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Introduction: Multidrug regimens for glaucoma treatment often result in adherence issues due to inconvenience; these issues may be improved with fixed-dose combination drugs. The ophthalmic solution of ripasudil-brimonidine fixed-dose combination (RBFC; K-232) is the first treatment combining a Rho kinase inhibitor and an α 2 -adrenoceptor agonist, and has demonstrated ability to lower intraocular pressure (IOP) and have various effects on conjunctival hyperemia and corneal endothelial cell morphology. This study evaluates the pharmacologic effects of RBFC treatment versus its separate components-ripasudil or brimonidine., Methods: This single-center, prospective, randomized, open-label, blinded endpoint study with 3 × 3 crossover design randomly assigned healthy adult men to three groups (1:1:1) to undergo consecutive 8-day administration phases (with drug-free intervals of at least 5 days). Subjects received twice-daily instillation of RBFC → ripasudil → brimonidine (group A), ripasudil → brimonidine → RBFC (group B), or brimonidine → RBFC → ripasudil (group C). Endpoints included change in IOP, severity of conjunctival hyperemia, corneal endothelial cell morphology, pupil diameter, and pharmacokinetics., Results: Eighteen subjects were assigned in total (six to each group). RBFC significantly reduced IOP from baseline at 1 h post-instillation on days 1 and 8 (12.7 vs. 9.1 and 9.0 mmHg, respectively; both P < 0.001), and provided significantly greater IOP reductions than ripasudil or brimonidine at several time points. The most common adverse drug reaction with all three treatments was mild conjunctival hyperemia, which transiently increased in severity with RBFC or ripasudil, peaking at 15 min post-instillation. In post hoc analyses, conjunctival hyperemia scores were lower with RBFC than with ripasudil at several time points. Transient morphologic changes in corneal endothelial cells occurred for up to several hours with RBFC or ripasudil, but not with brimonidine. Pupil diameter did not change with RBFC., Conclusion: RBFC significantly reduced IOP compared with each agent alone. A combination of each agent's pharmacologic profile was observed in that of RBFC., Trial Registration: Japan Registry of Clinical Trials; Registration No. jRCT2080225220., (© 2023. The Author(s).)

Purpose: To confirm the superiority of the intraocular pressure (IOP)-lowering effect of the ripasudil-brimonidine fixed-dose combination (RBFC, K-232) to ripasudil 0.4% or brimonidine 0.1% ophthalmic solution., Design: Two prospective multicenter, randomized, double- or single-masked, active-controlled, phase 3 trials., Methods: Patients with primary open-angle glaucoma or ocular hypertension whose IOP level was ≥18 mm Hg during treatment with ripasudil or brimonidine alone were randomized to 2 groups (RBFC and ripasudil) in a 1:1 ratio in the ripasudil-controlled trial and to 3 groups (RBFC, brimonidine, and ripasudil-brimonidine combination) in a 2:2:1 ratio in the brimonidine-controlled trial. The allocated study drugs were instilled twice daily for 8 weeks. The primary efficacy endpoint was the change in IOP 2 hours after instillation (11 AM) from the baseline to weeks 4, 6, and 8., Results: There were 206 patients randomized in the ripasudil-controlled trial. Changes in IOP were -2.6 and -1.2 mm Hg in the RBFC and ripasudil groups, respectively, with a difference of -1.4 mm Hg (95% CI = -1.8 to -1.0 mm Hg; P < .001). There were 282 randomized patients in the brimonidine-controlled trial. Changes in IOP were -3.4 and -1.5 mm Hg in the RBFC and brimonidine groups, respectively, with a difference of -1.8 mm Hg (95% CI = -2.3 to -1.4 mm Hg; P < .001). The most frequent adverse event was conjunctival hyperemia., Conclusions: The IOP-lowering effect of RBFC was superior to that of ripasudil or brimonidine., (Copyright © 2022. Published by Elsevier Inc.)

Background: The nasal to temporal amplitudes ratio (N/T) of multifocal electroretinography (mfERG) scans measured within 5° of the macula can be used to detect glaucomatous change. The photopic negative response (PhNR) of mfERG elicited by a circular stimulus centered on the fovea was significantly reduced in eyes with glaucoma. The PhNR to B-wave ratio (PhNR/B) is the optimal measure of the PhNR. However, clinical superiority for evaluating glaucoma patients has not been determined between N/T and PhNR/B yet., Methods: For morphological assessments, ganglion cell complex (GCC) in six regions and the average were measured by optical coherence tomography (OCT). For functional assessment, Humphrey visual fields (VF) with mean sensitivities (MT) and mfERG scans with parameters of N/T and the multifocal photopic negative response to B-wave ratio (mfPhNR/B) were measured. Sixty-nine eyes of 44 glaucoma patients were included and correlations between mfERG parameters and OCT or VF parameters were evaluated., Results: The mean age of patients was 59.4 years. The mean deviation for all eyes obtained with the VF 30-2 and VF 10-2 was - 7.00 and - 6.31 dB, respectively. Significant correlations between GCC thickness or VF parameter and the N/T were found, especially in the inferior and inforotemporal retinal areas corresponding to superior and superonasal VF sectors (GCC vs N/T; coefficient = - 7.916 and - 7.857, and MT vs N/T; coefficient = - 4.302 and - 4.437, in the inferior and inforotemporal retinal areas, respectively, all p values < 0.05). However, similar associations were not obtained between mfPhNR/B and OCT or VF parameters. The mfPhNR/B only in the inferotemporal sector was significantly correlated with the average thickness of GCC (coefficient = 4.823, P = 0.012)., Conclusions: The N/T was correlated with GCC and VF in more numbers of measurement areas than the mfPhNR/B in the current study, however, a future study modifying the stimuli and amplitudes to obtain the spatial correspondence to OCT and VF measurement will be required to evaluate the value of mfERG., (© 2021. The Author(s).)

Purpose: To investigate localization in glaucomatous visual field defects that are vulnerable to posture-induced intraocular pressure (IOP) changes., Design: Prospective cross-sectional study., Methods: Ninety-three eyes of 93 newly diagnosed cases with normal tension glaucoma were examined. The IOP was measured in both the sitting and lateral decubitus positions with an Icare rebound tonometer. Visual field tests were performed with a Humphrey Field Analyzer with the Central 30-2 program using Swedish Interactive Threshold Algorithm standard strategies. The total deviation (TD) map values of 51 tested points were used for the analysis. A regression analysis was conducted to investigate relationships between TD in each point or cluster and posture-induced IOP changes. A linear mixed-effects model was used to identify factors associated with TD changes in each visual field cluster. Main outcome measures included the relationship between posture-induced IOP changes and localization of visual field defects., Results: There were 54 women and 39 men (mean age, 53.4 ± 12.5 years). The mean IOP per Icare rebound tonometer was 15.5 ± 3.2 mm Hg in the sitting position and 18.8 ± 3.1 mm Hg in the lateral decubitus position. The postural IOP difference was 3.3 ± 1.8 mm Hg (P < .001; range, -1.0 to 7.7 mm Hg). There was a significant negative correlation between TD and posture-induced IOP changes in 4 contiguous central points located just above the horizontal meridian. A linear mixed-effects model revealed a significant association between the difference in postural IOP change and decreased TD in the superior paracentral visual field according to multivariate analysis (P = .010)., Conclusions: Posture-induced IOP variations have been shown to be associated with glaucomatous superior paracentral visual field defects., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To study the frequencies and factors associated with 4 disc patterns in primary open-angle glaucoma (POAG) identified in population-based studies: focal glaucomatous (FG type), generalized enlargement of cup (GE type), myopic glaucomatous (MG type), and senile sclerotic glaucomatous (SS type) patterns., Subjects: In total, 270 disc photographs of acceptable quality were extracted from the records of 270 definitive POAG cases diagnosed according to the International Society of Geographical and Epidemiological Ophthalmology Criteria in 2 Japanese population-based glaucoma surveys. One randomly chosen eye from the bilateral POAG cases was included., Results: Using a method of κ coefficient of reproducibility of classification of 0.80 according to a preliminary study, 143 discs were classified as FG, GE, MG, or SS types with respective frequencies of 57% (95% confidence interval [CI], 48-66), 33% (95% CI, 25-42), 7% (95% CI, 3-13), and 3% (95% CI, 0-7), and 127 discs as the miscellaneous type. Multinomial logistic regression analysis showed that the MG type was associated (P=0.052, 0.025, 0.019, and 0.018) with younger age, lower body mass index (BMI), and greater disc area and ovality, and the GE type was associated (P<0.001, 0.036, and 0.056) with greater disc area, corneal radius, and hyperopic refraction than the FG type., Conclusions: The FG type occurs most frequently in Japanese POAG followed by the GE type. The MG and SS types occurred much less often than previously reported in Japanese. Associations with age, BMI, disc area and ovality, refraction, and corneal radius differed among the FG, GE, and MG types.

