV(⫺)* (four months) ⫺ RPE atrophy, CNV(⫺) (six months) RPE atrophy, CNV(⫺) (four months) n.p., CNV(⫺) (four months) RPE atrophy, CNV(⫺) (one month) RPE atrophy, CNV(⫺) (six months) n.p., CNV(⫺) (six months)
RPE atrophy Drusen Drusenoid PED, RPE atrophy Drusen, RPE atrophy Peripheral drusen RPE atrophy RPE atrophy n.p.
CNV ⫽ choroidal neovascularization; FA ⫽ fluorescein angiograpy; ICGA ⫽ indocyanine green angiography; n.p. ⫽ not present; PED ⫽ pigment epithelial detachment; RPE ⫽ retinal pigment epithelium. *Negative sign indicates no FA/ICGA performed in a six-month period before exudative changes.
TABLE 3. Findings of Polypoidal Choroidal Vasculopathy Just Before Exudative Changes No
Subtype (macular vs peridisk)
FA/ICGA Findings (months before exudative change)
Funduscopic findings
1 2 3 4 5 6 7
Macular Macular Macular Macular Macular Peridisk Macular
Polyp (⫹), net (⫹), RPE atrophy (six months) ⫺ ⫺ Polyp (⫹), net (⫹), RPE atrophy (five months) Polyp (⫺)*, net (⫹), RPE atrophy (four months) Polyp (⫹), net (⫹), RPE atrophy (five months) ⫺
RPE atrophy RPE atrophy sPED, RPE atrophy RPE atrophy RPE atrophy RPE atrophy RPE atrophy
CNV ⫽ choroidal neovascularization; FA ⫽ fluorescein angiograpy; ICGA ⫽ indocyanine green angiography; net ⫽ abnormal choroidal vascular network; Polyp ⫽ polypoidal lesion; RPE ⫽ retinal pigment epithelium; sPED ⫽ serous pigment epithelial detachment. Positive sign indicates presence of the findings on FA/ICGA, respectively. *Negative sign indicates no FA/ICGA performed in a six-month period before exudative changes.
FA and ICGA were performed within a year of each patient’s most recent visit for 163 patients (75.5%). Throughout the follow-up period the fellow eye was involved in eight (8.8%) of the 91 typical AMD patients and seven (5.6%) of the 125 PCV patients. Diagnosis in the fellow eyes, if involved, was always the same type of AMD, that is, either typical AMD or PCV, as in the first eye. Development of AMD in fellow eyes occurred in three of 67 patients (4.5%) at one year, two of 33 patients (6.1%) at three years, and one of 17 patients (5.9%) at five years for the typical AMD group, and three of 85 patients (3.5%), four of 31 patients (12.9%), and zero of 12 patients (0%) at one, three, and five years, respectively, for the PCV group. In two other cases typical AMD developed in the fellow eye in the eighth year after the patients’ first visits. Kaplan-Meier analysis demonstrated that the cumulative incidence of involvement in fellow eyes with overall exudative AMD, including both typical AMD and PCV, was 3.4% over a year, 9.3% over three years, and 11.3% over five years (Figure 1). That of the typical AMD was 3.6%, 7.3%, and 11.2% in one, three, and five years respectively, and 3.2%, 11.1%, and 11.1%, respectively, in
RESULTS DURING THE STUDY PERIOD A TOTAL OF 248 PATIENTS AGE
50 years or older were found to have unilateral CNV. Of these, the following were excluded: eight patients with RAP, two patients with angioid streaks, 18 patients with pathologic myopia, two patients with the coexistence of typical AMD and PCV at the first presentation, and two patients with inconsistent diagnosis made by the experienced specialists. As a result, 216 Japanese patients were enrolled in this study. Ninety-one patients had typical AMD and 125 patients had PCV in the first eyes. The average follow-up period was 25.1 months for PCV patients and 33.6 months for typical AMD patients. Males made up 75.0% of the two groups. Seventy-one patients (78.1%) of the typical AMD group and ninety-one (72.8%) of the PCV group were males (P ⫽ .383). The average age was 70.4 and 70.2 years, respectively (P ⫽ .823). Demographic features were not significantly different between the two disorders (Table 1). All patients received more than one funduscopic photograph, with an average of 2.75 FA and ICGA examinations per year. The 98
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FIGURE 3. PCV before and after exudative change. (Top row) Six months before the onset of exudative change. (Middle row) Three months before the onset of exudative change. (Bottom row) Exudative change showing the hemorrhagic retinal pigment epithelial detachment. From left to right: a fundus photograph, fluorescein angiography, and indocianine green angiography. Of note are a gradually developing choroidal vascular network and a polypoidal lesion at the border of the vascular network. This gradual loss of integrity in choroidal vasculature was not observed in patients with typical AMD.
