Naohiko Tanabe

Association of LOC387715 A69S with vitreous hemorrhage in polypoidal choroidal vasculopathy.

PURPOSE To investigate whether the LOC387715 polymorphism is associated with polypoidal choroidal vasculopathy (PCV) and with vitreous hemorrhage (VH), one of the most severe clinical phenotypes, in the Japanese population. DESIGN Cross-sectional case-control association study. METHODS One hundred and nine Japanese patients with PCV, composed of nine patients associated with VH (VH group) and 100 patients without VH (non-VH group), and 85 control subjects were analyzed for the LOC387715 polymorphism (rs = 10490924), using denaturing high-performance chromatography. RESULTS There was a significant difference in the T allele frequency between PCV patients and control subjects (P < .0001). In comparison with wild-type homozygosity (GG), homozygosity for the at-risk allele genotype (TT) increased the likelihood for PCV 8.4-fold (3.6 to 19.5, 95% confidence interval [CI]) and heterozygosity for the at-risk allele genotype (TG) increased the likelihood for PCV 4.0-fold (1.9 to 8.4, 95% CI). There was a significant difference in the genotypic frequency at the LOC387715 site between the VH and non-VH groups (P = .0099, Chi-square test) with the TT genotype occurring in 88.9% in the VH group and 37.0% in the non-VH group. The frequency of the T allele in the VH group was significantly greater than that in the non-VH group (0.944 vs 0.610; P = .0039, Fisher exact test). CONCLUSIONS The LOC387715 polymorphism is associated with PCV and clinical severity in the subgroups of PCV in the Japanese population.

Association of LOC387715 A69S genotype with visual prognosis after photodynamic therapy for polypoidal choroidal vasculopathy.

Purpose: To investigate whether there is an association of the LOC387715 A69S genotype with visual prognosis after photodynamic therapy in eyes with polypoidal choroidal vasculopathy (PCV). Methods: Photodynamic therapy was repeated every 3 months until the disappearance of angiographic signs of active lesions in 71 eyes of 71 patients with PCV who were followed-up for at least 12 months. All patients were genotyped for LOC387715 A69S polymorphism (rs10490924, risk-allele T). Results: Although there was no statistically significant difference in the mean baseline visual acuity (P = 0.53) among the 3 genotypes, there was a statistically significant difference in the visual acuity both at the 12-month and final visits (P = 0.002 and P < 0.001, respectively) with the poorer acuity in patients with the higher “T-”allele frequency. “T” allele was more frequently observed in those with the recurred PCV lesions (odds ratio: 5.8, 95% confidential interval: 2.3-15.1, T vs. G). Conclusion: There is a pharmacogenetic association between the LOC387715 A69S variant and the long-term results after photodynamic therapy in eyes with PCV. The LOC387715 A69S genotype is of clinical importance to predict the visual prognosis after photodynamic therapy in eyes with PCV. These results should be confirmed or refuted by replication studies.

Angiographic lesion size associated with LOC387715 A69S genotype in subfoveal polypoidal choroidal vasculopathy.

Purpose: To investigate whether the LOC387715/ARMS2 variants are associated with an angiographic phenotype, including lesion size and composition, in subfoveal polypoidal choroidal vasculopathy. Methods: Ninety-two subjects with symptomatic subfoveal polypoidal choroidal vasculopathy, whose visual acuity was from 0.1 to 0.5 on the Landolt chart, were genotyped for the LOC387715 polymorphism (rs10490924) using denaturing high-performance chromatography. The angiographic phenotype, including lesion composition and size, was evaluated by evaluators who were masked for the genotype. Lesion size was assessed by the greatest linear dimension based on fluorescein or indocyanine green angiography. Results: Although there was no statistically significant difference in lesion size on indocyanine green angiography (P = 0.36, Kruskal-Wallis test) and in lesion composition (P = 0.59, chi-square test) among the 3 genotypes, there was a statistically significant difference in lesion size on fluorescein angiography (P = 0.0022, Kruskal-Wallis test). Conclusion: The LOC387715 A69S genotype is not associated with lesion composition or size on indocyanine green angiography but with lesion size on fluorescein angiography in patients with subfoveal polypoidal choroidal vasculopathy. Because fluorescein angiography findings represent secondary exudative changes, including subretinal hemorrhages and retinal pigment epithelial detachment, the results in the present study likely indicate that the T allele at the LOC387715 gene is associated with the exudative activity of polypoidal lesions.

