Akio Oishi

Choroidal Thickness, Vascular Hyperpermeability, and Complement Factor H in Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

PURPOSE To investigate the relationship between subfoveal choroidal thickness, choroidal vascular hyperpermeability, and complement factor H (CFH) gene polymorphism in typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). METHODS Fifty-eight patients with typical AMD and 63 patients with PCV underwent fluorescein angiography, indocyanine green angiography (IA), and spectral-domain optical coherence tomography (OCT) using enhanced depth imaging (EDI). Subfoveal choroidal thickness was measured using EDI-OCT images, and choroidal hyperpermeability was evaluated using late-phase IA images. The major AMD-associated single-nucleotide polymorphisms were genotyped in 86 patients. RESULTS Mean subfoveal choroidal thickness was significantly lower in eyes with typical AMD than that in eyes with PCV (P = 0.025). Subfoveal choroidal thickness was greater in eyes with choroidal hyperpermeability than that in eyes without it in typical AMD (P < 0.001) and PCV (P = 0.020), and in the fellow eyes of typical AMD (P < 0.001) and PCV (P = 0.027). In eyes without choroidal hyperpermeability, the mean subfoveal choroidal thickness was greater in PCV than that in typical AMD (P = 0.001). Choroidal thickness decreased after photodynamic therapy combined with intravitreal ranibizumab in typical AMD (P = 0.016) and PCV (P = 0.036). In eyes with PCV, the I62V polymorphism in the CFH gene contributed to choroidal thickness (P = 0.043). CONCLUSIONS Choroidal thickness is related to the AMD subtypes, choroidal hyperpermeability, and I62V CFH gene polymorphism. In eyes without choroidal hyperpermeability, EDI-OCT is useful as an auxiliary measure for differentiating typical AMD and PCV.

The significance of cone outer segment tips as a prognostic factor in epiretinal membrane surgery.

PURPOSE To evaluate the prognostic value of the cone outer segment tips (COST) and other features using spectral-domain optical coherence tomography (SD-OCT) in patients undergoing epiretinal membrane (ERM) surgery. DESIGN Retrospective observational case series. METHODS Fifty eyes of 49 patients that underwent vitrectomy for idiopathic ERM were studied. Best-corrected visual acuity (BCVA) and SD-OCT images were examined preoperatively and at 1 and 6 months postoperatively. The SD-OCT features evaluated included central foveal thickness (CFT) and the status and defect diameter of the external limiting membrane (ELM), the photoreceptor inner/outer segment (IS/OS) junction, and the COST line. The associations between SD-OCT parameters and BCVA were analyzed. RESULTS There was no ELM disruption found, and thus the eyes were categorized into 3 groups: Group A, with a continuous IS/OS and COST line; Group B, with a continuous IS/OS but disrupted COST line; and Group C, with a disrupted IS/OS and COST line. At 6 months, Group A showed a significantly better BCVA than Group B (P<.005), and poorer BCVA was noted in Group C (P=.034). Defect diameters of IS/OS and COST line were also significantly correlated with BCVA postoperatively. The BCVA at 6 months was better in order of Group A, B, and C as assigned at baseline (P<.05) or 1 month (P<.001). There was no significant correlation between CFT and BCVA. CONCLUSIONS The status of the COST line, in conjunction with the IS/OS junction, is a useful prognostic factor after ERM surgery.

The Significance of External Limiting Membrane Status for Visual Acuity in Age-Related Macular Degeneration

PURPOSE To evaluate status of the external limiting membrane (ELM) as a contributor of visual acuity (VA) in age-related macular degeneration (AMD). DESIGN Hospital-based, cross-sectional study. METHODS We retrospectively reviewed spectral-domain optical coherence tomography images of 158 patients with AMD who had undergone photodynamic therapy and classified them based on the status of the ELM: absent, discontinuous, or complete. We simultaneously assessed foveal thickness, presence or absence of subretinal fluid/mass, presence or absence of subretinal pigment epithelium fluid/mass, status of the inner segment/outer segment (IS/OS) junction, and status of the intermediate line between the IS/OS junction and retinal pigment epithelium. Correlation coefficients between each parameter and VA were analyzed. RESULTS There was a strong correlation between ELM status and VA (r = -0.75, P < .001), and that was higher than that of the IS/OS (r = -0.69, P < .001). Multivariate analysis showed that ELM status is the most important factor for VA. Other parameters that correlated with VA included age, status of the intermediate line, and presence of subretinal or subretinal pigment epithelium fibrosis. Foveal thickness showed V-shaped correlation, with the dividing line around 200 mum. CONCLUSION ELM status may be more useful than is IS/OS status in evaluation of retinal morphology and function in patients with AMD.