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.

Purpose: To compare changes in the macular ganglion cell layer and inner plexiform layer (mGCIPL) thickness over 5 years between surgically treated eyes (STE) and medically treated eyes (MTE) with advanced glaucoma., Design: Retrospective, comparative case series., Methods: Eighty-six patients comprising 43 with open-angle glaucoma (OAG) with trabeculectomy and 43 with medically treated OAG. The mGCIPL thickness was measured more than 5 times during follow-up by optical coherence tomography. Main outcome measure was differences in mGCIPL thickness thinning rate between the groups., Results: The mean age at study initiation was 62.5 ± 9.2 years in STE and 62.7 ± 9.5 years in MTE. The mean deviations (MD), according to the Humphrey Field Analyzer central program 30-2, and the mGCIPL thickness in each sector showed no significant differences at initial measurement. The averaged intraocular pressure (IOP) throughout follow-up was 10.5 ± 2.0 mm Hg in STE and 10.8 ± 0.8 mm Hg in MTE (P = .429; Mann-Whitney U test). There was no significant difference in the MD changes over 5 years between the 2 groups (P = .405; Mann-Whitney U test). Changes in the mGCIPL thickness over 5 years in MTE were significantly greater than that in STE in all sectors (all 6 sectors P < .0001, Mann-Whitney U test). The IOP fluctuation over 5 years in STE was significantly less than that in MTE (P < .0001, Mann-Whitney U test)., Conclusions: The structure of the mGCIPL was better preserved in STE than in MTE, even when the IOPs during follow-up were similar., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the effect of filtering surgery using the EX-PRESS device on intraocular pressure (IOP), flare count, anterior chamber (AC) depth, and the corneal endothelium in primary open-angle glaucoma (POAG), including normal-tension glaucoma (NTG)., Patients and Methods: The study comprised 63 consecutive patients with POAG or NTG. They underwent complete ophthalmologic examinations, including measurement of visual acuity (VA), IOP, flare count, AC depth, and cell density of the corneal endothelium (CE). Two outcomes were used for surgical success: outcome 1 was defined as a ≥20% reduction in the IOP from the preoperative value, with an IOP ≥ 5 mmHg but ≤18 mmHg, and outcome 2 was defined as a ≥20% reduction in the IOP, with an IOP ≥ 5 mmHg but ≤15 mmHg., Results: The IOP significantly decreased from 17.7 preoperatively to 12.4 mmHg postoperatively (P < 0.0001). The success rates for outcome 1 at 24 months were 81.3 and 46.7% for POAG and NTG, respectively (P = 0.0065); the corresponding success rates for outcome 2 were 79.4 and 46.7% (P = 0.0120). The flare count significantly increased on postoperative day 1 (P = 0.0002) but recovered to insignificant levels by day 3 (P = 0.0686). A transient decrease in AC depth was observed by 4 weeks after surgery (P = 0.0017). The CE changed from 2529 preoperatively to 2428/mm 2 at 24 months (P = 0.0089)., Conclusion: The advantage of filtering surgery using the EX-PRESS device includes reduced inflammation, and the disadvantages include loss of the CE and reduced effectiveness of NTG.

Purpose: To assess the intraocular pressure (IOP)-lowering effects and safety of a carteolol/latanoprost fixed combination drug (OPC-1085EL) vs latanoprost (Study 1) and carteolol (Study 2) in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH)., Design: Multicenter, randomized, evaluator-masked (Study 1)/double-masked (Study 2), parallel-group studies., Methods: Setting: Twenty-eight clinical sites (Study 1) and 19 clinical sites (Study 2) in Japan., Study Population: Outpatients with bilateral POAG or OH whose predose IOP was 18 to <35 mm Hg in the study eye after 4 weeks' treatment with latanoprost (Study 1) or carteolol (Study 2) (defined as baseline)., Intervention: In Study 1, 237 patients applied OPC-1085EL (n = 118) or latanoprost (n = 119) for 8 weeks. In Study 2, 193 patients applied OPC-1085EL (n = 78), carteolol (n = 78), or carteolol/latanoprost concomitant therapy (n = 37) for 8 weeks., Main Outcome Measure: Adjusted mean IOP reduction at predose from baseline to week 8., Results: In Study 1, the adjusted mean IOP reductions (95% confidence interval [CI]) were 2.9 (2.5-3.3) mm Hg and 1.6 (1.2-2.0) mm Hg in the OPC-1085EL and latanoprost groups, respectively (P < .0001). In Study 2, the adjusted mean IOP reductions (95% CI) were 3.5 (3.1-3.9) mm Hg and 1.6 (1.2-2.0) mm Hg in the OPC-1085EL and carteolol groups, respectively (P < .0001). All adverse drug reactions of OPC-1085EL observed in both studies were mild in severity and only 1 patient in each study discontinued because of an adverse drug reaction., Conclusions: OPC-1085EL is superior to latanoprost or carteolol alone in terms of lowering IOP, and was well tolerated., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To compare surgical outcomes between the first and second operated eyes in patients who underwent trabeculectomy in both eyes., Methods: This retrospective clinical cohort study at five clinical centers in Japan included 84 patients with open-angle glaucoma who underwent primary trabeculectomy in both eyes. The primary outcome was surgical success or failure, with failure being defined according to three criteria: <20% reduction of the preoperative intraocular pressure (IOP), or Criterion A, IOP >21 mmHg; Criterion B, IOP >18 mmHg; or Criterion C, IOP >15 mmHg. Cases of reoperation, a loss of light perception vision, or hypotony were also considered as "failures"., Results: There were no significant differences in success rate for any of the three criteria between the first and second operated eyes. For patients whose first trabeculectomy was successful, when the second trabeculectomy was performed ≥2 months after the first, the survival curves for all three criteria for the second trabeculectomy were significantly worse than those for patients waiting a shorter interval between trabeculectomies (Criterion A, 52.0% vs 83.6%, P = 0.0031; Criterion B, 51.5% vs 80.4%, P = 0.026; Criterion C, 51.1% vs 80.4%, P = 0.048). In multivariable analyses, a longer interval between trabeculectomies was a significant prognostic factor for surgical failure (Criterion A, P = 0.0055; Criterion B, P = 0.0023; Criterion C, P = 0.027). However, no dependency on the interval between trabeculectomies was found among patients whose first trabeculectomy failed., Conclusions: If the first trabeculectomy is successful, a long interval before the second trabeculectomy increases the risk of surgical failure in the second eye. This result has clinical implications for developing surgical strategies for patients with bilateral glaucoma., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To investigate the intra-ocular pressure (IOP)-lowering effects and safety of 0.4% ripasudil (K-115), a Rho kinase inhibitor, twice daily for 52 weeks, in patients with open-angle glaucoma or ocular hypertension (OHT)., Methods: In this multicentre, prospective, open-label study, 388 patients with primary open-angle glaucoma, OHT or exfoliation glaucoma were enrolled and 354 of them were subdivided into four cohorts (monotherapy, 173; additive therapy to prostaglandin analogs, 62; β-blockers, 60; or fixed combination drugs, 59). The IOP reduction at trough and peak from baseline and adverse events was investigated., Results: Ripasudil showed IOP-lowering effects over 52 weeks in all the analyses of monotherapy, additive therapy and both subgroups (baseline IOP ≥21 mmHg and <21 mmHg) of monotherapy. The mean IOP reductions at trough and peak at week 52 were -2.6 and -3.7 mmHg for monotherapy, and -1.4 and -2.4, -2.2 and -3.0, and -1.7 and -1.7 mmHg, respectively, for additive therapy described above. The most frequently observed adverse events were conjunctival hyperaemia (n = 264, 74.6%), blepharitis (n = 73, 20.6%) and allergic conjunctivitis (n = 61, 17.2%). Most of the conjunctival hyperaemia findings were mild (97.0%), transient and resolved spontaneously (78.0%). Although 51 patients discontinued from the study due to blepharitis and/or allergic conjunctivitis (blepharitis, 28; allergic conjunctivitis, 17; both, 6), all the events resolved with or without treatment after the discontinuation of ripasudil administration., Conclusion: Fifty-two week administration of 0.4% ripasudil revealed IOP-lowering effects and an acceptable safety profile when administered as monotherapy or as additive therapy, in patients with open-angle glaucoma or OHT., (© 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To verify, by use of data collected by the Japan Glaucoma Society Survey of Bleb-related Infection (JGSSBI), that bleb morphology changes within 12 months of the development of bleb-related infection., Methods: JGSSBI data from 57 eyes of 57 patients with primary open-angle glaucoma and normal tension glaucoma who developed a bleb-related infection were analyzed. Morphological features of the blebs were graded by use of a predetermined grading system. Multiple logistic regression analysis was conducted to identify factors relating to bleb morphology which were associated with poor outcome., Results: Bleb sizes, including both circumferential and tangential lengths, were significantly smaller for stage IIIa/IIIb infections than for stage I/II bleb infections (P = 0.009 and P = 0.026 for the circumferential and tangential lengths, respectively; Fisher's direct probability test). The bleb wall also became significantly thicker during stage IIIa/IIIb infections (P = 0.003). After infection, intraocular pressure (IOP) increased significantly for all cases but was no different in the three subgroups (i.e. stage I, stage II, and stage IIIa/IIIb bleb infections). Multiple logistic regression analysis revealed that a stage III infection was significantly associated with a poor outcome for the bleb., Conclusions: This study revealed that the filtering bleb became smaller, both tangentially and circumferentially, and thicker, after stage III infections than after stage I or II infections.

