Abilities of circumpapillary retinal nerve fiber layer thickness and vascular density to discriminate stages in primary open-angle glaucoma.

PURPOSE: To clarify the abilities of circumpapillary retinal nerve fiber layer thickness (cpRNFLT) obtained by optical coherence tomography (OCT) and circumpapillary vessel density (cpVD) measured by OCT-angiography to distinguish different stages in primary open-angle glaucoma determined by 24-2 or 30-2 static visual field (VF) testing. METHODS: This retrospective study includes 25 healthy normal eyes of 25 subjects and 87 primary open-angle glaucoma eyes of 87 patients. Areas under the receiver operating characteristic curves (AUROC) were evaluated for determining glaucoma stages using cpRNFLT and cpVD. The absolute errors of the estimated mean total deviation (mTD) using optimal models with cpRNFLT and cpVD were also compared. RESULTS: The AUROCs for discriminating glaucomatous eyes from normal eyes was significantly higher for cpRNFLT than the respective AUROCs for cpVD (0.969 [95% CI 0.939 to 0.998] vs. 0.872 [95% CI 0.806 to 0.938], p = 0.006), whereas cpVD had significantly higher AUROC for discriminating severe glaucoma eyes from moderate glaucoma eyes than cpRNFLT (0.771 [95% CI 0.655 to 0.886] vs. 0.578 [95% CI 0.420 to 0.736], p = 0.022). The mean absolute error in estimating mTD using both cpRNFLT and cpVD was significantly less than the error using cpRNFLT alone (4.56 ± 3.76 dB vs. 5.39 ± 4.00 dB, p = 0.027). CONCLUSION: Our results suggest that cpVD is better for follow-ups after moderate stage. The combination of cpRNFLT and cpVD may improve VF estimation compared to cpRNFLT alone.

Genetic variants associated with glaucomatous visual field loss in primary open-angle glaucoma.

Primary open-angle glaucoma (POAG) is characterized by a progressive optic neuropathy with visual field loss. To investigate the genetic variants associated with visual field loss in POAG, Japanese POAG patients (n = 426) and control subjects (n = 246) were genotyped for 22 genetic variants predisposing to POAG that can be classified into those associated with intraocular pressure (IOP) elevation (IOP-related genetic variants) and optic nerve vulnerability independent of IOP (optic nerve-related genetic variants). The genetic risk score (GRS) of the 17 IOP-related and five optic nerve-related genetic variants was calculated, and the associations between the GRS and the mean deviation (MD) of automated static perimetry as an indicator of the severity of visual field loss and pattern standard deviation (PSD) as an indicator of the focal disturbance were evaluated. There was a significant association (Beta = - 0.51, P = 0.0012) between the IOP-related GRS and MD. The severity of visual field loss may depend on the magnitude of IOP elevation induced by additive effects of IOP-related genetic variants. A significant association (n = 135, Beta = 0.65, P = 0.0097) was found between the optic nerve-related, but not IOP-related, GRS and PSD. The optic nerve-related (optic nerve vulnerability) and IOP-related (IOP elevation) genetic variants may play an important role in the focal and diffuse visual field loss respectively. To our knowledge, this is the first report to show an association between additive effects of genetic variants predisposing to POAG and glaucomatous visual field loss, including severity and focal/diffuse disturbance of visual field loss, in POAG.

Evaluation of Bleb Characteristics after Trabeculectomy and Glaucoma Implant Surgery in the Rabbit.

