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

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

Associations between changes in radial peripapillary capillaries and occurrence of disc hemorrhage in normal-tension glaucoma.

PURPOSE: In order to clarify the association between peripapillary vascular changes and disc hemorrhage (DH) occurrences over time, we analyzed the density of radial peripapillary capillary (RPC) and clinical parameters during follow-up periods in patients with normal-tension glaucoma (NTG). METHODS: Seventy-seven eyes of 77 NTG patients were subjected to analysis. We selected patients who had an initial optical coherence tomography angiography (OCTA) scan in 2015 and who had another OCTA scan in 2018 with both OCTA scans showing good-quality images. We investigated the relationships between DH occurrence and each of the following parameters: RPC density, circumpapillary retinal nerve fiber layer (cpRNFL) thickness slope and total deviation (TD) slope. RESULTS: In the period between the initial and final OCTA, we categorized the patients into 53 sides with DH (DH group) and 101 sides without DH (non-DH group). The ΔRPC density of sides with DH was significantly greater than that of sides without DH (DH, - 4.42 ± 6.43%; without DH, - 2.48 ± 5.29%; p = 0.0469). The cpRNFL thickness slope of sides with DH was significantly faster than that of sides without DH (DH, - 2.85 ± 3.17; without DH, - 0.74 ± 2.46 µm/y; p < 0.0001). The TD slope of sides with DH was significantly faster than that of sides without DH (DH, - 0.50 ± 0.77; without DH, - 0.22 ± 0.53 dB/y; p = 0.0163). As DH occurrence increased, the RPC density significantly decreased (r = -0.255, p = 0.0014). Stepwise multiple regression analysis to identify factors influencing RPC changes showed that frequency of DH (ß = - 0.224, p = 0.008) and central corneal thickness (ß = - 0.220, p = 0.009) were significantly associated with RPC changes. CONCLUSIONS: DH occurrence may prompt the structural and vascular deterioration of NTG.

Estimation of the Disc Damage Likelihood Scale in primary open-angle glaucoma: the Glaucoma Stereo Analysis Study.

PURPOSE: The Glaucoma Stereo Analysis Study (GSAS), a cross-sectional multicenter collaborative study, used a stereo fundus camera (nonmyd WX) to assess various morphological parameters of the optic nerve head (ONH) in glaucoma patients. We examined the associations between the Disc Damage Likelihood Scale (DDLS), a grading system for estimating glaucomatous ONH damage, and each parameter. METHODS: The study included 187 eyes of 187 patients with primary open-angle glaucoma or normal-tension glaucoma. ONH morphological parameters including the DDLS stage were calculated with prototype analysis software. Three independent graders classified each optic disc appearance into four different types: focal ischemic, myopic glaucomatous, senile sclerotic, and generalized enlargement. The correlations between the DDLS and patient characteristics or each ONH parameter were analyzed with Spearman's rank correlation coefficient. RESULTS: The DDLS was correlated positively with baseline intraocular pressure and visual field pattern standard deviation, and negatively with visual field mean deviation. The DDLS was strongly correlated with vertical cup-to-disc ratio and horizontal cup-to-disc ratio positively, and with minimum rim-disc ratio negatively. The mean DDLS stage in the myopic glaucomatous type tended to be higher than the scores in other types. CONCLUSION: The DDLS obtained through three-dimensional ONH analysis correlates well with the severity of glaucomatous ONH and visual field damage.

Efficacy and safety of first-line or second-line selective laser trabeculoplasty for normal-tension glaucoma: a multicentre cohort study.

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).

[Results of selective laser trabeculoplasty (SLT) as initial treatment for normal tension glaucoma].

