Yumiko Akagi-Kurashige

Factors Associated With the Response of Age-Related Macular Degeneration to Intravitreal Ranibizumab Treatment

PURPOSE To investigate factors affecting patient response to intravitreal ranibizumab treatment for age-related macular degeneration (AMD). DESIGN Retrospective chart review. METHODS We reviewed medical records of 105 consecutive eyes with AMD treated with intravitreal ranibizumab injections and followed for more than 1 year after treatment. Response to ranibizumab treatment was compared between typical neovascular AMD and polypoidal choroidal vasculopathy (PCV). Furthermore, we investigated associations of age, lesion size, and single nucleotide polymorphisms (SNPs) in CFH and ARMS2 genes with treatment response. RESULTS Forty-nine eyes were diagnosed with typical neovascular AMD and 56 eyes with PCV. Serous retinal detachment and retinal edema resolved similarly in both typical neovascular AMD and PCV after treatment. However, visual acuity (VA) significantly improved in eyes with PCV, whereas VA was maintained in typical neovascular AMD. At the third and twelfth months after injection, VA was better in PCV than in typical neovascular AMD (P = .027 and P = .044, respectively), although there were no differences in baseline VA between the 2 groups. Age and size of greatest linear dimension were significantly associated with visual prognosis in typical neovascular AMD but not in PCV. There was no clear association between 3 SNPs and responsiveness to ranibizumab treatment. CONCLUSIONS Although exudative changes were equivalent following ranibizumab treatment in both typical neovascular AMD and PCV, there was a significant increase in VA in PCV compared to typical neovascular AMD. Age and greatest linear dimension correlated with visual prognosis only in typical neovascular AMD and not in PCV.

One-Year Result of Aflibercept Treatment on Age-Related Macular Degeneration and Predictive Factors for Visual Outcome

PURPOSE To investigate the efficacy of periodic injection of aflibercept in each subtype of age-related macular degeneration (AMD) and to explore the predictive factors for visual outcome in clinical settings. DESIGN Prospective nonrandomized interventional case series. METHODS Patients with AMD were recruited and were administered aflibercept injections once a month for 3 months followed by once every 2 months for 8 months. The logarithm of the minimal angle of resolution (logMAR) at 12 months and improvement of vision from baseline were compared among polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and typical AMD. Regression rate of polypoidal lesions was assessed. We also performed regression analysis with logMAR at 12 months as the dependent variable. RESULTS The study sample consisted of 98 patients: 46 had typical AMD, 42 had PCV, and 10 had RAP. Mean logMAR improved from 0.36 to 0.21 in 12 months. While there was no difference in visual improvement between typical AMD and PCV, final logMAR was better in PCV (0.32 ± 0.09 vs 0.08 ± 0.04, P = .016). Thirty-nine PCV patients underwent follow-up angiography, and regression of polyps was observed in 27 cases (69.2%). Multiple regression analysis showed that the presence of external limiting membrane (ELM), smaller greatest linear dimension, and the presence of polypoidal lesion were associated with better visual outcome (R(2) = 0.53, P = 2.73 × 10(-14)). CONCLUSIONS Periodic injection of aflibercept is effective for PCV as well as for typical AMD. The statuses of ELM, greatest linear dimension, and polypoidal lesion are predictive for visual outcome.

Age- and hypertension-dependent changes in retinal vessel diameter and wall thickness: an optical coherence tomography study.

PURPOSE To validate and evaluate the reliability of retinal vessel diameter measurements by optical coherence tomography (OCT). The effects of age and hypertension on vessel diameter were also examined. DESIGN Prospective, cross-sectional study. METHODS Two hundred thirty-eight eyes (238 subjects) with no ocular disease were included. Hypertension was present in 106 subjects and absent in 132 subjects. Spectralis HRA+OCT was used to scan a circular region around the optic disc. Outer and inner diameters of the 4 largest retinal arteries and veins were measured using OCT vascular wall reflections, and vessel wall thickness was calculated. RESULTS Intervisit, interexaminer, and interevaluator intraclass correlation coefficients of randomly selected vessel measurements were all greater than 0.90. Mean inner arterial and venous diameters were 87.8 ± 9.4 μm and 113.7 ± 12.5 μm, respectively. The OCT-measured mean inner arterial and venous diameters were significantly correlated to fundus photography caliber measurements (P = .005 and P = .001, respectively). Arterial and venous wall thicknesses were 17.4 ± 2.4 μm and 13.7 ± 2.1 μm, respectively, both of which were highly correlated with subject age (arterial: r = 0.612, P < .001, venous: r = 0.455, P < .001). Additionally, both mean arterial and venous wall thicknesses were significantly greater in subjects with hypertension than in age-matched subjects without hypertension (P = .020 and P = .015, respectively). CONCLUSIONS Retinal vessel diameter measurements obtained with OCT were highly reproducible and vessel wall thicknesses, calculated using outer and inner diameter measurements, were significantly thickened by both aging and systemic hypertension.