Importance: Ripasudil hydrochloride hydrate (K-115), a novel rho kinase inhibitor, provides statistically significant intraocular pressure (IOP)-lowering effects and has a tolerable safety profile. However, no studies have evaluated ripasudil combined with β-blockers and prostaglandin analogues., Objective: To evaluate the additive IOP-lowering effects and the safety of ripasudil, 0.4%, combined with timolol, 0.5%, or latanoprost, 0.005%, in patients with primary open-angle glaucoma or ocular hypertension., Design, Setting, and Participants: We conducted 2, multicenter, randomized, double-masked, parallel group comparison studies of ripasudil-timolol and ripasudil-latanoprost in 29 and 36 Japanese clinical centers, respectively. Analyses were performed on an intention-treat-treat basis. After appropriate run-in periods with timolol or latanoprost, 208 and 205 patients whose IOP levels were 18 mm Hg or higher were enrolled in the ripasudil-timolol and ripasudil-latanoprost groups, respectively. Enrollment began December 1, 2011, and follow-up was completed on September 7, 2012, in the ripasudil-timolol study. Enrollment began December 1, 2011, and follow-up was completed on September 27, 2012, in the ripasudil-latanoprost study., Interventions: Patients were subdivided into 2 groups in each study and were treated with ripasudil or placebo twice daily for 8 weeks., Main Outcomes and Measures: The IOP reductions in the ripasudil and placebo groups were analyzed with a repeated-measures analysis of variance model at weeks 4, 6, and 8, at trough (before instillation [9 am]) and peak (2 hours after instillation [11 am]) levels., Results: In the ripasudil-timolol study, the mean IOP reductions from baseline in the ripasudil and placebo groups were -2.4 and -1.5 mm Hg at 9 am for a difference of 0.9 mm Hg (95% CI, 0.4-1.3 mm Hg; P < .001) and -2.9 and -1.3 mm Hg at 11 am for a difference of 1.6 mm Hg (95% CI, 1.1-2.1 mm Hg; P < .001), respectively. In the ripasudil-latanoprost study, those IOP reductions were -2.2 and -1.8 mm Hg at 9 am for a difference of 0.4 mm Hg (95% CI, -0.0 to 0.9 mm Hg; P = .06) and -3.2 and -1.8 mm Hg at 11 am for a difference of 1.4 mm Hg (95% CI, 0.9-1.9 mm Hg; P < .001), respectively. The most frequently reported adverse event was conjunctival hyperemia, which was mild and in most cases resolved without treatment before the next instillation., Conclusions and Relevance: These clinical trials found additive IOP-lowering effects of ripasudil from placebo at trough and peak levels in combination with timolol and at peak level in combination with latanoprost. However, a definitive difference in the addition of placebo to latanoprost was not identified in the trough level., Trial Registration: clinicaltrials.jp Identifiers: JAPIC111700 and JAPIC111701.

Purpose: To investigate the intra-ocular pressure (IOP)-lowering effects of a selective Rho kinase inhibitor, ripasudil (K-115), over 24 hr in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT)., Methods: In this multicenter, prospective, randomized, open-label, 3-period, Latin-square crossover clinical study, 28 patients with POAG or OHT whose IOP level was 21 mmHg or higher were subdivided into three groups. Each patient was treated with placebo and ripasudil in concentrations of 0.2 and 0.4%, at 9:00 and 21:00 on day 1 through a total of 3 periods separated by washout periods. IOP was measured at 9:00, 10:00, 11:00, 13:00, 16:00, 19:00, 21:00, 22:00 and 23:00 on day 1, and 1:00, 4:00, 7:00 and 9:00 on day 2 in sitting position using Goldmann applanation tonometer. Main outcome measure was the IOP reduction of placebo and ripasudil from baseline., Results: The mean IOP reduction was -5.2 mmHg for 0.2%, -6.4 mmHg for 0.4% and -2.0 mmHg for placebo at 2 hr after the first instillation. Also, the corresponding values were -6.8 mmHg for 0.2%, -7.3 mmHg for 0.4% and -4.1 mmHg for placebo at 2 hr after the second instillation. Statistically significant IOP reduction, compared with placebo, was found for both 0.2 and 0.4% from 1 through 7 hr after each instillation. In safety, conjunctival hyperaemia was observed in 22 patients (79%) for 0.2%, 27 patients (96%) for 0.4% and three patients (11%) for placebo., Conclusion: Ripasudil is a promising new topical medication to lower IOP for at least 7 hr after instillations in patients with POAG or OHT., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To estimate the risk of blindness following bleb-related infection after trabeculectomy with mitomycin C in open angle glaucoma, utilizing data obtained from two prospective multicenter studies., Methods: The incidence of bleb-related infection in open angle glaucoma after the first or second glaucoma surgery was calculated using a Kaplan-Meier analysis and data from the Collaborative Bleb-related Infection Incidence and Treatment Study (CBIITS). The rate of blindness following bleb-related infection was calculated using data from the Japan Glaucoma Society Survey of Bleb-related Infection (JGSSBI). Finally, the rate of blindness following bleb-related infection after filtering surgery was estimated based on the above two data sets. Blindness was defined as an eye with a visual acuity of 0.04 or less., Results: The incidences of development of bleb-related infection at 5 years were 2.6 ± 0.7 % (calculated cumulative incidence ± standard error) for all infections and 0.9 ± 0.4 % for endophthalmitis in all cases in the CBIITS data. The rates of blindness in the JGSSBI data were 14 % for the total cases with bleb-related infection and 30 % for the endophthalmitis subgroup. The rate of blindness developing within 5 years following trabeculectomy was estimated to be approximately 0.24-0.36 %., Conclusions: The rate of blindness following bleb-related infection within 5 years after trabeculectomy is considerable and thus careful consideration must be given to the indication for trabeculectomy and the selection of surgical techniques.

Purpose: Intraocular pressure (IOP)-lowering effects of 0.03 % bimatoprost in eyes with open angle glaucoma (OAG) was compared with that of 0.005 % latanoprost., Methods: Thirty-one patients with OAG who had received three kinds of ocular hypotensive agents (latanoprost, beta-blocker, and topical carbonic anhydrase inhibitor) were included in this study. In these patients, bimatoprost was administered for 8 weeks after switching from latanoprost. The IOP was measured with a goldmann applanation tonometer (GAT) at the baseline, and Weeks 2, 4 and 8 after switching the treatment. The IOP at the baseline and at the end of treatment period was measured at 10:00, 12:00, and 16:00. The central corneal thickness (CCT) was measured at each visit using an ultrasonic pachymeter., Results: At the baseline, the mean IOP was 18.8 ± 1.4 mmHg, and the CCT was 530.7 ± 29.5 μm. At Week 8 after switching treatment, bimatoprost significantly reduced the IOP by 2.0 ± 1.6 mmHg from the baseline (p < 0.001). The CCT tended to be reduced (p = 0.009; Repeated ANOVA) and Bonferroni test indicated a statistically significant decrease of the CCT at Week 8 in comparison with that at the baseline (p = 0.013)., Conclusions: Bimatoprost has an IOP-lowering effect superior to that of latanoprost in glaucoma patients after switching from latanoprost. The use of bimatoprost can decrease the CCT for a relatively short period in a linear regression fashion.