PCV (Figure 2). The difference between the two groups was statistically insignificant (P ⫽ .876). Funduscopic, FA, and ICGA findings in the six-month period before exudative change are shown in Tables 2 and 3. Patients with typical AMD had a variety of funduscopic findings including retinal pigment epithelium (RPE) atrophy in five eyes (62.5%), drusen in three eyes (37.5%), drusenoid PED in one eye (12.5%), and normal macula in one eye (12.5%), although none of the patients had had prior preexisting angiographically evident CNV before the onset of exudative change. Notably, PCV patients, on the other hand, had funduscopic findings of RPE atrophy without drusen in seven eyes (100.0%) and serous PED in one eye (12.5%). On FA and ICGA four eyes (100.0%) had inner choroidal vascular abnormality of the vascular network and three eyes (75.0%) had had polypoidal formation before clinical manifestation of exudative changes (Figure 3). For comparison, the fundus features in fellow eyes that did not develop AMD were examined. This revealed: 1) at least one large drusen for 39 patients (47.0%) in the typical AMD group and 47 patients (39.8%) in the PCV group, 2) RPE atrophy with characVOL. 146, NO. 1
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teristic window defect on FA for 19 patients (22.9%) in the typical AMD group and 30 patients (25.4%) in the PCV group, and 3) serous PED for no patients (0%) in the typical AMD group and three patients (2.5%) in the PCV group. Multiple or confluent drusen were observed in eight patients (9.6%) in the AMD group and four patients (3.4%) in the PCV group. No abnormalities were detected in 34 patients (41.0%) in the typical AMD group and 48 patients (40.1%) in the PCV group.
DISCUSSION PATIENTS WITH AMD IN THE FIRST EYE ARE KNOWN TO
have high risk of bilateral involvement. In prospective studies in the White populations, the annual rate of fellow eye involvement was reported to be around 6% to 9%.1,14,15 In Japanese patients the rate is reported to be relatively low, with a cumulative incidence of about 12% in five years having been documented.16,17 Cumulative incidences of fellow-eye involvement in literature deal with both typical AMD and PCV together and the PCV
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Before fellow eyes show exudative changes, a variety of findings such as drusen, RPE atrophy, drusenoid PED, or even normal macula were observed, but no CNV formation was disclosed in typical AMD patients. On the contrary, RPE atrophy was a prevailing finding in the fellow eyes of PCV patients and the choroidal vascular network and polypoidal formation seem to gradually increase before exudative changes are observed. The gradually progressive impairment of the integrity of the choroidal vascular architecture may imply a different pathogenesis of PCV lesions other than the CNV discussed in typical AMD. Okubo and associates proposed a pathogenesis of PCV as an abnormality in the inner choroidal vasculature resulting from sclerotic choroidal arteriovenous crossing phenomena based on their pathologic investigation.22 Yuzawa and associates had similar opinions and observed tortuous choroidal vessels with constriction and dilation, but not CNV in PCV lesions on confocal scanning laser ophthalmoscopy,23 although the exact pathogenesis of PCV remains to be elucidated. CNV as a pathogenesis of PCV has also been proposed.24 In clinical settings the ICGA is important to detect subclinical PCV lesions and should therefore be performed bilaterally even in unilaterally affected patients to predict potential clinical deterioration in fellow eyes of PCV patients. A limitation of this study is that it was a retrospective and observational case-control study. Most follow-up visits were as frequent as at one-month to six-month intervals and 163 patients (75.5%) of the enrolled patients had records of a set of bilateral funduscopic photographs, FA, and ICGA during the last year of the follow-up period. However, there is still the possibility of underestimating the rate at which AMD develops in fellow eyes because some patients may have had AMD without exudative change, which would not have been detected on routine fundus check-ups. Of note, according to the present study, PCV may develop before exudative change occurs, which can be depicted on ICGA; therefore the development in fellow eyes may have been underestimated in such cases. To avoid this limitation, a prospective study with strictly scheduled FA and ICGA as well as fundus photography would be more suitable. A second limitation is that the Kaplan-Meier survival curves of the two groups were close enough to conclude that the rate of development in fellow eyes was very similar, although considering that a relatively small portion of Japanese patients develops bilateral AMD, a larger-scale study will be necessary. A final limitation is that because most of the patients were originally referred from branch hospitals or community clinics, the patients presented may be at the more severe end of the general spectrum of exudative AMD, as patients with naturally remitting lesions without an aggressive intervention might not have been referred. There is, however, no evidence regarding the relationship between the severity of AMD and probability of bilateral involvement.
