Yoichi Sakurada

Aqueous Humor Cytokine Levels in Patients with Polypoidal Choroidal Vasculopathy and Neovascular Age-Related Macular Degeneration

Purpose: To investigate the possible roles of various cytokines or growth factors in the pathogenesis of exudative age-related macular degeneration (AMD) by comparing aqueous humor levels of 14 cytokines between eyes with polypoidal choroidal vasculopathy (PCV) and those with neovascular AMD. Methods: Forty eyes from 40 patients with treatment-naïve exudative AMD consisting of 18 eyes with neovascular AMD and 22 eyes with PCV were studied. Twenty eyes from 20 patients with no retinal pathology who underwent cataract surgery served as controls. Aqueous humor samples were collected just before intravitreal ranibizumab injection in 40 eyes with exudative AMD and before cataract surgery in 20 control eyes. Concentrations of 14 cytokines were determined by chemiluminescence-based ELISA: interleukin (IL)-1α, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, vascular endothelial growth factor (VEGF), monocyte chemoattractant protein 1, interferon-γ-inducible protein (IP)-10 and C-reactive protein (CRP). Results: After adjusting for gender, age and axial length, concentrations of CRP and IP-10 were significantly higher in eyes with neovascular AMD or PCV compared with control eyes (p < 0.05), and IP-10 levels were strongly associated with lesion size (p = 0.002). None of the 14 cytokines, including VEGF, were significantly different between eyes with neovascular AMD and those with PCV. Conclusion: Aqueous humor concentrations of CRP and IP-10 were elevated in eyes with PCV or neovascular AMD. IP-10 could be associated with the pathogenesis of neovascular AMD and 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.

Involvement of genetic variants associated with primary open-angle glaucoma in pathogenic mechanisms and family history of glaucoma.

PURPOSEnTo investigate the associations between the non-intraocular pressure (IOP)-related genetic variants (genetic variants associated with vulnerability of the optic nerve independent of IOP) and primary open-angle glaucoma (POAG), including normal-tension glaucoma (NTG) and high-tension glaucoma (HTG), and between the non-IOP-related genetic variants and a family history of glaucoma.nnnDESIGNnCase-control study.nnnMETHODSnJapanese patients with NTG (n = 213) and HTG (n = 212) and 191 control subjects were genotyped for 5 non-IOP-related genetic variants predisposing to POAG near the SRBD1, ELOVL5, CDKN2B/CDKN2B-AS1, SIX1/SIX6, and ATOH7 genes. The load of these genetic variants was compared between the control subjects and patients with NTG or HTG and between the POAG patients with and without a family history of glaucoma.nnnRESULTSnThe total number of POAG risk alleles and the product of the odds ratios (POAG risk) of these genetic variants were significantly larger (P < .0025) in patients with both NTG and HTG than in the control subjects, and were significantly larger (P = .0042 and P = .023, respectively) in POAG patients with a family history of glaucoma than in those without. As the number of relatives with glaucoma increased, the total number of risk alleles and the product of the odds ratios increased (P = .012 and P = .047, respectively).nnnCONCLUSIONSnNon-IOP-related genetic variants contribute to the pathogenesis of HTG as well as NTG. A positive family history of glaucoma in cases of POAG is thought to reflect the influence of genetic variants predisposing to POAG.

Comparison of initial treatment between 3-monthly intravitreal aflibercept monotherapy and combined photodynamic therapy with single intravitreal aflibercept for polypoidal choroidal vasculopathy