Role of Complement Factor H I62V and Age-Related Maculopathy Susceptibility 2 A69S Variants in the Clinical Expression of Polypoidal Choroidal Vasculopathy

PURPOSE To investigate the role of complement factor H (CFH) I62V (rs800292) and age-related maculopathy susceptibility 2 (ARMS2) A69S (rs10490924) variants in the clinical characteristics of polypoidal choroidal vasculopathy (PCV). DESIGN Cross-sectional study. PARTICIPANTS A total of 226 Japanese patients with PCV in both eyes (44 cases) or in 1 eye (182 cases). METHODS Genotyping was performed in all cases for CFH I62V using TaqMan technology and for ARMS2 A69S by denaturing high-performance chromatography. The incidence of 5 characteristic funduscopic findings was studied, including serous retinal detachment, subretinal hemorrhage, serous pigment epithelial detachment (PED), hemorrhagic PED, and classic choroidal neovascularization (CNV). MAIN OUTCOME MEASURES The association of clinical phenotypes, including the incidence of each of 5 specific fundus findings, bilaterality of the disease, and age at onset, with variants of CFH I62V or ARMS2 A69S. RESULTS Although there was no association of CFH I62V variants with any of the phenotypes in PCV, at-risk variants of ARMS2 A69S were associated with higher incidences of subretinal hemorrhage, serous PED, and hemorrhagic PED. In particular, the at-risk allele homozygosity of ARMS2 A69S increased the likelihood for hemorrhagic PED by 12.4-fold compared with non-carriers of the allele (confidence interval, 1.60-95.1, P = 0.0001). However, the at-risk allele of ARMS2 A69S was associated with a lower incidence of serous retinal detachment (P = 0.0092). Classic CNV was not associated with either variant. The mean age at the onset of PCV was significantly younger (68.8 years) in those with homozygosity of the at-risk allele of ARMS2 A69S than in those with heterozygosity (71.6 years) or in non-carriers (72.6 years) (P = 0.026). Moreover, the at-risk allele frequencies of the ARMS2 A69S were significantly higher in bilateral cases than in unilateral cases (75.0% vs. 59.3%, P = 0.007). CONCLUSIONS ARMS2 A69S variants were significantly associated with hemorrhagic or subpigment epithelium lesions of PCV, and with earlier onset and bilateral involvement. The genotyping of ARMS2 A69S is more informative than that of CFH I62V in understanding the clinical features in patients with PCV.

Prevalence and Genetic Characteristics of Geographic Atrophy among Elderly Japanese with Age-Related Macular Degeneration

Objective To investigate the prevalence and genetic characteristics of geographic atrophy (GA) among elderly Japanese with advanced age-related macular degeneration (AMD) in a clinic-based study. Methods Two-hundred and ninety consecutive patients with advanced AMD were classified into typical neovascular AMD, polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP) or geographic atrophy (GA). Genetic variants of ARMS2 A69S (rs10490924) and CFH I62V (rs800292) were genotyped using TaqMan Genotyping Assays. The clinical and genetic characteristics were compared between patients with and without GA. Results The number of patients diagnosed as having typical neovascular AMD, PCV, RAP and GA were 98 (33.8%), 151 (52.1%), 22 (7.5%) and 19 (6.6%), respectively. Of 19 patients with GA, 13 patients (68.4%) had unilateral GA with exudative AMD in the contralateral eye. Patients with GA were significantly older, with a higher prevalence of reticular pseudodrusen, bilateral involvement of advanced AMD and T-allele frequency of ARMS2 A69S compared with those with typical AMD and PCV; although there were no differences in the genetic and clinical characteristics among patients with GA and RAP. Conclusions The prevalence of GA was 6.6% among elderly Japanese with AMD. Patients with GA and RAP exhibited genetic and clinical similarities.

