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Keiji Yoshikawa,1 Shiro Mizoue,2,3 Koji Nitta,4 Hiroshi Onishi,5 Masaharu Ikeda,5 Akemi Mizuno,5 Kaori Kawazoe,5 Yoshiyuki Tamada,5 Ryuji Takeda,6 Shun Matsumoto7 1Yoshikawa Eye Clinic, Tokyo, Japan; 2Ehime University Hospital, Toon, Ehime, Japan; 3Minami-Matsuyama Hospital, Matsuyama, Ehime, Japan; 4Fukui-ken Saiseikai Hospital, Fukui, Japan; 5Senju Pharmaceutical Co. Ltd., Hyogo, Japan; 6Kansai University of Welfare Sciences, Osaka, Japan; 7Ideta Eye Hospital, Kumamoto, JapanCorrespondence: Keiji YoshikawaYoshikawa Eye Clinic, 1-3-1 Nakamachi, Machida, Tokyo, 194-0021, JapanTel +81-42-739-0781Fax +81-42-739-0782Email mayokasyg51@galaxy.ocn.ne.jpPurpose: We previously investigated the efficacy and safety of adding 0.1% brimonidine (Brim) or 0.5% timolol (Tim) to prostaglandin analogue (PGA) monotherapy to treat patients with normal-tension glaucoma (NTG) with intraocular pressure (IOP) of ≤ 16 mmHg. Herein, we describe an additional post-hoc stratifying analysis of the possible differences in the effect of IOP-lowering and pulse rate (PR) after adjunctive Brim or Tim to PGA.Patients and Methods: This study included 128 subjects. Patients with NTG treated with PGA were stratified based on their baseline IOP. The changes in IOP from baseline and the effect of patient factors on IOP changes were investigated. Patients were stratified by age for investigation of their PR and blood pressure (BP). The change and the effect of patient factors on PR and BP were investigated.Results: After stratification analysis, in 52 eyes treated with Brim and 61 eyes with Tim with baseline IOP 12 ≤ IOP ≤ 16 mmHg, both eye drops lowered IOP significantly (P < 0.0001), and the IOP-lowering efficacy of Brim was non-inferior to that of Tim. However, in 9 Brim- and 6 Tim-treated eyes with baseline IOP of < 12 mmHg, no statistically significant decrease in IOP was evident with either eye drop. In the Tim group, PR decreased significantly (P < 0.05) after stratification by age.Conclusion: The IOP-lowering efficacy of Brim was non-inferior to that of Tim after stratification by baseline IOP (12 ≤ IOP ≤ 16 mmHg). The discrepancy in the IOP-lowering effects of Brim and Tim observed in the previous study was thought to be related to enrolled subjects with low baseline IOP. PR decreased significantly in the Tim group even after age stratification. PR should be considered when selecting β-blockers for glaucoma treatment.Keywords: adjunctive therapy, brimonidine, intraocular pressure reduction, post-hoc analysis, pulse rate, timolol

Tadashi Nakano,1 Shiro Mizoue,2 Nobuo Fuse,3 Aiko Iwase,4 Shun Matsumoto,5 Keiji Yoshikawa6 On behalf of the I.CHANGE2 study group 1Department of Ophthalmology, The Jikei University School of Medicine, Nishi-Shimbashi, Minato-ku, Tokyo, 2Department of Ophthalmology, Ehime University Graduate School of Medicine, Shitsukawa, Toon-city, Ehime, 3Department of Integrative Genomics, Tohoku Medical Megabank Organization, Seiryo-machi, Sendai, Miyagi, 4Tajimi Iwase Eye Clinic, Hon-machi, Tajimi, Gifu, 5Department of Ophthalmology, Tokyo Teishin Hospital, Fujimi, Chiyoda-ku, 6Yoshikawa Eye Clinic, Naka-machi, Machida, Tokyo, Japan Background: We have shown a decrease in mean intraocular pressure (IOP) by switching to travoprost/timolol fixed combination (TTFC) in subjects receiving prostaglandin analogue (PGA) monotherapy and requiring additional medication in a previous report. For analyzing factors affecting IOP reduction, baseline IOP and preceding PGA were selected as statistically and clinically significant factors. In this report, we examine IOP-lowering effect and adverse drug reactions by preceding PGA.Methods: Patients with primary open angle glaucoma or ocular hypertension who received monotherapy with one of four PGAs (travoprost, latanoprost, tafluprost, or bimatoprost) for at least 3 months at 26 institutions and were determined to require additional medication by their primary physician were included. IOP reduction and adverse events were examined at 4, 8, and 12 weeks for each of four PGAs after switching to TTFC.Results: In total, 157 patients who could be followed up for at least 4 weeks after switching to TTFC were included in the efficacy analysis. Multiple regression analysis was performed, and baseline IOP and PGA were found to be significant factors to IOP reduction. IOP reduction at week 12, adjusted with the regression model, was -3.5, -1.8, and -1.4 mmHg in the tafluprost, latanoprost, and travoprost groups, whereas it was -0.5 mmHg in the bimatoprost group. Along with differences in baseline IOP between groups, an IOP-lowering effect of >1 mmHg was noted in the tafluprost, latanoprost, and travoprost groups after the switch. IOP was maintained at 13.8–14.8 mmHg throughout the follow-up period. No serious adverse events or noteworthy issues were observed in any group after the switch.Conclusion: Clinically significant IOP-reducing effects of TTFC were observed in the latanoprost, travoprost, and tafluprost groups when switching from each PGA monotherapy, while there were some differences in effects between groups, with minimal safety concerns. Keywords: adverse event intraocular pressure, prostaglandin analogue, switching therapy, travoprost/timolol fixed combination

Tomoko Naito,1 Keiji Yoshikawa,2 Shiro Mizoue,3 Mami Nanno,4 Tairo Kimura,5 Hirotaka Suzumura,6 Yuzo Umeda,7 Fumio Shiraga1 1Department of Ophthalmology, Okayama University Graduate School of Medicine, Okayama, Japan; 2Yoshikawa Eye Clinic, Tokyo, Japan; 3Department of Ophthalmology, Ehime University Graduate School of Medicine, Ehime, Japan; 4Kagurazaka Minamino Eye Clinic, 5Ueno Eye Clinic, 6Suzumura Eye Clinic, Tokyo, Japan; 7Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Okayama, Japan Purpose: To analyze the relationship between visual field (VF) progression and baseline refraction in Japanese patients with primary open-angle glaucoma (POAG) including normal-tension glaucoma.Patients and methods: In this retrospective study, the subjects were patients with POAG who had undergone VF tests at least ten times with a Humphrey Field Analyzer (Swedish interactive thresholding algorithm standard, Central 30-2 program). VF progression was defined as a significantly negative value of mean deviation (MD) slope at the final VF test. Multivariate logistic regression models were applied to detect an association between MD slope deterioration and baseline refraction.Results: A total of 156 eyes of 156 patients were included in this analysis. Significant deterioration of MD slope was observed in 70 eyes of 70 patients (44.9%), whereas no significant deterioration was evident in 86 eyes of 86 patients (55.1%). The eyes with VF progression had significantly higher baseline refraction compared to those without apparent VF progression (-1.9±3.8 diopter [D] vs -3.5±3.4 D, P=0.0048) (mean ± standard deviation). When subject eyes were classified into four groups by the level of baseline refraction applying spherical equivalent (SE): no myopia (SE > -1D), mild myopia (-1D ≥ SE > -3D), moderate myopia (-3D ≥ SE > -6D), and severe myopia (-6D ≥ SE), the Cochran–Armitage trend analysis showed a decreasing trend in the proportion of MD slope deterioration with increasing severity of myopia (P=0.0002). The multivariate analysis revealed that baseline refraction (P=0.0108, odds ratio [OR]: 1.13, 95% confidence interval [CI]: 1.03–1.25) and intraocular pressure reduction rate (P=0.0150, OR: 0.97, 95% CI: 0.94–0.99) had a significant association with MD slope deterioration.Conclusion: In the current analysis of Japanese patients with POAG, baseline refraction was a factor significantly associated with MD slope deterioration as well as intraocular pressure reduction rate. When baseline refraction was classified into four groups, MD slope in myopia groups was less deteriorated as compared to those in the emmetropic/hyperopic group.Keywords: primary open-angle glaucoma, normal-tension glaucoma, myopia, refraction, visual field progression, MD slope, intraocular pressure reduction rate

