Reduction of lipid accumulation rescues Bietti's crystalline dystrophy phenotypes.

Bietti's crystalline dystrophy (BCD) is an intractable and progressive chorioretinal degenerative disease caused by mutations in the CYP4V2 gene, resulting in blindness in most patients. Although we and others have shown that retinal pigment epithelium (RPE) cells are primarily impaired in patients with BCD, the underlying mechanisms of RPE cell damage are still unclear because we lack access to appropriate disease models and to lesion-affected cells from patients with BCD. Here, we generated human RPE cells from induced pluripotent stem cells (iPSCs) derived from patients with BCD carrying a CYP4V2 mutation and successfully established an in vitro model of BCD, i.e., BCD patient-specific iPSC-RPE cells. In this model, RPE cells showed degenerative changes of vacuolated cytoplasm similar to those in postmortem specimens from patients with BCD. BCD iPSC-RPE cells exhibited lysosomal dysfunction and impairment of autophagy flux, followed by cell death. Lipidomic analyses revealed the accumulation of glucosylceramide and free cholesterol in BCD-affected cells. Notably, we found that reducing free cholesterol by cyclodextrins or δ-tocopherol in RPE cells rescued BCD phenotypes, whereas glucosylceramide reduction did not affect the BCD phenotype. Our data provide evidence that reducing intracellular free cholesterol may have therapeutic efficacy in patients with BCD.

Anti-fumarase antibody promotes the dropout of photoreceptor inner and outer segments in diabetic macular oedema.

AIMS/HYPOTHESIS: In diabetic macular oedema (DMO), blood components passing through the disrupted blood-retinal barrier cause neuroinflammation, but the mechanism by which autoantibodies induce neuroglial dysfunction is unknown. The aim of this study was to identify a novel autoantibody and to evaluate its pathological effects on clinically relevant photoreceptor injuries. METHODS: Biochemical purification and subsequent peptide fingerprinting were applied to identify autoantigens. The titres of autoantibodies in DMO sera were quantified and their associations with clinical variables were evaluated. Two animal models (i.e. passive transfer of autoantibodies and active immunisation) were characterised with respect to autoimmune mechanisms underlying photoreceptor injuries. RESULTS: After screening serum IgG from individuals with DMO, fumarase, a Krebs cycle enzyme expressed in inner segments, was identified as an autoantigen. Serum levels of anti-fumarase IgG in participants with DMO were higher than those in diabetic participants without DMO (p < 0.001) and were related to photoreceptor damage and visual dysfunction. Passively transferred fumarase IgG from DMO sera in concert with complement impaired the function and structure of rodent photoreceptors. This was consistent with complement activation in the damaged photoreceptors of mice immunised with fumarase. Fumarase was recruited to the cell surface by complement and reacted to this autoantibody. Subsequently, combined administration of anti-fumarase antibody and complement elicited mitochondrial disruption and caspase-3 activation. CONCLUSIONS/INTERPRETATION: This study has identified anti-fumarase antibody as a serum biomarker and demonstrates that the generation of this autoantibody might be a pathological mechanism of autoimmune photoreceptor injuries in DMO.

Five major sequence variants and copy number variants in the EYS gene account for one-third of Japanese patients with autosomal recessive and simplex retinitis pigmentosa.

Purpose: To elucidate the variant spectrum of the EYS gene in a large cohort of Japanese patients with autosomal recessive and simplex retinitis pigmentosa (arRP and sRP). Methods: We performed a direct sequencing analysis of 44 exons of the EYS gene in 469 patients with RP (including 144 arRP, 288 sRP, and 17 autosomal dominant RP (adRP) cases) in eastern and western regions of Japan and a multiplex ligation-dependent probe amplification (MLPA) of patients who had a single heterozygous pathogenic variant. Results: We identified six pathogenic and 16 likely pathogenic variants from a total of 186 nucleotide sequence variants, of which five variants, c.2528G>A (p.(Gly843Glu)), c.4957dupA (p.(Ser1653Lysfs*2)), c.6557G>A (p.(Gly2186Glu)), c.6563T>C (p.(Ile2188Thr)), and c.8868C>A (p.(Tyr2956*)), were prevalent in patients with arRP and sRP. The homozygous and heterozygous combinations of these five variants accounted for 32.4% (140/432) of Japanese patients with arRP and sRP. Five patients with adRP also had these variants. These five variants segregated with the phenotype in 15 families with RP. MLPA revealed seven copy number variations (CNVs) of the EYS exon(s). Conclusions: This study showed that five major sequence variants and CNVs in the EYS gene account for one-third of Japanese patients with arRP and sRP, and these variants are also responsible for RP showing an autosomal dominant inheritance pattern. This is the first report showing the pathogenicity of three missense variants (p.(Gly843Glu), p.(Gly2186Glu), and p.(Ile2188Thr)) and the presence of CNVs in the EYS gene of Japanese patients with arRP and sRP.