incidence of the two, now recognized as distinctly separate clinical entities, has not been compared before. In the current study, the rate of development of overall exudative AMD was 11.3% in five years, which was compatible with previous studies.16,17 Exudative AMD is less likely to affect the fellow eyes of Japanese patients than White patients. With technical improvements in FA and ICGA images as well as the increasing recognition of PCV, the reported proportion of PCV against typical AMD seems still to be on the increase.5 Furthermore, a substantial proportion of exudative AMD in Japanese patients is PCV, as demonstrated in this study as well as previous studies.5 This raises the importance of investigating the difference between typical AMD and PCV. Demographic features of PCV patients resembled those of typical AMD patients in this study as well as in literature.5,9,11,12 PCV in Japanese patients differs from that in White populations in that elderly males, not females, are predominantly affected; in Japanese patients the macula is most likely affected; and most cases are unilateral.9,11,12 In fact, Yannuzzi and associates reported that 90 patients (58.4%) of 154 typical AMD patients and six (46.2%) of 13 PCV patients had bilateral lesions,8 whereas Uyama and associates documented that 322 (81%) of 398 typical AMD patients and 29 (91%) of 32 PCV patients were unilaterally affected.11 More recently, Maruko and associates reported 96 (94.1%) of 102 typical AMD patients and 129 (81.6%) of 158 PCV patients had unilateral cases.5 Therefore, PCV is considered to be generally unilateral in Japanese patients; however, neither the exact incidence in fellow eyes nor the difference between typical AMD and PCV has been studied. According to the analysis in this study, typical AMD and PCV have very similar probabilities for the fellow eye to become involved in unilaterally affected Japanese patients and the cumulative incidence was about 11% over five years. In order to assess the potential to develop exudative AMD in fellow eyes, that drusen is a paramount precursor has been well documented in literature.1,7,18 –20 In Asian populations (including both Japanese and Chinese), the prevalence of drusen is not as common as in patients.5,16,21 This may be a reflection of the relatively low incidence of bilateral exudative AMD in Asian populations. Maruko and associates documented 31 patients (24%) of PCV patients and 29 (30%) of 96 typical AMD patients had large drusen in unaffected fellow eyes.5 In the current study, small number of drusen was a common feature of unaffected fellow eyes for both groups but multiple or confluent drusen were rare, especially in the PCV group. Furthermore, more than 40% of patients of both groups had no findings of early age-related maculopathy. In 15 patients whose fellow eyes became involved, drusen in the central macula was always observed in the typical AMD patients, but not in the PCV patients. Therefore, lower prevalence of drusen in PCV than typical AMD seems to be true in Japanese patients. 100
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THIS STUDY WAS SUPPORTED IN PART BY A GRANT-IN-AID FROM THE MINISTRY OF EDUCATION, CULTURE, SPORTS, SCIENCE and Technology of Japan, Chiyoda-ku, Tokyo, Japan. Involved in design of study (T.U., Y.Y.); conduct of study (T.U., A.I., J.F., H.T., T.A., R.O., Y.I., Y.T.); collection, management, analysis, and interpretation of the data (T.U., R.O., Y.Y.); and preparation of the manuscript (T.U., Y.Y.). Institutional Review Board approval from the University of Tokyo Hospital was obtained.
REFERENCES 1. Sandberg MA, Weiner A, Miller S, Gaudio AR. High-risk characteristics of fellow eyes of patients with unilateral neovascular age-related macular degeneration. Ophthalmology 1998;105:441– 447. 2. Klein R, Wang Q, Klein BE, Moss SE, Meuer SM. The relationship of age-related maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 1995;36: 182–191. 3. Muñoz B, West SK, Rubin GS, et al. Causes of blindness and visual impairment in a population of older Americans: the Salisbury Eye Evaluation Study. Arch Ophthalmol 2000;118: 819 – 825. 4. Attebo K, Mitchell P, Smith W. Visual acuity and the causes of visual loss in Australia: the Blue Mountains Eye Study. Ophthalmology 1996;103:357–364. 5. Maruko I, Iida T, Saito M, Nagayama D, Saito K. Clinical characteristics of exudative age-related macular degeneration in Japanese patients. Am J Ophthalmol 2007;144:15–22. 6. Spaide RF, Yannuzzi LA, Slakter JS, Sorenson J, Orlach DA. Indocyanine green videoangiography of idiopathic polypoidal choroidal vasculopathy. Retina 1995;15:100 –110. 7. Yannuzzi LA, Ciardella A, Spaide RF, Rabb M, Freund KB, Orlock DA. The expanding clinical spectrum of idiopathic polypoidal choroidal vasculopathy. Arch Ophthalmol 1997; 115:478 – 485. 8. Yannuzzi LA, Wong DW, Sforzolini BS, et al. Polypoidal choroidal vasculopathy and neovascularized age-related macular degeneration. Arch Ophthalmol 1999;117:1503–1510. 9. Uyama M, Wada M, Nagai Y, et al. Polypoidal choroidal vasculopathy: natural history. Am J Ophthalmol 2002;133: 639 – 648. 10. Stern RM, Zakov ZN, Zegarra H, Gutman FA. Multiple recurrent serosanguineous retinal pigment epithelial detachments in black women. Am J Ophthalmol 1985;100:560 – 569. 11. Uyama M, Matsubara T, Fukushima I, et al. Idiopathic polypoidal choroidal vasculopathy in Japanese patients. Arch Ophthalmol 1999;117:1035–1042. 12. Sho K, Takahashi K, Yamada H, et al. Polypoidal choroidal vasculopathy: incidence, demographic features, and clinical characteristics. Arch Ophthalmol 2003;121:1392–1396.