Shinichi Okuma,1 Shiro Mizoue,2,3 Yuichi Ohashi3 1Department of Ophthalmology, Sumitomo Besshi Hospital, Niihama-shi, 2Department of Ophthalmology, Minami-Matsuyama Hospital, Matsuyama-shi, 3Department of Ophthalmology, Ehime University School of Medicine, Toon-shi, Ehime, Japan Background/aims: To examine the characteristics of visual field defects and optical coherence tomography (OCT) findings in eyes with intrachoroidal cavitation (ICC) and investigate the similarities between these results and glaucomatous changes.Methods: We retrospectively analyzed patients diagnosed with ICC based on peripapillary radial cross-sectional scans performed with OCT. Visual field was measured with the Humphrey automated visual field analyzer SITA standard central 24-2 program, and macular ganglion cell complex (GCC) thickness was measured in 9×9 mm areas on OCT. The positive rates for the Anderson criteria, site of visual field defect, and mean GCC thickness in each quadrant were compared; the association between these results and ICC location was assessed.Results: Fifteen eyes from eleven patients (five males and six females; mean age, 54.6±10.7 years) were selected for investigation. ICC was detected in the inferior temporal side of the optic disc in all studied eyes. The positive rate for the Anderson criteria was 73.3% (11/15 eyes). Visual field defects were most commonly observed in the cluster that corresponded to the superior Bjerrum area (53.3%; 8/15 eyes). GCC thickness was significantly lower in the inferior side, where the ICC was located, than the superior side, where the ICC was absent (P=0.0001). GCC thinning that correlated with ICC was observed in 66.7% (10/15 eyes) of the ICC eyes.Conclusion: Visual field and GCC findings on OCT in ICC eyes are extremely similar to those observed in superior visual field defect-type early glaucoma, indicating a possible difficulty in distinguishing the two conditions. Keywords: intrachoroidal cavitation, visual field, ganglion cell complex, glaucoma

Tomoko Naito,1 Keiji Yoshikawa,2 Shiro Mizoue,3 Mami Nanno,4 Tairo Kimura,5 Hirotaka Suzumura,6 Ryuji Takeda,7 Fumio Shiraga1 1Department of Ophthalmology, Okayama University Graduate School of Medicine, Okayama, 2Yoshikawa Eye Clinic, Tokyo, 3Department of Ophthalmology, Ehime University Graduate School of Medicine, Ehime, 4Kagurazaka Minamino Eye Clinic, 5Ueno Eye Clinic, 6Suzumura Eye Clinic, Tokyo, 7Department of Agriculture, Kinki University, Nara, Japan Purpose: To analyze the relationship between consecutive deterioration of mean deviation (MD) value and glaucomatous visual field (VF) progression in open-angle glaucoma (OAG), including primary OAG and normal tension glaucoma.Patients and methods: The subjects of the study were patients undergoing treatment for OAG who had performed VF tests at least 10 times with a Humphrey field analyzer (SITA standard, C30-2 program). The VF progression was defined by a significantly negative MD slope (MD slope worsening) at the final VF test during the follow-up period. The relationship between the MD slope worsening and the consecutive deterioration of MD value were retrospectively analyzed.Results: A total of 165 eyes of 165 patients were included in the analysis. Significant progression of VF defects was observed in 72 eyes of 72 patients (43.6%), while no significant progression was evident in 93 eyes of 93 patients (56.4%). There was significant relationship between the frequency of consecutive deterioration of MD value and MD slope worsening (P

Tomoko Naito,1 Keiji Yoshikawa,2 Shiro Mizoue,3 Mami Nanno,4 Tairo Kimura,5 Hirotaka Suzumura,6 Fumio Shiraga1 1Department of Ophthalmology, Okayama University Graduate School of Medicine, Okayama, Japan; 2Yoshikawa Eye Clinic, Tokyo, Japan; 3Department of Ophthalmology, Ehime University Graduate School of Medicine, Ehime, Japan; 4Kagurazaka Minamino Eye Clinic, 5Ueno Eye Clinic, 6Suzumura Eye Clinic, Tokyo, Japan Purpose: To analyze the relationship between intraocular pressure (IOP) and the progression of visual field defects in Japanese primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG) patients.Patients and methods: The subjects of the study were patients undergoing treatment for POAG or NTG who had performed visual field tests at least ten times with a Humphrey field analyzer (Swedish interactive thresholding algorithm standard, C30-2 program). The progression of visual field defects was defined by a significantly negative value of the mean deviation slope at the final visual field test during the follow-up period. The relationships between the progression of visual field defects and IOP, as well as other clinical factors, were retrospectively analyzed.Results: A total of 156 eyes of 156 patients were included in the analysis. Significant progression of visual field defects was observed in 70 eyes of 70 patients (44.9%), while no significant progression was evident in 86 eyes of 86 patients (55.1%). The eyes with visual field defect progression had significantly lower baseline IOP (P

Shiro Mizoue,1 Tadashi Nakano,2 Nobuo Fuse,3 Aiko Iwase,4 Shun Matsumoto,5 Keiji Yoshikawa6 On behalf of the IOP CHANGE Study Group7 1Department of Ophthalmology, Ehime University Graduate School of Medicine, Ehime, Japan; 2Department of Ophthalmology, Jikei University School of Medicine, Tokyo, Japan; 3Department of Integrative Genomics, Tohoku Medical Megabank Organization, Miyagi, Japan; 4Tajimi Iwase Eye Clinic, Gifu, Japan; 5Department of Ophthalmology, Tokyo Teishin Hospital, 6Yoshikawa Eye Clinic, Tokyo, Japan; 7IOP CHecked and Assessed in Normal tension Glaucoma by Exceptional Glaucomatologists Study Group, Japan Background: This study aimed to evaluate the effect of travoprost with sofZia® preservative system for lowering the intraocular pressure (IOP) of Japanese normal tension glaucoma (NTG) patients. Methods: In this prospective, multicenter, open-label study, Japanese NTG patients with baseline IOPs

Hirotaka Suzumura,1 Keiji Yoshikawa,2 Shiro Mizoue,3 Ryoko Hyodo,4 Tairo Kimura5 1Eye Department, Nakano General Hospital, Tokyo, 2Yoshikawa Eye Clinic, Tokyo, 3Department of Ophthalmology, Ehime University, Ehime, 4Eye Department, Minami Matsuyama Hospital, Ehime, 5Ueno Eye Clinic, Tokyo, JapanBackground: The purpose of this study was to compare retinal sensitivities in normal individuals obtained using the Swedish Interactive Threshold Algorithm Standard (SITA-S) on the Humphrey field analyzer with those obtained using the Dynamic strategy on the Octopus.Methods: Prior to visual field examinations, the background luminance, stimulus size, and exposure time with the Octopus 101 were conformed to the Humphrey field analyzer II settings. Volunteers over 20 years of age without apparent ophthalmic abnormalities were examined with the SITA-S central 30-2 program followed by the Dynamic 32 program. Eye with corrected visual acuity ≥0.8, refraction ≥ −6.0 diopters, and fields with satisfactory levels of reliability in SITA-S and Dynamic were selected.Results: Sixty-seven eyes from 67 normal individuals of mean age 51.3 ± 16.3 (range 22–76) years satisfied the selection criteria and were analyzed. Mean retinal sensitivity was significantly (P < 0.0001) higher with SITA-S (29.0 ± 2.4 dB) than with Dynamic (26.8 ± 2.1 dB). Changes in retinal sensitivity with increasing age were significantly (P = 0.0003) greater with Dynamic (−0.09 ± 0.04 dB/year; 95% confidence interval [CI] −0.10 to −0.08 dB/year) than with SITA-S (−0.07 ± 0.04 dB/year, 95% CI −0.08 to −0.06 dB/year). When classifying the visual field into three areas (central, mid-peripheral, and peripheral), retinal sensitivities with SITA-S were significantly higher in all areas than with Dynamic (P < 0.0001 for all three areas).Conclusion: Differences in Dynamic and SITA-S strategies may contribute to the differences in retinal sensitivities observed in normal individuals.Keywords: time-saving strategy, frequency-of-seeing curve, dynamic, Swedish Interactive Threshold Algorithm Standard, Octopus perimeter, Humphrey field analyzer

