Ryo Obata

Background Comparison of Typical Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy in Japanese Patients

OBJECTIVE To compare background factors of the 2 most dominant subtypes of exudative age-related macular degeneration (AMD) in the Japanese population: typical AMD and polypoidal choroidal vasculopathy (PCV). DESIGN Cross-sectional comparison. PARTICIPANTS Consecutive patients with typical AMD (n = 89) and PCV (n = 138) for the primary survey. For the secondary survey, the number of participants was extended to include 148 typical AMD and 170 PCV patients. All the patients included in the present study had been followed up at The University of Tokyo Hospital outpatient macular clinic. METHODS Background data on gender; age; body mass index; smoking; alcohol consumption; and histories of hypertension, diabetes mellitus (DM), hyperlipidemia, ischemic heart disease, stroke, intensive light exposure, central serous chorioretinopathy (CSC), cataract surgery, glaucoma, and steroid use were obtained mainly through interview. The interviewers were masked to the subtype diagnosis of AMD. Univariate and multivariate logistic regression analyses were performed to identify differences in the background factors between typical AMD and PCV. In the secondary survey, the association of a history of CSC and PCV was confirmed further, and funduscopic findings of an atrophic retinal pigment epithelial (RPE) tract and focal photocoagulation scars that could indicate a history of CSC were investigated. MAIN OUTCOME MEASURES Frequency and mean of background factors in patients with typical AMD or PCV. RESULTS The 2 groups showed similar backgrounds with the exception of their histories of DM and CSC. A history of DM was more frequent in typical AMD (24.7% vs. 13.0% in the primary survey; P = 0.027), whereas a history of CSC was more prevalent in PCV (3.4% vs. 14.7% in the secondary survey; P = 0.0005). Funduscopic findings of an atrophic RPE tract or focal photocoagulation scars were found more frequently in PCV (0.7% vs. 7.6%; P = 0.002). CONCLUSIONS Background factors of typical AMD and PCV are similar but not identical. A history of DM and CSC are more frequent in typical AMD and PCV, respectively.

Inhibition of choroidal neovascularization by blocking vascular endothelial growth factor receptor tyrosine kinase.

PurposeTo investigate the role played by receptors of vascular endothelial growth factors, Flt-1 and KDR/Flk-1, on an experimental model of choroidal neovascularization (CNV).MethodsThe vascular endothelial growth factor-A (VEGF-A) receptor-specific tyrosine kinase inhibitor SU5416 was administered to a laser-induced mouse model of CNV. The formation of CNV and the degree of vascular permeability in Flt-1 tyrosine kinase domain-deficient mice were also investigated.ResultsSU5416 reduced vascularity and vascular endothelial cell proliferation, and promoted endothelial cell apoptosis within CNV. Furthermore, the formation of CNV and the degree of vascular permeability were significantly reduced in Flt-1 tyrosine kinase domain-deficient mice, and this effect was enhanced by the administration of SU5416.ConclusionsBoth Flt-1 and KDR/Flk-1 have a significant role in CNV formation. Suppression of apoptosis may be involved in the process.

Vitreomacular interface in typical exudative age-related macular degeneration and polypoidal choroidal vasculopathy.

PURPOSE To investigate the association in Japanese between posterior vitreous attachment and the pathologies of typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV), 2 major forms of exudative AMD. DESIGN Retrospective observational case series. PARTICIPANTS A total of 378 eyes from 302 subjects (132 with typical AMD, 126 with PCV, 120 controls) from the University of Tokyo Hospital. METHODS Posterior vitreous detachment (PVD) and vitreomacular adhesion (VMA) were investigated by B-mode ultrasonography and spectral-domain optical coherence tomography (SD-OCT), respectively. The greatest linear dimension (GLD) of initial photodynamic therapy (PDT) in a subset of the patients (n=92) receiving PDT was also investigated. MAIN OUTCOME MEASURES Number of eyes with complete PVD and with VMA. The GLD of initial PDT. RESULTS In typical AMD eyes, the frequency of complete PVD was significantly lower (63 [56.8%] of 111 eyes) than in the controls (52 [70.3%] of 74 eyes, risk ratio [RR] 0.76, P=0.021) and the frequency of VMA tended to be higher (14/115 [12.2%] in typical AMD eyes and 6/86 [7.0%] in the controls, RR 2.15, P=0.099). The frequency of complete PVD [77 [63.1%] of the 122 eyes] and VMA (9/108 [8.3%]) in PCV eyes was the same as the controls (RR 0.91, P=0.415 and RR 1.29, P=0.615). In patients with unilateral exudative AMD, the frequency of complete PVD was lower in typical AMD eyes than in fellow eyes (odds ratio [OR] 0.111, P=0.026) and VMA was observed in 7 (17.5%) and 3 (7.5%) typical AMD and fellow eyes, respectively (OR 2.33, P=0.34), whereas in PCV eyes, the frequency of complete PVD was higher (OR 8.00, P=0.045) and the frequency of VMA was the same as in the fellow eyes (OR 0.80, P=1.00). The GLD of the eyes without complete PVD or with VMA was significantly larger than that in the eyes with complete PVD in typical AMD eyes (P=0.042) and the same as that in the eyes with complete PVD in PCV eyes (P=0.67). CONCLUSIONS There is an association between posterior vitreous attachment and typical AMD. However, this association is not evident in PCV.