Achieving LDL cholesterol target levels <1.81 mmol/L may provide extra cardiovascular protection in patients at high risk: Exploratory analysis of the Standard Versus Intensive Statin Therapy for Patients with Hypercholesterolaemia and Diabetic Retinopathy study.

AIMS: To assess the benefits of intensive statin therapy on reducing cardiovascular (CV) events in patients with type 2 diabetes complicated with hyperlipidaemia and retinopathy in a primary prevention setting in Japan. In the intension-to-treat population, intensive therapy [targeting LDL cholesterol <1.81 mmol/L (<70 mg/dL)] was no more effective than standard therapy [LDL cholesterol ≥2.59 to <3.10 mmol/L (≥100 to <120 mg/dL)]; however, after 3 years, the intergroup difference in LDL cholesterol was only 0.72 mmol/L (27.7 mg/dL), and targeted levels were achieved in <50% of patients. We hypothesized that the intergroup difference in CV events would have been statistically significant if more patients had been successfully treated to target. MATERIALS AND METHODS: This exploratory post hoc analysis focused on intergroup data from patients who achieved their target LDL cholesterol levels. The primary endpoint was the composite incidence of CV events. A Cox proportional hazards model was used to estimate hazard ratios (HRs) for incidence of the primary endpoint in patients who achieved target LDL cholesterol levels in each group. RESULTS: Data were analysed from 1909 patients (intensive: 703; standard: 1206) who achieved target LDL cholesterol levels. LDL cholesterol at 36 months was 1.54 ± 0.30 mmol/L (59.7 ± 11.6 mg/dL) in the intensive group and 2.77 ± 0.46 mmol/L (107.1 ± 17.8 mg/dL) in the standard group (P < 0.05). After adjusting for baseline prognostic factors, the composite incidence of CV events or deaths associated with CV events was significantly lower in the intensive than the standard group (HR 0.48; 95% confidence interval 0.28-0.82; P = 0.007). CONCLUSIONS: This post hoc analysis suggests that achieving LDL cholesterol target levels <1.81 mmol/L may more effectively reduce CV events than achieving target levels ≥2.59 to <3.10 mmol/L in patients with hypercholesterolaemia and diabetic retinopathy.

Phase II/III Clinical Trial of Sub-Tenon Injection of Triamcinolone Acetonide (WP-0508ST) for Diabetic Macular Edema.

PURPOSE: To assess the efficacy and safety of sub-Tenon injection of triamcinolone acetonide (WP-0508ST) for the patients with diabetic macular edema (DME). METHODS: This multicenter, randomized, double-masked, comparative, controlled study was performed in 95 patients with DME. The patients were randomly divided into 20 mg WP-0508ST, 40 mg WP-0508ST, and control groups. RESULTS: A significant improvement in central macular thickness (CMT) was observed (p < 0.001) at 12 weeks after a single sub-Tenon injection of 20 mg WP-0508ST. The 40 mg group also demonstrated improvement in CMT, but the difference was not significant. In addition, the best-corrected visual acuity was improved in both the 20 mg and 40 mg groups at 12 weeks. The major side effects were increased intraocular pressure (9.4% in the 20 mg group and 13.3% in the 40 mg group) and lenticular opacity (6.3% in the 20 mg group and 10.0% in the 40 mg group). However, none of the patients with increased intraocular pressure required surgery. CONCLUSION: The efficacy and tolerability of WP-0508ST in the treatment of DME were confirmed, and 20 mg was determined to be the optimal dose.