PurposeTo compare the efficacy of two different initial treatment modalities on visual outcome, need for retreatment, and angiographic improvement during 12-month follow-up for polypoidal choroidal vasculopathy (PCV).MethodsA retrospective medical chart review was performed for 66 eyes from 66 patients with treatment-naïve PCV. Visual and angiographic improvements and the incidence of retreatment for recurrence or residual pathology were compared between two groups that underwent either intravitreal aflibercept injection (IAI) monotherapy (nu2009=u200933) or combined photodynamic therapy (PDT) with IAI (nu2009=u200933).ResultsBest-corrected visual acuity improved significantly (Pu2009<u20090.001) in both groups at each of the 3-monthly visits during the 12-month follow-up period, with no difference between groups at 12xa0months (Pu2009=u20090.56). The relative risk of the need for retreatment was significantly lower in the combined PDT and IAI group than in the IAI monotherapy group (Pu2009=u20090.007). Angiographic regression of polypoidal vascular lesions occurred more frequently in the combined PDT group than in the IAI monotherapy group at 3 (87.5xa0% vs 56.7xa0%) and 12xa0months (68.8xa0% vs 60.0xa0%) (pu2009=u20090.0065 and pu2009=u20090.47 respectively).ConclusionsThe combination of PDT with IAI as the initial treatment for PCV may be superior to IAI monotherapy in terms of disease-stabilizing efficacy, but with equivalent visual gain at 12xa0months.

The Association of Elastin Gene Variants with Two Angiographic Subtypes of Polypoidal Choroidal Vasculopathy

Objective To compare the association of elastin (ELN) gene variants between two different angiographic phenotypes of polypoidal choroidal vasculopathy (PCV). Methods We included 411 treatment-naïve PCV patients and 350 controls in the present study. PCV was classified into two phenotypes (152 Type 1 and 259 Type 2) according to the presence or absence of feeding vessels found in indocyanine-green angiography. Single nucleotide polymorphisms (SNPs) in the ELN region including rs868005, rs884843, rs2301995, rs13239907 and rs2856728 were genotyped using TaqMan Genotyping Assays. Results In the allelic association analyses, rs868005 showed the strongest association with Type 2 PCV (allelic odds ratio 1.56; p = 7.4x10-6), while no SNP was significantly associated with Type 1 PCV. Genotype association analyses revealed the significant association of rs868005 with Type 2 PCV in log additive model and predominant model (odds ratio 1.75; p = 1.5x10-6 and odds ratio 1.60; p = 0.0044, respectively), but not with Type 1 PCV. These findings were further corroborated by another control group in the literature. Conclusions There may be significantly different associations in genetic variants of elastin between two angiographic phenotypes of PCV.

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 (nu2009=u200971) or polypoidal choroidal vasculopathy (PCV) (nu2009=u200969) 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 0.45u2009±u20090.39 to 0.26u2009±u20090.33 (Pu2009=u20094.1u2009×u200910−11). Multiple regression analysis revealed that better baseline BCVA (Pu2009=u20093.6u2009×u200910−14) and thicker subfoveal choroidal thickness (Pu2009=u20090.039) 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 (Pu2009=u20097.2u2009×u200910−3) and T-allele of ARMS2 A69S (rs10490924) variants (Pu2009=u20091.9u2009×u200910−3) were associated with retreatment. Cox-regression analysis revealed that older age (Pu2009=u20091.0u2009×u200910−2) and T-allele of the ARMS2 gene (Pu2009=u20096.0u2009×u200910−3) were associated with retreatment-free period. The number of retreatment episodes was significantly different among the ARMS2 genotypes (Pu2009=u20098.1u2009×u200910−4). 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%) (pu2009=u2009.0025 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 (Pu2009=u20090.014 and Pu2009=u20090.008, 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.

CHOROIDAL THICKNESS AS A PROGNOSTIC FACTOR OF PHOTODYNAMIC THERAPY WITH AFLIBERCEPT OR RANIBIZUMAB FOR POLYPOIDAL CHOROIDAL VASCULOPATHY.