The characteristics of the conjunctival bleb are some of the most important factors for the surgical success of glaucoma filtering surgery. To improve surgical outcome, we investigated bleb histology after 3 different glaucoma surgeries. Surgery was performed in 21 white rabbits. Rabbits were randomized to trabeculectomy or implantation with EX-PRESS or a silicone tube (each n = 7). Bleb survival, intraocular pressure (IOP), and vascularity were evaluated. At 6 weeks, eyes were enucleated for histological analysis. Postoperative IOP at 2 weeks was significantly lower in the trabeculectomy and the EX-PRESS group than in the silicone tube group (p = 0.037) but not thereafter. Postoperative bleb survival (p = 0.542) and vascularity (p = 0.988) were similar among the 3 groups. Histologically, a capsule showing mild fibroblast proliferation associated with intercellular collagen was present around the surgical site. The thickness of the bleb was similar among all experimental groups, but it was significantly greater than in controls (p < 0.05). The inflammatory area did not differ between the EX-PRESS and the silicone tube group but was significantly greater in the trabeculectomy group than in the tube group (p = 0.031). A correlation between the thickness of the bleb wall and inflammation was found (r = 0.56, p < 0.01). EX-PRESS and silicone tube implants appear to be relatively inert, with little difference in biocompatibility and bleb survival. Since some degree of inflammation was still observed histologically in the bleb, more noninvasive surgical methods and more biocompatible materials may be desirable.

A case of childhood glaucoma with a combined partial monosomy 6p25 and partial trisomy 18p11 due to an unbalanced translocation.

Background: Chromosomal deletion involving the 6p25 region results in a clinically recognizable syndrome characterized by anterior eye chamber anomalies with risk of glaucoma and non-ocular malformations (6p25 deletion syndrome). We report a newborn infant case of childhood glaucoma with a combination of partial monosomy 6p25 and partial trisomy 18p11 due to an unbalanced translocation.Materials and methods: The patient was a 0-year-old girl. Both eyes showed aniridia and left eye Peters anomaly with multiple malformations. To identify the chromosomal aberrations in the patient with clinically suspected 6p25 deletion syndrome, we performed cytogenetic analysis (G-banding and multicolor fluorescent in-situ hybridization) and array-based comparative genomic hybridization (array-CGH) analysis.Results: Cytogenetic analyses revealed a derivative chromosome 6 with its distal short arm replaced by an extra copy of the short arm of chromosome 18. Array-CGH analysis detected a 4.6-Mb deletion at 6pter to 6p25.1 and 8.9-Mb duplication at 18pter to 18p11.22. To determine the breakpoint of the unbalanced rearrangement at the single-base level, we performed a long-range PCR for amplifying the junctional fragment of the translocation breakpoint. By sequencing the junctional fragment, we defined the unbalanced translocation as g.chr6:pter_4594783delinschr18:pter_8911541.Conclusions: A phenotype corresponding to combined monosomy 6p25 and trisomy 18p11 presented as childhood glaucoma associated with non-acquired (congenital) ocular anomalies consist of aniridia and Peters anomaly and other systemic malformations. To the best of our knowledge, this is the first report which demonstrated the breakpoint sequence of an unbalanced translocation in a Japanese infant with childhood glaucoma.

Genetic Variants Associated With the Onset and Progression of Primary Open-Angle Glaucoma.

PURPOSE: We sought to investigate the genetic variants associated with the onset and progression of primary open-angle glaucoma (POAG). DESIGN: Case-control genetic association study. METHODS: Japanese POAG patients (n = 505) and control subjects (n = 246) were genotyped for 22 genetic variants predisposing to POAG that can be classified into those associated with intraocular pressure (IOP) elevation (IOP-related genetic variants) and optic nerve vulnerability independent of IOP (non-IOP-related genetic variants). The total number of risk alleles of the 17 IOP-related and 5 non-IOP-related genetic variants were calculated as the genetic risk score (GRS), and the associations between the GRS and family history of glaucoma as an indicator of POAG onset and age at the diagnosis of glaucoma as an indicator of POAG progression were evaluated. RESULTS: There was a significant association (P = .014; odds ratio 1.26 per GRS) between the non-IOP-related GRS, but not IOP-related GRS, and a family history of glaucoma in POAG. As the non-IOP-related GRS increased, the risk of a family history of glaucoma increased. In contrast, a significant association (P = .0014; ß = -0.14) was found between the IOP-related GRS, but not non-IOP-related GRS, and age at the diagnosis of glaucoma. As the IOP-related GRS increased, age at the diagnosis of glaucoma decreased. CONCLUSION: The results indicate that non-IOP-related (optic nerve vulnerability) rather than IOP-related (IOP elevation) genetic variants may play an important role in the onset of POAG (family history of glaucoma) and that IOP-related rather than non-IOP-related genetic variants may play an important role in its progression (age at the diagnosis of glaucoma).