EVALUATION OF MACULAR ISCHEMIA IN EYES WITH BRANCH RETINAL VEIN OCCLUSION: An Optical Coherence Tomography Angiography Study.

PURPOSE: To quantitatively assess macular morphology and perfusion status using optical coherence tomography, and optical coherence tomography angiography in eyes with branch retinal vein occlusion when macular edema has completely resolved, and to investigate the impact on visual function. METHODS: Thirty consecutive eyes with branch retinal vein occlusion-macular edema that resolved after treatment with intravitreal ranibizumab injections were included. Macular sensitivity was measured by microperimetry; defect length of foveal ellipsoid zone band was measured using optical coherence tomography; foveal avascular zone and parafoveal nonperfusion areas (NPA) were measured by optical coherence tomography angiography. RESULTS: The logarithm of minimum angle of resolution visual acuity was significantly associated with the defect length of the foveal ellipsoid zone band (P = 0.005), the parafoveal NPA in the superficial capillary plexus (P = 0.007), and the parafoveal NPA in the deep capillary plexus (P = 0.006). Macular sensitivity correlated with parafoveal thickness on the affected side (P = 0.034), the defect length of the foveal ellipsoid zone band (P = 0.048), parafoveal NPA in the superficial capillary plexus (P = 0.008), and parafoveal NPA in the deep capillary plexus (P = 0.012). Multivariate analysis where the only significant parameters in the univariate analyses were used as the independent variables showed that parafoveal NPA was most significantly associated with the logarithm of minimum angle of resolution visual acuity (ß = 0.500, P = 0.005) and macular sensitivity (ß = -0.480, P = 0.007). CONCLUSION: In eyes with branch retinal vein occlusion-macular edema resolved by intravitreal ranibizumab treatments, visual function was strongly associated with parafoveal NPA size.

INFLUENCE OF VITRECTOMY SURGERY ON THE INTEGRITY OF OUTER RETINAL LAYERS IN DIABETIC MACULAR EDEMA.

PURPOSE: To investigate the influence of pars plana vitrectomy (PPV) on the integrity of photoreceptor layers in eyes with diabetic macular edema (DME) by using parallelism (a parameter that comprehensively reflects photoreceptor-retinal pigment epithelium [RPE] complex alterations) in spectral-domain optical coherence tomography (SD-OCT) imaging. METHODS: A consecutive series of 64 eyes in 55 patients with diabetic macular edema who underwent pars plana vitrectomy were recruited into the study. Spectral-domain optical coherence tomography images were obtained preoperatively and 6 months after surgery. The morphologic features of the outer retinal layers were assessed quantitatively using parallelism and qualitatively by graders, including continuity of the external limiting membrane (ELM) line, continuity of the photoreceptor inner and outer segment (IS/OS) junction line, and the presence of hyperreflective foci in the outer retinal layers. The relationships between parallelism, visual acuity (VA), and photoreceptor layer status were evaluated. RESULTS: After surgery, foveal thickness significantly decreased (P < 0.0001) and visual acuity improved (P < 0.0001) from baseline level. Postoperative parallelism (0.632 ± 0.137) was significantly higher than preoperative parallelism (0.531 ± 0.172) (P < 0.0001). A number of eyes with hyperreflective foci reduced after surgery, while separate evaluation of the inner and outer segment junction and external limiting membrane lines did not show significant changes. Moreover, preoperative and postoperative parallelism values showed significant correlations with postoperative visual acuity and serum lipid levels. Foveal thickness and logMAR visual acuity did not show significant correlations with any blood test data. CONCLUSION: Pars plana vitrectomy might be effective for resolution of hyperreflective foci in outer retinal layers. Parallelism is a potential marker for localization of hyperreflective foci and useful as a predictive factor for postoperative visual acuity.

EVALUATION OF MACULAR ISCHEMIA IN EYES WITH CENTRAL RETINAL VEIN OCCLUSION: An Optical Coherence Tomography Angiography Study.