Purpose: To determine whether intraocular pressure (IOP) is significantly altered after visual field (VF) testing in eyes with open-angle glaucoma (OAG)., Methods: A prospective clinical trial of 106 OAG patients who had not had any previous surgical interventions. IOP was measured with a non-contact tonometer and refractive error with an auto refractometer. The measurements were made before and immediately after the VF test of the first eye (OD) and the second eye (OS)., Results: The baseline refractive error (spherical equivalent) was -4.13 ± 3.61 diopters (D) OD and -4.05 ± 3.63 D OS. The average VF testing time was 7.5 ± 1.4 min OU. The average baseline IOP was 12.8 ± 2.9 mmHg OD and 12.6 ± 2.8 mmHg OS. After the VF testing OD, the average IOP decreased significantly to 12.3 ± 2.6 mmHg (P = 0.001), but the IOP (12.5 ± 2.6 mmHg) OS was not significantly unchanged (P = 0.190). Following the VF testing OS, the IOP OD was 12.2 ± 2.6 mmHg (P = 0.252) and OS was 12.4 ± 2.7 mmHg (P = 0.487). An elevation of ≥2 mmHg in the IOP after the VF testing was found in 2.8 % of the right eyes and 0.9 % of the left eyes. The refractive error was not significantly changed after the VF testing. Multivariate analysis showed statistically significant correlations between the IOP decrease after the VF testing and the baseline IOP (P = 0.000) and the central corneal thickness (P = 0.034)., Conclusions: In the majority of eyes with OAG, VF testing did not lead to an increase in the IOP. The amount of IOP reduction after VF testing is significantly correlated with the baseline IOP and central corneal thickness.

Purpose: To evaluate the prevalence of and risk factors for primary open-angle glaucoma (POAG) in a rural population of southwestern Japan., Design: Population-based cross-sectional study., Participants: All residents 40 years of age and older in Kumejima, Okinawa, Japan., Methods: Of the eligible 4632 residents 40 years of age and older, 3762 subjects (participant rate, 81.2%) underwent screening examinations, including visual acuity (VA) measurement, slit-lamp examination, Goldmann applanation tonometry, gonioscopy, undilated stereoscopic fundus photographs, autorefractometry, noncontact specular microscopy, pachymetry, and visual field (VF) testing using frequency-doubling technology. If glaucoma or other related ocular disorders were suspected, subjects were referred for definitive examinations including VF testing with the Humphrey Field Analyzer. The diagnosis of POAG was based on the criteria of the International Society for Geographical and Epidemiological Ophthalmology., Main Outcome Measures: Prevalence and risk factors of POAG., Results: The prevalence of POAG was 4.0% (95% confidence interval [CI], 3.4%-4.7%); 82% of patients had an intraocular pressure (IOP) less than 22 mmHg, resulting in a prevalence of 3.3% (95% CI, 2.8%-3.9%). Because of POAG, 3 subjects had a VA worse than 20/400 in only 1 eye, and 1 subject had VA loss of worse than 20/400 bilaterally. The average IOP values (mean ± standard deviation) were 14.9 ± 3.2 and 14.6 ± 3.3 mmHg in the right and left eyes, respectively; the IOP values were higher in patients with POAG (15.4 ± 3.3 and 15.2 ± 3.3 mmHg, respectively) than in subjects without glaucoma (14.8 ± 3.1 and 14.4 ± 3.1 mmHg, respectively; P<0.045, Student t test). Multivariate analysis showed that male gender (P = 0.003), older age (P<0.001), higher IOP (P<0.001), longer axial length (P<0.001), and thinner central cornea (P = 0.006) were associated with POAG., Conclusions: High prevalence rates of POAG (4.0%) and POAG with normal IOP levels (3.3%), which were comparable with those on the Japanese mainland, were found in a southwestern rural island of Japan, where the prevalence of primary angle-closure glaucoma (previously reported as 2.2%) was considerably higher than on the Japanese mainland (0.6% in the Tajimi Study) or other countries. The risk factors for POAG included male gender, older age, higher IOP, myopia, and a thinner cornea., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To elucidate the relationship between the macular ganglion cell complex thickness (GCCT) and its corresponding superior or inferior visual hemifield defects, and the apparently normal visual hemifield, and to explore the relationship between the macular GCCT of the corresponding apparently normal hemifield and the severity of the glaucomatous visual field defects in the same eye., Methods: Sixty-seven eyes of 67 patients with open-angle glaucoma showed superior or inferior hemifield defects. We measured the visual field using the Humphrey Field Analyzer programs Central 30-2 and 10-2, and the GCCT using spectral domain optical coherence tomography. For the GCCT measurement, we selected 3 points each in the inner or outer sectors of the parafovea., Results: We observed a significant correlation between the macular GCCT of the inner or outer sector of the parafovea and in the change of the visual field in each hemifield defect or the apparently normal hemifield. The decrease of the GCCT corresponding to the apparently normal hemifield correlated with the progression of the severity of the glaucomatous defects, using the Anderson classification., Conclusions: The macular GCCT is a sensitive marker of early glaucomatous change, allowing detection of structural changes associated with glaucoma even in the apparently normal hemifield.

Purpose: To compare the posture-induced IOP changes in medically treated eyes with those in surgically treated eyes having open-angle glaucoma (OAG) and low IOP., Methods: Fifty-one posttrabeculectomized OAG eyes with a cystic filtering bleb and 51 nonoperated, medically treated OAG eyes were studied. The IOP measured with a Goldmann applanation tonometer (GAT) was 12 mm Hg or less in both groups. It was measured in the sitting and lateral decubitus positions with a rebound tonometer. The IOP was measured in the upper eye 5 minutes after assuming the lateral decubitus position., Results: The mean (SD) IOP measured with the GAT was 9.7 (1.5) mm Hg in the trabeculectomized eyes and 9.7 (1.4) mm Hg in the medically treated eyes (P = 0.892, unpaired t-test). In the surgically treated group, the mean (SD) IOP measured with the rebound tonometer was 10.3 (2.3) mm Hg in the sitting position and 11.3 (2.8) mm Hg in the lateral decubitus position (P < 0.001, paired t-test). In the medically treated group, the mean (SD) IOP measured with the rebound tonometer was 10.8 (2.0) mm Hg in the sitting position and 14.1 (2.9) mm Hg in the lateral decubitus position (P < 0.001, paired t-test). The greater IOP increase of 3.3 mm Hg in the medically treated group compared with the 1.0 mm Hg in the surgically treated group was significant (P < 0.001, unpaired t-test)., Conclusions: The lower posture-induced IOP change in the successfully trabeculectomized eyes indicates that trabeculectomy will not only lead to a decrease in the IOP but also lower the posture-induced IOP change.

Purpose: To identify the optimal dose of a novel Rho kinase inhibitor, K-115, by assessing dose dependency of the intraocular pressure (IOP)-lowering effects and the safety in patients with primary open-angle glaucoma or ocular hypertension., Designs: Multicenter, prospective, randomized, placebo-controlled, double-masked, parallel group comparison clinical study., Methods: After appropriate washout periods, 210 patients with primary open-angle glaucoma or ocular hypertension were subdivided into 4 groups and were treated with K-115 in concentrations of 0.1%, 0.2%, and 0.4% or placebo twice daily for 8 weeks. The dose response of IOP reduction and the incidence of adverse events by K-115 or placebo were investigated., Results: The mean baseline IOP was between 23.0 and 23.4 mm Hg. The mean IOP reductions of the last visit from baseline were -2.2 mm Hg, -3.4 mm Hg, -3.2 mm Hg, and -3.5 mm Hg, respectively, in the placebo, 0.1%, 0.2%, and 0.4% groups at before instillation (9:00); -2.5 mm Hg, -3.7 mm Hg, -4.2 mm Hg, and -4.5 mm Hg at 2 hours after instillation (11:00); and -1.9 mm Hg, -3.2 mm Hg, -2.7 mm Hg, and -3.1 mm Hg at 8 hours after instillation (17:00). The dose-dependent IOP-lowering effect of K-115 was statistically significant at all time points. Also, conjunctival hyperemia was found in 7 (13.0%) of 54 patients for placebo, 23 (43.4%) of 53 patients for the 0.1% group, 31 (57.4%) of 54 patients for the 0.2% group, and 32 (65.3%) of 49 patients for the 0.4% group., Conclusions: On the basis of this dose-response study, K-115 0.4% has been selected to be the optimal dose and has the potential to be a promising new agent for glaucoma to control 24-hour IOP by twice-daily dosing., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Glaucoma is the leading cause for blindness affecting 60 million people worldwide. The optineurin (OPTN) E50K mutation was first identified in familial primary open-angle glaucoma (POAG), the onset of which is not associated with intraocular pressure (IOP) elevation, and is classified as normal-tension glaucoma (NTG). Optineurin (OPTN) is a multifunctional protein and its mutations are associated with neurodegenerative diseases such as POAG and amyotrophic lateral sclerosis (ALS). We have previously described an E50K mutation-carrying transgenic (E50K-tg) mouse that exhibited glaucomatous phenotypes of decreased retinal ganglion cells (RGCs) and surrounding cell death at normal IOP. Further phenotypic analysis of these mice revealed persistent reactive gliosis and E50K mutant protein deposits in the outer plexiform layer (OPL). Over-expression of E50K in HEK293 cells indicated accumulation of insoluble OPTN in the endoplasmic reticulum (ER). This phenomenon was consistent with the results seen in neurons derived from induced pluripotent stem cells (iPSCs) from E50K mutation-carrying NTG patients. The E50K mutant strongly interacted with TANK-binding kinase 1 (TBK1), which prohibited the proper oligomerization and solubility of OPTN, both of which are important for OPTN intracellular transition. Treatment with a TBK1 inhibitor, BX795, abrogated the aberrant insolubility of the E50K mutant. Here, we delineated the intracellular dynamics of the endogenous E50K mutant protein for the first time and demonstrated how this mutation causes OPTN insolubility, in association with TBK1, to evoke POAG.