The long-term outcome of trabeculotomy: comparison with filtering surgery in Japan.

BACKGROUND: To investigate the long-term outcome of trabeculotomy and to compare it with that of trabeculectomy. METHODS: We retrospectively reviewed the medical records of patients who had undergone standalone trabeculotomy. Inclusion criteria included a follow-up period of at least 6 years, availability of reliable static visual field results, etc. Age- and preoperative intraocular pressure -matched trabeculectomy cases served as controls. A Kaplan-Meier analysis was employed as a measure of surgical success. Additional clinical factors were also analyzed. RESULTS: Twenty-five eyes of 25 trabeculotomy patients and 20 eyes of 20 trabeculectomy patients with a mean postoperative follow-up period of 8.0 years were selected. The Kaplan-Meier analysis estimated that the success probability defined as intraocular pressure < 16 mmHg was 44.0 ± 9.9% and 75.0 ± 9.7% at 6 years for trabeculotomy and trabeculectomy, respectively. The final mean deviation significantly progressed in trabeculotomy cases in Central 30-2 programs of the Humphrey Field Analyzer (P = 0.025). Patient characteristics and postoperative clinical data were analyzed by Mann-Whitney's U test and Wilcoxon signed-rank test. CONCLUSIONS: While trabeculotomy was inferior to trabeculectomy in terms of intraocular pressure control and visual field stability in our series, surgical indications should always be determined on an individual basis, pending further research.

Postoperative outcome of three different procedures for childhood glaucoma.

PURPOSE: To investigate the long-term postoperative outcome of three surgical procedures for childhood glaucoma. PATIENTS AND METHODS: In this retrospective study, the patients were divided into a goniotomy group, a trabeculotomy group, and a filtering surgery group, based on the initial surgical procedure. Failure was defined as an IOP ≥21 mmHg with medication at two consecutive visits. A Kaplan-Meier analysis was applied to calculate the probability of success. Additional metrics included IOP, number of additional operations, eye drop scores, and visual acuity. RESULTS: We studied 40 eyes of 25 patients, 21 eyes of 15 patients, and 12 eyes of 7 patients in the goniotomy, trabeculotomy, and filtering surgery groups, respectively. The 10- and 20-year probability of success was 65.2% and 65.2%, 42.2% and NA (no data for 20 years), and 91.7% and 80.2% for the goniotomy, trabeculotomy, and filtering surgery groups, respectively. CONCLUSION: All three procedures maintained an IOP of less than 21 mmHg for up to 10 years in 65.2%, 42.2%, and 91.7% of childhood glaucoma cases.

Effect of Timolol on Optineurin Aggregation in Transformed Induced Pluripotent Stem Cells Derived From Patient With Familial Glaucoma.