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13. Yannuzzi LA, Negrão S, Iida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 2001;21:416 – 434. 14. Five-year follow-up of fellow eyes of patients with age-related macular degeneration and unilateral extrafoveal choroidal neovascularization. Macular Photocoagulation Study Group. Arch Ophthalmol 1993;111:1189 –1199. 15. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS Report No. 8. Arch Ophthalmol 2001;119:1417– 1436. 16. Uyama M, Takahashi K, Ida N, et al. The second eye of Japanese patients with unilateral exudative age-related macular degeneration. Br J Ophthalmol 2000;84:1018 –1023. 17. Yuzawa M, Hagita K, Egawa T, Minato H, Matsui M. Macular lesions predisposing to senile disciform macular degeneration. Jpn J Ophthalmol 1991;35:87–95. 18. Bressler SB, Maguire MG, Bressler NM, Fine SL. Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. The Macular Photocoagulation Study Group. Arch Ophthalmol 1990;108:1442–1447. 19. Ferris FL, Davis MD, Clemons TE, et al. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol 2005;123:1570 –1574. 20. Macular Photocoagulation Study Group. Risk factors for choroidal neovascularization in the second eye of patients with juxtafoveal or subfoveal choroidal neovascularization secondary to age-related macular degeneration. Arch Ophthalmol 1997;115:741–747. 21. Sivaprasad S, Membrey WL, Sivagnanavel V, et al. Second eye of patients with unilateral neovascular age-related macular degeneration: Caucasians vs Chinese. Eye 2006;20:923– 926. 22. Okubo A, Sameshima M, Uemura A, Kanda S, Ohba N. Clinicopathological correlation of polypoidal choroidal vasculopathy revealed by ultrastructural study. Br J Ophthalmol 2002;86:1093–1098. 23. Yuzawa M, Mori R, Kawamura A. The origins of polypoidal choroidal vasculopathy. Br J Ophthalmol 2005;89:602– 607. 24. Terasaki H, Miyake Y, Suzuki T, Nakamura M, Nagasaka T. Polypoidal choroidal vasculopathy treated with macular translocation: clinical pathological correlation. Br J Ophthalmol 2002;86:321–327.
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Biosketch Takashi Ueta, MD, graduated from the University of Tokyo School of Medicine, Tokyo, Japan in 2002. He is currently serving as an Assistant Professor of the Department of Ophthalmology at the University of Tokyo Hospital, with special interest in age-related macular degeneration. Dr Ueta has a unique background of three years training in both open and endovascular neurosurgery at the University of Tokyo Hospital.
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Biosketch Yasuhiro Tamaki, MD, is an Associate Professor at the Department of Ophthalmology, the University of Tokyo, Tokyo, Japan with special interest in basic and clinical research in age-related macular degeneration, angiogenesis, retinal regeneration, and drug delivery system using nanotechnology. He received a PhD from the University of Tokyo in 1994. Dr Tamaki trained in Manhattan Eye, Ear, and Throat Hospital, New York, New York sponsored by Ministry of Education. He is the first Japanese researcher to receive the MSD award.
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To investigate the development of typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) in fellow eyes of Japanese patients with exudative AMD. ● DESIGN: Retrospective observational consecutive case series. ● METHODS: Two hundred and sixteen Japanese patients were enrolled in this study from the outpatient clinic of the University of Tokyo Hospital. Ninety-one patients had typical AMD and one hundred and twenty-five patients had PCV. The average follow-up period was 33.6 and 25.1 months for typical AMD and PCV patients. ● RESULTS: The cumulative incidence of involvement in fellow eyes with overall exudative AMD, including both typical AMD and PCV, was 3.4% in one year, 9.3% in three years, and 11.3% in five years. It was 3.6%, 7.3%, and 11.2% in typical AMD, and 3.2%, 11.1%, and 11.1% in PCV in one, three, and five years, respectively. Before the development of exudative AMD, patients with typical AMD had a variety of funduscopic findings including retinal pigment epithelium (RPE) atrophy, drusen, drusenoid pigment epithelial detachments (PED), and normal macula. PCV patients, on the other hand, had funduscopic findings of RPE atrophy. Inner choroidal vascular abnormality of vascular network and polypoidal formation was observed in several eyes before the clinical manifestation of exudative changes. ● CONCLUSIONS: Typical AMD and PCV had similar probabilities of involving the fellow eye in unilaterally affected Japanese patients. RPE atrophy was a prevailing finding in fellow eyes of patients who developed PCV. In PCV, choroidal vascular network and polypoidal formation gradually grow before exudative changes. (Am J Ophthalmol 2008;146:96 –101. © 2008 by Elsevier Inc. All rights reserved.) Accepted for publication Mar 3, 2008. From the Department of Ophthalmology, University of Tokyo School of Medicine, Bunkyo-ku, Tokyo, Japan (T.U., A.I., H.T., T.A., R.O., Y.I., Y.T., Y.Y.); and the New York Eye and Ear Infirmary, New York, New York (J.F.). Inquiries to Yasuo Yanagi, Department of Ophthalmology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 1138655, Japan; e-mail: [email protected]