Prevalence and Genomic Association of Reticular Pseudodrusen in Age-Related Macular Degeneration

PURPOSE To survey the prevalence of reticular pseudodrusen in late age-related macular degeneration (AMD) using multiple imaging methods, and to investigate the association between reticular pseudodrusen and polymorphisms in complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes. DESIGN Retrospective case series. METHODS This study included 216 consecutive patients with late AMD (typical AMD, polypoidal choroidal vasculopathy [PCV], retinal angiomatous proliferation [RAP], or geographic atrophy). Eyes were assessed for reticular pseudodrusen using the blue channel of color fundus photography, infrared reflectance, fundus autofluorescence, and spectral-domain optical coherence tomography. The major AMD-associated single nucleotide polymorphisms (CFH Y402 rs1061170, CFH I62V rs800292, and ARMS2 A69S rs10490924) were genotyped. RESULTS Forty-nine eyes of 30 patients had a reticular pattern in ≥2 imaging modalities and were diagnosed with reticular pseudodrusen. Of these, 16 had bilateral late AMD, whereas 32 of 186 patients without reticular pseudodrusen had bilateral late AMD (P < .001). The prevalence of reticular pseudodrusen was 83% in RAP, 50% in geographic atrophy, 9% in typical AMD, and 2% in PCV. The frequency of the T allele in ARMS2 A69S in patients with and without reticular pseudodrusen was 78.6% and 59.9%, respectively (P=.007). CONCLUSIONS The prevalence of reticular pseudodrusen was low in PCV cases. About 50% of patients with reticular pseudodrusen had bilateral late AMD. The connection of ARMS2 risk allele and reticular pseudodrusen was confirmed in a Japanese population.

Comparison of the Effect of Ranibizumab and Verteporfin for Polypoidal Choroidal Vasculopathy: 12-Month LAPTOP Study Results

PURPOSE To compare the effect of photodynamic therapy (PDT) and intravitreal ranibizumab in patients with polypoidal choroidal vasculopathy (PCV). DESIGN Randomized clinical trial. METHODS SETTING Multicenter. STUDY POPULATION Total of 93 patients with treatment-naïve PCV. INTERVENTION Patients were randomized to 2 arms. Patients in the PDT arm underwent a single session of PDT with verteporfin, and patients in the ranibizumab arm received 3 monthly ranibizumab injections at baseline. Additional treatment was performed as needed in each arm. MAIN OUTCOME MEASURES Primary outcome measurement was the proportion of patients gaining or losing more than 0.2 logarithm of minimal angle of resolution (logMAR) units from baseline. Mean change of logMAR and central retinal thickness (CRT) were also evaluated. RESULTS In the PDT arm (n = 47), 17.0% achieved visual acuity gain, 55.3% had no change, and 27.7% experienced visual acuity loss. The results were 30.4%, 60.9%, and 8.7%, respectively, in the ranibizumab arm (n = 46), significantly better than the PDT arm (P = .039). In the PDT arm, mean CRT improved (366.8 ± 113.6 μm to 289.1 ± 202.3 μm, P < .001), but logMAR was unchanged (0.57 ± 0.31 to 0.62 ± 0.40). The ranibizumab arm demonstrated improvement in both CRT (418.9 ± 168.6 μm to 311.2 ± 146.9 μm, P < .001) and logMAR (0.48 ± 0.27 to 0.39 ± 0.26, P = .003). Mean change of logMAR was also greater in the ranibizumab arm (P = .011). CONCLUSION Intravitreal injection of ranibizumab is more effective than PDT for treatment-naïve PCV.

Sensitivity and specificity of detecting reticular pseudodrusen in multimodal imaging in Japanese patients.

Purpose: To identify reticular pseudodrusen (RPD) in age-related macular degeneration using multiple imaging modalities, including the blue channel image of fundus photography, infrared reflectance (IR), fundus autofluorescence, near-infrared fundus autofluorescence, confocal blue reflectance, indocyanine green angiography, and spectral-domain optical coherence tomography (SD-OCT), and to compare the sensitivities and specificities of these modalities for detecting RPD. Methods: This study included 220 eyes from 114 patients with newly diagnosed age-related macular degeneration. Patients underwent fundus photography, IR, fundus autofluorescence, near-infrared fundus autofluorescence, confocal blue reflectance, indocyanine green angiography, and SD-OCT in both eyes. Eyes were diagnosed with RPD if they showed reticular patterns on at least two of the seven imaging modalities. Results: Thirty-seven eyes were diagnosed with RPD. However, SD-OCT and IR had the highest sensitivity (94.6%), and at the same time, SD-OCT had a high specificity (98.4%). The blue channel of color fundus photography, confocal blue reflectance, and indocyanine green angiography had a specificity of 100% but had lower sensitivity than that of SD-OCT and IR. Conclusion: For detecting RPD, IR and SD-OCT had the highest sensitivity. Although SD-OCT had the highest sensitivity and specificity, RPD detection should be confirmed using more than one modality for increased accuracy.