Purpose: To determine a chemical agent that can reduce the aggregation of optineurin (OPTN) in cells differentiated from induced pluripotent stem cells obtained from a patient with normal-tension glaucoma (NTG) caused by an E50K mutation in the OPTN gene (OPTNE50K-NTG). Methods: Retinal ganglion cells (RGCs) were created from induced pluripotent stem cells derived from a healthy individual (wild-type [WT]-iPSCs) and from a patient with NTG due to OPTNE50K (E50K-iPSCs) mutation. The death of the induced RGCs was evaluated by counting the number of TUNEL- and ATH5-positive cells. Axonal growth was determined by measuring the axonal length of TUJ1-positive cells. OPTN aggregation was assessed by measuring the OPTN-positive area by immunofluorescence and by Western blotting. Autophagic flux assay was investigated by determining the light chain 3 (LC3)B-II/LC3B-I ratio and p62 expression by Western blotting. Results: The results showed OPTNE50K aggregation, activation of astrocytes, reduction in the number of RGCs, and enhancement of apoptotic cell death in the in vitro OPTNE50K model of NTG. Timolol was found to reduce the OPTNE50K-positive area and decreased the insoluble OPTNE50K, suggesting that it has the potential of reducing the OPTNE50K aggregation. Timolol also increased the ATH5-positive cells, decreased TUNEL-positive cells, increased the LC3B-II/LC3B-I ratio, and decreased the expression of p62. These findings suggest that timolol might enhance autophagic flux, leading to reduced OPTNE50K aggregation. Conclusions: Timolol should be considered a potential therapeutic agent specific to OPTNE50K-NTG because it can reduce the OPTNE50K aggregation in E50K-iPSCs-RGCs by enhancing autophagic flux and neuroprotective effects.

Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.

Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7.

PURPOSE: To test the genetic association between Japanese patients with primary open-angle glaucoma (POAG) and the previously reported POAG susceptibility loci and to perform genotype-phenotype analysis. METHODS: Genetic associations for 27 SNPs from 16 loci previously linked to POAG were assessed using genome-wide SNP data of the primary cohort (565 Japanese POAG patients and 1,104 controls). Reproducibility of the assessment was tested in 607 POAG cases and 455 controls (second cohort) with a targeted genotyping approach. For POAG-associated variants, a genotype-phenotype correlation study (additive, dominant, recessive model) was performed using the objective clinical data derived from 598 eyes of 598 POAG patients. RESULTS: Among 27 SNPs from 16 loci previously linked to POAG, genotypes for total of 20 SNPs in 13 loci were available for targeted association study. Among 8 SNPs in 3 loci that showed at least nominal association (P < 5.00E-02) in the primary cohort, a representative SNP for each loci (rs2157719 for CDKN2B-AS1, rs33912345 for SIX6, and rs9913911 for GAS7) were selected. For these SNPs the association was found significant in both the second cohort analysis and meta-analysis. The genotype-phenotype analysis revealed significant correlations between CDKN2B-AS1 (rs2157719) and decreased intraocular pressure (ß = -6.89 mmHg, P = 1.70E-04; dominant model) after multiple corrections. In addition, nominal correlation was observed between CDKN2B-AS1 (rs2157719) and optic nerve head blood flow (ß = -0.54 and -0.67 arbitrary units (AU), P = 2.00E-02 and 1.39E-02), between SIX6 (rs33912345) and decreased total peripapillary retinal nerve fiber layer thickness (ß = -2.16 and -2.82 µm, P = 4.68E-02 and 2.40E-02, additive and recessive model, respectively) and increased optic nerve head blood flow (ß = 0.44 AU, P = 2.20E-02; additive model) and between GAS7 (rs9913911) and increased cup volume (ß = 0.03 mm3, P = 4.60E-02) and mean cup depth (ß = 0.03 mm3, P = 4.11E-02; additive model) and decreased pattern standard deviation (ß = -0.87 dB, P = 2.44E-02; dominant model). CONCLUSION: The association between SNPs near GAS7 and POAG was found in Japanese patients for the first time. Clinical characterization of the risk variants is an important step toward understanding the pathology of the disease and optimizing treatment of patients with POAG.

Genomic Organization of TBK1 Copy Number Variations in Glaucoma Patients.