Purpose: To elucidate the relationship between macular retinal thickness and corresponding superior or inferior visual hemifield defects in glaucoma patients., Methods: Thirty-nine eyes of 39 patients with open-angle glaucoma showed superior or inferior hemifield defects (superior hemifield defects, 27 eyes; inferior hemifield defects, 12 eyes). We measured the retinal thickness of the parafovea and fovea centralis corresponding to a defect or an apparently normal hemifield by spectral domain optical coherence tomography. We then analyzed the relationship between the retinal thickness corresponding to an apparently normal hemifield and the severity of the glaucomatous visual field defect on the other side of the same eye., Results: We found that the retinal thickness of the parafovea and fovea centralis significantly decreased, as the hemifield defect increased. The retinal thickness of the parafovea, the inner sector, outer sector, and inner and outer sectors, corresponding to the apparently normal hemifields significantly decreased with the progression of the hemifield defect on the other side. The mean±SD age of patients was 66.5±9.1 years and the refraction was -1.3±2.4 D., Conclusions: Macular retinal thickness decreases with a corresponding visual hemifield defect in glaucoma patients. Retinal structural changes precede the loss of the visual field in the apparently normal side.

Purpose: To determine whether significant correlations existed between the morphological and functional parameters of the macular region of eyes with open-angle glaucoma (OAG)., Methods: Forty eyes of 40 OAG patients were studied. The morphological parameters were obtained by optical coherence tomography (OCT), and the functional parameters were acquired by automated Humphrey Field Analyzer (HFA) and multifocal electroretinograms (mfERGs). All of the tests were performed within 6 months of each other. The retinal thickness was determined by OCT in the nine Early Treatment of Diabetic Retinopathy Study (ETDRS) sectors of the macula, the fovea, and the four quadrants of the inner and an outer ring. The amplitudes of the second-order kernel responses of the mfERGs in the central 5° including the amplitude ratio of the nasal to temporal hemispheres (N/T amplitude ratio) were analyzed. The total mean deviation of the HFA corresponding to each OCT region was measured. The correlation between the different parameters was determined by coefficients of correlation and linear regression analyses., Results: The N/T amplitude ratio of the second-order kernel responses of the mfERGs was significantly correlated with the retinal thickness in the inferior quadrant (r = -0.44; P = 0.004). There was a significant correlation between the N/T amplitude ratio and the threshold in the superior quadrant measured by the HFA Central 10-2 program (r = -0.40; P = 0.011) and also between the N/T amplitude ratio and the total deviation in the superior quadrant (r = -0.40; P = 0.010). There were significant correlations between the inferior retinal thickness and the average threshold and the TD in superior (r = 0.70, P < 0.001; r = 0.692, P < 0.001, respectively), nasal (r = 0.53, P < 0.001; r = 0.53, P < 0.001, respectively), and temporal (r = 0.46, P = 0.003; r = 0.44, P = 0.004, respectively) quadrants., Conclusions: Functional glaucomatous changes determined by mfERGs and perimetry are significantly correlated with the morphological changes determined by OCT.

Purpose: To compare the posture-induced intraocular pressure (IOP) changes in eyes with open-angle glaucoma (OAG), primary angle closure (PAC) with or without glaucoma medications, and healthy control eyes with normal IOPs., Methods: The IOP was measured in the sitting position (SP) and the lateral decubitus position (LDP) with a rebound tonometer. The IOP in the LDP was measured in the upper eyes 5 minutes after assuming this posture., Results: Fifty-two patients with OAG, 52 with PAC, and 52 controls with normal IOPs were studied. The IOP in the SP measured with the rebound tonometer was 14.3 ± 4.0 mm Hg in eyes with OAG, 15.8 ± 4.5 mm Hg in eyes with PAC, and 13.9 ± 3.7 mm Hg in eyes with normal IOPs. None of these differences was significant (P = 0.060; ANOVA). The IOP in the LDP was significantly increased to 18.3 ± 4.6 mm Hg in eyes with OAG, 19.3 ± 4.4 mm Hg in eyes with PAC, and 17.3 ± 3.5 mm Hg in eyes with normal IOPs (P = 0.000 for all; paired t-tests). The postural IOP difference was +4.0 ± 2.2 mm Hg in OAG eyes, +3.5 ± 2.2 mm Hg in PAC eyes, and +3.4 ± 1.8 mm Hg in normal eyes, and these increases were not significantly different among the three groups (P = 0.309; ANOVA). The correlation between the posture-induced IOP changes and the axial length was not significant in each group., Conclusions: Postural IOP changes are comparable among eyes with OAG, PAC with and without glaucoma medications, and control eyes.

Introduction: To determine whether trabeculectomy affects postural-induced changes in intraocular pressure (IOP), and whether it is maintained., Methods: Thirty-six eyes of 36 patients with open-angle glaucoma who were scheduled for their initial trabeculectomy with adjunctive mitomycin C were prospectively examined. The IOP was measured in the sitting and the lateral decubitus position with an ICare rebound tonometer before, and 1, 3, and 12 months after trabeculectomy., Results: Twenty-nine eyes of 29 patients completed this study. The mean baseline IOP measured with the ICare tonometer was 17.4 ± 4.9 mmHg in the sitting position and 21.3 ± 5.6 mmHg in the lateral decubitus position (p < 0.001). This postural IOP difference, +3.9 mmHg, was reduced to +1.3 ± 1.7 mmHg at 1 month and to +0.8 ± 1.5 mmHg at 3 months after the trabeculectomy (p < 0.001 and p = 0.004 respectively). This decrease in the degree of posture-dependent IOP change was maintained at +1.7 ± 2.2 mmHg at 1 year postoperatively (p < 0.001). In three cases, the postural IOP changes returned to the baseline level, and all three had a failed bleb., Conclusions: Our results indicate that trabeculectomy not only reduces the IOP but also reduces the degree of posture-induced changes in the IOP. Our findings also speculate that measuring the postural IOP changes after trabeculectomy might provide a clue on the functioning of a filtering bleb.

Purpose: To report two Japanese cases of pigmentary glaucoma (PG) treated with laser peripheral iridotomy (LPI) that were followed for 15 and 16 years, respectively., Methods: The medical records of two patients with PG who were successfully treated with LPI were reviewed. Changes in the intraocular pressure (IOP) were followed., Results: Case 1 was that of a 35-year-old man with LPI who underwent argon laser trabeculoplasty twice. He required ocular hypotensive drugs to maintain the IOP at normal levels. Case 2 involved a 36-year-old man with LPI who required ocular hypotensive drugs to maintain his IOP at the low-teen level. The IOP of both patients was unstable during the first 6-8 years following the LPI, but showed a decrease at each annual follow-up examination up to the age of 50 years., Conclusions: Although only two cases were followed, we conclude that the long-term effects of LPI may play a role, at least partly, in stabilizing the IOP at the low-teen level. Both patients were relatively young at the time of the LPI, and age may have been a factor in the stabilization process. Our findings confirm similar findings in Western countries.