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(AMD) is a leading cause of legal blindness in developed countries.1– 4 It is considered that exudative AMD in Japanese patients is classified into three subtypes:5 1) typical AMD characterized by choroidal neovascularization (CNV), 2) polypoidal choroidal vasculopathy (PCV) characterized by orange-red lesions found by fundus examination or characteristic polypoidal lesions on an indocyanine green angiography (ICGA), and 3) retinal angiomatous proliferation (RAP). With the advent of ICGA,6 PCV is generally recognized as a condition mimicking the clinical manifestation of AMD and has generally become considered a subtype of exudative AMD.7–9 Although PCV was originally described in Black women with multiple recurrent serosanguineous pigment epithelial detachments (PED),10 this condition is now considered to be more common in all ethnic groups, especially in Asian and Black populations.7–9,11,12 In Japanese patients, PCV occupies a substantial proportion of exudative AMD.5,13 On the other hand, the proportion of RAP is considerably lower than in White populations.5,13 Regarding the risk of bilateral involvement of exudative AMD, prospective studies from White populations have documented that unilaterally affected patients have around a 6% to 9% annual risk of the fellow eye becoming affected.1,14,15 Japanese patients, on the other hand, were reported to have a relatively low risk of being bilaterally affected. For example, Uyama and associates16 and Yuzawa and associates17 reported a cumulative incidence of about 12% of the fellow eye becoming affected by exudative AMD over a five-year period. However, to the best of the authors’ knowledge, the difference of the fellow eye involvement between the two major subtypes of Japanese AMD, typical AMD and PCV, has not been investigated to date. The primary goal of this study was to assess the cumulative incidence of typical AMD and PCV in fellow eyes of unilaterally affected patients. The secondary objective was to assess the funduscopic, fluorescein angiography (FA), and ICGA findings of the fellow eyes just before the onset of the exudative changes. Data on funduscopic features of those who did not develop AMD in fellow eyes were also
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TABLE 1. Demographic Features of Patients with Typical Exudative Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy
Number of patients Fellow eyes involved Male Age at first visit (years)
Typical AMD
PCV
P value
91 8 (8.8%) 71 (78.1%) 70.4
125 7 (5.6%) 91 (72.8%) 70.2
.383 .823
FIGURE 1. Kaplan-Meier survival curve of overall patients with age-related macular degeneration (AMD).
AMD ⫽ age-related macular degeneration; PCV ⫽ polypoidal choroidal vasculopathy.
collected for comparison. In order to elucidate very first angiographic change of typical AMD and PCV, the current study carefully investigates the findings before the first recognition of any exudative changes. FIGURE 2. Kaplan-Meier survival curve of typical exudative AMD and polypoidal choroidal vasculopathy (PCV). Red line: PCV; blue line: typical exudative AMD.
METHODS ● PATIENTS:
This is a retrospective observational consecutive case series. Patients equal to or older than 50 years with a definitive diagnosis of exudative AMD who visited the authors’ outpatient macular clinic from April 2006 to March 2007 were considered to be potential candidates and their charts were investigated retrospectively. Patients enrolled in this study had both FA and ICGA within the first several visits and were diagnosed as unilateral exudative AMD, with the fellow eyes free of exudative change or dry AMD. The patients were classified as having either typical AMD or PCV. Diagnostic decision was made by at least two of the experienced specialists (Y.Y., R.O., Y.I., and Y.T.) for each patient, on the basis of fundus examination, FA, and ICGA. Distinction between typical AMD and PCV was made based on the characteristic CNV or polypoidal lesions depicted on the angiography. Cases with inconsistent diagnosis between the specialists or typical AMD accompanied by PCV at first presentation were excluded from this study. Patients with other neovascularized maculopathies, such as pathologic myopia, angioid streaks, and RAP, were also excluded. No patient had presumed ocular histoplasmosis syndrome.
● PATIENT FOLLOW-UP: Most follow-up visits to the clinic were at one-month to six-month intervals, depending on the activity of the patient’s exudative AMD, and all patients returned within a year for regular examinations. Patients who had recently undergone interventions such as photodynamic therapy (PDT) or intravitreal bevacizumab injection were more closely followed up. At every visit patients underwent a best-corrected visual acuity test, a binocular ophthalmoscopy, and a slit-lamp biomicroscopy with contact lenses or noncontact lenses. Color fundus
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photography and optical coherence tomography (OCT) (OCT3; Carl Zeiss, Dublin, California, USA) were conducted when necessary from the therapeutic point of view. Both FA and ICGA were performed to diagnose the potential candidates of interventions such as PDT or intravitreal bevacizumab injection, and to evaluate the efficacy of these interventions. Bilateral fundus photography was routinely conducted with the angiography. FA/ ICGA and fundus photographs were taken in both eyes for each patient to detect possible subclinical angiographic changes. Patients were usually diagnosed as having the fellow eye involved when both exudative change on fundus and consistent neovascularization on the FA and ICGA were found. However, in some cases, before the onset of clinical symptoms, an abnormality in the choroidal vessels such as polypoidal lesions and/or abnormal inner choroidal vascular abnormalities were detected on ICGA without exudative changes; in such cases, the patients were diagnosed as having the fellow eye involved at the point when the choroidal abnormalities were first detected by the angiography. The follow-up period was defined from the first to the most recent visit at the time of writing. ● STATISTICAL ANALYSIS:
Statistical analysis was performed with SPSS software version 11.0 (SPSS Inc, Chicago, Illinois, USA). Mann–Whitney U test was used for numerical data and the Fisher exact test for categorical data. Log-rank test was used for the analysis of the difference between the cumulative incidences of typical AMD and PCV.