Background/aims: This study aimed to investigate and compare the efficacy and safety of first-line and second-line selective laser trabeculoplasty (SLT) in Japanese patients with normal-tension glaucoma (NTG)., Methods: 100 patients with NTG were enrolled in this study. Patients were treated with SLT as a first-line or second-line treatment for NTG. Main outcome measures were intraocular pressure (IOP) reduction rate, outflow pressure improvement rate (ΔOP), success rate at 1 year and complications. Success was defined as ΔOP≥20% (criterion A) or an IOP reduction ≥20% (criterion B) without additional IOP-lowering eye-drops, repeat SLT or additional glaucoma surgeries. The incidence of transient IOP spike (>5 mm Hg from the pretreatment IOP), conjunctival hyperaemia, inflammation in the anterior chamber and visual impairment due to SLT were assessed., Results: A total of 99 patients (99 eyes) were initially enrolled in this study, including 74 eyes assigned to the first-line SLT group and 25 eyes to the second-line SLT group. The mean IOP of 16.3±2.1 mm Hg before SLT decreased by 17.1%±9.5% to 13.4±1.9 mm Hg at 12 months after SLT in the first-line group (p<0.001), and the mean IOP of 15.4±1.5 mm Hg before SLT decreased by 12.7%±9.7% to 13.2±2.0 mm Hg at 12 months after SLT (p=0.005) in the second-line group. Both groups showed significant reductions in IOP. Higher pre-SLT IOP and thinner central corneal thickness were associated with greater IOP reduction. The success rate at 1 year was higher in the first-line compared with the second-line group, with lower pretreatment IOP and the use of IOP-lowering medication before SLT being associated with treatment failure. Most post-treatment complications were minor and transient., Conclusions: SLT may be an effective and safe treatment option for NTG, as either a first-line or second-line treatment., Trial Registration Number: The study was registered in the UMIN-CTR (UMIN Test ID: UMIN R000044059)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: A brimonidine tartrate 0.1%/brinzolamide 1% fixed-dose combination (BBFC) was recently approved for glaucoma and ocular hypertension treatment in Japan. We investigated the efficacy and safety of BBFC used concomitantly with prostaglandin analogs (PG) or a PG/beta-blocker fixed-dose combination (PG/beta FC)., Study Design: This was a prospective, open-label, multicenter study., Patients and Methods: We enrolled Japanese patients with open-angle glaucoma. BBFC (Ailamide) was concomitantly administered to either the PG or the PG/beta FC group, and intraocular pressure (IOP) and safety were evaluated at 4 and 12 weeks. The groups were stratified into low and high IOP baseline groups based on the median baseline IOP., Results: We enrolled 100 patients, 91 of whom completed the 12-week follow-up. The mean ages were 67.1 and 65.7 years in the PG group (n = 45, baseline IOP of 15.7 ± 2.3 mmHg) and the PG/beta FC group (n = 46, baseline IOP of 16.3 ± 2.3 mmHg), respectively. After BBFC administration, IOPs at 4 and 12 weeks were 13.0 ± 2.0 and 13.0 ± 2.6 mmHg (P < 0.0001) in the PG group, respectively, and 13.7 ± 2.4 and 13.7 ± 2.2 mmHg (P < 0.0001) in the PG/beta FC group, respectively. IOP decreased by - 2.0 ± 1.8 mmHg (P < 0.0001) and -1.9 ± 1.4 mmHg (P < 0.0001) in the low baseline PG group (14.1 mmHg) and low baseline PG/beta FC group (14.8 mmHg) at 12 weeks, respectively. Sixteen adverse events were identified, all of which were common and did not affect visual acuity., Conclusions: BBFC can be used concomitantly with PG or PG/beta FC to reduce IOP without serious complications., (© 2023. Japanese Ophthalmological Society.)

Purpose: To examine primary open-angle glaucoma patients after undergoing combined cataract surgery with microhook ab interno trabeculotomy (μLOT-Phaco) or iStent inject W implantation (iStent-Phaco), and then evaluate the surgical outcomes after a minimum of 6 months of follow-up., Methods: Between October 2020 and July 2022, 39 μLOT-Phaco eyes and 55 iStent-Phaco eyes that underwent surgery were evaluated in this retrospective, multicenter comparative case series. Data that included preoperative and postoperative intraocular pressure (IOP), number of glaucoma medications, and occurrence of complications were collected from medical records and then examined. Surgical failure was defined as patients exhibiting a  < 20% reduction in the preoperative IOP or an IOP > 18 mmHg on two consecutive follow-up visits, or when patients were required to undergo reoperation. Success rates were determined based on a Kaplan-Meier survival analysis., Results: At 3, 6 and 12 months postoperatively, there was a significant postoperative reduction in the IOP ( p  < 0.001) and in the medications scores ( p  < 0.001) for both of the groups. In the μLOT-Phaco and iStent-Phaco groups, the probabilities of success at 6 and 12 months were 55.3 and 45.5%, and 48.4 and 45.5% ( p  = 0.38; log-rank test), respectively. In the iStent-Phaco group, there was a significant decrease in the hyphema., Conclusion: Comparable surgical outcomes occurred for both the μLOT and iStent inject W procedures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Onoe, Hirooka, Namiguchi, Mizoue, Hosokawa, Mochizuki, Okada, Tokumo, Okumichi and Kiuchi.)

Purpose: To elucidate the noninferiority of ab interno microhook trabeculotomy (μTLO) using a recently developed reusable stainless spatula-type microhook device to incise the trabecular meshwork to Trabectome (Neomeix, Inc) surgery in terms of the 1-year postoperative outcomes of Japanese patients with glaucoma by means of propensity score analyses., Design: Multicenter, retrospective cohort study., Participants: We enrolled 553 and 392 patients who underwent Trabectome surgery and μTLO, respectively, between January 2014 and March 2020 at 10 facilities., Methods: Logistic regression analysis was conducted to calculate the propensity score, which indicates the likelihood of treatment assignment (Trabectome or μTLO). We set the following factors as outcome-related covariates: age, sex, facility, glaucoma disease types, preoperative intraocular pressure (IOP), glaucoma drug score, mean deviation of Humphrey visual field test results, antithrombotic drug use, the presence or absence of combined cataract surgery, and incision range of the trabecular meshwork (1 or 2 quadrants). We analyzed 4 different methods (matching, inverse probability of treatment weighting [IPTW], stratification, and regression adjustment) using the propensity score. We set 15% as the noninferiority margin based on previous Trabectome meta-analysis results., Main Outcome Measures: The primary outcome was surgical success at 1 year after surgery. We defined surgical success as satisfying all 3 criteria: (1) IOP within 5 to 21 mmHg, (2) IOP reduction of 20% or more from preoperative IOP, and (3) no additional glaucoma surgery., Results: The 95% confidence interval of risk difference of surgical failure in μTLO in reference to Trabectome surgery was -12.1% to +9.5% in matching, -12.7% to +11.1% in IPTW, -12.2 to +7.0 in stratification, and -9.7% to +8.1% in regression adjustment, all of which fell within the predetermined noninferiority margin of 15%., Conclusions: Surgical success of μTLO at 1 year after was not inferior to that of Trabectome surgery., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The Glaucoma Stereo Analysis Study (GSAS) is a multicenter collaborative study of the characteristics of glaucomatous optic disc morphology using a stereo fundus camera. This study evaluated the retinal vessel calibers and correlations using GSAS fundus photographs between retinal vessels and 38 optic nerve head (ONH) morphologic parameters comprehensively. In all 240 eyes, the mean central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were 138.4 and 216.5 μm, respectively; the CRAE correlated with age, visual field scores and 19 ONH parameters and CRVE correlated with age, intraocular pressure, visual field scores and 11 ONH parameters. Among the different optic disc appearances including focal ischemia (FI) (n = 53, 22%), generalized enlargement (GE) (n = 53, 22%), myopic glaucoma (MY) (n = 112, 47%), and senile sclerosis (SS) (n = 22, 9%), the CRAE did not differ significantly; CRVE was significantly narrower in SS than in FI and MY. In FI, GE, MY, and SS disc types, CRAE correlated with 3, 14, 9, and 2 ONH parameters, respectively, and CRVE corelated with 9, 0, 12, and 6 ONH parameters, respectively. We confirmed previous observations on the effect of retinal vessel narrowing on glaucomatous changes in the ONH and visual field. The associations between retinal vessel caliber and ONH morphologic parameters vary among different optic disc appearances, suggesting different effects of vascular changes in each disc type., Competing Interests: Drs. Maki Katai, Yasushi Kitaoka, Yu Yokoyama, Kazuko Omodaka, Tomoko Naito, Takehiro Yamashita, Shiro Mizoue, and Toru Nakazawa used a stereo fundus camera provided by Kowa Company, Ltd., to conduct the study. Drs. Masaki Tanito, Koji Nitta, Yu Yokoyama, and Toru Nakazawa have received lecture honoraria and/or consultation fees from Kowa Company, Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have no conflict to declare.

Purpose: To investigate the reproducibility for the iridocorneal angle evaluations using the pictures obtained by a gonioscopic camera, Gonioscope GS-1 (Nidek Co., Gamagori, Japan)., Methods: The pragmatic within-patient comparative diagnostic evaluations for 140 GS-1 gonio-images obtained from 35 eyes of 35 patients at four ocular sectors (superior, temporal, inferior, and nasal angles) were conducted by five independent ophthalmologists including three glaucoma specialists in a masked fashion twice, 1 week apart. We undertook the observer agreement and correlation analyses of Scheie's angle width and pigmentation gradings and detection of peripheral anterior synechia and Sampaolesi line., Results: The respective Fleiss' kappa values for the four elements between manual gonioscopy and automated gonioscope by the glaucoma specialist were 0.22, 0.40, 0.32 and 0.58. Additionally, the respective intraobserver agreements for the four elements by the glaucoma specialist each were 0.32 to 0.65, 0.24 to 0.71, 0.35 to 0.70, and 0.20 to 0.76; the Fleiss' kappa coefficients for the four elements among the three glaucoma specialists were, respectively, 0.31, 0.38, 0.31, and 0.17; the Fleiss' kappa coefficients for the angle width and pigmentation gradings between the two glaucoma specialists each were 0.30 to 0.35, and 0.29 to 0.43, respectively. Overall, the Kendall's tau coefficients for the angle gradings reflected the positive correlations in the evaluations., Conclusion: Our findings suggested slight-to-substantial intraobserver agreement and slight-to-fair (among the three) or fair-to-moderate (between the two each) interobserver agreement for the angle assessments using GS-1 gonio-photos even by glaucoma specialists. Sufficient training and a solid consensus should allow us to perform more reliable angle assessments using gonio-photos with high reproducibility., Competing Interests: The authors have declared that no competing interests exist.