Activation of Bone Marrow-Derived Microglia Promotes Photoreceptor Survival in Inherited Retinal Degeneration

The role of microglia in neurodegeneration is controversial, although microglial activation in the retina has been shown to provide an early response against infection, injury, ischemia, and degeneration. Here we show that endogenous bone marrow (BM)-derived microglia play a protective role in vascular and neural degeneration in the retinitis pigmentosa model of inherited retinal degeneration. BM-derived cells were recruited to the degenerating retina where they differentiated into microglia and subsequently localized to the degenerating vessels and neurons. Inhibition of stromal-derived factor-1 in the retina reduced the number of BM-derived microglia and accelerated the rate of neurovascular degeneration. Systemic depletion of myeloid progenitors also accelerated the degenerative process. Conversely, activation of BM-derived myeloid progenitors by systemic administration of both granulocyte colony-stimulating factor and erythropoietin resulted in the deceleration of retinal degeneration and the promotion of cone cell survival. These data indicate that BM-derived microglia may play a protective role in retinitis pigmentosa. Functional activation of BM-derived myeloid progenitors by cytokine therapy may provide a novel strategy for the treatment of inherited retinal degeneration and other neurodegenerative diseases, regardless of the underlying genetic defect.

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.

Identifying Pathogenic Genetic Background of Simplex or Multiplex Retinitis Pigmentosa Patients: A Large-Scale Mutation Screening Study

Background and purpose: More than half of the retinitis pigmentosa (RP) cases are genetically simplex or multiplex. To date, 37 causative genes of RP have been identified; however, the elucidation of gene defects in simplex or multiplex RP patients/families remains problematic. The aim of our study was to identify the genetic causes of RP in patients with unknown or non-Mendelian inheritance. Methods and results: Since 2003, 52 simplex RP patients, 151 patients from 141 multiplex RP families, and six sporadic patients with retinal degeneration were studied. A total of 108 exons of 30 RP-causing genes that harboured the reported mutations were screened by an efficient denaturing high performance liquid chromatography (dHPLC) based assay. Aberrant fragments were subsequently analysed by automatic sequencing. Twenty-six mutations, including two frameshift mutations, one single amino acid deletion, and 23 missense mutations, were identified in 28 probands (14.07%). Eighteen mutations have not been reported to date. Three pairs of combined mutations in different genes were identified in two sporadic cases and one multiplex family, indicating the possibility of novel digenic patterns. Of the 23 missense mutations, 21 were predicted as deleterious mutations by computational methods using PolyPhen, SIFT, PANTHER, and PMut programs. Conclusion: We elucidated the mutation spectrum in Japanese RP patients and demonstrated the validity of the mutation detection system using dHPLC sequencing for genetic diagnosis in RP patients independent of familial incidence, which may provide a model strategy for identifying genetic causes in other diseases linked to a wide range of genes.

Comprehensive Molecular Diagnosis of a Large Cohort of Japanese Retinitis Pigmentosa and Usher Syndrome Patients by Next-Generation Sequencing

PURPOSE Retinitis pigmentosa (RP), a major cause of blindness in developed countries, has multiple causative genes; its prevalence differs by ethnicity. Usher syndrome is the most common form of syndromic RP and is accompanied by hearing impairment. Although molecular diagnosis is challenging, recent technological advances such as targeted high-throughput resequencing are efficient screening tools. METHODS We performed comprehensive molecular testing in 329 Japanese RP and Usher syndrome patients by using a custom capture panel that covered the coding exons and exon/intron boundaries of all 193 known inherited eye disease genes combined with Illumina HiSequation 2500. Candidate variants were screened using systematic data analyses, and their potential pathogenicity was assessed according to the frequency of the variants in normal populations, in silico prediction tools, and compatibility with known phenotypes or inheritance patterns. RESULTS Molecular diagnoses were made in 115/317 RP patients (36.3%) and 6/12 Usher syndrome patients (50%). We identified 104 distinct mutations, including 66 novel mutations. EYS, USH2A, and RHO were common causative genes. In particular, mutations in EYS accounted for 15.0% of the autosomal recessive/simplex RP patients or 10.7% of the entire RP cohort. Among the 189 previously reported mutations detected in the current study, 55 (29.1%) were found commonly in Japanese or other public databases and were excluded from molecular diagnoses. CONCLUSIONS By screening a large cohort of patients, this study catalogued the genetic variations involved in RP and Usher syndrome in a Japanese population and highlighted the different distribution of causative genes among populations.