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TABLE 2. Findings of Typical Exudative Age-Related Macular Degeneration Just Before Exudative Changes No
CNV Type
FA/ICGA Findings (months before exudative change)
Funduscopic Findings
1 2 3 4 5 6 7 8
Occult Occult Occult Occult Classic Occult Occult Occult
RPE atrophy, CNV(⫺)* (four months) ⫺ RPE atrophy, CNV(⫺) (six months) RPE atrophy, CNV(⫺) (four months) n.p., CNV(⫺) (four months) RPE atrophy, CNV(⫺) (one month) RPE atrophy, CNV(⫺) (six months) n.p., CNV(⫺) (six months)
RPE atrophy Drusen Drusenoid PED, RPE atrophy Drusen, RPE atrophy Peripheral drusen RPE atrophy RPE atrophy n.p.
CNV ⫽ choroidal neovascularization; FA ⫽ fluorescein angiograpy; ICGA ⫽ indocyanine green angiography; n.p. ⫽ not present; PED ⫽ pigment epithelial detachment; RPE ⫽ retinal pigment epithelium. *Negative sign indicates no FA/ICGA performed in a six-month period before exudative changes.
TABLE 3. Findings of Polypoidal Choroidal Vasculopathy Just Before Exudative Changes No
Subtype (macular vs peridisk)
FA/ICGA Findings (months before exudative change)
Funduscopic findings
1 2 3 4 5 6 7
Macular Macular Macular Macular Macular Peridisk Macular
Polyp (⫹), net (⫹), RPE atrophy (six months) ⫺ ⫺ Polyp (⫹), net (⫹), RPE atrophy (five months) Polyp (⫺)*, net (⫹), RPE atrophy (four months) Polyp (⫹), net (⫹), RPE atrophy (five months) ⫺
RPE atrophy RPE atrophy sPED, RPE atrophy RPE atrophy RPE atrophy RPE atrophy RPE atrophy
CNV ⫽ choroidal neovascularization; FA ⫽ fluorescein angiograpy; ICGA ⫽ indocyanine green angiography; net ⫽ abnormal choroidal vascular network; Polyp ⫽ polypoidal lesion; RPE ⫽ retinal pigment epithelium; sPED ⫽ serous pigment epithelial detachment. Positive sign indicates presence of the findings on FA/ICGA, respectively. *Negative sign indicates no FA/ICGA performed in a six-month period before exudative changes.
FA and ICGA were performed within a year of each patient’s most recent visit for 163 patients (75.5%). Throughout the follow-up period the fellow eye was involved in eight (8.8%) of the 91 typical AMD patients and seven (5.6%) of the 125 PCV patients. Diagnosis in the fellow eyes, if involved, was always the same type of AMD, that is, either typical AMD or PCV, as in the first eye. Development of AMD in fellow eyes occurred in three of 67 patients (4.5%) at one year, two of 33 patients (6.1%) at three years, and one of 17 patients (5.9%) at five years for the typical AMD group, and three of 85 patients (3.5%), four of 31 patients (12.9%), and zero of 12 patients (0%) at one, three, and five years, respectively, for the PCV group. In two other cases typical AMD developed in the fellow eye in the eighth year after the patients’ first visits. Kaplan-Meier analysis demonstrated that the cumulative incidence of involvement in fellow eyes with overall exudative AMD, including both typical AMD and PCV, was 3.4% over a year, 9.3% over three years, and 11.3% over five years (Figure 1). That of the typical AMD was 3.6%, 7.3%, and 11.2% in one, three, and five years respectively, and 3.2%, 11.1%, and 11.1%, respectively, in
RESULTS DURING THE STUDY PERIOD A TOTAL OF 248 PATIENTS AGE
50 years or older were found to have unilateral CNV. Of these, the following were excluded: eight patients with RAP, two patients with angioid streaks, 18 patients with pathologic myopia, two patients with the coexistence of typical AMD and PCV at the first presentation, and two patients with inconsistent diagnosis made by the experienced specialists. As a result, 216 Japanese patients were enrolled in this study. Ninety-one patients had typical AMD and 125 patients had PCV in the first eyes. The average follow-up period was 25.1 months for PCV patients and 33.6 months for typical AMD patients. Males made up 75.0% of the two groups. Seventy-one patients (78.1%) of the typical AMD group and ninety-one (72.8%) of the PCV group were males (P ⫽ .383). The average age was 70.4 and 70.2 years, respectively (P ⫽ .823). Demographic features were not significantly different between the two disorders (Table 1). All patients received more than one funduscopic photograph, with an average of 2.75 FA and ICGA examinations per year. The 98
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FIGURE 3. PCV before and after exudative change. (Top row) Six months before the onset of exudative change. (Middle row) Three months before the onset of exudative change. (Bottom row) Exudative change showing the hemorrhagic retinal pigment epithelial detachment. From left to right: a fundus photograph, fluorescein angiography, and indocianine green angiography. Of note are a gradually developing choroidal vascular network and a polypoidal lesion at the border of the vascular network. This gradual loss of integrity in choroidal vasculature was not observed in patients with typical AMD.