Aim: To investigate the usefulness of data augmentation in visual field (VF) trend analyses in patients with glaucoma., Method: This study included 6380 VFs from 638 eyes of 417 patients with open-angle glaucoma. Various affine transformations were applied to augment the VF data: (1) rotation, (2) scaling, (3) vertical and horizontal shift and (4) a combination of these different transformations. Using pointwise linear regression (PLR), the total deviation (TD) values of a patient's 10th VF were predicted using TD values from shorter VF series (from first to third VFs (VF1-3) to first to ninth VFs (VF1-9)) with and without VF data augmentation, and the root mean squared error (RMSE) was calculated., Results: With PLR, mean RMSE without VF augmentation averaged from 3.95 (VF1-3) to 19.01 (VF1-9) dB. The RMSE was significantly improved by applying the different transformations: (1) rotation (from VF1-3 to VF1-7), (2) scaling (from VF1-3 to VF1-6), (3) vertical and horizontal shifts (from VF1-3 to VF1-4) and (iv) a combination of these (from VF1-3 to VF1-7). Progression rates in VF1-10 had better agreement with those in shorter VF series when a combination of affine transformation was applied. The differences in rates were between 1.9 (VF1-3) and 0.39 (VF1-9) dB if augmentation was used, which was significantly smaller than that observed when augmentation was not applied (from 2.6 with VF1-3 to 0.26 dB with VF1-9)., Conclusion: It is useful to apply VF data augmentation techniques when predicting future VF progression in glaucoma using PLR, especially with short VF series., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim of the study was to investigate the usefulness of processing visual field (VF) using a variational autoencoder (VAE). The training data consisted of 82,433 VFs from 16,836 eyes. Testing dataset 1 consisted of test-retest VFs from 104 eyes with open angle glaucoma. Testing dataset 2 was series of 10 VFs from 638 eyes with open angle glaucoma. A VAE model to reconstruct VF was developed using the training dataset. VFs in the testing dataset 1 were then reconstructed using the trained VAE and the mean total deviation (mTD) was calculated (mTD VAE ). In testing dataset 2, the mTD value of the tenth VF was predicted using shorter series of VFs. A similar calculation was carried out using a weighted linear regression where the weights were equal to the absolute difference between mTD and mTD VAE . In testing dataset 1, there was a significant relationship between the difference between mTD and mTD VAE from the first VF and the difference between mTD in the first and second VFs. In testing dataset 2, mean squared prediction errors with the weighted mTD trend analysis were significantly smaller than those form the unweighted mTD trend analysis.

Background/aim: We previously reported the benefit of applying binomial pointwise linear regression (PLR: binomial PLR) to detect 10-2 glaucomatous visual field (VF) progression. The purpose of the current study was to validate the usefulness of the binomial PLR to detect glaucomatous VF progression in the central 24°., Methods: Series of 15 VFs (Humphrey Field Analyzer 24-2 SITA-standard) from 341 eyes of 233 patients, obtained over 7.9±2.1 years (mean±SD), were investigated. PLR was performed by regressing the total deviation of all test points. VF progression was determined from the VF test points analyses using the binomial test (one side, p<0.025). The time needed to detect VF progression was compared across the binomial PLR, permutation analysis of PLR (PoPLR) and mean total deviation (mTD) trend analysis., Results: The binomial PLR was comparable with PoPLR and mTD trend analyses in the positive predictive value (0.18-0.87), the negative predictive value (0.89-0.95) and the false positive rate (0.057-0.35) to evaluate glaucomatous VF progression. The time to classify progression with binomial PLR (5.8±2.8 years) was significantly shorter than those with mTD trend analysis (6.7±2.8 years) and PoPLR (6.6±2.7 years)., Conclusions: The binomial PLR method, which detected glaucomatous VF progression in the central 24° significantly earlier than PoPLR and mTD trend analyses, shows promise for improving our ability to detect visual field progression for clinical management of glaucoma and in clinical trials of new glaucoma therapies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: The Glaucoma Stereo Analysis Study (GSAS) is a multicentre collaborative study of the characteristics of glaucomatous optic disc morphology using a stereo fundus camera. Using the GSAS dataset, we previously established a formula for predicting different appearances of glaucomatous optic discs, although the formula lacked validation in an independent dataset. In this study, the formula was validated in another testing dataset., Subjects and Methods: Testing dataset contained three-dimensionally analysed optic disc topographic parameters from 93 eyes with primary open-angle glaucoma; six topographic parameters (temporal and nasal rim-disc ratios, mean cup depth, height variation contour, disc tilt angle and rim decentring absolute value) were used for predicting different appearances of glaucomatous optic discs. The agreement between grader-classified optic disc types, that is, focal ischemic (FI), generalized enlargement, myopic glaucomatous (MY), and senile sclerotic (SS) and formula-predicted optic disc types, that is, pFI, pGE, pMY and pSS, were assessed., Results: Based on this formula, the eyes were classified with pFI (21 eyes, 22.6%), pGE (27 eyes, 29.0%), pMY (26 eyes, 28.0%) and pSS (19 eyes, 20.4%) when the top predictive element based on the formula was considered as the optic disc appearance in each eye. The six topographic parameters used in the formula differed significantly among the four predicted optic disc types. Substantial agreement (κ = 0.7496) was seen for the top two predictive elements based on the formula that agreed with the graders' classification in 76 (81.7%) eyes. Among the four optic disc types, the levels of agreement were relatively lower in the SS type (κ = 0.3863-0.5729) compared with the other three optic disc types (κ = 0.7898-0.8956) even though the unclassifiable and mixed optic disc types were excluded from the testing dataset., Conclusion: The GSAS classification formula can predict and quantify each component of different optic disc appearances in each eye and provide a novel parameter to describe glaucomatous optic disc characteristics., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To compare the success rates of eye drop instillation in the sitting position and supine position among Japanese patients with ocular diseases (cataract, glaucoma, or retinal and vitreous diseases)., Methods: Patients who were hospitalized in Okayama University Hospital for eye surgery were studied. Instillation procedures of each patient in both the sitting and supine positions were recorded using a video camera at the time of instillation. We defined "success" when one drop fell accurately onto the ocular surface at the first attempt. Instillation of two or more drops, drops delivered to a site other than the eye surface, and touching the eyelashes, eyelids, or conjunctiva with the tip of the eye drop bottle were regarded as "failure". We excluded patients with vision below counting finger., Results: One-hundred and two patients (54 males and 58 females, aged 70.2 ± 12.3 years) with ocular disease who were hospitalized for surgery (cataract: 61.8%, glaucoma: 15.7%, retinal and vitreous diseases: 22.5%) were included in this prospective observational study. The mean duration of eye drop use was 3.1 ± 5.2 years. The success rate of eye drop instillation was significantly higher in the supine position than in the sitting position (64.7% vs. 50%, P = 0.0039). The mean age was significantly higher in the failure group than in the success group (74.0 ± 11.5 vs. 67.7 ± 12.4 years, P = 0.0085) for the sitting position, but not significantly different for the supine position (72.3 ± 12.9 vs. 70.1 ± 12.0 years, P = 0.3849). No significant differences in mean duration of drop use, mean corrected VA, and mean spherical equivalent refraction were observed between success and failure groups, for both sitting and supine positions., Conclusions: In the present study, the success rate of eye drop instillation was significantly higher when applied in the supine position than in the sitting position., Competing Interests: The authors have declared that no competing interests exist.