Purpose: To investigate factors associated with visual improvement and retreatment 12 months after a combination therapy of intravitreal injection of ranibizumab or aflibercept followed by photodynamic therapy for polypoidal choroidal vasculopathy. Methods: Changes in the best-corrected visual acuity and the subfoveal thickness of the retina and choroid were studied in 56 consecutive eyes with polypoidal choroidal vasculopathy treated initially with a combination therapy of either intravitreal ranibizumab injection (n = 23) or intravitreal aflibercept injection (n = 33) followed by photodynamic therapy. Factors associated with visual improvement and retreatment were investigated. Results: Best-corrected visual acuity significantly improved with significant reduction in central macular thickness and subfoveal choroidal thickness at all points irrespective of treatment modalities (P < 0.001). Better best-corrected visual acuity and improvement of best-corrected visual acuity at 12 months were associated with baseline greater subfoveal choroidal thickness (P = 0.028 and P = 0.028) and baseline smaller greatest linear dimension (P = 0.0077 and P = 0.0077). Retreatment during 12-month follow-up was associated with baseline lesser subfoveal choroidal thickness (P = 0.036). Conclusion: Irrespective of treatment modalities, the visual outcome at 12 months is favorable in eyes with polypoidal choroidal vasculopathy treated by photodynamic therapy combined with intravitreal ranibizumab or aflibercept. Baseline greater subfoveal choroidal thickness was associated with a better visual outcome and with reduction in the need for retreatment.

Retreatment of polypoidal choroidal vasculopathy after photodynamic therapy combined with intravitreal ranibizumab.

PurposeTo investigate the incidence, risk factors and effect on visual improvement of retreatment within 60xa0months after initial photodynamic therapy (PDT) combined with intravitreal ranibizumab (IVR) in eyes with treatment-naïve polypoidal choroidal vasculopathy (PCV).MethodsWe retrospectively reviewed the medical records of 61 eyes from 60 patients with PCV, who were followed up for at least 12xa0months after undergoing combination therapy. Retreatment, including combination therapy or IVR alone, was administered if residual or recurrent exudative changes were present.ResultsDuring the follow-up period (mean 44xa0±xa013xa0months, median 48xa0months), 46 eyes (75.4xa0%) underwent retreatment. Survival analysis revealed that the proportions of eyes that were retreatment-free were 59xa0% at the 12-month visit, 41xa0% at the 24xa0month, 31xa0% at the 36xa0month, and 20xa0% at the 60-month visit. The median retreatment-free period was 15.0 [95xa0% confidence interval (CI) 7.4–22.7] months, and the mean period was 24.9 (95xa0% CI 19.3–30.6) months. Cox regression analysis revealed that older age (Pxa0=xa00.010, hazard ratio 1.06, CI 1.02–1.11) and male gender (Pxa0=xa00.043, hazard ratio 2.41, CI 1.03–5.62) were associated with retreatment. Visual improvement was significantly better in eyes without retreatment compared with those with retreatment at the 12-, 24- and 48-month visits.ConclusionsAbout 80xa0% of eyes with PCV require retreatment within 5xa0years after combination therapy with PDT and IVR. Retreatment is associated with older age and male gender and is related to reduced improvement of visual acuity.

Risk Factors for Second Eye Involvement in Eyes with Unilateral Polypoidal Choroidal Vasculopathy

Abstract Purpose: To investigate risk factors associated with developing polypoidal choroidal vasculopathy (PCV) lesions in the unaffected fellow eye of patients with unilateral PCV. Methods: We studied 179 patients with initial unilateral PCV who were followed up for a period of 24 months or longer to monitor for second eye involvement. All patients underwent genotyping for CFH I62V (rs800292) and ARMS2 A69S (rs10490924) using TaqMan technology. Results: During the follow-up period ranging from 5–180 months, 20 (11.2%) of 179 patients developed PCV in the initially unaffected fellow eye. The risk allele (T) of ARMS2 A69S was significantly more prevalent in patients with second eye involvement compared to those without PCV in the fellow eye (pu2009=u20090.0046). Cox regression analysis demonstrated that the ARMS2 A69S genotype is a risk factor for developing PCV in the fellow eye (pu2009=u20090.027, odds ratio 2.53, confidence interval 1.11–5.73). Survival analysis revealed that the fellow eye of patients with the risk-associated homozygous genotype (TT) of ARMS2 A69S was affected significantly earlier than those with other genotypes (pu2009=u20090.0177, log rank test). Conclusions: Development of PCV in the unaffected fellow eye is associated with ARMS2 A69S genotype in patients with unilateral PCV.