PURPOSE: To quantitatively assess macular perfusion status using optical coherence tomography angiography in eyes with aflibercept-treated central retinal vein occlusion and resolved macular edema and to investigate the impact of macular morphology and perfusion status on visual function. METHODS: This prospective consecutive case series included 23 patients with central retinal vein occlusion. All patients received intravitreal aflibercept injections before analysis. Visual acuity, macular sensitivity, and the macular nonperfusion area (NPA) were evaluated in eyes without macular edema. The macular NPA was evaluated by optical coherence tomography angiography using 3 mm × 3 mm images of the macula. Foveal ellipsoid zone disruption was also analyzed. RESULTS: The superficial macular NPA measured 4.15 mm ± 0.71 mm (95% confidence interval 3.85-4.46), and the deep macular NPA measured 4.23 mm ± 0.97 mm (95% confidence interval 3.82-4.56). The logarithm of the minimum angle of resolution visual acuity was significantly associated with foveal ellipsoid zone disruption (P = 0.001), the superficial macular NPA (P = 0.015), and the deep macular NPA (P = 0.018). Macular sensitivity correlated negatively with logarithm of the minimum angle of resolution visual acuity (P = 0.007), the superficial macular NPA (P = 0.029), and the deep macular NPA (P = 0.040), but not with the foveal ellipsoid zone disruption (P = 0.435). CONCLUSION: Optical coherence tomography angiography is a novel technique that enables segmented evaluation of the macular perfusion status in eyes with central retinal vein occlusion and provides visual prognostic information. Enlargement of the macular NPA in the superficial and deep layers was significantly correlated with impaired visual acuity and with decreased macular sensitivity in patients with aflibercept-treated central retinal vein occlusion and resolved macular edema.

MACULAR ATROPHY AND MACULAR MORPHOLOGY IN AFLIBERCEPT-TREATED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate the incidence and predictors of macular atrophy during treatment with aflibercept for neovascular age-related macular degeneration in Japanese patients. METHODS: This study included patients with treatment-naive subfoveal neovascular age-related macular degeneration treated from December 2012 through January 2015. Patients were treated with bi-monthly aflibercept injections after 3 monthly loading injections for the first year. Diagnosis of retinal pigment epithelial atrophy was made based on color fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence. Baseline characteristics and morphological features were analyzed for their association with the development of macular atrophy. RESULTS: This study included 123 eyes that had no baseline macular atrophy and treated with aflibercept injections for 12 months. Thirteen eyes (10.6%) developed new macular atrophy at 12 months. Logistic regression analysis showed that the presence of intraretinal fluid and thinner subfoveal choroidal thickness at baseline were associated with the development of macular atrophy after aflibercept treatment. CONCLUSION: Macular atrophy developed in about 10% of eyes with neovascular age-related macular degeneration during 12 months of treatment with a fixed regimen of aflibercept. Intraretinal fluid and subfoveal choroidal thickness seem to be predictors for development of macular atrophy after anti-vascular endothelial growth factor (VEGF) therapy.

Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus.

Exfoliation syndrome (XFS) is a common, age-related, systemic fibrillinopathy. It greatly increases risk of exfoliation glaucoma (XFG), a major worldwide cause of irreversible blindness. Coding variants in the lysyl oxidase-like 1 (LOXL1) gene are strongly associated with XFS in all studied populations, but a functional role for these variants has not been established. To identify additional candidate functional variants, we sequenced the entire LOXL1 genomic locus (∼40 kb) in 50 indigenous, black South African XFS cases and 50 matched controls. The variants with the strongest evidence of association were located in a well-defined 7-kb region bounded by the 3'-end of exon 1 and the adjacent region of intron 1 of LOXL1. We replicated this finding in US Caucasian (91 cases/1031 controls), German (771 cases/1365 controls) and Japanese (1484 cases/1188 controls) populations. The region of peak association lies upstream of LOXL1-AS1, a long non-coding RNA (lncRNA) encoded on the opposite strand of LOXL1. We show that this region contains a promoter and, importantly, that the strongly associated XFS risk alleles in the South African population are functional variants that significantly modulate the activity of this promoter. LOXL1-AS1 expression is also significantly altered in response to oxidative stress in human lens epithelial cells and in response to cyclic mechanical stress in human Schlemm's canal endothelial cells. Taken together, these findings support a functional role for the LOXL1-AS1 lncRNA in cellular stress response and suggest that dysregulation of its expression by genetic risk variants plays a key role in XFS pathogenesis.