Objective: To determine the effect of botulinum toxin A (BTX-A) on the eyelid pressure in patients with benign essential blepharospasm (BEB)., Methods: Twenty normal volunteers (10 men, 10 women; average age 59.7 ± 11.3 years) and 33 patients (12 men, 21 women; average age 61.1 ± 14.7 years) with BEB were studied. The upper and lower eyelid pressures were measured with a blepharo-tensiometer in the normal subjects (N group). The eyelid pressures and intraocular pressures (IOP) were measured before and after the BTX-A injections in the BEB patients (B group)., Results: The mean eyelid pressure in the N group was 31.0 ± 6.8 mmHg for the upper eyelid and 29.9 ± 6.5 mmHg for the lower eyelid (P > 0.05). The mean eyelid pressure in the B group before treatment was 35.3 ± 7.0 mmHg for the upper eyelid and 37.8 ± 6.6 mmHg for the lower eyelid. The eyelid pressure in the B group was significantly higher than in the N group for the upper and lower eyelids (both P < 0.001). The eyelid pressure was significantly decreased after BTX-A treatment for the upper (29.9 ± 7.5 mmHg) and the lower (32.8 ± 7.0 mmHg) eyelids (both P < 0.001). The mean IOP was 15.1 ± 2.9 mmHg before, and it significantly decreased to 14.5 ± 2.8 mmHg (P = 0.020) after the BTX-A injections. The IOP was significantly correlated with the lower eyelid pressure (P = 0.0435), but not with the upper eyelid pressure (P = 0.175)., Conclusion: The eyelid pressure was higher in the patients with BEB. The eyelid pressure and the IOP were significantly reduced after the BTX-A injections. In addition, the IOPs were significantly correlated with the eyelid pressure of the lower eyelid.

Purpose: To validate the prediction accuracy of variational Bayes linear regression (VBLR) with two datasets external to the training dataset., Method: The training dataset consisted of 7268 eyes of 4278 subjects from the University of Tokyo Hospital. The Japanese Archive of Multicentral Databases in Glaucoma (JAMDIG) dataset consisted of 271 eyes of 177 patients, and the Diagnostic Innovations in Glaucoma Study (DIGS) dataset includes 248 eyes of 173 patients, which were used for validation. Prediction accuracy was compared between the VBLR and ordinary least squared linear regression (OLSLR). First, OLSLR and VBLR were carried out using total deviation (TD) values at each of the 52 test points from the second to fourth visual fields (VFs) (VF2-4) to 2nd to 10th VF (VF2-10) of each patient in JAMDIG and DIGS datasets, and the TD values of the 11th VF test were predicted every time. The predictive accuracy of each method was compared through the root mean squared error (RMSE) statistic., Results: OLSLR RMSEs with the JAMDIG and DIGS datasets were between 31 and 4.3 dB, and between 19.5 and 3.9 dB. On the other hand, VBLR RMSEs with JAMDIG and DIGS datasets were between 5.0 and 3.7, and between 4.6 and 3.6 dB. There was statistically significant difference between VBLR and OLSLR for both datasets at every series (VF2-4 to VF2-10) (P < 0.01 for all tests). However, there was no statistically significant difference in VBLR RMSEs between JAMDIG and DIGS datasets at any series of VFs (VF2-2 to VF2-10) (P > 0.05)., Conclusions: VBLR outperformed OLSLR to predict future VF progression, and the VBLR has a potential to be a helpful tool at clinical settings.

Background/aims: To investigate the usefulness of the Octopus (Haag-Streit) EyeSuite's cluster trend analysis in glaucoma., Methods: Ten visual fields (VFs) with the Humphrey Field Analyzer (Carl Zeiss Meditec), spanning 7.7 years on average were obtained from 728 eyes of 475 primary open angle glaucoma patients. Mean total deviation (mTD) trend analysis and EyeSuite's cluster trend analysis were performed on various series of VFs (from 1st to 10th: VF1-10 to 6th to 10th: VF6-10). The results of the cluster-based trend analysis, based on different lengths of VF series, were compared against mTD trend analysis., Result: Cluster-based trend analysis and mTD trend analysis results were significantly associated in all clusters and with all lengths of VF series. Between 21.2% and 45.9% (depending on VF series length and location) of clusters were deemed to progress when the mTD trend analysis suggested no progression. On the other hand, 4.8% of eyes were observed to progress using the mTD trend analysis when cluster trend analysis suggested no progression in any two (or more) clusters., Conclusion: Whole field trend analysis can miss local VF progression. Cluster trend analysis appears as robust as mTD trend analysis and useful to assess both sectorial and whole field progression. Cluster-based trend analyses, in particular the definition of two or more progressing cluster, may help clinicians to detect glaucomatous progression in a timelier manner than using a whole field trend analysis, without significantly compromising specificity., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: To investigate the success rate of eye drop instillation in glaucoma patients with visual field defect as well as non-glaucoma volunteers. Factors that may affect the success rate of eye drop instillation were also evaluated., Design: A prospective, observational study., Participants: Seventy-eight glaucoma patients and 85 non-glaucoma volunteers were recruited in this study., Methods: Open angle glaucoma patients with visual field defect as well as non-glaucoma volunteers were asked to video record their procedures of eye drop instillation using a 5-mL plastic bottle of artificial tear solution. Success of eye drop instillation was judged on video based on the first one drop of solution successfully applied on the cornea, by two investigators., Main Outcome Measures: Success rate of eye drop instillation in glaucoma patients and non-glaucoma volunteers. Factors related to success rate of eye drop instillation, such as visual field defect and clinical characteristics, were also analyzed using multivariable logistic regression., Results: No significant deference in mean age was observed between two groups (glaucoma: 64.5 ± 14.4 years, non-glaucoma: 60.9 ± 14.1 years, P = 0.1156). Success rate of eye drop instillation was significantly lower (P = 0.0215) in glaucoma patients (30/78; 38.5%) than in non-glaucoma volunteers (48/85; 56.5%). The most frequent reason of instillation failure in glaucoma patients was touching the bulbar conjunctiva, cornea, eyelid or eyelashes with the tip of the bottle (29.5%). Multivariable logistic regression analysis identified lower corrected visual acuity (VA) (≤ 1.0; odds ratio [OR] = 0.20, 95% confidence interval [CI] 0.04-0.93, P = 0.0411), lower mean deviation (MD) (< -12 dB; OR = 0.20, 95% CI 0.05-0.86, P = 0.0307) and visual field defect (VFD) in the inferior hemifield (OR = 0.11, 95% CI 0.02-0.34, P < 0.001) to be significantly related to instillation failure in glaucoma patients., Conclusions: Success rate of eye drop instillation was significantly lower in glaucoma patients than in non-glaucoma volunteers. Corrected VA ≤ 1.0, MD < -12 dB and/or VFD in the inferior hemifield may be related to failure of eye drop instillation.

Background/aim: To investigate the effects of ocular and systemic risk factors for glaucomatous progression in different sectors of the visual field (VF)., Method: 409 eyes from 268 patients with 10 reliable VFs from the Japanese Archive of Multicentral Databases in Glaucoma (JAMDIG) were investigated. VFs were divided into six sectors (mean total deviation (mTD) s20+ , mTD s10-20 and mTD s0-10 , >20°, 10-20° and <10° in the superior hemifield, respectively; and mTD i20+ , mTD i10-20 and mTD i0-10 , >20°, 10-20° and <10° in the inferior hemifield, respectively). The relationship between sectorial progression rate and eight variables (age, mTD at baseline VF, average intraocular pressure (IOP), SD of IOP, systemic hypertension, migraine, family history of glaucoma and smoking status) was investigated., Result: The mTD progression rate was -0.21 dB/year. Older age was related to progression of mTD s20+ , mTD s10-20 , mTD i20+ and mTD i10-20 . Mean IOP was not related to progression in any VF sector; however, a larger SD of IOP was related to progression of mTD s20+ , mTD i0-10 , mTD i10-20 and mTD i20+ . Smoking status was related to progression in all inferior VF sectors (mTD i0-10 , mTD i10-20 and mTD i20+ )., Conclusions: Smoking status is related to glaucomatous VF progression in all sectors of the inferior hemifield., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Introduction: This study compared the efficacy and safety of adjunctive brimonidine tartrate 0.1% ophthalmic solution (brimonidine) and timolol maleate 0.5% ophthalmic solution (timolol) in prostaglandin analogue (PGA)-treated normal-tension glaucoma (NTG), assessing the non-inferiority of brimonidine in terms of intraocular pressure (IOP) reduction., Methods: In this multicenter, randomized, investigator-masked, parallel-group, clinical study, adjunctive brimonidine or timolol was administered twice daily for 12 weeks in eyes with NTG that had been treated with PGA for at least 90 days and required additional treatment despite an IOP of 16 mmHg or less. IOP was measured on at least three visits before add-on therapy (mean baseline IOP), and at weeks 4, 8, and 12 after adjunctive administration. Systolic/diastolic blood pressure, pulse rate, and adverse events (AEs) were recorded at each visit., Results: A total of 152 individuals were enrolled and 128 (84.2%) were eligible for efficacy analyses. IOP in both groups at each visit decreased significantly from baseline (P < 0.001). However, the difference in the change from baseline IOP at week 12 between the brimonidine (-1.05 ± 1.81 mmHg) and timolol (-1.41 ± 1.40 mmHg) groups was 0.36 mmHg (95% confidence interval [CI] [-0.21, 0.92]), which exceeded the value of the non-inferiority margin (0.75 mmHg). Baseline systolic/diastolic blood pressure decreased significantly in both groups at certain visits (P < 0.05), while baseline pulse rates decreased significantly in the timolol group (P < 0.001), with no significant differences in the brimonidine group. AE-related treatment discontinuation occurred in 2/71 (2.8%) and 2/75 (2.7%) patients in the brimonidine and timolol groups, respectively., Conclusion: This study demonstrated an add-on effect of brimonidine to PGAs, although non-inferiority of brimonidine to timolol as adjunctive therapy in PGA-treated NTG in terms of IOP reduction was not observed. Brimonidine was associated with no adverse effects on pulse rate., Funding: Senju Pharmaceutical Co., Ltd., Trial Registration: UMIN Clinical Trials Registry identifier, UMIN000014810.