Focal Choroidal Excavation in Eyes With Central Serous Chorioretinopathy

PURPOSE To study the prevalence and 3-dimensional (3-D) tomographic features of focal choroidal excavations in eyes with central serous chorioretinopathy (CSC) using swept-source optical coherence tomography (OCT). DESIGN Prospective, cross-sectional study. METHODS We examined 116 consecutive eyes with CSC with a prototype 3-D swept-source OCT. 3-D images of the shape of the macular area, covering 6 × 6 mm(2), were reconstructed by segmentation of the outer surface of the retinal pigment epithelium (RPE). RESULTS The 3-D swept-source OCT detected focal choroidal excavations in 9 eyes (7.8%). The 3-D scanning protocol, coupled with en face scans, allowed for clear visualization of the excavation morphology. In 5 eyes with focal excavations, unusual choroidal tissue was found beneath the excavation, bridging the bottom of the excavation and the outer choroidal boundary. Additionally, 3 of those 5 eyes showed a suprachoroidal space below the excavation, as if the outer choroidal boundary is pulled inward by this bridging tissue. The focal choroidal excavations were located within fluorescein leakage points and areas of choroidal hyperpermeability. Eyes with focal choroidal excavations were more myopic (-4.42 ± 2.92 diopters) than eyes without excavations (-0.27 ± 1.80 diopters, P = .001). Subfoveal choroidal thickness was significantly thinner (301.3 ± 60.1 μm) in eyes with focal excavations than in eyes without the excavations (376.6 ± 104.8 μm, P = .036). CONCLUSIONS Focal choroidal excavations were present in 7.8% of eyes with CSC. In these eyes, focal choroidal excavations may have formed from RPE retraction caused by focal scarring of choroidal connective tissue.

Prevalence and Characteristics of Age-Related Macular Degeneration in the Japanese Population: The Nagahama Study

PURPOSE To estimate the age- and sex-specific prevalence of early age-related macular degeneration (AMD; drusen and retinal pigment abnormalities) and late AMD (exudative AMD and geographic atrophy) in the Japanese population. DESIGN Community-based, cross-sectional study. METHODS The study was held in Nagahama, Japan, and included 6065 Japanese individuals (aged ≥50 years) recruited in 2008-2010. We graded fundus photographs of both eyes for the AMD phenotype based on drusen size, the presence of retinal pigment abnormalities, and late AMD. The associations between smoking and AMD phenotypes were also evaluated. RESULTS We assessed 5595 subjects (women, 65%) with a gradable macular condition. Early and late AMD prevalence increased from 16.1% and 0.27% at 50-59 years to 31.2% and 0.98%, respectively, at 70-74 years and was predominant in male subjects in each age group. Smoking was associated with both early and late AMD stages and retinal pigment abnormalities (P < .0001), but not with drusen (P = .305). The prevalence of retinal pigment abnormalities was significantly higher in men (P < .0001), which was associated with high rates of cigarette smoking. We found no sex difference for the prevalence of large drusen (P = .264). CONCLUSIONS The prevalence of early AMD among adult Japanese persons was similar to the rates in white populations. The prevalence of late AMD in Japanese people aged <70 years was similar to that observed in white populations, whereas that in Japanese people aged ≥70 years was relatively lower.

Significance of C2/CFB variants in age-related macular degeneration and polypoidal choroidal vasculopathy in a Japanese population

PURPOSE To determine whether genetic variants in the complement component 2 and factor B gene (C2/CFB) locus are associated with the risk for typical age-related macular degeneration (AMD) or polypoidal choroidal vasculopathy (PCV) in a Japanese population. METHODS Four single nucleotide polymorphisms (SNPs) were genotyped across the C2/CFB locus of patients with typical AMD (n = 455) or PCV (n = 581) and of 865 controls. Differences in the observed genotypic distribution between the case and control groups were tested by logistic regression analysis for age and sex adjustments. Significant associations were confirmed using a second control group of 336 cataract patients. A further model adjusting for age-related maculopathy susceptibility 2 (ARMS2) A69S, complement factor H (CFH) I62V, age, sex and smoking status was performed, to confirm their independent association from other covariates. RESULTS C2 rs547154 and CFB rs541862 were significantly associated with typical AMD and PCV in this Japanese sample (P < 0.05). These two SNPs were also significantly associated with typical AMD and PCV in evaluation of the second control cohort (P < 0.05). Furthermore, an independent association of C2/CFB variants was found for both typical AMD and PCV with age, sex, smoking, and genetic background of ARMS2 A69S and CFH I62V (vs. typical AMD: P = 0.0073, odds ratio [OR] = 0.47; vs. PCV: P = 0.0083, OR = 0.53). CONCLUSIONS C2/CFB variants play a protective role in the risk of developing neovascular AMD and PCV in the Japanese.

Relationship between retinal morphological findings and visual function in age-related macular degeneration.