Shared genetic variants for polypoidal choroidal vasculopathy and typical neovascular age-related macular degeneration in East Asians.

Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD) more frequently seen in East Asians, has both common and distinct clinical manifestations with typical neovascular AMD (tAMD). We aim to examine the extent to which common genetic variants are shared between these two subtypes. We performed the meta-analysis of association in a total of 1062 PCV patients, 1157 tAMD patients and 5275 controls of East Asian descent from the Genetics of AMD in Asians Consortium at the 34 known AMD loci. A total of eight loci were significantly associated with PCV, including age-related maculopathy susceptibility 2 (ARMS2)-HtrA serine peptidase 1 (HTRA1), complement factor H (CFH), C2-CFB-SKIV2L, CETP, VEGFA, ADAMTS9-AS2 and TGFBR1 (P<5 × 10-4) from the single-nucleotide polymorphism-based test and COL4A3 from the gene-based tests (Pgene=2.02 × 10-4). PCV and tAMD are genetically highly correlated (rg=0.69, P=4.68 × 10-3), with AMD known loci accounting for up to 36% variation. Weaker association for PCV was observed at ARMS2-HTRA1 (Pdif=4.39 × 10-4) and KMT2E-SRPK2(Pdif=4.43 × 10-3), compared with tAMD. Variants at CFH, CETP and VEGFA exhibited different association signals in East Asians, in contrast to those in European individuals. Our data suggest a substantially shared genetic susceptibility for PCV and tAMD, while also highlight the unique associations for PCV, which is useful in understanding the pathogenesis of PCV.

RECURRENCE OF CHOROIDAL NEOVASCULARIZATION LESION ACTIVITY AFTER AFLIBERCEPT TREATMENT FOR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To examine the recurrence rate of choroidal neovascularization (CNV) lesion activity in age-related macular degeneration (AMD) and associated factors after 1-year aflibercept treatment. METHODS: Age-related macular degeneration eyes with 1-year aflibercept fixed-regimen treatment and a follow-up period of at least 18 months from the initial aflibercept injection for treatment-naive exudative AMD were retrospectively evaluated. The recurrence rate was examined. Age, gender, visual acuity, AMD subtype, greatest linear dimension, and retinal and choroidal thicknesses at the 12th month examination were compared between eyes with and without recurrence. Presence of remnant polyps and pigment epithelial detachment (PED) morphology were also compared in polypoidal choroidal vasculopathy (PCV) eyes. RESULTS: Of the 98 eyes studied, 69 displayed a dry macula at the 12th month examination; 43.7% exhibited recurrence during the subsequent 12-month period in Kaplan-Meier analysis. Although no factors associated with recurrence were detected in AMD, remnant polyps and pigment epithelial detachment morphology at the 12th month examination were significantly associated with recurrence in polypoidal choroidal vasculopathy (P = 0.018 and 0.048, respectively). CONCLUSION: Continuous, proactive treatment would be considered overtreatment for more than half of the AMD eyes that achieved a dry macula. Angiography and optical coherence tomography analyses may be useful for predicting recurrence in polypoidal choroidal vasculopathy eyes.

RETINAL PIGMENT EPITHELIAL ATROPHY AFTER ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTIONS FOR RETINAL ANGIOMATOUS PROLIFERATION.