Introduction: To compare the intraocular pressure (IOP)-lowering effects of 0.005% latanoprost to that of 0.004% travoprost in eyes with open-angle glaucoma (OAG)., Methods: Forty-two patients with OAG who received either latanoprost or travoprost every evening for 12 weeks, and then switched to the other medication for another 12 weeks. The IOP measurements were made with a Goldmann applanation tonometer (GAT) at the baseline, and at 1, 3, 4, and 6 months after the treatment. The IOP at the untreated baseline and at the end of each treatment period was measured at 10:00, 12:00, and 16:00 hours. The central corneal thickness (CCT) was measured at each visit using an ultrasonic pachymeter., Results: The mean baseline IOP was 13.9 ± 2.5 mmHg, and the CCT was 536.7 ± 30.5 μm. Latanoprost reduced the IOP by 2.5 ± 1.7 mmHg and travoprost by 2.6 ± 1.5 mmHg from the baseline (p = 0.6807). The CCT decreased significantly to 531.9 ± 30.3 at 3 months (p = 0.0160) and to 529.4 ± 30.5 μm at 6 months (p = 0.0002) after the therapy. The decrease was significantly greater in eyes after travoprost (p = 0.0049)., Conclusions: Travoprost has similar effect as latanoprost in reducing the IOP in glaucoma patients with relatively low IOPs. The use of prostaglandin analogs can decrease the CCT, and this change should be considered when the IOPs obtained by GAT are analyzed.

Purpose: We investigated the effectiveness, safety and plasma concentration of long-acting carteolol hydrochloride 2% ophthalmic solution (LA) as compared with the original carteolol hydrochloride 2% ophthalmic solution(CA)., Methods: Patients with primary open angle glaucoma and ocular hypertension were randomized to 62 patients of LA group (LA once a day) and 62 patients of CA group (CA twice a day) in this multicenter, open-label trial. The intraocular pressure (IOP), pulse rate, blood pressure and plasma concentration were examined for 8 weeks., Results: The IOP reduction and reduction rate were not significant at any point between the two groups. Systolic blood pressure decreased significantly in both groups, however, diastolic blood pressure decreased only in the CA group. The plasma concentration of the LA group was significantly lower than that of the CA group., Conclusions: The IOP reduction effect of the LA group was the same as the CA group. This study suggests that long-acting treatment with alginic acid can be useful for reducing systemic side effects.

Purpose: To explore the relationship between central corneal thickness (CCT) and visual field defect in open-angle glaucoma (OAG)., Methods: In this cross-sectional study, we tested 344 eyes in 344 eligible patients, including 233 with normal-tension glaucoma (NTG) and 111 with primary open-angle glaucoma (POAG). The association among variables, especially that between visual field defect and CCT, was probed by multivariate regression in eyes with NTG or POAG, and in all eyes. All eyes were divided into early, moderate, or severe visual field defect groups according to Anderson's classification. Statistical analysis was performed for all cases, and for the three CCT groups., Results: Multivariate regression analysis revealed an association between CCT and visual field defect in eyes with NTG but not in eyes with POAG or in all eyes. The eyes with early visual field defect had greater CCT than did those with severe visual field defect (533.2 versus 519.0 microm). The eyes with greater CCT had better visual field indices than did those with thinner CCT (-6.91 versus -9.17 dB)., Conclusions: Central corneal thickness is a factor associated with the status of the visual field defect: a greater CCT is associated with a better visual field index. Other factors such as the glaucoma subtype play a role in the effect of CCT on visual field defect.

Purpose: Toll-like receptor 4 (TLR4) is a transmembrane receptor that mediates immune responses to exogenous and endogenous ligands and interacts with heat shock proteins, which are reportedly involved in normal tension glaucoma (NTG). This study was undertaken to investigate whether TLR4 polymorphisms are associated with NTG., Methods: Two hundred fifty Japanese patients with NTG and 318 Japanese healthy control subjects were recruited. Eight single-nucleotide polymorphisms (SNPs) in the TLR4 gene were genotyped, and allelic and phenotypic diversity was assessed between cases and control subjects., Results: Strong linkage disequilibrium was observed among all SNPs (D' >or= 0.85), which were located in one haplotype block. With respect to allelic diversity, the minor allele of three SNPs (rs10759930, rs1927914, and rs7037117) carried a significantly increased risk of NTG. With regard to genotypic diversity, individuals with the minor allele of six SNPs (rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, and rs7037117) had a 1.47- to 1.65-fold increased risk of NTG. rs7037117, located in the 3'-untranslated region of TLR4, was most strongly associated with NTG, and when incorporated into a haplotype with rs10759930, the strongest association was detected (P = 0.0038, P(c) = 0.0095)., Conclusions: Multiple SNPs in the TLR4 gene are associated with the risk of NTG. This finding suggests that the ligands and/or cytokines involved in the TLR4 signaling network may be risk factors for the development of NTG.

Purpose: To determine whether multifocal electroretinograms (mfERGs) can provide an index for identification of glaucomatous optic neuropathy in patients with normal-tension glaucoma (NTG)., Methods: mfERGs were recorded in 30 normal volunteers (30 eyes) and 20 patients (20 eyes) with normal-tension glaucoma (NTG). Visual field examinations were performed with a Humphrey field analyzer, and all NTG patients had unilateral hemifield defects. The mfERGs were elicited by a binary m-sequence of flashes from 37 hexagonal elements that subtended an overall visual angle of 50 degrees x 40 degrees. The mfERGs were summed and analyzed for predetermined retinal loci. These mfERGs were compared with the perimetric findings of the corresponding visual fields., Results: In normal volunteers, the amplitude of the second-order kernel within the central 5 degrees of the nasal hemisphere was significantly smaller than in that of the temporal hemisphere (Wilcoxon signed-rank test, P = 0.0001). In NTG patients, this asymmetry of the two hemispheres was reduced or not present. The ratio of the amplitude of the mfERGs from the nasal and temporal hemispheres (N/T amplitude ratio) in normal control volunteers was significantly different from that of NTG patients with a hemifield defect (analysis of variance, P = 0.0001). When the cutoff value for the N/T amplitude ratio was set at 0.83 for discriminating glaucomatous eyes from normal eyes, the sensitivity was 65.0% with a specificity of 96.7%. The area under the receiver-operating characteristic curve of the N/T amplitude ratio was 0.86. The N/T amplitude ratio and the visual field indices were significantly correlated., Conclusion: A decrease in the nasal-temporal asymmetry in the amplitude of the second-order kernel responses within the central 5 degrees of glaucoma patients' eyes indicated a dysfunction of the inner retinal layers, including of the retinal ganglion cells.

Purpose: To compare the ocular hypotensive activity and safety profile of long-acting 1% carteolol hydrochloride eye drops (long-acting formulation) to those of 1% carteolol hydrochloride eye drops(currently prescribed drug) for reduction of intraocular pressure., Subjects and Methods: Patients with primary open-angle glaucoma or ocular hypertension (146 cases) were assigned randomly to the long-acting drug group (74 cases) and the currently-prescribed drug group (72 cases). Long-acting eye drops were instilled once a day in the morning (along with one drop of placebo at night), and currently-prescribed eye drops were instilled twice a day in the morning and at night. Eye drops were administered for 8 weeks. Intraocular pressure was monitored at 2, 4, and 8 weeks after the initiation of drug instillation for evaluation of equivalence., Results: Intraocular pressure was significantly reduced during the entire follow-up period in both groups. In the long-acting drug group, the reduction of intraocular pressure was--3.5 +/- 0.2,--4.3 +/- 0.2 and--4.6 +/- 0.3 mmHg at 2, 4, and 8 weeks, respectively (paired t test). In the currently-prescribed drug group, the reduction of intraocular pressure was--4.1 +/- 0.2,--4.4 +/- 0.3 and--4.6 +/- 0.2 mmHg at 2, 4, and 8 weeks(paired t test). The safety profile was similar in both groups, and the tolerance for the long-acting eye drops was as good as for the currently-prescribed eye drops., Conclusion: Because the efficacy of both drugs was equivalent, with an identical safety profile, the long-acting eye drops seem to be an efficacious formulation for clinical use in Japanese glaucoma patients.

Objective: To determine the phenotype of an Australian pedigree with the myocilin (MYOC) Gly252Arg mutation, comparing it with other pedigrees carrying the same mutation., Methods: All recruited subjects underwent a comprehensive clinical examination, including optic disc assessment, applanation tonometry, and visual field measurement. Mutation analysis was performed through direct sequencing. Haplotype analysis was performed using microsatellite markers around the MYOC gene., Results: Eight Gly252Arg mutation carriers with glaucoma were identified from the same pedigree. Carriers' mean +/- SD age at diagnosis was 46.3 +/- 11.4 years (range, 31-60 years). Highest recorded intraocular pressure ranged from 27 to 42 mm Hg (mean +/- SD, 32.4 +/- 5.6 mm Hg). Cup-disc ratios in the worst eye ranged from 0.6 to 0.9. Six of the 8 individuals had undergone filtration surgery. A common founding haplotype between MY5 and D1S218 was found for Caucasian individuals tested with this mutation. One subject was compound heterozygotic for the MYOC Gly252Arg mutation and a novel MYOC Gly244Val variant., Conclusions: Although a common founder for Gly252Arg across Caucasian subjects was found, the phenotype from this Australian MYOC mutation-carrying pedigree is less severe than previously described. The severity of glaucoma caused by the Gly252Arg mutation may be similar to the Thr377Met MYOC mutation, yet is more severe than the most common Gln368Stop mutation., Clinical Relevance: Since its implication in glaucoma, much work has been performed investigating the clinical features of MYOC-related glaucoma. Given the strong genotype-phenotype correlations with MYOC disease-causing variants, health care professionals armed with such molecular information are able to accurately counsel patients on their likely disease course. Our work suggests that the disease associated with MYOC Gly252Arg is less severe than previously described in other pedigrees with this specific mutation.