PCV (Figure 2). The difference between the two groups was statistically insignificant (P ⫽ .876). Funduscopic, FA, and ICGA findings in the six-month period before exudative change are shown in Tables 2 and 3. Patients with typical AMD had a variety of funduscopic findings including retinal pigment epithelium (RPE) atrophy in five eyes (62.5%), drusen in three eyes (37.5%), drusenoid PED in one eye (12.5%), and normal macula in one eye (12.5%), although none of the patients had had prior preexisting angiographically evident CNV before the onset of exudative change. Notably, PCV patients, on the other hand, had funduscopic findings of RPE atrophy without drusen in seven eyes (100.0%) and serous PED in one eye (12.5%). On FA and ICGA four eyes (100.0%) had inner choroidal vascular abnormality of the vascular network and three eyes (75.0%) had had polypoidal formation before clinical manifestation of exudative changes (Figure 3). For comparison, the fundus features in fellow eyes that did not develop AMD were examined. This revealed: 1) at least one large drusen for 39 patients (47.0%) in the typical AMD group and 47 patients (39.8%) in the PCV group, 2) RPE atrophy with characVOL. 146, NO. 1
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teristic window defect on FA for 19 patients (22.9%) in the typical AMD group and 30 patients (25.4%) in the PCV group, and 3) serous PED for no patients (0%) in the typical AMD group and three patients (2.5%) in the PCV group. Multiple or confluent drusen were observed in eight patients (9.6%) in the AMD group and four patients (3.4%) in the PCV group. No abnormalities were detected in 34 patients (41.0%) in the typical AMD group and 48 patients (40.1%) in the PCV group.
DISCUSSION PATIENTS WITH AMD IN THE FIRST EYE ARE KNOWN TO
have high risk of bilateral involvement. In prospective studies in the White populations, the annual rate of fellow eye involvement was reported to be around 6% to 9%.1,14,15 In Japanese patients the rate is reported to be relatively low, with a cumulative incidence of about 12% in five years having been documented.16,17 Cumulative incidences of fellow-eye involvement in literature deal with both typical AMD and PCV together and the PCV
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Before fellow eyes show exudative changes, a variety of findings such as drusen, RPE atrophy, drusenoid PED, or even normal macula were observed, but no CNV formation was disclosed in typical AMD patients. On the contrary, RPE atrophy was a prevailing finding in the fellow eyes of PCV patients and the choroidal vascular network and polypoidal formation seem to gradually increase before exudative changes are observed. The gradually progressive impairment of the integrity of the choroidal vascular architecture may imply a different pathogenesis of PCV lesions other than the CNV discussed in typical AMD. Okubo and associates proposed a pathogenesis of PCV as an abnormality in the inner choroidal vasculature resulting from sclerotic choroidal arteriovenous crossing phenomena based on their pathologic investigation.22 Yuzawa and associates had similar opinions and observed tortuous choroidal vessels with constriction and dilation, but not CNV in PCV lesions on confocal scanning laser ophthalmoscopy,23 although the exact pathogenesis of PCV remains to be elucidated. CNV as a pathogenesis of PCV has also been proposed.24 In clinical settings the ICGA is important to detect subclinical PCV lesions and should therefore be performed bilaterally even in unilaterally affected patients to predict potential clinical deterioration in fellow eyes of PCV patients. A limitation of this study is that it was a retrospective and observational case-control study. Most follow-up visits were as frequent as at one-month to six-month intervals and 163 patients (75.5%) of the enrolled patients had records of a set of bilateral funduscopic photographs, FA, and ICGA during the last year of the follow-up period. However, there is still the possibility of underestimating the rate at which AMD develops in fellow eyes because some patients may have had AMD without exudative change, which would not have been detected on routine fundus check-ups. Of note, according to the present study, PCV may develop before exudative change occurs, which can be depicted on ICGA; therefore the development in fellow eyes may have been underestimated in such cases. To avoid this limitation, a prospective study with strictly scheduled FA and ICGA as well as fundus photography would be more suitable. A second limitation is that the Kaplan-Meier survival curves of the two groups were close enough to conclude that the rate of development in fellow eyes was very similar, although considering that a relatively small portion of Japanese patients develops bilateral AMD, a larger-scale study will be necessary. A final limitation is that because most of the patients were originally referred from branch hospitals or community clinics, the patients presented may be at the more severe end of the general spectrum of exudative AMD, as patients with naturally remitting lesions without an aggressive intervention might not have been referred. There is, however, no evidence regarding the relationship between the severity of AMD and probability of bilateral involvement.