Purpose: To assess the effect of switching 1 eye to topical travoprost 0.004% preserved with SofZia (TRAVATAN Z solution) in patients who had chronic superficial punctate keratitis (SPK) in both eyes treated with benzalkonium chloride-preserved latanoprost 0.005% (XALATAN)., Methods: This was a prospective, randomized, controlled, multicenter, open-label, comparative 3-month follow-up study. Patients with open-angle glaucoma or ocular hypertension who received XALATAN monotherapy for at least 3 months and had SPK in both eyes were enrolled at 9 facilities. For each patient, 1 eye was randomly selected and switched to TRAVATAN Z solution (T-group); the contralateral control eye was treated with XALATAN (X-group). SPK in 5 corneal regions, conjunctival hyperemia, tear breakup time (TBUT), and intraocular pressure (IOP) were examined in a masked manner at baseline, 1 month, and 3 months. Changes in SPK, hyperemia, TBUT, and IOP were compared within treatment groups and between treatment groups., Results: Fifty-six patients completed the study. The frequency of SPK significantly decreased from baseline in the T-group and the X-group at 1 and 3 months (T-group, P<0.001; X-group, P<0.05). In the T-group, SPK scores were significantly improved in 4 corneal regions, excluding the superior region, at 1 and 3 months (all P<0.05), whereas in the X-group, SPK scores were significantly improved only in the temporal region at 1 month and in the inferior region at 3 months (P<0.05 for both). The total SPK score at 1 and 3 months in the T-group was significantly lower compared with the score in the X-group (P=0.0023 and 0.0102, respectively). The SPK score for the superior and central corneal region at 3 months in the T-group was significantly lower compared with the score in the X-group (P=0.0212 and 0.022, respectively). There were no substantial intergroup or intragroup differences in changes from baseline for hyperemia scores, TBUT, or IOP reduction., Conclusions: Switching therapy from benzalkonium chloride-preserved latanoprost to travoprost preserved with SofZia ameliorated chronic SPK. There were no clinically relevant changes in hyperemia, TBUT, or IOP.

Purpose: To develop a large-scale real clinical database of glaucoma (Japanese Archive of Multicentral Databases in Glaucoma: JAMDIG) and to investigate the effect of treatment., Methods: The study included a total of 1348 eyes of 805 primary open-angle glaucoma patients with 10 visual fields (VFs) measured with 24-2 or 30-2 Humphrey Field Analyzer (HFA) and intraocular pressure (IOP) records in 10 institutes in Japan. Those with 10 reliable VFs were further identified (638 eyes of 417 patients). Mean total deviation (mTD) of the 52 test points in the 24-2 HFA VF was calculated, and the relationship between mTD progression rate and seven variables (age, mTD of baseline VF, average IOP, standard deviation (SD) of IOP, previous argon/selective laser trabeculoplasties (ALT/SLT), previous trabeculectomy, and previous trabeculotomy) was analyzed., Results: The mTD in the initial VF was -6.9 ± 6.2 dB and the mTD progression rate was -0.26 ± 0.46 dB/year. Mean IOP during the follow-up period was 13.5 ± 2.2 mm Hg. Age and SD of IOP were related to mTD progression rate. However, in eyes with average IOP below 15 and also 13 mm Hg, only age and baseline VF mTD were related to mTD progression rate., Conclusions: Age and the degree of VF damage were related to future progression. Average IOP was not related to the progression rate; however, fluctuation of IOP was associated with faster progression, although this was not the case when average IOP was below 15 mm Hg.

Introduction: We examined the sustainability of the intraocular pressure (IOP)-lowering efficacy of travoprost (0.004%) ophthalmic solution in subjects with normal tension glaucoma (NTG)., Methods: Travoprost ophthalmic solution was given once daily at 9 PM to subjects with newly diagnosed NTG or with NTG who had not received any ocular hypotensives within the previous 30 days. IOP was measured at three time points (9 AM, 1 PM, and 5 PM) at baseline and week 12 visits, and at one time point (9 AM) at week 4 and week 8 visits. Conjunctival hyperemia, superficial punctate keratopathy, and other adverse events were evaluated during the observation period., Results: Thirty subjects (12 males and 18 females; mean age 65.6 years) from 32 subjects enrolled were included in the efficacy analysis. The mean IOPs (±standard deviation) of 16.6 ± 1.4, 15.7 ± 1.8, and 15.7 ± 2.2 mmHg at 9 AM, 1 PM, and 5 PM, respectively, at baseline reduced significantly to the mean IOPs of 13.0 ± 1.8, 12.7 ± 1.8, and 12.8 ± 1.6 mmHg, respectively, at week 12 (P < 0.0001 for every time point). Together with the mean IOPs of 13.4 ± 1.9 mmHg at week 4 and 13.2 ± 1.9 mmHg at week 8, the pooled IOP during the observation period for up to 12 weeks showed a statistically and clinically significant reduction of IOP at 9 AM. (3.4 mmHg or 20.3% reduction from baseline, P < 0.0001). There were no adverse events leading to treatment discontinuation., Conclusion: This multi-center collaborative study suggests that IOP-lowering efficacy of travoprost ophthalmic solution persists during the day at the clinically relevant level in subjects with NTG., Funding: Alcon Japan Ltd., Trial Registration: University Hospital Medical Information Network, UMIN ID: 000011621.

Purpose . To quantify changes in anterior segment (AS) parameters after laser peripheral iridotomy (LPI) using AS-optical coherence tomography (OCT) of iris bombe. Method . AS images of eight eyes were captured before and after iris bombe and more than 2 weeks after LPI (post-LPI) using AS-OCT. We compared the following AS parameters: anterior chamber depth (ACD), anterior chamber volume (ACV), iris curvature (IC), iris thickness at 500  μ m from the scleral spur (IT-1) in the middle between the iris root and pupillary margin (IT-2) and 500  μ m from the pupillary margin (IT-3) to the anterior chamber angle (ACA) (angle opening distance [AOD750]), and trabecular iris space area. Results . Mean IT-1 and IT-3, but not IT-2, were lower after iris bombe (IT-1, P = 0.001; IT-2, P = 0.081; and IT-3, P = 0.001). There were no significant differences between ACD at pre-LPI and before iris bombe ( P = 0.096). The mean ACV and AOD750 of iris bombe increased at post-LPI (ACV, P < 0.01, and AOD750, P < 0.05). The mean IT-1, IT-2, and IT-3 increased at post-LPI (all, P ≤ 0.01). IC decreased at post-LPI ( P < 0.001), and ACD at post-LPI did not change. Conclusions . The iris extends and becomes thinner during iris bombe. LPI during bombe decreases the IC and increases the ACV and ACA.

Introduction: The efficacy of lowering intraocular pressure (IOP) and safety of switching to travoprost/timolol fixed combination ophthalmic solution (Duotrav(®), Alcon Laboratories, Inc., Fort Worth, TX, USA) in patients with primary open-angle glaucoma, normal tension glaucoma or ocular hypertension undergoing prostaglandin analog (PGA) monotherapy was investigated., Methods: Patients treated with travoprost, latanoprost, tafluprost, or bimatoprost for ≥3 months and requiring additional medication were switched to Duotrav without washout. Baseline IOP was calculated from measurements at two visits during PGA monotherapy. IOP reductions at 4, 8, and 12 weeks after switching to Duotrav and adverse events were assessed., Results: Of 162 patients enrolled, 157 patients (96.9%) with ≥4 weeks of follow-up after switching to Duotrav were analyzed. The mean IOP decreased significantly (baseline = 16.3 ± 3.1 mmHg; 4 weeks = 14.6 ± 3.1 mmHg, 8 weeks = 14.7 ± 3.3 mmHg, 12 weeks = 14.6 ± 3.2 mmHg; all P < 0.0001). When study eyes were divided into three groups according to baseline IOP (≥19 mmHg: 33 eyes, 21.0%; ≥15 to <19 mmHg: 78 eyes, 49.7%; <15 mmHg: 46 eyes, 29.3%), all groups showed significant IOP reductions (P = 0.0324 ~ P < 0.0001) after switching to Duotrav. Twenty-seven of 166 patients (16.3%) in the safety analysis experienced adverse events and 26/166 patients (15.7%) experienced adverse events, for which a relationship to Duotrav could not be ruled out. Adverse events in five patients led to treatment discontinuation (eye pruritus; eye irritation; increased blood pressure and rash; increased blurred vision; deepening of the eyelid sulcus and blepharoptosis). Twelve weeks after treatment switching, eyelash changes, blepharal pigmentation and deepening of the eyelid sulcus occurred in 42 (26.8%), 29 (18.5%), and 13 (8.3%) cases, respectively, among 157 patients with follow-up. There was no significant worsening from baseline for superficial punctate keratopathy (SPK) or conjunctival hyperemia after switching (SPK score: baseline = 0.58 ± 1.31; 12 weeks = 0.92 ± 1.76, P = 0.1819; conjunctival hyperemia score: baseline = 0.41 ± 0.64; 12 weeks = 0.49 ± 0.63, P = 0.3774)., Conclusion: Our findings confirm that switching to Duotrav(®) in PGA monotherapy patients shows IOP-lowering effect with minimal safety concerns., Funding: Japan Association of Health Service and Alcon Japan. Ltd., Trial Registration: UMIN Clinical Trials Registry identifier, UMIN000007028.