BACKGROUND: Approximately 1% of normal tension glaucoma (NTG) cases are caused by TANK-binding kinase 1 (TBK1) gene duplications and triplications. However, the precise borders and orientation of these TBK1 gene copy number variations (CNVs) on chromosome 12 are unknown. METHODS: We determined the exact borders of TBK1 CNVs and the orientation of duplicated or triplicated DNA segments in 5 NTG patients with different TBK1 mutations using whole-genome sequencing. RESULTS: Tandemly duplicated chromosome segments spanning the TBK1 gene were detected in 4 NTG patients, each with unique borders. Four of 5 CNVs had borders located within interspersed repetitive DNA sequences (Alu and long interspersed nuclear element-L1 elements), suggesting that mismatched homologous recombinations likely generated these CNVs. A fifth NTG patient had a complex rearrangement including triplication of a chromosome segment spanning the TBK1 gene. CONCLUSIONS: No specific mutation hotspots for TBK1 CNVs were detected, however, interspersed repetitive sequences (ie, Alu elements) were identified at the borders of TBK1 CNVs, which suggest that mismatch of these elements during meiosis may be the mechanism that generated TBK1 gene dosage mutations.

Additive effects of genetic variants associated with intraocular pressure in primary open-angle glaucoma.

To investigate the association between the additive effects of genetic variants associated with intraocular pressure (IOP) and IOP, vertical cup-to-disc ratio (VCDR), and high tension glaucoma (HTG) or normal tension glaucoma (NTG) as phenotypic features of primary open-angle glaucoma (POAG), and to evaluate the clinical usefulness of the additive effects of IOP-related genetic variants for predicting IOP elevation, Japanese patients with HTG (n = 255) and NTG (n = 261) and 246 control subjects were genotyped for nine IOP-related genetic variants near CAV2, GAS7, GLCCI1/ICA1, ABCA1, ARHGEF12, FAM125B, FNDC3B, ABO, and PTPRJ/AGBL2. The total number of risk alleles of these genetic variants was calculated for each participant as a genetic risk score (GRS), and the association between the GRS and the maximum IOP, mean VCDR, and phenotype (HTG or NTG) of POAG was evaluated. As the GRS increased, the maximum IOP (P = 0.012) and VCDR (P = 0.010) significantly increased. The GRS (9.1±1.9) in patients with HTG was significantly higher (P = 0.011) than that (8.7±1.8) in control subjects. The patients with GRS≥12 as a cut-off value had a 2.54 times higher (P = 0.0085) risk on HTG (maximum IOP≥22mmHg) compared with all patients. The IOP-related GRS approach substantiated that the IOP and VCDR were increased by the additive effects of IOP-related genetic variants in POAG. The high IOP-related GRS in patients with HTG but not NTG shows that there are differences in the genetic background between HTG and NTG and supports the notion that the phenotype (HTG or NTG) in patients with POAG depends on the additive effects of IOP-related genetic variants. The above-mentioned cut-off value of IOP-related GRS may be clinically useful for predicting the risk of IOP elevation.

Apolipoprotein E2 and E3, but Not E4, Promote Retinal Pathologic Neovascularization.

Purpose: To determine the relationship between the different isoforms of apolipoprotein E (ApoE) and retinal neovascularization. Methods: The concentrations of ApoE and VEGF in vitreous humor samples with either a macular hole (MH), or diabetic macular edema (DME), or proliferative diabetic retinopathy (PDR) with or without intravitreal injection of bevacizumab (IVB) were measured by ELISA. The effects of each isoform of ApoE on human retinal microvascular endothelial cells (HRMECs) in culture or on the retina of oxygen-induced retinopathy (OIR) mice were investigated. Results: The concentrations of ApoE and VEGF were significantly higher in the vitreous humor of patients with PDR and DME than in patients with an MH. There was a significant positive correlation between the concentrations of ApoE and VEGF in vitreous humor of patients. In vitro assays showed that ApoE2 and ApoE3, but not ApoE4, promoted the VEGF-induced cell proliferation and migration. In vivo assays showed that intravitreal injections of ApoE2 and ApoE3 increased the number and area of nodes in the retina of OIR mice. Moreover, ApoE was expressed in the vascular endothelial cell in both normal and OIR retinas, but their expression levels were different at postnatal day (P) 12 and P17. Conclusions: These results demonstrate that ApoE2 and ApoE3, but not ApoE4, have proangiogenic effects, and the increased expression of ApoE in the vitreous humor of patients with PDR and DME indicates that ApoE2 and ApoE3 are involved in the development of retinal neovascularization in eyes.