Purpose: To identify the risk factors associated with primary open-angle glaucoma (POAG) in the Tajimi Study., Design: Population-based cross-sectional epidemiologic study., Participants: One hundred nineteen POAG patients and 2755 controls., Methods: Univariate and multivariate comparison of ocular factors and systemic factors between POAG patients and controls., Main Outcome Measures: Difference in factors between POAG patients and controls, factors associated with POAG patients, and their odds ratio (OR)., Results: Intraocular pressure (IOP), age, myopia, and history of hypertension differed between POAG patients and controls in univariate analyses. Multivariate analysis with logistic regression with stepwise selection of variables demonstrated that higher IOP (OR, 1.12 [95% confidence interval (CI), 1.04-1.21]), myopia (ORs, 1.85 [95% CI, 1.03-3.31] for low myopia and 2.60 [95% CI, 1.56-4.35] for moderate to high myopia), and older age (OR, 1.06 [95% CI, 1.04-1.08]) were associated with an increased risk of having POAG., Conclusions: Although the majority (92%) of POAG patients diagnosed in the Tajimi Study had IOP within the normal range, IOP was still identified as a significant risk factor for POAG. Together with IOP, myopia and age were significant risk factors for having POAG.

Purpose: To assess diurnal variations of intraocular pressure (IOP) in suspected normal-tension glaucoma (NTG) patients with subsequent long-term observation to detect changes that may lead to a new diagnosis., Methods: Diurnal variation of IOP was measured in a sitting position at 2-h intervals for 24 h in a total of 569 subjects with suspected NTG., Results: Thirty of the 569 subjects (5.3%) showed IOP values exceeding 20 mmHg during the 24-h monitoring and were diagnosed as having primary open-angle glaucoma (POAG). In subjects in whom NTG was definitely diagnosed based on the results of the 24-h monitoring, the average maximum, minimum, and mean IOP was 16.1, 11.7, and 13.9 mmHg, respectively, and the mean diurnal variation in IOP was 4.4 mmHg. The peak time was observed outside clinic hours (1800-0800) in 41.4% of patients, and the trough time was observed during clinic hours (1000-1600) in 15.9%. In 2.9% of NTG subjects, the diagnosis was eventually changed to POAG during follow-up., Conclusion: Assessment of diurnal variations of IOP in suspected NTG patients is useful for the differential diagnosis of POAG from NTG and for establishment of a baseline, which may affect the management plan., (Copyright Japanese Ophthalmological Society 2006.)

Purpose: To investigate the effects of reduction of intraocular pressure (IOP) by surgical intervention on the frequency of disc hemorrhages in eyes with primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG)., Design: Retrospective study., Methods: We studied 99 eyes of 99 patients with POAG and 50 eyes of 50 patients with NTG, who underwent trabeculectomy with adjunctive mitomycin C (MMC) and were followed regularly at 1 to 3-month intervals at the Glaucoma Service of Gifu University Hospital. We applied Kaplan-Meier life-table analysis for the detection of disc hemorrhages before and after trabeculectomy., Results: Trabeculectomy significantly reduced IOP (in POAG: 19.6 +/- 4.4 down to 11.1 +/- 4.2 mm Hg; in NTG: 15.3 +/- 1.5 down to 11.3 +/- 4.5 mm Hg; mean +/- SD). Life-table analysis revealed that the final cumulative probability of detecting a disc hemorrhage after surgery in POAG was 5.5 +/- 2.2% (calculated probability +/- SE) and was significantly lower than that (33.4 +/- 7.8%) before surgery (P < 0.0001, log-rank test). Likewise, the final probability after surgery in NTG was 23.1 +/- 6.3% and was significantly lower than that (42.1 +/- 8.8%) before surgery (P = 0.0063, log-rank test)., Conclusions: IOP reduction via surgical intervention significantly decreases the frequency of disc hemorrhages in open-angle glaucoma patients.

Purpose: The amount of intraocular pressure (IOP) reduction achieved by the use of latanoprost eyedrops varies among patients, and there are even nonresponders. This report examines whether there is any correlation between the amount of individual variability in IOP reduction and the uveoscleral outflow facility after latanoprost eyedrop instillation in normal-tension glaucoma patients., Methods: Sixteen normal-tension glaucoma patients (mean age, 56.4 years) were enrolled in the study to investigate the relationship between the amount of IOP reduction and outflow facility. Before treatment, subjects underwent circadian IOP measurement and then tonography, and the outflow facility was calculated. Subsequently, patients began treatment once daily with latanoprost instillation in one eye. After 4 weeks of daily latanoprost treatment, circadian IOP was measured again., Results: Mean pretreatment outflow facility was 0.23 +/- 0.05 microl/min per mmHg. On average, latanoprost instillation decreased IOP by 2.8 mmHg, but the reduction varied among individuals from -0.3 mmHg to 5.8 mmHg. No significant correlation was noted between the outflow facility and the IOP decline associated with latanoprost., Conclusion: Because there was no significant correlation between individual IOP reduction by latanoprost and outflow facility, the differences in substantial change in uveoscleral outflow after latanoprost administration may be one explanation for the individual variation in IOP reduction after treatment with this drug., (Copyright Japanese Ophthalmological Society 2006.)

Objective: To evaluate trend-type analyses to judge the progression of visual field damage (VFD) of glaucoma in terms of ratios of making judgments of progression and specificity, and to report a new method., Design: Retrospective analysis of visual field (VF) results of actual glaucoma cases and those simulated by computer, and receiver operating characteristic curve analysis of performance of methods to judge the progression of VFD., Participants: One hundred five eyes of 105 open-angle glaucoma (OAG) patients with progressing VFD and 355 eyes of 355 clinically stable OAG patients for VF simulation from 4 university-based referral practices., Methods: Methods using regression analysis of total deviation (TD), mean deviation (MD), mean TD of a sectored VF, and original scoring used in the Advanced Glaucoma Intervention Study (AGIS) were compared. A VF test was repeated twice in a short period on the 355 stable OAG eyes, and test-retest fluctuation, including variance at each test point and covariance between 2 test points, was calculated to simulate stable glaucomatous VF series by computer. The sensitivity of each method was calculated with 105 progressing VF series, and specificity was calculated with 10,000 simulated stable glaucomatous VF series., Main Outcome Measures: Sensitivity (ratios of making judgments of progression), specificity, and diagnostic power., Results: The methods using the TD slope on one test location showed a sensitivity of 0.848 to 1.000, with a specificity of 0.105 to 0.721, and on 2 adjacent test locations showed a sensitivity of 0.848, with a specificity of 0.722. A significant negative MD slope with P<0.05 showed a sensitivity of 0.524, with a specificity of 0.945. The method using a sectored VF showed a sensitivity of 0.695, with a high specificity of 0.946. The AGIS method showed a sensitivity of 0.305 to 0.467, with a very high specificity of 0.999 to 1.000. The method using previously reported mathematically sectored VFs showed a sensitivity of 0.790, with a specificity of 0.900, and higher diagnostic power (1.69) than the others in this study population., Conclusions: Most of the methods using the TD slope were characterized by high sensitivity, the AGIS method had a very high specificity, and those using VF sectors had reasonable sensitivity and specificity.

