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Carriers of functionally deficient mutations in the CYP39A1 gene have been recently reported to have a 2-fold increased risk of exfoliation syndrome (XFS). The aim of this study was to evaluate the risk of blindness and related clinical phenotypes of XFS patients carrying the loss-of-function CYP39A1 G204E mutation in comparison with XFS patients without any CYP39A1 mutation.Retrospective case study.A total of 35 patients diagnosed with XFS carrying the CYP39A1 G204E mutation and 150 XFS patients without any CYP39A1 mutation who were randomly selected from the Japanese XFS cohort.Two-sided Fisher exact test with an alpha level0.05 was used to estimate the significance of the calculated odds ratio (OR) for all categorical measures. Comparisons between groups of subjects were performed using linear mixed effect models with group as random effect and taking possible dependence between eyes within a subject into account.Primary analysis compared the incidence of blindness (defined as visual acuity [VA]0.05 decimal), prevalence of exfoliation glaucoma (XFG), history of glaucoma surgery, and indices of glaucoma severity such as visual field (VF) mean deviation (MD), intraocular pressure (IOP), and vertical cup-disc ratio (CDR) between CYP39A1 G204E carriers and those without any CYP39A1 mutation.The overall risk for blindness was significantly higher in XFS patients carrying the CYP39A1 G204E variant (10/35 [28.6%]) compared with XFS patients without any CYP39A1 mutations (8/150 [5.4%]; odds ratio [OR], 7.1; 95% confidence interval [CI], 2.7-20.2]; P0.001). A higher proportion of XFS patients with the CYP39A1 G204E mutation (23/35 [65.7%]) had evidence of XFG in at least 1 eye compared with the comparison group (41/150 [27.3%]; OR, 5.1; 95% CI, 2.4-11.4]; P0.0001). Significantly higher peak IOP, larger vertical CDR, and worse VF MD were also found in CYP39A1 G204E variant carriers (P0.001). Additionally, patients with the CYP39A1 G204E mutation (18/35 [51.4%]) required more laser or glaucoma surgical interventions compared with those without any CYP39A1 mutation (32/150 [21.3%], P0.001).Patients with XFS carrying the CYP39A1 G204E mutation had significantly increased risk of blindness, higher occurrence of XFG, and more severe glaucoma compared with patients with XFS without any CYP39A1 mutation.

Glaucoma is a leading cause of blindness worldwide. Purpose of this study was to identify molecular markers that were significantly correlated with presence of glaucoma and outcome of glaucoma surgery. To accomplish this, we determined the profiles of pro-inflammatory cytokines in the aqueous humor of 101 glaucoma patients; 31 primary open angle glaucoma (POAG), 38 pseudoexfoliation glaucoma (PEG), and 32 neovascular glaucoma (NVG). We also studied 100 normal subjects as controls. In eyes with POAG or PEG, the level of interleukin (IL)-1α, IL-2, IL-4, IL-8, IL-23, and CCL2 were significantly elevated. In the NVG eyes, many inflammatory cytokines were also highly elevated. IL-8 had the highest odds ratio, and levels of IL-8 and CCL2 were significantly correlated with preoperative IOP or visual field defects in PEG eyes. Principal component analysis showed that IL-8 had the highest association to the IOP-cytokine component, and Cox proportional hazard model indicated that an elevation of IL-8 was a significant risk of filtering surgery failure. Together with modeling of their interactions and prognosis, IL-8 elevation is a significant risk factor both for detecting and managing glaucoma and may serve as a therapeutic target candidate to improve the prognosis of glaucoma surgery.

PURPOSE To compare the 1-year outcomes of treat-and-extend (TAE) and every-other-month (2M) regimens with intravitreal aflibercept in Japanese wet age-related macular degeneration (AMD) patients. METHODS Prospective, multicenter, randomized clinical trial. The primary outcome measure was the proportion of eyes in which the best-corrected visual acuity (BCVA) was maintained at week 52 [with a loss of