PURPOSE: To investigate the incidence rate and risk factors for development of retinal pigment epithelial (RPE) atrophy during anti-vascular endothelial growth factor (anti-VEGF) treatment for retinal angiomatous proliferation. METHODS: This study included 46 eyes with treatment-naive retinal angiomatous proliferation. All patients were treated with ranibizumab or aflibercept injections. Color fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence were evaluated for RPE atrophy diagnosis. Baseline characteristics and gene polymorphisms of ARMS2 A69S, and CFH I62V were analyzed for association with development and progression of RPE atrophy. RESULTS: Among 21 eyes treated with ranibizumab without preexisting RPE atrophy at baseline, 5 eyes (23.8%) developed RPE atrophy at 12 months. Among 20 eyes treated with aflibercept without preexisting RPE atrophy at baseline, 10 eyes (50.0%) developed RPE atrophy at 12 months. Refractile drusen at baseline was associated with RPE atrophy development at 12 months (P = 0.014), and the progression rate of RPE atrophy area was negatively correlated with subfoveal choroidal thickness at baseline (R = -0.595, P = 0.019). Gene polymorphisms were not associated with RPE atrophy. CONCLUSION: Retinal pigment epithelial atrophy developed in 36.6% during 12 months after anti-VEGF treatment for retinal angiomatous proliferation. The presence of refractile drusen at baseline was identified as a novel significant risk factor for RPE atrophy development.

ASSOCIATIONS BETWEEN MACULAR EDEMA AND CIRCULATORY STATUS IN EYES WITH RETINAL VEIN OCCLUSION: An Adaptive Optics Scanning Laser Ophthalmoscopy Study.

PURPOSE: To investigate associations between parafoveal microcirculatory status and foveal pathomorphology in eyes with macular edema (ME) secondary to retinal vein occlusion (RVO). METHODS: Ten consecutive patients (10 eyes) with acute retinal vein occlusion were enrolled, 9 eyes of which received intravitreal ranibizumab (IVR) injections. Foveal morphologic changes were examined via optical coherence tomography (OCT), and parafoveal circulatory status was assessed via adaptive optics scanning laser ophthalmoscopy (AO-SLO). RESULTS: The mean parafoveal aggregated erythrocyte velocity (AEV) measured by adaptive optics scanning laser ophthalmoscopy in eyes with retinal vein occlusion was 0.99 ± 0.43 mm/second at baseline, which was significantly lower than that of age-matched healthy subjects (1.41 ± 0.28 mm/second, P = 0.042). The longitudinal adaptive optics scanning laser ophthalmoscopy examinations of each patient showed that parafoveal AEV was strongly inversely correlated with optical coherence tomography-measured central foveal thickness (CFT) over the entire observation period. Using parafoveal AEV and central foveal thickness measurements obtained at the first and second examinations, we investigated associations between differences in parafoveal AEV and central foveal thickness, which were significantly and highly correlated (r = -0.84, P = 0.002). CONCLUSION: Using adaptive optics scanning laser ophthalmoscopy in eyes with retinal vein occlusion macular edema, we could quantitatively evaluate the parafoveal AEV. A reduction or an increase in parafoveal AEV may be a clinical marker for the resolution or development/progression of macular edema respectively.

ASSOCIATION BETWEEN RETINAL HEMORRHAGIC PATTERNS AND PERFUSION STATUS IN EYES WITH ACUTE CENTRAL RETINAL VEIN OCCLUSION.

PURPOSE: To evaluate peripheral retinal hemorrhagic patterns in eyes with acute central retinal vein occlusion, and to explore their clinical relevance in differentiating for the retinal perfusion status, through a prospective, and cross-sectional study. METHODS: Fifty eyes with acute central retinal vein occlusion were included. Retinal hemorrhagic patterns at the equator and retinal perfusion status were evaluated by ultra-wide field fundus photography and fluorescein angiography. RESULTS: Retinal perfusion was categorized as nonischemic in 29 eyes, ischemic in 18 eyes, and undeterminable in 3 eyes. None of the examined eyes had flame-shaped retinal hemorrhages in the periphery. All hemorrhages were rounded-dot or blot and were variable in size. Particle analysis was performed to quantify hemorrhage size, and showed higher values in eyes having larger blot hemorrhages, and lower values in eyes having dot or smaller blot hemorrhages. Mean size of maximum peripheral dot or blot hemorrhage was larger in eyes classified as ischemic (10,763.0 ± 5,946.3 pixels) than as nonischemic (2,839.9 ± 1,153.6 pixels, P < 0.001). The authors calculated area under the curve to investigate the ability of continuous variables to discriminate retinal perfusion status, which was 0.963 (P < 0.001) for mean size of maximum peripheral blot hemorrhages. CONCLUSION: The authors objectively evaluated retinal hemorrhagic patterns at the equator in eyes with acute central retinal vein occlusion using particle analysis. The resulting hemorrhage size measurement was considered to be often useful in determining retinal perfusion status. Because they can be noninvasively evaluated with readily available equipment, peripheral hemorrhagic patterns might be good clinical markers of retinal perfusion.

