Wataru Matsumiya

Polypoidal Choroidal Vasculopathy: Clinical Features and Genetic Predisposition

Polypoidal choroidal vasculopathy (PCV) is currently recognized as a phenotype of age-related macular degeneration (AMD). PCV is believed to be a type of choroidal neovascularization, although some cases of PCV show a distinct vascular abnormality of the choroidal vessels. PCV often shows several unique clinical manifestations which are apparently different from typical neovascular AMD (tAMD). In addition, the natural course and response to treatment are often different between tAMD and PCV. Moreover, recent genetic studies suggested a possible difference in the genetic susceptibility to disease between tAMD and PCV, as well as the existence of heterogeneity among PCV cases. In viewing the accumulation of knowledge about PCV, we have summarized the recent literature regarding PCV in this review article to improve the understanding of this clinical entity including possible susceptibility genes. We will also discuss the optimal treatment strategies for PCV in accordance with the results of recent clinical and genetic studies.

Early Responses to Intravitreal Ranibizumab in Typical Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy

Purpose. To evaluate the early response to intravitreal ranibizumab (IVR) in two different phenotypes of age-related macular degenerations (AMD): typical neovascular AMD (tAMD) and polypoidal choroidal vasculopathy (PCV). Methods. Sixty eyes from 60 patients (tAMD 28, PCV 32 eyes) were recruited. Three consecutive IVR treatments (0.5 mg) were performed every month. Change in the best-corrected visual acuity (BCVA) and central retinal thickness (CRT) was then compared between the tAMD and PCV groups. Results. The mean BCVA logMAR was significantly improved at month 1 and month 3 after the initial IVR in the tAMD group, but there was no change in the PCV group. Both phenotypes showed significant improvements in the CRT during the 3 months after the initial IVR. There were no significant differences in the improvements of the CRT in the tAMD versus the PCV group. In the stepwise analysis, a worse pretreatment BCVA and tAMD lesions were significantly beneficial for a greater improvement of BCVA at 3 months after the initial IVR. Conclusions. The phenotype of tAMD showed a significantly better early response to IVR than PCV in terms of BCVA improvement.

A Common Complement C3 Variant Is Associated with Protection against Wet Age-Related Macular Degeneration in a Japanese Population

Background Genetic variants in the complement component 3 gene (C3) have been shown to be associated with age-related macular degeneration (AMD) in Caucasian populations of European descent. In particular, a nonsynonymous coding variant, rs2230199 (R102G), is presumed to be the most likely causal variant in the C3 locus based on strong statistical evidence for disease association and mechanistic functional evidence. However, the risk allele is absent or rare (<1%) in Japanese and Chinese populations, and the association of R102G with AMD has not been reported in Asian populations. Genetic heterogeneity of disease-associated variants among different ethnicities is common in complex diseases. Here, we sought to examine whether other common variants in C3 are associated with wet AMD, a common advanced-stage manifestation of AMD, in a Japanese population. Methodology/Principal Findings We genotyped 13 tag single nucleotide polymorphisms (SNPs) that capture the majority of common variations in the C3 locus and tested for associations between these SNPs and wet AMD in a Japanese population comprising 420 case subjects and 197 controls. A noncoding variant in C3 (rs2241394) exhibited statistically significant evidence of association (allelic P = 8.32×10−4; odds ratio = 0.48 [95% CI = 0.31–0.74] for the rs2241394 C allele). Multilocus logistic regression analysis confirmed that the effect of rs2241394 was independent of the previously described loci at ARMS2 and CFH, and that the model including variants in ARMS2 and CFH plus C3 rs2241394 provided a better fit than the model without rs2241394. We found no evidence of epistasis between variants in C3 and CFH, despite the fact that they are involved in the same biological pathway. Conclusions Our study provides evidence that C3 is a common AMD-associated locus that transcends racial boundaries and provides an impetus for more detailed genetic characterization of the C3 locus in Asian populations.

Evaluation of clinical and genetic indicators for the early response to intravitreal ranibizumab in exudative age-related macular degeneration

AIM This study was conducted to evaluate the possible clinical and genetic indicators for an early response to intravitreal ranibizumab (IVR) in exudative age-related macular degeneration (AMD). PATIENTS & METHODS The records of 120 eyes from 120 Japanese patients with treatment-naive exudative AMD were retrospectively reviewed. Three consecutive IVR treatments were performed every month. Achievement of anatomical resolution was evaluated by ophthalmoscopy and optical coherence tomography. Multivariable logistic regression analysis was conducted by analyzing SNPs in the ARMS2 locus (A69S) and in the CFH gene (I62V and Y402H), in addition to clinical factors. RESULTS The mean central retinal thickness of overall patients was significantly decreased (-120.1 ± 122.8 µm, p = 2.7 × 10(-19)) at 3 months after the initial treatment. In the logistic regression analysis, the poor anatomical resolution of the lesion at 3 months was associated with the combination of CFH I62V + CFH Y402H variants (p = 0.0021), and the polypoidal choroidal vasculopathy lesions (p = 0.044). CONCLUSION The CFH variants and the polypoidal choroidal vasculopathy lesion may influence the early anatomical resolution with IVR in exudative AMD.