Tomographic and angiographic characteristics of eyes with macular focal choroidal excavation.

Purpose: To describe detailed clinical features of eyes with focal choroidal excavation. Methods: Twenty-one eyes of 17 patients with focal choroidal excavation were retrospectively studied. All eyes underwent thorough examination including funduscopy, visual field analysis, fundus autofluorescence imaging, fluorescein angiography, indocyanine green angiography, and B-scan ultrasonography. Results: Patients’ age ranged between 25 years and 70 years. Four patients (24%) were affected bilaterally. Spherical equivalent of refractive error ranged from 0.5 diopters to −10.0 diopters (D). Funduscopic examination showed hypopigmentation (n = 12) and yellowish plaquelike appearances (n = 2). Indocyanine green angiography showed not only filling defects at the excavation (n = 16) but also choroidal vascular hyperpermeability (n = 7) and punctate hyperfluorescent spots (n = 7). Cicatrized subretinal neovascularization was seen in three eyes. The mean follow-up period was 37 months (6–66 months). There was no change in the appearance of excavation. Central serous chorioretinopathy (n = 1) and choroidal neovascularization (n = 1) developed during follow-up. Conclusion: Background factors and ophthalmic findings are similar to those that have been reported previously, including relatively stable findings even after a long observation and the occurrence of central serous chorioretinopathy and choroidal neovascularization. Bilateral cases are not rare in the current cohort, and choroidal vascular hyperpermeability is frequently observed in indocyanine green angiography, suggesting there were choroidal hemodynamic changes around the excavation.

Development of Typical Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy in Fellow Eyes of Japanese Patients with Exudative Age-related Macular Degeneration

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.

Polypoidal choroidal vasculopathy and retinochoroidal anastomosis in Japanese patients eligible for photodynamic therapy for exudative age-related macular degeneration.

PurposeTo determine the percentage of Japanese patients with age-related macular degeneration (AMD) who are eligible for photodynamic therapy (PDT) with verteporfin who have either polypoidal choroidal vasculopathy (PCV) or choroidal neovascularization (CNV) with retinochoroidal anastomosis (RCA).MethodsThe medical charts of 82 consecutive patients (83 eyes) with subfoveal CNV due to AMD were reviewed. Initially, we determined which of these eyes were eligible for PDT by using the criteria reported by two large randomized control studies, that is, the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) study and the Verteporfin in Photodynamic Therapy (VIP) study. Among the PDT-eligible patients, the percentage of eyes with PCV or CNV with RCA was determined by indocyanine green angiography (ICGA).ResultsIn total, 36 eyes (43%) of the 83 eyes were PDT-eligible; 17 (20%) based on the TAP study criteria, and 19 (23%) based on the VIP study criteria. Among these PDT-eligible eyes, ICGA revealed that 12 (33%) had PCV and 2 (6%) had CNV with RCA.ConclusionsWith ICGA, PCV or CNV with RCA were recognized in a substantial proportion of cases eligible for PDT based on the two clinical studies. Considering that the treatment efficacy of PDT for PCV or RCA has not been established, detection of PCV or RCA prior to PDT with ICGA is highly recommended. Jpn J Ophthalmol 2006;50:354–360

Triamcinolone acetonide suppresses early proangiogenic response in retinal pigment epithelial cells after photodynamic therapy in vitro.

Objective: To investigate the expression of proangiogenic and antiangiogenic factors, vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in retinal pigment epithelial (RPE) cells after photodynamic therapy (PDT), especially focusing on their change in the presence of triamcinolone acetonide. Methods: Firstly, the cellular uptake of verteporfin was quantified after confluent ARPE-19 (human retinal pigment epithelial) cells were exposed to 5 μg/ml verteporfin combined with or without 1 μg/ml triamcinolone acetonide for 1 h. Secondly, ARPE-19 cells exposed to various doses of verteporfin were irradiated with 120 mJ/cm2 light. After incubation with or without 1 μg/ml triamcinolone acetonide for 2 days, cell viability and expressions of VEGF and PEDF were assessed. Results: Cellular uptake of verteporfin was not significantly changed by the presence of 1 μg/ml triamcinolone acetonide. In addition, 0.01–0.1 μg/ml of verteporfin showed a dose-dependent toxicity on the ARPE-19 cells 2 days after the light exposure. The presence of verteporfin at a concentration of 0.01 μg/ml did not affect the cell viability but significantly increased VEGF (p<0.001) and reduced PEDF (p = 0.03) expression. Administration of triamcinolone acetonide significantly suppressed both this increase in VEGF (p<0.001) and decrease in PEDF (p = 0.001). Conclusions: VEGF was increased and PEDF reduced in cultured RPE cells shortly after PDT even at a sublethal dose. Triamcinolone acetonide suppressed this proangiogenic response.