CHOROIDAL AND RETINAL ATROPHY OF BIETTI CRYSTALLINE DYSTROPHY PATIENTS WITH CYP4V2 MUTATIONS COMPARED TO RETINITIS PIGMENTOSA PATIENTS WITH EYS MUTATIONS.

PURPOSE: To compare atrophy of the choroid and retina between Bietti crystalline dystrophy (BCD) patients and EYS-related retinitis pigmentosa (RP) patients with a similar degree of central visual field defects, age, and axial length (AL). METHODS: Nine eyes of nine BCD patients with CYP4V2 mutations (BCD group) were examined. Moreover, we selected 10 eyes of 10 RP patients with EYS mutations matched for age, axial length, and mean deviation (measured with the 10-2 SITA standard program; EYS-RP group), and 10 eyes of 10 normal volunteers matched for age and axial length (control group). Macular thicknesses of the choroid and retina were measured via swept-source optical coherence tomography. RESULTS: The macular choroid was significantly thinner in the BCD group than in the EYS-RP and control groups, although the thickness did not significantly differ between the EYS-RP and control groups. The macular retina was significantly thinner in the BCD and EYS-RP groups than in the control group, although the thickness did not significantly differ between the BCD and EYS-RP groups at most sites. CONCLUSION: Bietti crystalline dystrophy patients with CYP4V2 mutations showed more severe macular choroid atrophy as compared to EYS-related RP patients. These different damage patterns suggest differences in choroidal expression between CYP4V2 and EYS.

INCIDENCE AND CAUSES OF VISION LOSS DURING AFLIBERCEPT TREATMENT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: One-Year Follow-up.

PURPOSE: To investigate the incidence rate, risk factors, and final outcomes of patients with age-related macular degeneration (AMD) who have experienced vision loss despite periodic aflibercept treatment. METHODS: Subjects with treatment-naive AMD were prospectively recruited and treated with three monthly injections followed by two monthly injections of aflibercept. The incidence rate and risk factors of more than two lines of vision loss at any visit were investigated. RESULTS: We included 196 eyes of 196 patients. Vision loss was observed in 16 patients (8.2%). Eleven of 16 patients developed vision loss during the initial 3 months (68.8%). Vision loss remained in 11 eyes (68.8%) at the final visit. The maximum pigment epithelium detachment (PED) height (odds ratio = 1.46 for a 100-µm increase in the PED height) and disruption of the external limiting membrane (odds ratio = 4.45) were identified as risk factors for developing vision loss on logistic regression analysis. CONCLUSION: The incidence rate of vision loss during aflibercept treatment was relatively low. Identifying high-risk patients, those with a high PED height and disruption of the external limiting membrane, would be helpful in ensuring appropriate informed consent before treatment. Further studies are needed to establish optimal treatment for these patients.

RANIBIZUMAB FOR MACULAR EDEMA AFTER BRANCH RETINAL VEIN OCCLUSION: One Initial Injection Versus Three Monthly Injections.