Significance of optineurin mutations in glaucoma and other diseases.

Glaucoma is one of the leading causes of bilateral blindness, affecting nearly 57 million people worldwide. Glaucoma is characterized by a progressive loss of retinal ganglion cells and is often associated with intraocular pressure (IOP). Normal tension glaucoma (NTG), marked by normal IOP but progressive glaucoma, is incompletely understood. In 2002, Sarfarazi et al. identified FIP-2 gene mutations responsible for hereditary NTG, renaming this gene "optineurin" (OPTN). Further investigations by multiple groups worldwide showed that OPTN is involved in several critical cellular functions, such as NF-κB regulation, autophagy, and vesicle transport. Recently, OPTN mutations were found to cause amyotrophic lateral sclerosis (ALS). Surprisingly, a mutation in the OPTN interacting protein, i.e., the duplication of TANK binding protein 1 (TBK1) gene, also can cause both NTG and ALS. These phenotypically distinct neuronal diseases are now merging into one common pathological mechanism by these two genes. TBK1 inhibition has emerged as a potential therapy for NTG. In this manuscript, we focus on the OPTN E50K mutation, the most common mutation for NTG, to describe the molecular mechanism of NTG by expressing a mutant Optn gene in cells and genetically modified mice. Patient iPS cells were developed and differentiated into neural cells to observe abnormal behavior and the impact of the E50K mutation. These in vitro studies were further extended to identify the inhibitors BX795 and amlexanox, which have the potential to reverse the disease-causing phenomenon in patient's neural cells. Here we show for the first time that amlexanox protects RGCs in Optn E50K knock-in mice.

Non-Descemet Stripping Automated Endothelial Keratoplasty for Bullous Keratopathy in Buphthalmic Eye.

PURPOSE: To report the 2-year follow-up findings in a patient with buphthalmic bullous keratopathy (BK) who was successfully treated with non-Descemet stripping automated endothelial keratoplasty (nDSAEK). METHODS: A 39-year-old man had an endothelial graft of 8.0 mm diameter placed uneventfully using the nDSAEK method for phakic BK with buphthalmos of the left eye. He had had a penetrating keratoplasty in the right eye due to aphakic BK 5 years earlier, which, however, resulted in the invasion of blood vessels and graft failure. Since the left eye was phakic, Descemetorhexis was not performed because the instruments might touch the crystalline lens. The best-corrected visual acuity (BCVA), intraocular pressure (IOP), and endothelial cell density (ECD) were determined at 2 weeks, and at 1, 3, 6, 12, 18 and 24 months after nDSAEK. RESULTS: Twenty-four months after nDSAEK, his left cornea and lens remained clear, and the decimal BCVA was 0.8. However, the ECD of the graft had decreased from 2,274 cells/mm(2) before nDSAEK to 539 cells/mm(2) 24 months after the surgery, and the rate of decrease appeared to be slightly faster than that of former reports. An IOP of $1003e;30 mm Hg was recorded at around 2 months after the surgery, but was well controlled by tapering the topical steroids and the addition of topical brinzolamide and latanoprost. CONCLUSION: Our findings show that nDSAEK can be successfully used to treat buphthalmic BK. We recommend that nDSAEK be considered especially in phakic eyes with a smooth posterior surface around the pupillary area.

Long-term Safety and Efficacy of Latanoprostene Bunod 0.024% in Japanese Subjects with Open-Angle Glaucoma or Ocular Hypertension: The JUPITER Study.