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Purpose Cone/cone-rod dystrophy is a large group of retinal disorders with both phonotypic and genetic heterogeneity. The purpose of this study was to characterize the phenotype of eight patients from seven families harboring POC1B mutations in a cohort of the Japan Eye Genetics Consortium (JEGC). Methods Whole-exome sequencing with targeted analyses identified homozygous or compound heterozygous mutations of the POC1B gene in 7 of 548 families in the JEGC database. Ophthalmologic examinations including the best-corrected visual acuity, perimetry, fundus photography, fundus autofluorescence imaging, optical coherence tomography, and full-field and multifocal electroretinography (ERGs) were performed. Results There were four men and four women whose median age at the onset of symptoms was 15.6 years (range, 6-23 years) and that at the time of examination was 40.3 years (range, 22-67 years). The best-corrected visual acuity ranged from -0.08 to 1.52 logMAR units. The funduscopic appearance was normal in all the cases except in one case with faint mottling in the fovea. Optical coherence tomography revealed an absence of the interdigitation zone and blurred ellipsoid zone in the posterior pole, but the foveal structures were preserved in three cases. The full-field photopic ERGs were reduced or extinguished with normal scotopic responses. The central responses of the multifocal ERGs were preserved in two cases. The diagnosis was either generalized cone dystrophy in five cases or cone dystrophy with foveal sparing in three cases. Conclusions Generalized or peripheral cone dystrophy with normal funduscopic appearance is the representative phenotype of POC1B-associated retinopathy in our cohort.

IMPORTANCE Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. OBJECTIVE To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. DESIGN, SETTING, AND PARTICIPANTS A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. EXPOSURES Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. MAIN OUTCOMES AND MEASURES The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 x 10(-6). The secondary outcomes included biochemical enzymatic assays and gene expression analyses. RESULTS The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 x 10(-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4%[interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. CONCLUSIONS AND RELEVANCE In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings. National Research Foundation of SingaporeNational Research Foundation, Singapore [NRF-NRFI2018-01]; US National Eye Institute of the National Institutes of Health [R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, EY015473]; Glaucoma Research Foundation of Canada [X052, CIRG17may053]; National Medical Research Council of SingaporeNational Medical Research Council, Singapore The study was funded by grant NRF-NRFI2018-01 from the National Research Foundation of Singapore. Additional support was provided by grants R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, and EY015473 from the US National Eye Institute of the National Institutes of Health, funding from the Glaucoma Research Foundation of Canada, and grants X052 and CIRG17may053 from the National Medical Research Council of Singapore.

To assess the efficacy and safety of filtration surgery using the EX-PRESS glaucoma filtration device in patients with normal-tension glaucoma (NTG).Prospective, single-arm, multicenter interventional case series.Eyes with NTG underwent EX-PRESS implantation with or without cataract surgery. The efficacy and safety were assessed at 1 day; 1 and 2 weeks; and 1, 3, 6, and 12 months after surgery. The main outcome measure was reduction in intraocular pressure (IOP) from baseline at 3, 6, and 12 months after surgery. Safety assessments included adverse event incidence, postoperative inflammation, and corneal endothelial cell density.Thirty-two Japanese patients (37 eyes) with NTG were enrolled. The mean IOP decreased from 14.8 ± 2.3 mmHg at baseline to 10.0 ± 3.1 mmHg at 12 months after surgery (mean reduction 4.9 ± 4.2 mmHg [31.1%]; P .0001). IOP-lowering medication use decreased from a mean of 3.3 medications per eye before surgery to 0.1 medications per eye at 12 months after surgery. IOP reductions 20% were achieved by 61.5% of the eyes at 12 months. Adverse events were typical for filtration procedures, and none was deemed device-related. Postoperative inflammation was mild and self-limiting. The mean corneal endothelial cell density had decreased by 3.3% at 12 months after surgery.The EX-PRESS glaucoma filtration device is safe and effective for filtration surgery in patients with NTG, providing mean IOP reduction consistent with recommendations based on the Collaborative NTG Study.