Purpose: To evaluate some clinically important features of benzalkonium chloride (BAK) toxicity by comparing tafluprost with 0.001% BAK and travoprost preserved with SofZia applied to the ocular surface of the eyes with glaucoma., Methods: This was a prospective, randomized, observer unmasked, multicenter crossover trial. A total of 195 patients were randomized and 174 patients completed the study at 19 clinics between November 2011 and August 2012. Topical BAK-preserved tafluprost or SofZia-preserved travoprost was newly administered or continued. Superficial punctate keratopathy (SPK), tear break-up time (BUT), the conjunctival hyperemia score, and intraocular pressure (IOP) were compared at the baseline visit, 4, and 12 weeks after the start of therapy. The eye drops were switched to another eye drop after 12 weeks of observation., Results: The total SPK and conjunctival hyperemia scores were significantly lower in the tafluprost compared with those in the travoprost phase (both P=0.038). There were no significant differences in the SPK scores of the superior area (P=0.679), central area (P=0.089), inferior area (P=0.090), and tear BUT (P=0.271). The IOP-lowering effects were similar (P=0.155)., Conclusions: SPK, hyperemia score, and tear BUT while using tafluprost with 0.001% BAK were not inferior compared with those caused by travoprost with SofZia.

Purpose: To investigate risk factors for initial visual field pattern in normal tension glaucoma (NTG)., Patients and Methods: We studied 107 subjects, who underwent 24-2 or 30-2 Swedish interactive threshold algorithm standard visual fields as part of a multicenter study of newly diagnosed NTG patients. Only the eyes with initial parafoveal scotoma (IPFS) or initial nasal step (INS) Were included. IPFS was defined as a glaucomatous visual field (VF) defect in 1 hemifield (≥ 3 adjacent points with p < 5% within the central 10 degrees of fixation, ≥ 1 point with p < l% lying at the innermost paracentral points, and no VF abnormality outside the central 10 degrees). INS was defined in 1 hemifield (≥ 3 adjacent points with p < 5% in the nasal periphery outside 10 degrees of fixation, the nasal- most point with p < 1%, and no VF abnormality within the central 10 degrees). Clinical characteristics were compared between the 2 groups., Results: Mean untreated intraocular pressure (IOP) (14.0 ± 1.3 vs. 16.0 ± l.4 mmHg; p = 0.0102) was significantly lower in patients with an IPFS than in patients with an INS. There were no significant differences in age (p = 0.6487) or spherical equivalent (p = 0.7561)., Conclusion: Initial visual field pattern of NTG is influenced by untreated IOP level.

Purpose: To compare the morphology of the anterior chamber angle (ACA) and iris in eyes with pseudoexfoliation (PEX) syndrome to that of their clinically unaffected fellow eyes and normal control eyes., Methods: Forty-two patients with unilateral PEX syndrome and 42 normal subjects were studied. Eyes were separated into those with PEX, their clinically unaffected fellow eyes, and normal eyes. The dark-light changes of the ACA and iris were documented by anterior segment optical coherence tomography (AS-OCT) video recordings. The nasal ACA parameters including the angle opening distance at 500 μm (AOD500), the trabecular-iris space at 500 μm (TISA500), and the trabecular-iris angle at 500 μm (TIA500); anterior chamber depth (ACD); iris-lens contact distance (ILCD), and iris configuration were analyzed with the built-in software and a customized program., Results: The ACA parameters were not significantly different among all three groups in the dark. The PEX eyes had significantly smaller ACA parameters than their fellow eyes and normal control eyes in the light. PEX eyes also had significantly shallower ACD, longer ILCD, and greater iris convexity (both in dark and light), and thinner iris (in dark) than their fellow eyes. The fellow eyes had significantly lower ACD both in the dark and light, and smaller angle opening distance at 500 μm and ILCD in the light than normal controls. There were no significant differences in the iris area among the three groups., Conclusions: Differences in the anterior segmental morphology are present between PEX and fellow eyes. These disparities may be related to the asymmetry in patients with the unilateral PEX syndrome.

Purpose: To evaluate the newly developed Ocular Surface Thermographer (TOMEY Corporation) for dry eye screening., Design: Prospective, controlled study., Methods: We studied 30 eyes of 30 patients diagnosed with dry eye (mean age ± standard deviation, 52.9 ± 17.1 years) and 30 eyes of 30 normal subjects (42.7 ± 17.0 years). The ocular surface temperature was measured immediately after eye opening and every second during 10 seconds of eye opening. The reliability of the measurements was determined by calculating intraclass correlation coefficients. Then, the correlations between the change in the ocular surface temperature and tear film break-up time, Schirmer I test values, and fluorescein staining scores were determined., Results: The measurements of the ocular surface temperature had a high degree of reliability. Immediately after eye opening, the temperature in the dry eye did not differ significantly from that in normal eyes in any of the 3 regions tested. The decrease in the ocular surface temperature in dry eyes was significantly greater than that in normal eyes (P < .001) at 10 seconds after eye opening. The decrease in the temperature of the cornea was correlated significantly with the tear film break-up time (r = -0.572; P < .001). When the changes in ocular surface temperature of the cornea were used as an index for dry eye, the sensitivity was 0.83 and the specificity was 0.80 after 10 seconds., Conclusions: Measurements of the ocular surface temperature obtained with our newly developed Ocular Surface Thermographer after 10 seconds of eye opening may provide a simple, noninvasive screening test for dry eyes., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To measure the density of cells in different layers of the cornea and to determine whether morphologic changes of the subbasal corneal nerve plexus are present in eyes with the pseudoexfoliation (PEX) syndrome., Methods: Twenty-seven patients with unilateral PEX syndrome and 27 normal controls were investigated. All eyes underwent corneal sensitivity measurements with an esthesiometer and in vivo confocal microscopic study. Densities of the epithelial, stromal, and endothelial cells were measured. The density and tortuosity of the subbasal corneal nerve plexus were also evaluated., Results: Eyes with PEX syndrome had significantly lower cell densities in the basal epithelium (P = 0.003), anterior stroma (P = 0.007), intermediate stroma (P = 0.009), posterior stroma (P = 0.012), and endothelium (P < 0.0001) than in the corresponding layers of normal eyes. PEX eyes also had lower subbasal nerve densities and greater tortuosity of the nerves than normal eyes. Fellow eyes of patients with PEX also had significantly lower densities of the basal epithelial and endothelial cells than the normal eyes. Corneal sensitivity was significantly decreased in PEX eyes, and this was significantly correlated with the decrease of basal epithelial cell and subbasal nerve densities., Conclusions: These results have shed light on understanding of the pathogenesis of decreased corneal sensitivity in eyes with PEX syndrome. PEX syndrome is probably a binocular condition for which keratopathy of the fellow eye also requires observation.

Purpose: Eye drops of carbonic anhydrase inhibitor (Brinzolamide) are known to case blurred vision after instillation. Using tear film stability analysis system (TSAS) and functional visual acuity measurement (FVAM) we studied the mechanism of blurred vision., Methods: Ten healthy volunteers were studied. Before instillation of brinzolamide 1%, immediately after and at 3, 5, 10 minutes after 1 minutes eye-closure after instillation the breakup index (BUI) of TSAS and FVAM were measured., Results: Before instillation of brinzolamide 1%, immediately after and at 3, 5, 10 minutes since 1 minutes eye-closure after instillation the BUI of TSAS was 88.3 +/- 1.2, 38.5 +/- 7, 72.1 +/- 4.2, 78.8 +/- 5.1, 83.7 +/- 2.2 respectively, and the FVAM was 1.013 +/- 0.0047, 0.925 +/- 0.029, 1 +/- 0.0075, 1.007 +/- 0.0072, 1.015 +/- 0.0052 respectively. Immediately after 1 minutes eye-closure both BUI and FVAM were low. From 3 minutes after instillation both BUI and FVAM recovered., Conclusions: It is suggested that blurred vision after instillation of brinzolamide 1% is associated with the unstableness of tear film. Analyses by TSAS and FVAM are useful to determine both the vision improvement and pharmacokinetics after instillation.