INTRODUCTION: Latanoprostene bunod (LBN) is a novel nitric oxide (NO)-donating prostaglandin F2α analog. We evaluated the long-term safety and intraocular pressure (IOP)-lowering efficacy of LBN ophthalmic solution 0.024% over 1 year in Japanese subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). METHODS: This was a single-arm, multicenter, open-label, clinical study. Subjects aged 20 years and older with a diagnosis of OAG or OHT instilled 1 drop of LBN ophthalmic solution 0.024% in the affected eye(s) once daily in the evening for 52 weeks and were evaluated every 4 weeks. Safety assessments included vital signs, comprehensive ophthalmic exams, and treatment-emergent adverse events (AEs). Absolute and percent reductions from baseline in IOP were also determined. RESULTS: Of 130 subjects enrolled, 121 (93.1%) completed the study. Mean age was 62.5 years, and mean (standard deviation) baseline IOP was 19.6 (2.9) and 18.7 (2.6) mmHg in study eyes and treated fellow eyes, respectively. Overall, 76/130 (58.5%) and 78/126 (61.9%) subjects experienced ≥1 AEs in study eyes and treated fellow eyes, respectively. In both study eyes and treated fellow eyes, the most common AEs were conjunctival hyperemia, growth of eyelashes, eye irritation, and eye pain. At 52 weeks, 9% of treated eyes had an increase in iris pigmentation compared with baseline based on iris photographs. No safety concerns emerged based on vital signs or other ocular assessments. Mean reductions from baseline in IOP of 22.0% and 19.5% were achieved by week 4 in study and treated fellow eyes, respectively. These reductions were maintained through week 52 (P < 0.001 vs. baseline at all visits). CONCLUSION: Once daily LBN ophthalmic solution 0.024% was safe and well-tolerated in Japanese subjects with OAG or OHT when used for up to 1 year. Long-term treatment with LBN ophthalmic solution 0.024% provided significant and sustained IOP reduction. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01895972. FUNDING: Bausch & Lomb, Inc. a division of Valeant Pharmaceuticals International Inc.

SLC1A1 Gene Variants and Normal Tension Glaucoma: An Association Study.

BACKGROUND: It has been hypothesized that dysfunction of the solute carrier family 1, member1 gene (SLC1A1), which encodes the glutamate aspartate transporter, may play a role in normal tension glaucoma. In this study we investigate whether SLC1A1 is associated with normal tension glaucoma in Japanese patients. METHODS: A total of 292 Japanese patients with normal tension glaucoma and 500 healthy control subjects were recruited. We genotyped 12 single-nucleotide polymorphisms in SLC1A1. We also performed an imputation analysis to evaluate the potential association of un-genotyped SLC1A1 single-nucleotide polymorphisms, and 165 single-nucleotide polymorphisms were imputed. RESULTS: We observed an increased frequency of the G allele of rs10739062 in patients compared to controls (p = 0.043, OR = 1.25). The rs10739062 polymorphism exhibited a dominant effect: individuals with genotype GG and GC showed a 1.91-fold increase in risk compared to genotype CC (p = 0.0082). However, the statistical significance disappeared after Bonferroni correction for multiple testing (pc > 0.05). We did not find any significant association between any of the remaining 176 single-nucleotide polymorphisms and disease risk. CONCLUSIONS: Our study showed a lack of association between SLC1A1 variants and normal tension glaucoma in Japanese patients, suggesting that the SLC1A1 gene does not play a critical role in the development of the disorder in this patient population. However, further genetic studies with larger sample sizes are needed to clarify whether SLC1A1 may make some contribution that affects the risk of developing normal tension glaucoma.

Development of Glaucomatous Visual Field Defects in Preperimetric Glaucoma Patients Within 3 Years of Diagnosis.