Objective: The annual incidence of rhegmatogenous retinal detachment (RRD) in Kumamoto, Japan was previously evaluated in 1990. However, the incidence has not been evaluated during the last 20 years. The purpose of this study was to estimate the current incidence and epidemiologic characteristics of RRD in Kumamoto, Japan.Methods: The study was based on a retrospective chart review of hospital patients living in Kumamoto, Japan. All patients were treated for primary RRD by conventional surgery (pars plana vitrectomy and/or scleral buckling) at Kumamoto University Hospital or Ideta Eye Hospital between January 1, 2009, and December 31, 2011. Information on age, gender, refractive status, and history of cataract surgery was collected.Results: A total of 897 RRD patients were identified during the 3-year study period. The annual incidence of RRD was 16.5 (21.9 in males, 11.7 in females) per 100,000 people, with a peak incidence of 35.4 in the 50-59 years of age group. The incidence of RRD in males was 1.88 times (95% confidence interval, 1.56-2.29) higher than in females (P

Purpose To describe observations by ultrahigh-resolution optical coherence tomography (OCT) in a secondary corneal amyloidosis (SCA) patient with histological analysis of excised tissue. A unique finding under OCT of her fellow eye is also described. Case A 39-year-old female had suffered from trichiasis in both of her eyes for more than 30 years. Slit-lamp examination showed a milky-white soft mass on her left cornea and a linear opacity on the fellow cornea at the cilia-attached region. OCT demonstrated the presence of a mass region within a thin epithelial layer and no destruction of Bowman's layer in her left cornea. In the fellow cornea, which exhibited a linear opacity, a high-density spot in Bowman's layer was observed at the cilia-attached region covered by the epithelial layer, with normal thickness. Histological examination of the excised cornea showed that the mass was positive with both Congo red and antilactoferrin antibody. Conclusion SCA, amyloid gradually accumulates above Bowman's layer, occupying the epithelial layer, with no destruction of Bowman's layer until the advanced stage. A high-density spot in Bowman's layer might be the first stage of SCA.

Photodynamic therapy (PDT) for exudative age-related macular degeneration (AMD) was evaluated using a supramolecular nanomedical device, that is, a novel dendritic photosensitizer (DP) encapsulated by a polymeric micelle formulation. The characteristic dendritic structure of the DP prevents aggregation of its core sensitizer, thereby inducing a highly effective photochemical reaction. With its highly selective accumulation on choroidal neovascularization (CNV) lesions, this treatment resulted in a remarkably efficacious CNV occlusion with minimal unfavorable phototoxicity.

We describe suturing an intraocular lens (IOL) after pars plana lensectomy and vitrectomy combined with gas tamponade in 4 patients with vitreoretinal disease and subluxated lenses that could not be managed with capsular tension rings. The IOL haptics were sutured before the fluid-gas exchange in a horizontal (case 1), oblique (cases 2 and 4), and vertical (case 3) manner. In a case of unavoidable horizontal fixation due to limited scleral space, the upper part of the IOL tilted anteriorly postoperatively because of the enhanced effect of the gas bubble. A peripheral anterior iris synechia also occurred. The IOL remained well positioned in cases with oblique and vertical fixations, and no other complications occurred. Careful preoperative planning of the surgical design can help avoid unnecessary horizontal fixation.

The purpose of this study was to report a patient with Oguchi disease whose ophthalmological characteristics were masked by retinitis pigmentosa (RP). The method used in this study was case report. A 53-year-old man had a progressive decrease in his visual acuity and was diagnosed with RP because of night blindness, fundoscopic findings, ring scotoma, and extinguished single-flash electroretinograms (ERGs). However, a faint golden-yellowish reflex of the retina prompted us to make a more detailed examination of the fundus after a long period of dark adaptation, ERGs, and genetic analysis. Examinations showed the Mizuo-Nakamura phenomenon, relative intact photopic ERGs, and a SAG mutation, and the patient was diagnosed with RP associated with Oguchi disease. When RP accompanies Oguchi disease, the clinical characteristics of Oguchi disease might be masked. In such a situation, the correct diagnosis is difficult. However, careful analysis of clinical findings will suggest Oguchi disease, which can be confirmed by molecular genetics.