Background: Two cases of West syndrome demonstrated changes in intraocular pressure (IOP) associated with adrenocorticotropic hormone (ACTH) therapy., Cases: A nine-month-old (Case 1) and a six-month-old (Case 2) female infant were treated for West syndrome. In Case 1, the IOP was 14 mmHg in the right eye and 16 mmHg in the left eye before ACTH therapy was started. Although the IOP did not change at the beginning of the treatment, it rose to 36 mmHg in the right eye and 25 mmHg in the left eye after an increase in ACTH dosage. In Case 2, the IOP was 10 mmHg in the right eye and 9 mmHg in the left eye before ACTH therapy, it increased to 18 mmHg in both eyes after treatment was started. The IOP returned to baseline levels in both cases after ACTH therapy concluded., Conclusion: These findings suggest that it is necessary to monitor IOP when ACTH therapy is given to patients with West syndrome.

Purpose: Using a tear film stability analysis system (TSAS), we analyzed the tear film with regard to blurred vision after instillation of 0.5% timolol gel-forming solutions., Methods: Tear film stability was recorded before and after instillation of timolol gel-forming solutions in 9 healthy volunteers (age: 30 +/- 5.6 years; mean +/- SD). Thermosetting gel (Rysmon TG), ion-activated gel (Timoptol XE), or conventional timolol solutions (Timoptol or TIMABAK which does not contain an antiseptic) was applied to only one eye at a time. The subject was administered a single instillation. After instillation, the subject closed his eyelid for one minute. TSAS was carried out immediately after the subject opened his eye. TSAS was also carried out 3 minutes, 5 minutes and 10 minutes after the subject had opened his eye. The grade of blurred vision after each test was evaluated in 5 levels., Results: The tear film was remarkably unstable just after the opening of the eyelids following instillation of Rysmon TG or Timoptol XE. On the breakup map, the most unstable area of the cornea was the lower part after instillation of Rysmon TG, and the center, after instillation of Timoptol XE. In the breakup index (range 0-100), where the high portion showed stability, both gels were low (p < 0.05). Timoptol XE was lower than Rysmon TG (p < 0.05). For timolol gel forming solutions, the index 5 minutes after eye-opening was lower than before instillation. As compared with before instillation, blurred vision increase just after the opening of the eyelids following instillation of Rysmon TG or Timoptol XE, and blurred vision increased at 3 minutes after opening of the eyelids following instillation of Timoptol XE., Conclusion: It seems that the analysis by TSAS was useful to measure the effect on visual performance and the pharmacokinetics after the instillation of the gel-forming solutions.

Purpose: Many studies have reported the relationship between facial morphology and stomatognathic functions. The steepness of the articular eminence is an important morphological factor to determine the mandibular movement or mandibular positioning. The present study analyzed the relationship between the condylar displacement during clenching and the condylar guide inclination related to simulated loss of posterior occlusal support., Methods: Nineteen clinical residents (4 females and 15 males, 24-31 years old) with healthy natural dentitions were recruited as subjects. To change the posterior occlusal support, occlusal splints fitted to maxillary dental arches were cut in sequence from the posterior toward the anterior side. The condylar displacements during maximum voluntary clenching under every occlusal condition were measured using a mandibular movement analyzing system with six-degrees of freedom. The sagittal condylar guide inclination was also measured using the same apparatus., Results: 1. A greater loss of posterior occlusal support was associated with increased displacement distance of both condyles, however these values varied with the subject. 2. A significant positive correlation was observed between the displacement distance without splint and the relative displacement distance with splint (difference between before and after loss of occlusal supports). 3. A significant negative correlation was observed between the displacement distance without splint and the sagittal condylar guide inclination, and was also observed between the relative displacement distance with splint (above-mentioned) and the sagittal condylar guide inclination., Conclusion: These results suggest that the sagittal condylar guide inclination is an important factor in condylar displacement during clenching.

Purpose: To investigate the role of angiotensin II (Ang II) receptor subtypes in subconjunctival injury., Methods: A wound-healing model was developed by subconjunctival blunt dissection in male wild-type, AT1a receptor-deficient (AT1aKO) and AT2 receptor-deficient (AT2KO) mice. Collagen deposition and cell infiltration were evaluated histologically. Expression of collagen, matrix metalloproteinase (MMP), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were determined by real-time PCR., Results: Subconjunctival injury increased the infiltration of inflammatory cells, collagen deposition in the subconjunctival space, and the expression of collagen type I and type III, TIMP-1 and MMP2. In AT1aKO mice, collagen deposition, cell infiltration, and expression of collagen and TIMP-1 were inhibited, but MMP2 expression was enhanced. In contrast, in AT2KO mice, the increase in collagen deposition, cell infiltration, and expression of collagen and TIMP-1 were further enhanced., Conclusions: These results indicate that AT1a and AT2 receptor stimulation may in addition to other mechanisms be antagonistically involved in the wound-healing process after subconjunctival injury.

Background: We report a successful treatment by plasma exchange(PE) in the case of Miller Fisher syndrome., Case: A 71-year-old woman rapidly developed diplopia and unsteady gait, and was admitted to Minami-matsuyama Hospital on day 3 of her illness. Ophthalmological and neurological examination on admission revealed bilateral complete external ophthalmoplegia with moderate mydriasis, cerebellar ataxia, and weakness of biceps reflexs, but her consciousness was intact. Protein concentration in the cerebrospinal-fluid was slightly increased and serum anti-GQlb IgG antibody was positive. With the diagnosis of Miller Fisher syndrome, PE was carried out on days 12, 14, and 16. After PE, ophthalmoplegia and cerebellar ataxia improved markedly. The ocular symptoms resolved after a month., Conclusion: The findings indicate that PE is a beneficial treatment in Miller Fisher syndrome during the acute phase of the disease.

Purpose: Selective laser trabeculoplasty (SLT) is a new laser procedure using a frequency-doubled Q-switched Nd: YAG laser (wavelength: 532 mm). The laser parameters are set to selectively target pigmented trabecular meshwork (TM) cells without coagulative damage to the TM structure or non-pigmented cells. We investigated the safety and efficacy of SLT in lowering intraocular pressure (IOP)., Subjects and Method: Sixty-seven eyes of 67 patients with uncontrolled open angle glaucoma were treated with the Coherent Selecta 7000 (Coherent Inc., Palo Alto, CA). Nineteen of 67 patients had previously received argon laser trabeculoplasty (ALT). A total of approximately 60 non-overlapping spots were placed over 180 degrees of the TM ranging from 0.5 to 1.0 mJ per pulse. The maximum energy level at which no bubble formation was observed determined choice., Results: The average preoperative IOP was 22.4 mmHg. Six months after the operation, mean IOP reduction was 4.4 mmHg, and mean outflow pressure (OP) reduction was 38.1%. One month after the operation 68.7% of patients responded to treatment with an OP reduction of at least 20% ("responders"). Transient IOP elevation of 5 mmHg or greater was seen in 25.4% of patients. The success rate at 6 months after operation was 64.6% for all patients (67 eyes) and 78.2% for the responders (46 eyes). An analysis using a Cox proportional hazard model showed that a low preoperative IOP was the significant determinant for success, and the hazard ratio for the IOP increase of 5 mmHg was 2.12. Other factors such as age, gender, past history of ALT, and goniopigment were not significantly related to success., Conclusion: SLT appears to be a safe and effective way to lower IOP.

Purpose: To evaluate changes in the ciliary body during accommodation using an ultrasound biomicroscope (UBM)., Subjects and Methods: Eleven healthy persons, aged from 24 to 33 years, served as subjects. They were asked to lie in the supine position and to fixate a target placed on the ceiling 2 m above with the left eye. A concave lens with the power of -6 to -8 diopters was then placed before the fixating left eye. The thickness of the ciliary body in the right eye was measured by UBM in the nonaccommodative and accommodative states., Findings: The anterior chamber in the right eye became significantly shallow during accommodation. The thickness of the ciliary body significantly increased during accommodation at 0.5 mm and 1.0 mm posterior to the scleral spur. It significantly decreased at 2.0 mm, 2.5 mm and 3.0 mm posterior to the scleral spur., Conclusion: During induced accommodation in the left eye, the anterior portion of the ciliary body in the right eye increased and the posterior portion decreased in thickness. The findings imply that the circular ciliary muscles are mainly involved in accommodation and not the longitudinal muscles.