incidence of the two, now recognized as distinctly separate clinical entities, has not been compared before. In the current study, the rate of development of overall exudative AMD was 11.3% in five years, which was compatible with previous studies.16,17 Exudative AMD is less likely to affect the fellow eyes of Japanese patients than White patients. With technical improvements in FA and ICGA images as well as the increasing recognition of PCV, the reported proportion of PCV against typical AMD seems still to be on the increase.5 Furthermore, a substantial proportion of exudative AMD in Japanese patients is PCV, as demonstrated in this study as well as previous studies.5 This raises the importance of investigating the difference between typical AMD and PCV. Demographic features of PCV patients resembled those of typical AMD patients in this study as well as in literature.5,9,11,12 PCV in Japanese patients differs from that in White populations in that elderly males, not females, are predominantly affected; in Japanese patients the macula is most likely affected; and most cases are unilateral.9,11,12 In fact, Yannuzzi and associates reported that 90 patients (58.4%) of 154 typical AMD patients and six (46.2%) of 13 PCV patients had bilateral lesions,8 whereas Uyama and associates documented that 322 (81%) of 398 typical AMD patients and 29 (91%) of 32 PCV patients were unilaterally affected.11 More recently, Maruko and associates reported 96 (94.1%) of 102 typical AMD patients and 129 (81.6%) of 158 PCV patients had unilateral cases.5 Therefore, PCV is considered to be generally unilateral in Japanese patients; however, neither the exact incidence in fellow eyes nor the difference between typical AMD and PCV has been studied. According to the analysis in this study, typical AMD and PCV have very similar probabilities for the fellow eye to become involved in unilaterally affected Japanese patients and the cumulative incidence was about 11% over five years. In order to assess the potential to develop exudative AMD in fellow eyes, that drusen is a paramount precursor has been well documented in literature.1,7,18 –20 In Asian populations (including both Japanese and Chinese), the prevalence of drusen is not as common as in patients.5,16,21 This may be a reflection of the relatively low incidence of bilateral exudative AMD in Asian populations. Maruko and associates documented 31 patients (24%) of PCV patients and 29 (30%) of 96 typical AMD patients had large drusen in unaffected fellow eyes.5 In the current study, small number of drusen was a common feature of unaffected fellow eyes for both groups but multiple or confluent drusen were rare, especially in the PCV group. Furthermore, more than 40% of patients of both groups had no findings of early age-related maculopathy. In 15 patients whose fellow eyes became involved, drusen in the central macula was always observed in the typical AMD patients, but not in the PCV patients. Therefore, lower prevalence of drusen in PCV than typical AMD seems to be true in Japanese patients. 100
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THIS STUDY WAS SUPPORTED IN PART BY A GRANT-IN-AID FROM THE MINISTRY OF EDUCATION, CULTURE, SPORTS, SCIENCE and Technology of Japan, Chiyoda-ku, Tokyo, Japan. Involved in design of study (T.U., Y.Y.); conduct of study (T.U., A.I., J.F., H.T., T.A., R.O., Y.I., Y.T.); collection, management, analysis, and interpretation of the data (T.U., R.O., Y.Y.); and preparation of the manuscript (T.U., Y.Y.). Institutional Review Board approval from the University of Tokyo Hospital was obtained.
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13. Yannuzzi LA, Negrão S, Iida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 2001;21:416 – 434. 14. Five-year follow-up of fellow eyes of patients with age-related macular degeneration and unilateral extrafoveal choroidal neovascularization. Macular Photocoagulation Study Group. Arch Ophthalmol 1993;111:1189 –1199. 15. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS Report No. 8. Arch Ophthalmol 2001;119:1417– 1436. 16. Uyama M, Takahashi K, Ida N, et al. The second eye of Japanese patients with unilateral exudative age-related macular degeneration. Br J Ophthalmol 2000;84:1018 –1023. 17. Yuzawa M, Hagita K, Egawa T, Minato H, Matsui M. Macular lesions predisposing to senile disciform macular degeneration. Jpn J Ophthalmol 1991;35:87–95. 18. Bressler SB, Maguire MG, Bressler NM, Fine SL. Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. The Macular Photocoagulation Study Group. Arch Ophthalmol 1990;108:1442–1447. 19. Ferris FL, Davis MD, Clemons TE, et al. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol 2005;123:1570 –1574. 20. Macular Photocoagulation Study Group. Risk factors for choroidal neovascularization in the second eye of patients with juxtafoveal or subfoveal choroidal neovascularization secondary to age-related macular degeneration. Arch Ophthalmol 1997;115:741–747. 21. Sivaprasad S, Membrey WL, Sivagnanavel V, et al. Second eye of patients with unilateral neovascular age-related macular degeneration: Caucasians vs Chinese. Eye 2006;20:923– 926. 22. Okubo A, Sameshima M, Uemura A, Kanda S, Ohba N. Clinicopathological correlation of polypoidal choroidal vasculopathy revealed by ultrastructural study. Br J Ophthalmol 2002;86:1093–1098. 23. Yuzawa M, Mori R, Kawamura A. The origins of polypoidal choroidal vasculopathy. Br J Ophthalmol 2005;89:602– 607. 24. Terasaki H, Miyake Y, Suzuki T, Nakamura M, Nagasaka T. Polypoidal choroidal vasculopathy treated with macular translocation: clinical pathological correlation. Br J Ophthalmol 2002;86:321–327.
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Biosketch Takashi Ueta, MD, graduated from the University of Tokyo School of Medicine, Tokyo, Japan in 2002. He is currently serving as an Assistant Professor of the Department of Ophthalmology at the University of Tokyo Hospital, with special interest in age-related macular degeneration. Dr Ueta has a unique background of three years training in both open and endovascular neurosurgery at the University of Tokyo Hospital.
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Biosketch Yasuhiro Tamaki, MD, is an Associate Professor at the Department of Ophthalmology, the University of Tokyo, Tokyo, Japan with special interest in basic and clinical research in age-related macular degeneration, angiogenesis, retinal regeneration, and drug delivery system using nanotechnology. He received a PhD from the University of Tokyo in 1994. Dr Tamaki trained in Manhattan Eye, Ear, and Throat Hospital, New York, New York sponsored by Ministry of Education. He is the first Japanese researcher to receive the MSD award.
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