We investigated by in vivo confocal microscopy alterations in the subepithelial nerve plexus in different types of herpes simplex keratitis (HSK). Seventeen patients (seven women and ten men, mean age 63.9 years) with a history of HSK were classified into three groups according to the classification of Herpetic Keratitis Infection Research Group. Slit-lamp examinations, corneal sensitivity measurements, and corneal in vivo confocal microscopy examinations [Rostock Corneal Module attached to the Heidelberg Retina Tomograph II (HRT II-RCM)] were performed. Among the 17 cases, three were classified as epithelial type, ten as stromal type, and four as endothelial type HSK. The average corneal sensitivities were 11.41 ± 9.46 mm in the affected eyes and 43.24 ± 12.2 mm in controls. Decreases in three parameters in the affected eyes (long nerve-fiber density, nerve-branch density, nerve thickness) were statistically significant compared with controls. Decreases in the three parameters were more remarkable in the epithelial and stromal types than in the endothelial type. The morphology of the corneal subepithelial nerve plexus may get gradually destroyed along with recurrent episodes of epithelial and stromal HSK. However, the destruction does not seem remarkable in the endothelial type of HSK, suggesting the possibility of a different route of virus recruitment in this type.

Anticardiolipin antibodies in the autoimmune mechanism can cause vasculitis, leading to hypercoagulability-related thrombosis. We report a case of retinal vein occlusion followed by ischemic optic neuropathy in a young woman with anticardiolipin IgG antibody.A 17-year-old woman with dilatation and tortuosity of the retinal veins and retinal hemorrhage in the superior quadrant of the retina OS. Fluorescein retinal angiography showed a delay of filling time in the upper quadrant of the retina and a 3mm-continuous stain along the superior retinal vein. Laboratory tests were repeatedly positive for anticardiolipin IgG antibodies. Although the retinal hemorrhage disappeared 2 months after subtennon injection of 20 mg triamcinolone acetonide (TA), ischemic optic neuropathy occurred 9 months later.The staining of the vessel wall and the effectiveness of TA suggest that vasculitis may be associated with the pathology of this condition. The presence of anticardiolipin IgG antibodies suggests that autoimmune mechanism is involved in the vasculitis.

To develop a prototype robotic system designed to assist vitreoretinal surgery and to evaluate its accuracy and maneuverability.Experimental study.This study used harvested porcine eyes.After development of a prototype robotic system, pointing accuracy tests of the system were performed on graph paper and in harvested porcine eyes. The average maximal deviation from the aiming point to the actual position of the tip of the instrument was compared between manually conducted procedures and those conducted with robotic assistance. The feasibility of creating posterior vitreous detachment (PVD), retinal vessel sheathotomy (RVS), and retinal vessel microcannulation also were evaluated in porcine eye models, and the success rates of 4 consecutive attempts for each kind of procedure were evaluated.The average maximum deviation in pointing accuracy tests both on graph paper and in animal eye models was a main outcome measure. The success rate of making PVD, RVS, and retinal vessel microcannulation was the other primary outcome measure.The pointing accuracy was superior with robotic assistance both on graph paper (327.0 microm vs. 32.3 microm) and in animal eye models (140.8 microm vs. 33.5 microm). Creating PVD, RVS, and retinal vessel microcannulation was feasible in 4 of 4 attempts, 4 of 4 attempts, and 2 of 4 attempts, respectively. The 2 failures in microcannulation were considered to be the result of difficulty in visual differentiation between the retinal vessel and retina in harvested porcine eyes.Improved accuracy and desirable feasibility of a prototype robotic system to assist vitreoretinal surgery were shown in this study. Research for wider implementation of robot-assisted surgery should be continued; there are some hurdles to overcome.

Corrigendum: A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Purpose To describe ocular manifestations in Japanese patients with congenital insensitivity to pain with anhidrosis (CIPA), focusing particularly on the status of the ocular surface. Design Observational case series. Methods Eighteen patients with CIPA underwent applicable ophthalmologic examinations, including visual acuity, refraction, slit-lamp examination, fundus examination, tear breakup time, Schirmer 1 test, corneal sensitivity, and corneal topography. Results Superficial punctate keratopathy (SPK) was observed at the interpalpebral area in 23 (64%) of 36 eyes. Corneal opacity was observed in three eyes (8.3%). Tear breakup time was below the lower limit of the normal range in all examined eyes, and the value of Schirmer 1 test was above the lower limit of the normal range in most of the examined eyes. Conclusions Superficial punctate keratopathy is observed in most cases of CIPA, which might predispose patients to corneal infection. Investigation of dry eye in patients with CIPA will provide unique opportunities to explore the critical roles of the autonomic sympathetic nervous system as well as the sensory nervous system in the physiology of tear production.