PURPOSE: To determine the characteristics of eyes diagnosed with preperimetric glaucoma (PPG) that developed glaucomatous visual field defects (VFDs) within 3 years of the diagnosis. PATIENTS AND METHODS: The medical charts of 77 eyes of 77 patients with PPG were reviewed. An eye was diagnosed with PPG when there was neuroretinal rim thinning, cupping of the optic disc, or a suspicious retinal nerve fiber layer (RNFL) defect, and had no conditions fulfilling Anderson's criteria for glaucoma. The Central 30-2 SITA-Standard program of the Humphrey Field Analyzer was used to determine the presence of VFDs and the thicknesses of the retinal layers was determined by spectral-domain optical coherence tomography. RESULTS: Ten of the 77 patients with PPG (13.0%) developed glaucomatous VFD. These 10 eyes had significantly thinner macular ganglion cell and inner plexiform layer (mGCIPL) thickness in the inferior and inferotemporal sectors, and also the circumpapillary retinal nerve fiber layer (cpRNFL) thickness at the 7 or 8 o'clock sectors. In the 3 years post-PPG period, these eyes had significant decreases in the mGCIPL thickness of all the inferior sectors, and cpRNFL at the 7 or 8 o'clock sectors. The mean intraocular pressure in eyes with VFDs (15.2±2.0 mm Hg) was significantly higher than that in those without VFDs (13.5±2.6 mm Hg; P=0.042). CONCLUSIONS: Significant structural changes were observed in the mGCIPL and cpRNFL at PPG diagnosis, before the development of a VFDs. Close monitoring of intraocular pressure is essential for the appropriate management of PPG.

Current Status of Glaucoma-related Data Management and Efforts toward Data Standardization.

Purpose: ï¼·e conducted a survey to evaluate the current status of glaucoma-related medical data management and standardization, aiming to improve the development of glaucoma care and research in Japan. Materials and methods: The survey was performed as a paper-based questionnaire of 14 universities that both participate in the glaucoma-related data standardization committee, established by the Japan Glaucoma Society in 2014, and actively perform glaucoma care. Results: All enrolled university hospitals installed an electronic hospital information system and used any of three ophthalmology-limited electronic chart systems. However, only 30.8% of the hospitals established a data extraction system from an electronic medical chart system, and only 14.3% could practically apply medical data for secondary research purposes. In all, 35.7% of the hospitals operate a medical cooperation system with local medical institutions and 42.9% electronically managed medical data inside their departments. Conclusion: This survey clarified the current state of medical data management and standardization.

TBK1 gene duplication and normal-tension glaucoma.

IMPORTANCE: Normal-tension glaucoma (NTG) is a common cause of vision loss. OBJECTIVE: To investigate the role of TANK binding kinase 1 (TBK1) gene duplications in NTG to gain insights into the causes of glaucoma that occurs at low intraocular pressure (IOP). DESIGN, SETTING, AND PARTICIPANTS: In this multicenter case-control study, we investigated patients who met the criteria for NTG, including glaucomatous optic neuropathy, visual field defects, and maximum recorded untreated IOP of 21 mm Hg or less, and matched controls. Participants (N = 755) were recruited from Southampton, United Kingdom (180 patients and 178 controls), Rochester, Minnesota (65 patients and 12 controls), New York, New York (96 patients and 16 controls), and Iowa City, Iowa (208 controls). MAIN OUTCOMES AND MEASURES: Detection of TBK1 gene duplications and comparison of the extent of the identified DNA that is duplicated with prior TBK1 copy number variations associated with NTG. RESULTS: A TBK1 gene duplication was detected in 1 of 96 patients (1.0%) from New York and none of the controls. Analysis of duplication borders with comparative genome hybridization demonstrated that this patient has a novel duplication that has not been previously reported. No gene duplications were detected in any of the other cohorts of patients or controls. CONCLUSIONS AND RELEVANCE: Duplication of the TBK1 gene is a rare cause of NTG. The identification of another case of NTG attributed to TBK1 gene duplication strengthens the case that this mutation causes glaucoma.