Factors Predictive of Visual Outcome 1 Year After Intravitreal Aflibercept Injection for Typical Neovascular Age-Related Macular Degeneration

PURPOSE Several factors have been reported to be associated with visual outcomes after intravitreal ranibizumab treatment for neovascular age-related macular degeneration (AMD). In the present study, we investigated the factors associated with visual outcomes after intravitreal aflibercept injection (IAI) for typical neovascular AMD. METHODS We retrospectively studied the visual changes in 47 eyes of 51 patients with typical neovascular AMD, who had been initially treated with 3 monthly IAI followed by as-needed IAI. RESULTS Mean best-corrected visual acuity (BCVA) improved during the 12-month follow-up period in 40 eyes of 37 patients without reticular pseudodrusen (RPD) in both eyes, whereas it deteriorated in 11 eyes of 10 patients with RPD in either eye. Multiple regression analysis revealed that visual gain at 12 months after the first IAI positively correlated with worse baseline BCVA and thicker baseline subfoveal choroidal thickness (P = 0.018, P = 0.004, respectively), but not with absence of RPD (P = 0.13). Subfoveal choroidal thickness was significantly thinner in eyes with RPD compared with that in eyes without RPD (P = 0.003). CONCLUSIONS Visual gain after IAI in eyes with typical neovascular AMD appears to be limited in patients with RPD, which may reflect the poor visual outcome after IAI in eyes with a thinner subfoveal choroid that is seen predominately in patients with RPD.

GENETIC FACTORS ASSOCIATED WITH CHOROIDAL VASCULAR HYPERPERMEABILITY AND SUBFOVEAL CHOROIDAL THICKNESS IN POLYPOIDAL CHOROIDAL VASCULOPATHY.

Purpose: To investigate genetic factors associated with choroidal vascular hyperpermeability (CVH) and subfoveal choroidal thickness in eyes with treatment-naive polypoidal choroidal vasculopathy. Methods: We studied 149 consecutive patients with polypoidal choroidal vasculopathy. The presence of CVH was evaluated using indocyanine green angiography. Subfoveal choroidal thickness and axial length were measured by spectral domain optical coherence tomography and optical biometry, respectively. Genotyping of three single nubleotide polymorphisms (SNPs), including age-related maculopathy susceptibility 2 (ARMS2) A69S (rs10490924), complement factor H (CFH) I62V (rs800292), and CFH (rs1329428), which are reportedly associated with central serous chorioretinopathy, was conducted using TaqMan technology. Results: Thicker subfoveal choroidal thickness was associated with younger age, shorter axial length, G-allele frequency in ARMS2 A69S (rs10490924), and T-allele frequency in CFH (rs1329428) (P = 0.001, P < 0.001, P = 0.004, and P = 0.002, respectively; multiple regression analysis). Among 149 eyes with polypoidal choroidal vasculopathy, 35 eyes (23.5%) exhibited CVH on indocyanine green angiography. Patients with CVH had a significantly higher frequency of the G allele of ARMS2 A69S (rs10490924) and the T allele of CFH (rs1329428), which are reported to be risk alleles for central serous chorioretinopathy (P = 0.006 and P = 0.032, respectively; multivariate regression analysis). Conclusion: Subfoveal choroidal thickness and CVH in eyes with treatment-naive polypoidal choroidal vasculopathy were associated with ARMS2 A69S (rs10490924) and CFH (rs1329428).