Purpose: To compare central corneal thickness (CCT) of patients with normal tension glaucoma (NTG) with that of age-matched normal subjects, patients with open-angle glaucoma (POAG) and ocular hypertension (OH) subjects in Japan. Methods: Central corneal thickness was measured in 79 NTG, 61 POAG, 73 OH, and 50 normal subjects with an ultrasonic pachymeter. One eye for 1 subject randomly selected in each group was used for inter-group comparison. The relationship between CCT and the maximum intraocular pressure (IOP) measured by Goldmann applanation tonometer with no ocular hypotensive medication (NTG, OH, and normal subjects) or under medication (POAG patients) was analyzed. Results: The CCT of OH subjects (582 ± 32 μm; mean ± SD) was significantly greater than that of the other groups (P < .001), while no difference was seen in CCT among normal (552 ± 36 μm), NTG (548 ± 33 μm) and POAG (550 ± 33 μm) subjects. In normal subjects, CCT and the maximum IOP were significantly correlated but the correlation coefficient was small (r = 0.420, P < .05). Conclusions: Central corneal thickness shows no significant difference among NTG, POAG, and normal subjects in Japan, while it is significantly greater in OH subjects. The CCT has little influence on the diagnosis of NTG in Japan.

Lattice degeneration of the retina is a vitreoretinal disorder characterized by a visible fundus lesion predisposing the patient to retinal tears and detachment. The etiology of this degeneration is still uncertain, but it is likely that both genetic and environmental factors play important roles in its development. To identify genetic susceptibility regions for lattice degeneration of the retina, we performed a genome-wide association study (GWAS) using a dense panel of 23,465 microsatellite markers covering the entire human genome. This GWAS in a Japanese cohort (294 patients with lattice degeneration and 294 controls) led to the identification of one microsatellite locus, D2S0276i, in the collagen type IV alpha 4 (COL4A4) gene on chromosome 2q36.3. To validate the significance of this observation, we evaluated the D2S0276i region in the GWAS cohort and in an independent Japanese cohort (280 patients and 314 controls) using D2S0276i and 47 single nucleotide polymorphisms covering the region. The strong associations were observed in D2S0276i and rs7558081 in the COL4A4 gene (Pc = 5.8 × 10(-6), OR = 0.63 and Pc = 1.0 × 10(-5), OR = 0.69 in a total of 574 patients and 608 controls, respectively). Our findings suggest that variants in the COL4A4 gene may contribute to the development of lattice degeneration of the retina.

Purpose To develop a prototype robotic system designed to assist vitreoretinal surgery and to evaluate its accuracy and maneuverability. Design Experimental study. Participants This study used harvested porcine eyes. Methods After development of a prototype robotic system, pointing accuracy tests of the system were performed on graph paper and in harvested porcine eyes. The average maximal deviation from the aiming point to the actual position of the tip of the instrument was compared between manually conducted procedures and those conducted with robotic assistance. The feasibility of creating posterior vitreous detachment (PVD), retinal vessel sheathotomy (RVS), and retinal vessel microcannulation also were evaluated in porcine eye models, and the success rates of 4 consecutive attempts for each kind of procedure were evaluated. Main Outcome Measures The average maximum deviation in pointing accuracy tests both on graph paper and in animal eye models was a main outcome measure. The success rate of making PVD, RVS, and retinal vessel microcannulation was the other primary outcome measure. Results The pointing accuracy was superior with robotic assistance both on graph paper (327.0 μm vs. 32.3 μm) and in animal eye models (140.8 μm vs. 33.5 μm). Creating PVD, RVS, and retinal vessel microcannulation was feasible in 4 of 4 attempts, 4 of 4 attempts, and 2 of 4 attempts, respectively. The 2 failures in microcannulation were considered to be the result of difficulty in visual differentiation between the retinal vessel and retina in harvested porcine eyes. Conclusions Improved accuracy and desirable feasibility of a prototype robotic system to assist vitreoretinal surgery were shown in this study. Research for wider implementation of robot-assisted surgery should be continued; there are some hurdles to overcome. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.