PURPOSE: A 3-year prospective study was performed to evaluate treatment outcomes following selective laser trabeculoplasty (SLT) used as initial treatment for normal tension glaucoma (NTG). SUBJECTS AND METHODS: SLT was performed as initial treatment in 42 NTG patients (42 eyes). Thirty-seven of the patients were untreated and 5 patients had discontinued antiglaucoma medications. Two patients were excluded because they did not visit our clinic during the study period. The study was conducted on the remaining subjects (40 eyes of 40 patients). RESULTS: The intraocular pressure (IOP) was 15.8 +/- 1.8 mmHg before SLT, 13.2 1.9 mmHg after one year, 13.5 +/- 1.9 mmHg after two years, and 13.5 +/- 1.9 mmHg after three years. The IOP after SLT was significantly lower than that before SLT. One month after SLT, the outflow pressure was improved at least 20% (deltaOP) in 92.5% of the patients. The success rate for the effect of IOP reduction at three years after SLT was 40.0% by Kaplan-Meier survival analysis. 27.5% of the patients who had two consecutive deltaOP less than 20%, 25.0% of the patients who had begun antiglaucoma ophthalmic solution, and 15.0% of the patients who had undergone repeated SLT were judged to have reached the endpoint. Kaplan-Meier survival analysis revealed that the success rate for the visual field at three years after SLT was 82.4% (the visual field loss progression was judged to have reached its endpoint when a significant sensitivity loss was first detected in two consecutive points of the same adjacent test points of at least 3 points in the Glaucoma Progressive Analysis for the Humphrey Visual Field Analyzer). Complications included conjunctival hyperemia (52.5%), eye discomfort (12.5%), visual disturbance (blurry vision and photophobia) (10.0%), and eye pain (5.0%). These complications resolved within a few days, and there were no severe complications such as increased IOP or iritis. CONCLUSION: Our results suggest that SLT is an effective initial treatment for NTG.

Association between Glaucoma Progression in Macular Ganglion Cell Complex and Disc Hemorrhage: Differences between Superior and Inferior Hemiretinas.

Disc hemorrhage (DH) is often associated with glaucoma progression. A vertically asymmetrical pattern is typical of glaucoma progression, but it remains unclear whether the association between DH and glaucoma progression differs between the superior and inferior hemiretinas. We compared the thickness changes of the macular ganglion cell complex (GCC) in the hemiretinas of normal-tension glaucoma patients with or without DH, as well as between hemiretinas positive and negative for DH, during five years. Both the superior and inferior hemiretinas in the DH-positive group had a more negative GCC thickness slope in association with more DH counts compared to those in the DH-negative group. Conversely, only the inferior hemiretina exhibited a significant relationship between GCC thickness slope and DH counts when hemiretinas positive and negative for DH in the DH-positive group were compared. In the superior hemifield, the slope of the total deviation changes in the DH-positive hemifield of the DH-positive group was more negative compared to that of the DH-negative group. The association between DH and glaucoma progression in the macular GCC may be stronger in the inferior hemiretina, suggesting that more attention should be paid to DH in the inferior disc area as a sign of glaucoma progression.

[Relationship between the frequency of disc hemorrhage and the enlargement of nerve fiber layer defects and the deterioration speed of visual field loss in normal-tension glaucoma with wedge-shaped nerve fiber layer defects].

PURPOSE: To examine progressive visual field loss in relation to disc hemorrhage (DH) and enlarged nerve fiber layer defects (NFLDs) in normal-tension glaucoma (NTG). SUBJECTS AND METHODS: There were 106 eyes of 106 NTG patients (mean follow-up: 9.1 years) with well-defined NFLD borders and at least 3 years of follow-up. Examination was performed on their rate of visual field loss (MD slope and hemifield TD slope) and their rate of NFLD angle enlargement. For the NFLD angle, we took color fundus photographs and converted color photos into black-white photos extracted the blue ingredient. The midpoint between the fovea and the disc center was determined. The center was established as the disc, and the distance to the midpoint was established as the radius of a circle. The NFLD angle was defined as the angle formed by the two points where this circle intersected the NFLD and a third point which was the disc center. RESULTS: DH was seen in 51/106 (48.1%)cases and it occurred 1.28 +/- 1.99 times. In the DH group, the MD slope was -0.30 dB/year, indicating a significantly faster rate of visual field loss than that of the non-DH group (-0.13 dB/year); the rate of NFLD enlargement was 1.90 degrees/year, indicating a significantly faster rate than that of the non-DH group at 0.64 degrees/year. As the occurrence of DH increased, the TD slope (r = -0.263, p = 0.0056) and the rate of NFLD enlargement (r = 0.410, p<0.0001) increased significantly. CONCLUSION: Examination was performed on NTG eyes with well-defined NFLD borders which were divided into the groups of with and without DH. The DH eyes had a faster rate of NFLD enlargement and faster progression of visual field loss compared with the non-DH eyes. In addition, the rate of NFLD enlargement and progression of visual field loss increased in the cases with frequent DHs.