Comparison of the Outcomes of Photodynamic Therapy between Two Angiographic Subtypes of Polypoidal Choroidal Vasculopathy

Background: To compare the outcomes of photodynamic therapy (PDT) between two different angiographic subtypes of polypoidal choroidal vasculopathy (PCV). Methods: Ninety-three consecutive cases of PCV were classified into two phenotypes (42 type 1 and 51 type 2) according to the presence or absence of feeding vessels found on indocyanine green angiography. Full-dose PDT and retreatments were performed every 3 months as needed based on the findings on angiography. The best-corrected visual acuity (BCVA) was compared as the main outcome between type 1 and type 2 PCV up to 12 months after the initial PDT. Results: The baseline greatest linear dimension (GLD) was significantly larger in type 1 PCV than type 2 PCV. The mean BCVA was significantly improved from baseline in type 2 PCV, while no improvement was found in type 1 PCV. Analysis with matching the GLD between both PCV subtypes did not change the original results. Conclusions: There may be a significantly different response to PDT between two angiographic phenotypes of PCV.

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.

Comparison of the Effectiveness and Prognostic Factors of Intravitreal Ranibizumab between Typical Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy over 24 Months of Follow-Up

Purpose: To compare the response to ranibizumab between patients with typical neovascular age-related macular degeneration (tAMD) and those with polypoidal choroidal vasculopathy (PCV), and to determine the predictors for the outcomes. Methods: Fifty-nine eyes from 59 consecutive patients (tAMD: 27 eyes, PCV: 32 eyes) were treated with three monthly ranibizumab injections followed by as-needed retreatment. Best-corrected visual acuity (BCVA) and morphological parameters were evaluated over 24 months of follow-up. Results: The mean BCVA in tAMD and PCV patients was significantly improved at 3 months (-0.22 and -0.09 logMAR units, respectively). The improvement in BCVA was sustained up to 24 months in tAMD (p = 0.01) but not in PCV patients. The significant predictor for good response to ranibizumab in tAMD patients was the improvement of BCVA at 3 months, whereas that in PCV patients was the anatomical resolution at 3 months. Conclusions: Ranibizumab is an effective therapy for tAMD and PCV over 24 months. The predictors for good outcome might be different between tAMD and PCV.

Evaluating Dissociated Optic Nerve Fiber Layer Appearance Using En Face Layer Imaging Produced by Optical Coherence Tomography

Purpose: To investigate the incidence of and risk factors for a dissociated optic nerve fiber layer (DONFL) appearance after pars plana vitrectomy (PPV). Methods: We retrospectively reviewed 189 eyes that underwent PPV with internal limiting membrane removal and judged the presence/absence of an apparent DONFL based on en face layer images produced by spectral-domain optical coherence tomography (SD-OCT). Results: An apparent DONFL was observed in 47 (24.9%) eyes. The incidence of an apparent DONFL was significantly higher in the macular hole (MH) group (76.5%) than in the non-MH group (epiretinal membrane, diabetic macular edema, retinal vein occlusion, and others; 4.9%; p < 0.001). In the logistic regression analysis, surgical indication for MH was identified as the most significant DONFL risk factor (odds ratio 63.7; p = 1.05 × 10-8). Conclusion: Postoperative OCT en face layer imaging clarified that MH eyes are liable to have an apparent DONFL following PPV.

Autologous antibodies to outer retina in acute zonal occult outer retinopathy

PurposeOur aim was to use molecular biological methods to study evidence of autoimmune disease in five patients with acute zonal occult outer retinopathy (AZOOR).MethodsOphthalmologic data and sera were collected from all patients, who underwent visual field (VF) examination, optical coherence tomography (OCT), and multifocal electroretinogram (mfERG) recording. Serum was prepared from each patient’s blood and analyzed for antiretinal antibody activity using immunohistochemistry and Western blot analysis on mouse and human retinas. We also searched for antigen proteins using mass spectrometry.ResultsSymptoms were blurred vision in three patients and VF defects in two; all had enlargement of the Mariotte blind spot by VF testing. OCT findings in areas corresponding to the scotoma revealed disruptions of junction borders between inner and outer segment lines. mfERGs amplitudes were reduced in each corresponding scotoma area. Immunohistochemical serum staining revealed the target antigen was present in all photoreceptors of the mouse sensory retina. Western blot analysis using patient serum samples revealed some possible candidate antigens. Mass spectrometry could not determine the causative antigen; however, a list of candidates was discovered.ConclusionWe determined that AZOOR could be an autoimmune disease. All AZOOR patients tested using molecular biological methods had antiretinal antigens.

Efficacy and visual prognostic factors of intravitreal bevacizumab as needed for macular edema secondary to central retinal vein occlusion

Purpose Our aim was to investigate the efficacy and prognostic factors of intraocular injections of bevacizumab as needed in patients with macular edema secondary to central retinal vein occlusion (CRVO). Methods This is a retrospective study including 28 eyes of 27 consecutive patients with macular edema due to CRVO and followed for at least 6 months. The mean age of the patients was 66.3 years. The patients underwent an intravitreal injection of bevacizumab (1.25 mg) at the initial visit. Retreatments were performed when macular edema was persistent or worsened (as-needed regimen). The primary outcome measure was the mean change in best-corrected visual acuity (BCVA). The change in central retinal thickness (CRT) was evaluated as the secondary outcome. Finally, the factors useful for predicting BCVA outcome were determined. Results The mean number of injections was 1.8 over a period of 6 months. The mean BCVA (logarithm of minimum angle of resolution) was significantly improved at 1 (−0.097), 3 (−0.14), and 6 months (−0.25) after the initial injection (P<0.05, <0.01, and <0.001, respectively). The mean CRT was also improved significantly at 1 (−250.4), 3 (−150.0), and 6 months (−187.2) (P<0.001 each). Earlier treatment and better improvement in BCVA at 1 month after the initial treatment were the prognostic factors significantly associated with better visual outcomes at 6 months (P=0.047 and 0.029, respectively). Conclusion Intravitreal injection of bevacizumab as needed significantly improved visual acuity and macular edema in CRVO patients. Time before the treatment and early response to the treatment were important factors for the visual outcome.