Purpose: To assess the prevalence of primary open-angle glaucoma (POAG) and its association with intraocular pressure (IOP) in Tajimi City in central Japan., Design: A cross-sectional epidemiologic study in a defined population., Participants: Subjects randomly selected from the population older than 40 years in Tajimi City., Intervention: Each subject underwent a screening examination comprised of an interview and ophthalmic examinations, including measurement of IOP by a Goldmann applanation tonometer, central corneal thickness (CCT), slit-lamp examination, fundus photography, and a screening visual field test using frequency doubling technology. When ocular diseases were suspected, the subjects were referred for definitive examination. During the definitive examination, slit-lamp examination, IOP measurement, a visual field test using Humphrey Field Analyzer 30-2 SITA Standard program (Humphrey Instruments, San Leandro, CA), optic disc and fundus examination, and gonioscopy were performed and stereoscopic disc photographs were obtained. A diagnosis of glaucoma was made based on optic disc appearance, perimetric results, and other ocular findings., Main Outcome Measures: Prevalence of POAG, mean IOP, and mean CCT., Results: Of 3870 eligible people, 3021 (78.1%) participated in the study. The estimated prevalence of POAG in the population older than 40 years was 3.9% (95% confidence interval [CI]), 3.2%-4.6%). The prevalence of cases of POAG with IOP levels of 21 mmHg or less was 3.6% (95% CI, 2.9%-4.3%), whereas the prevalence for those with IOP levels of more than 21 mmHg was 0.3% (95% CI, 0.1%-0.5%). The average IOP for eyes with POAG was 15.4+/-2.8 (standard deviation) in the right eye (n = 115) and 15.2+/-2.8 mmHg in the left eye (n = 115), which was significantly higher than that of nonglaucoma subjects (14.5+/-2.5 in the right eye; n = 2759; P = 0.0004; and 14.4+/-2.6 mmHg in the left eye; n = 2757; P = 0.0026). The mean CCT of POAG eyes with IOP levels of 21 mmHg or less was 518+/-29 (n = 109) in the right eye and 519+/-29 microm (n = 110) in the left eye, levels that were not significantly different from that of nonglaucoma eyes (520+/-32 microm [n = 2690]; and 522+/-32 microm [n = 2692]; P>0.05)., Conclusions: The prevalence of POAG in this population was 3.9%. In 92% patients with POAG, the IOP was 21 mmHg or less.

Purpose: To investigate the association of sequence variations in the optineurin (OPTN) gene in patients with open-angle glaucoma., Design: Prospective case control study., Methods: The OPTN gene was screened for sequence variations using a combination of single-strand conformational polymorphism analysis and automated DNA sequencing. A total of 1,299 subjects (1048 glaucoma patients and 251 controls) were screened for variations in the four portions of the gene that had been previously associated with glaucoma. A subset of these subjects (376 patients and 176 controls) was screened for variations in the entire coding sequence. Twenty-four percent of the patients and 35% of the controls were Japanese, whereas the remainder were predominantly Caucasian. Allele frequencies were compared with the Fisher exact test., Results: The OPTN sequence variations were not significantly associated with any form of high-tension open-angle glaucoma. One proband with familial normal-tension glaucoma was found to harbor the previously reported Glu50Lys variation. Another previously reported change, Met98Lys, was associated with normal-tension glaucoma in Japanese but not in Caucasian patients., Conclusions: This study provides some additional evidence for the association of the Glu50Lys OPTN sequence variation with familial normal tension glaucoma. However, because familial normal-tension glaucoma is so rare, this change seems to be responsible for less than 0.1% of all open-angle glaucoma. The Arg545Gln variation is likely to be a nondisease-causing polymorphism. The Met98Lys change may be associated with a fraction of normal-tension glaucoma in patients of Japanese ethnicity.

Purpose: To evaluate topographic changes in normal-tension glaucoma using serial optic disc images obtained by scanning laser tomography., Subjects and Methods: Fifty-six eyes of 30 patients with normal-tension glaucoma were imaged using the Heidelberg Retina Tomography (HRT) four or more times during follow-up periods of more than 3 years. Disc progression was determined by regression analysis of global and segmental changes in optic disc parameters. Visual field progression was determined by Humphrey Field Analyzer (HFA) program 30-2 and was compared with disc progression., Results: The global parameters of the optic disc showed progression in 21 of 56 eyes(37.5%). Progression was found in 30 eyes(53.6%) at the superotemporal segment, in 24 eyes(42.9%) at the temporal segment, in 27 eyes(48.2%) at the inferotemporal segment, in 21 eyes(37.5%) at the superonasal segment, in 23 eyes(41.1%) at the nasal segment, and in 27 eyes(48.2%) at the inferonasal segment. The visual field showed progression in 19 eyes (33.9%). The progression in the optic disc parameters did not necessarily agree with that in the visual field., Conclusions: Glaucomatous disc changes over time can be determined with HRT using regression analysis.

Purpose: To describe a new method of quantifying retinal nerve fiber layer defects (NFLD) in glaucomatous eyes using the Heidelberg Retina Tomograph (HRT)., Methods: Mean tomographic images including the optic disc and peripapillary area were constructed using HRT. An image field of 15 degrees x 15 degrees or 20 degrees x 20 degrees was used for the NFLD analysis. Data on the nerve fiber layer thickness was collected and further analyzed circumferentially across the NFLD at a position 500 microm away from the optic disc margin. We studied 31 patients with early to moderate open-angle glaucoma, ie, with visual field defects appearing earlier than stage 3 of the modified Aulhorn-Greve classification. We determined the width (W), maximum depth (D), and cross-sectional area of the NFLD (A), and we identified correlations between these parameters and the visual field indices from Humphrey Visual Field tests, mean deviation (MD) and corrected pattern standard deviation (CPSD)., Results: NFLD parameters could be obtained from 20 of 31 eyes (65%). There was a statistically significant correlation between the D and A parameters, and between these parameters and the maximum depression threshold in the corresponding visual field. No significant correlation was found between the NFLD parameters, the global visual field indices (MD, CPSD) and the mean value of the total deviation (TD) in the corresponding hemifield visual field., Conclusions: A cross-sectional NFLD image can be obtained using HRT. Among the three NFLD parameters, maximum depth (D), and area under the surface (A) correlated well with the visual field threshold.

Purpose: To study the characteristics of visual field progression in patients with normal-tension glaucoma (NTG) with optic disk hemorrhages., Design: Observational study., Methods: Fifty-eight eyes of 58 untreated patients with NTG who had at least five reliable visual fields of the Humphrey Field Analyzer (central 30-2) within the follow-up period of more than 24 months were enrolled. Of these, 27 eyes had optic disk hemorrhages in their clinical courses. Pointwise linear regression analysis was done using total deviation values of the fields at each of 74 test locations in each patient. Progression was defined as the points of negative slopes with P <.01. A whole visual field was concentrically divided into three clusters: the areas within 10 degrees, 10 to 20 degrees, and 20 to 30 degrees. Percentages of the progressed points of the three clusters and a whole field were compared between the groups with and without optic disk hemorrhages., Results: No significant differences were found in patients' backgrounds, including initial mean deviation values, follow-up periods, and the number of visual field examinations between the 27 patients with optic disk hemorrhages and the 31 without. The group with optic disk hemorrhages showed significantly higher percentages of progressed points within the 10-degree area compared with the group without optic disk hemorrhages (mean +/- SD: 13.1 +/- 13.7%; 5.1 +/- 8.5%, respectively; P =.0086, Student t test), whereas no significant differences were found in the other two clusters or in a whole field., Conclusions: Patients with NTG with optic disk hemorrhages tend to show visual field progression in areas within 10 degrees.

Objective: To investigate the effect of myopic refraction on the central visual field in patients with advanced open-angle glaucoma (OAG)., Design: Multicenter cross-sectional study., Participants: Three hundred thirteen OAG eyes (176 eyes of 176 primary open-angle glaucoma [POAG] patients and 137 eyes of 137 normal-tension glaucoma [NTG] patients) with clear ocular media and a mean deviation (MD) <-15 dB. Patients with a recorded maximum intraocular pressure (IOP) of 22 mmHg or greater were classified as POAG, and those with an IOP of 21 mmHg or less were classified as NTG., Methods: Multiple regression analysis was used to study the influence of refraction on 12 central test points of the C30-2 Humphrey program, and the differences in visual field defects between POAG and NTG eyes were examined using logistic discriminant analysis. In the multiple regression analysis, total deviation (TD) of the 12 test points was graded and used as the dependent variable, and MD and the spherical equivalent refraction were the explanatory variables. In the logistic discrimination analysis, TD, MD, and refraction were covariants that determined the OAG subtypes., Main Outcome Measures: TD values of the 12 central test points (C30-2 program)., Results: Higher myopic refraction was significantly associated with more damage at a point just temporal and inferior to the fixation point in POAG eyes, whereas it was significantly associated with less damage at test points just temporal and superior to the fixation point in NTG eyes. After correcting for the influence of refraction, POAG eyes had significantly more damage at a test point just temporal and inferior to the fixation point, whereas NTG eyes had significantly more damage at those test points nasal and inferior to the fixation point., Conclusions: High myopia constitutes a threat to the remaining lower cecocentral visual field and is one of the factors that interfere with the quality of vision in advanced OAG with high IOP but not low IOP.