Incidence and risk factors of retreatment after three-monthly aflibercept therapy for exudative age-related macular degeneration

Though anti-vascular endothelial growth factor therapy has become the standard treatment for exudative age-related macular degeneration (AMD), retreatment after the initial loading injection is inevitable in most eyes with residual or recurrent exudative changes. In the present study, we studied 140 treatment naïve eyes with typical neovascular AMD (n = 71) or polypoidal choroidal vasculopathy (PCV) (n = 69) and investigated the incidence and risk factors of retreatment after 3-monthly intravitreal aflibercept injection for exudative AMD during the 12-month period. At 12 months, best-corrected visual acuity (BCVA) improved significantly from 0.45 ± 0.39 to 0.26 ± 0.33 (P = 4.1 × 10−11). Multiple regression analysis revealed that better baseline BCVA (P = 3.6 × 10−14) and thicker subfoveal choroidal thickness (P = 0.039) were associated with better BCVA at 12-months. Retreatment was required in 94 out of 140 (67.1%) eyes. Multivariate logistic regression analysis revealed that older age (P = 7.2 × 10−3) and T-allele of ARMS2 A69S (rs10490924) variants (P = 1.9 × 10−3) were associated with retreatment. Cox-regression analysis revealed that older age (P = 1.0 × 10−2) and T-allele of the ARMS2 gene (P = 6.0 × 10−3) were associated with retreatment-free period. The number of retreatment episodes was significantly different among the ARMS2 genotypes (P = 8.1 × 10−4). These findings might be helpful for physicians when considering the optimal treatment regimen for exudative AMD.

Prevalence and characteristics of pseudodrusen subtypes in advanced age-related macular degeneration

PurposeThe purpose of our study was to investigate the clinical and genetic characteristics of pseudodrusen subtypes and their incidence in advanced age-related macular degeneration (AMD).MethodsWe studied 84 eyes from 84 patients with pseudodrusen associated with advanced AMD, including typical AMD, polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and geographic atrophy (GA). Multiple imaging modalities, including color fundus photography, spectral-domain optical coherence tomography (SD-OCT), near-infrared reflectance, and fundus autofluorescence, were employed to diagnose pseudodrusen and its subtypes. Subfoveal choroidal thickness was measured using SD-OCT. Subject eyes were classified into two subtypes, dot-dominant or ribbon-dominant, according to the maximum length of ribbon pseudodrusen. Genotyping was performed for ARMS2 A69S (rs10490924) and CFH I62V (rs800292) variants.ResultsThe percentage of ribbon-dominant type pseudodrusen was significantly higher in eyes with RAP (69.6%) and GA (78.6%) compared with those with typical AMD (31.1%) (p = .0025 and .0017, respectively). Multivariate logistic regression analysis disclosed that incidence of female patients and coexisting large soft drusen was significantly higher in ribbon- than dot-dominant types (P = 0.014 and P = 0.008, respectively), while age, subfoveal choroidal thickness, and risk allele frequency for both ARMS2 A69S (rs10490924) and CFH I62V (rs800292) were not different between the two pseudodrusen subtypes.ConclusionsAmong eyes with advanced AMD associated with pseudodrusen, ribbon-dominant type pseudodrusen were more prevalent in eyes with GA or RAP and were associated with large soft drusen and female patients.

A remote operating slit lamp microscope system. Development and its utility in ophthalmologic examinations.

OBJECTIVES To develop a remote-operating slit lamp microscope system (the remote slit lamp) as the core for highly specialized ophthalmology diagnoses, and to compare the utility of this system with the conventional slit lamp microscope system (the conventional slit lamp) in making a diagnosis. METHODS The remote slit lamp system was developed. Three factors were evaluated in comparison to the conventional slit lamp. The ability to acquire skills was investigated using a task loading system among specialists and residents in ophthalmology. Participants repeated a task up to ten times and the time required for each task was analyzed. The consistency of the two systems in making a diagnosis was investigated using eyes of patients with ocular diseases as well as healthy volunteers. RESULTS The remote slit lamp is composed of a patients unit and ophthalmologists unit connected by high-speed internet. The two units share images acquired by the slit lamp in addition to the images and voices of patients and ophthalmologists. Both ophthalmology specialists and residents could minimize the completion times after several trials. The remote slit lamp took more time than the conventional slit lamp. Both systems showed a high consistency in evaluations among eyes with healthy eyes or those with ocular diseases. CONCLUSIONS The remote slit lamp has a similar diagnostic ability, but required more examination time in comparison to the conventional slit lamp. The currently developed remote slit lamp has the potential to be employed for tele-medicine purposes in the field of ophthalmology.