BackgroundWe aimed to study the retinal morphological findings associated with exudative age-related macular degeneration (AMD) and their association with visual prognosis.MethodsWe retrospectively reviewed the medical records of 96 consecutive patients (96 eyes) with exudative AMD. Retinal structural changes were examined using optical coherence tomography (OCT).ResultsInitial OCT examination showed cystoid macular edema in 18 eyes (18.8%), fibrin exudate in 56 eyes (58.3%), and hyperreflective foci within the neurosensory retina in 78 eyes (81.3%). Upon initial examination, an external limiting membrane (ELM) line was detected under the fovea in 64 eyes (66.7%). Using Pearson’s correlation analyses, final visual acuity (VA) was correlated with initial VA (r = 0.61, p < 0.001), age (r = 0.34, p < 0.001), initial total foveal thickness (r = 0.41, p < 0.001), presence of hyperreflective foci (r = 0.40, p < 0.001), and detection of a foveal ELM line (r = 0.55, p < 0.001). After multiple regression analysis, final VA correlated with initial VA (r = 0.48, p < 0.001), initial presence of hyperreflective foci (r = 0.23, p = 0.054), and detection of a foveal ELM line (r = 0.36, p = 0.008).ConclusionsIn eyes with exudative AMD, final VA was most correlated with initial VA. In addition, the initial integrity of the foveal outer retina was partially correlated with the visual prognosis. The initial ELM condition was associated with good final VA, while the initial presence of hyperreflective foci in the foveal neurosensory retina was associated with poor final VA.

Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia

Myopia can cause severe visual impairment. Here, we report a two-stage genome-wide association study for three myopia-related traits in 9,804 Japanese individuals, which was extended with trans-ethnic replication in 2,674 Chinese and 2,690 Caucasian individuals. We identify WNT7B as a novel susceptibility gene for axial length (rs10453441, Pmeta=3.9 × 10(-13)) and corneal curvature (Pmeta=2.9 × 10(-40)) and confirm the previously reported association between GJD2 and myopia. WNT7B significantly associates with extreme myopia in a case-control study with 1,478 Asian patients and 4,689 controls (odds ratio (OR)meta=1.13, Pmeta=0.011). We also find in a mouse model of myopia downregulation of WNT7B expression in the cornea and upregulation in the retina, suggesting its possible role in the development of myopia.

Pachychoroid neovasculopathy and age-related macular degeneration

Pachychoroid neovasculopathy is a recently proposed clinical entity of choroidal neovascularization (CNV). As it often masquerades as neovascular age-related macular degeneration (AMD), it is currently controversial whether pachychoroid neovasculopathy should be distinguished from neovascular AMD. This is because its characteristics have yet to be well described. To estimate the relative prevalence of pachychoroid neovasculopathy in comparison with neovascular AMD and to investigate the phenotypic/genetic differences of the two diseases, we evaluated 200 consecutive Japanese patients who agreed to participate in the genetic study and diagnosed with pachychoroid neovasculopathy or neovascular AMD. Pachychoroid neovasculopathy was observed in 39 individuals (19.5%), which corresponds to one fourth of neovascular AMD. Patients with pachychoroid neovasculopathy were significantly younger (p = 5.1 × 10−5) and showed a greater subfoveal choroidal thickness (p = 3.4 × 10−14). Their genetic susceptibility to AMD was significantly lower than that of neovascular AMD; ARMS2 rs10490924 (p = 0.029), CFH rs800292 (p = 0.013) and genetic risk score calculated from 11 AMD susceptibility genes (p = 3.8 × 10−3). Current results implicate that the etiologies of the two conditions must be different. Thus, it will be necessary to distinguish these two conditions in future studies.

Association between the cholesteryl ester transfer protein gene and polypoidal choroidal vasculopathy.

PURPOSE To determine whether genetic variants in the lipid-associated genes are related to the risk of developing polypoidal choroidal vasculopathy (PCV) in a Japanese population. METHODS Five hundred eighty-one patients with PCV and 793 controls were enrolled in the study. Association analysis of allele and genotype frequencies was performed for the following single-nucleotide polymorphisms (SNPs) that are associated with high-density lipoprotein cholesterol levels in blood: rs493258 at the hepatic lipase gene (LIPC), rs3764261 at the cholesteryl ester transfer protein gene (CETP), and rs12678919 at the lipoprotein lipase gene (LPL). A further model adjusting for age-related maculopathy susceptibility 2 (ARMS2) A69S, complement factor H (CFH) I62V, age, sex, and smoking status was used to confirm the independent association of these SNPs with other covariates. RESULTS CETP rs3764261 was significantly associated with the development of PCV; the frequency of the minor allele A was higher in the PCV cases (24.0%) than in the control subjects (18.5%) (P = 0.0025; odds ratio [OR], 1.41; 95% confidence interval, 1.13-1.75). Furthermore, we found an independent association of CETP variants with age, sex, smoking status, and genetic background of ARMS2 A69S, CFH I62V, LIPC rs493258, and LPL rs12678919 (P = 0.0013; OR, 1.50). LIPC rs493258 and LPL rs12678919 did not show significant associations with the development of PCV (P > 0.05). CONCLUSION CETP variants are associated a risk of developing PCV among the Japanese population.