PURPOSE: To compare the 12-month-efficacy of 1 initial intravitreal ranibizumab injection (IVR) followed by pro re nata (PRN) dosing with that of three initial monthly IVR followed by PRN dosing in patients with macular edema (ME) after branch retinal vein occlusion. DESIGN: Prospective, interventional study. METHODS: Of 81 eyes, 42 received 1 initial IVR injection (1+PRN group) and 39 eyes received 3 monthly IVRs (3+PRN). Pro re nata injections were performed when fovea exudative changes were evident. RESULTS: At Month 12, the visual acuity (VA) changes from baseline were -0.245 ± 0.227 and -0.287 ± 0.222, in the 1+PRN and 3+PRN groups, respectively; there were no significant difference between groups (P = 0.728). The stratified analysis showed that patients with better VA (baseline VA >20/40) had similar significant improvement in VA at Month 12 (P < 0.001) to that of those with poorer VA (≤20/40). Better VA at Month 12 was significantly associated with younger age, better baseline VA, and thinner baseline central foveal thickness (P = 0.003, < 0.001, and < 0.001, respectively). Mean total number of IVR injections in the 1+PRN and 3+PRN groups were 3.8 ± 1.8 and 4.6 ± 1.4, respectively (P = 0.060). In both groups, shorter durations to the first PRN injection were associated with greater total PRN injection number (1+PRN, P = 0.006; 3+PRN; group, P < 0.001). CONCLUSION: In IVR treatment for ME after branch retinal vein occlusion, 1+PRN and 3+PRN regimens achieved similar 12-month functional outcomes. Patients with shorter durations to initial PRN injection may require more PRN treatments.

Structural and Functional Analyses in Nonarteritic Anterior Ischemic Optic Neuropathy: Optical Coherence Tomography Angiography Study.

BACKGROUND: Retinal and optic disc perfusion in nonarteritic anterior ischemic optic neuropathy (NAION) is incompletely understood. Our aim was to investigate the characteristics of the microvascular structures at the peripapillary area and optic disc, and their associations with retinal structure and function in patients with NAION. METHODS: We conducted a prospective, observational case series study. Thirty-four eyes, consisting of 15 NAION eyes and 19 normal eyes, were included. Optical coherence tomography (OCT) angiography was used to measure the vessel densities in the peripapillary superficial retina and whole-depth mode inside the optic disc. Measurement of circumpapillary retinal nerve fiber layer (cpRNFL) thickness was performed using OCT. Sectorial division analysis of cpRNFL was performed by eliminating the influences of the difference in disc rotation between OCT images and OCT angiography images. RESULTS: The vessel densities of peripapillary retina and inside the optic disc were significantly reduced in the NAION compared to the normal (both P < 0.001). Both the severity of visual field defect and cpRNFL thinning were significantly associated with the peripapillary vessel density (P = 0.006, P = 0.046), but not with the optic disc vessel density (P = 0.981, P = 0.856). cpRNFL and peripapillary vessel density showed reduction predominantly in the superior sectors, corresponding to the visual field defect. However, the correlations showed discrepancy of the sectors. CONCLUSIONS: The microvascular structures in the peripapillary retina and optic disc were reduced, but the cpRNFL thinning was associated with vessel density only in the peripapillary retina, indicating that the vessel densities in the peripapillary retina and optic disc may be differently affected in the pathological process of NAION.

CMPK1 and RBP3 are associated with corneal curvature in Asian populations.

Corneal curvature (CC) measures the steepness of the cornea and is an important parameter for clinically diseases such as astigmatism and myopia. Despite the high heritability of CC, only two associated genes have been discovered to date. We performed a three-stage genome-wide association study meta-analysis in 12 660 Asian individuals. Our Stage 1 was done in multiethnic cohorts comprising 7440 individuals, followed by a Stage 2 replication in 2473 Chinese and Stage 3 in 2747 Japanese. The SNP array genotype data were imputed up to the 1000 Genomes Project Phase 1 cosmopolitan panel. The SNP association with the radii of CC was investigated in the linear regression model with the adjustment of age, gender and principal components. In addition to the known genes, MTOR (also known as FRAP1) and PDGFRA, we discovered two novel genes associated with CC: CMPK1 (rs17103186, P = 3.3 × 10(-12)) and RBP3 (rs11204213 [Val884Met], P = 1.1 × 10(-13)). The missense RBP3 SNP, rs11204213, was also associated with axial length (AL) (P = 4.2 × 10(-6)) and had larger effects on both CC and AL compared with other SNPs. The index SNPs at the four indicated loci explained 1.9% of CC variance across the Stages 1 and 2 cohorts, while 33.8% of CC variance was explained by the genome-wide imputation data. We identified two novel genes influencing CC, which are related to either corneal shape or eye size. This study provides additional insights into genetic architecture of corneal shape.