Quantitative analysis of cone photoreceptor distribution and its relationship with axial length, age, and early age-related macular degeneration.

Purpose It has not been clarified whether early age-related macular degeneration (AMD) is associated with cone photoreceptor distribution. We used adaptive optics fundus camera to examine cone photoreceptors in the macular area of aged patients and quantitatively analyzed its relationship between the presence of early AMD and cone distribution. Methods Sixty cases aged 50 or older were studied. The eyes were examined with funduscopy and spectral-domain optical coherence tomography to exclude the eyes with any abnormalities at two sites of measurement, 2° superior and 5° temporal to the fovea. High-resolution retinal images with cone photoreceptor mosaic were obtained with adaptive optics fundus camera (rtx1, Imagine Eyes, France). After adjusting for axial length, cone packing density was calculated and the relationship with age, axial length, or severity of early AMD based on the age-related eye disease study (AREDS) classification was analyzed. Results Patient’s age ranged from 50 to 77, and axial length from 21.7 to 27.5 mm. Mean density in metric units and that in angular units were 24,900 cells/mm2, 2,170 cells/deg2 at 2° superior, and 18,500 cells/mm2, 1,570 cels/deg2 at 5° temporal, respectively. Axial length was significantly correlated with the density calculated in metric units, but not with that in angular units. Age was significantly correlated with the density both in metric and angular units at 2° superior. There was no significant difference in the density in metric and angular units between the eyes with AREDS category one and those with categories two or three. Conclusion Axial length and age were significantly correlated with parafoveal cone photoreceptor distribution. The results do not support that early AMD might influence cone photoreceptor density in the area without drusen or pigment abnormalities.

Dietary n-3 Fatty Acid, α-Tocopherol, Zinc, vitamin D, vitamin C, and β-carotene are Associated with Age-Related Macular Degeneration in Japan.

This case-control study reports the association between nutrient intake and neovascular age-related macular degeneration (AMD) in Japan. The nutrient intake of 161 neovascular AMD cases from two university hospitals and 369 population-based control subjects from a cohort study was assessed using a brief-type self-administered questionnaire on diet history, which required respondent recall of the usual intake of 58 foods during the preceding month. Energy-adjusted nutrient intake values were compared between the groups. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% CIs adjusted for smoking history, age, sex, chronic disease history, supplement use, and alcohol consumption. Logistic regression analysis demonstrated that low intakes of n-3 fatty acid, α-tocopherol, zinc, vitamin D, vitamin C, and β-carotene were associated with neovascular AMD (Trend P < 0.0001 for n-3 fatty acid, Trend P < 0.0001 for α-tocopherol, Trend P < 0.0001 for zinc, Trend P = 0.002 for vitamin D, Trend P = 0.04 for vitamin C, Trend P = 0.0004 for β-carotene). There was no association with retinol or cryptoxanthin intake and neovascular AMD (P = 0.67, 0.06).

Identification of a novel vascular endothelial growth factor receptor 2 inhibitor and its effect for choroidal neovascularization in vivo.

Purpose: To select a novel orally administered VEGFR-2 (KDR/flk-1) specific tyrosine kinase inhibitor in a murine model of choroidal neovascularization (CNV). Methods: From a compound library, potent VEGFR2 inhibitors were selected by VEGF-induced phosphorylation of VEGFR-2 and RAF kinases and the proliferation analysis by HUVEC cultures and in vitro tube formation assay. CNV was induced in C57/BL6 mice using diode laser photocoagulation. The antiangiogenic effect of selected compounds was assessed by angiographic examination, in which extent of fluorescein leakage was scored and histological analysis, allowing for measurement of CNV membrane under light microscope. In addition, C57/BL6 mice were treated with daily oral administration of selected compounds for 14 days and body weights were measured. Results: Six compounds that potently inhibited VEGFR-2 were selected for further investigation. Selected compounds-treated conditions showed a dose-dependent inhibition of phosphorylation of VEGFR-2 tyrosine kinase with an IC50 of 0.0022 to 0.098 μm. Selected compounds did not inhibit the HCT116 proliferation but did demonstrate a strong inhibition effect for VEGFR-2 dependant HUVEC (IC50 = 0.0018 to 0.058 μm). Selected compounds treatment also resulted in a dose-dependent attenuation of in vitro tube formation. In the murine CNV model, #0451 is the most effective compound. The intensity of fluorescein leakage was significantly lower in doses of 12.5, 25, 50, and 100 mg/kg #0451-treated eyes compared to controls. Histologically, CNV membrane volumes were significantly reduced in #0451-treated eyes in a dose-dependent manner. At therapeutic doses of 100 mg/kg or less, there was no significant weight loss between the treated and untreated groups. Conclusion: Oral administration of #0451, a novel VEGFR-2 (KDR/flk-1)-specific tyrosine kinase inhibitor, demonstrates anti-angiogenic effects in our murine model of CNV. #0451 may be useful to treat the choroidal neovascularization associated with AMD.