Intraobserver and interobserver agreement among anterior chamber angle evaluations using automated 360-degree gonio-photos.

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.

Characterization of laser speckle flowgraphy pulse waveform parameters for the evaluation of the optic nerve head and retinal circulation.

To characterize laser speckle flowgraphy (LSFG) pulse waveform parameters for ocular circulation evaluation, a multicenter, prospective, cross-sectional study was conducted in 111 eyes of 86 healthy Japanese individuals. Optic nerve head (ONH) tissue-area, vessel-area mean blur rate (MT and MV, respectively), and MT and MV pulse waveform parameters were obtained using LSFG and ONH structural parameters using planimetry. Multivariate linear mixed-effects modeled regression analysis identified factors contributing to MT- or MV-waveforms using age, gender, smoking history, body mass index, systolic and diastolic blood pressure, heart rate, intraocular pressure, axial length, disc, rim, and ß-peripapillary atrophy areas, MT or MV, central retinal artery, and vein equivalents (CRAE and CRVE) as explanatory variables. MT- and MV-waveforms significantly correlated with one or more systemic factors, consistent with previous studies. Following confounding factor adjustment, MT-Skew significantly negatively correlated with ß-PPA area (P = 0.026); MT- and MV-flow acceleration index positively correlated with CRAE, MT, and MV (P = 0.041-< 0.001), compatible with these parameters' observed correlations to systemic factors. Significantly negative correlations of the blowout score and acceleration time index to CRAE partly conflicted with their correlations to systemic factors, and other waveform parameters showed little correlation to ocular factors. Thus, Skew and flow acceleration index assisted the in vivo ocular circulation characterization.

Comparing Perimetric Loss at Different Target Intraocular Pressures for Patients with High-Tension and Normal-Tension Glaucoma.

PURPOSE: To compare forecasted changes in mean deviation (MD) for patients with normal-tension glaucoma (NTG) and high-tension open-angle glaucoma (HTG) at different target intraocular pressures (IOPs) using Kalman filtering, a machine learning technique. DESIGN: Retrospective cohort study. PARTICIPANTS: From the Collaborative Initial Glaucoma Treatment Study or Advanced Glaucoma Intervention Study, 496 patients with HTG; from Japan, 262 patients with NTG. METHODS: Using the first 5 sets of tonometry and perimetry measurements, each patient was classified as a fast progressor, slow progressor, or nonprogressor. Using Kalman filtering, personalized forecasts of MD changes over 2.5 years' follow-up were generated for fast and slow progressors with HTG and NTG with IOPs maintained at hypothetical IOP targets of 9 to 21 mmHg. Future MD loss with different percentage IOP reductions from baseline (0%-50%) were also assessed for the groups. MAIN OUTCOME MEASURES: Mean forecasted MD change at different target IOPs. RESULTS: The mean (± standard deviation) patient age was 63.5 ± 10.5 years for NTG and 66.5 ± 10.9 years for HTG. Over the 2.5-year follow-up, at target IOPs of 9, 15, and 21 mmHg, respectively, the mean forecasted MD losses for fast progressors with NTG were 2.3 ± 0.2, 4.0 ± 0.2, and 5.7 ± 0.2 dB; for slow progressors with NTG, losses were 0.63 ± 0.02, 1.02 ± 0.03, and 1.49 ± 0.07 dB; for fast progressors with HTG, losses were 1.8 ± 0.1, 3.4 ± 0.1, and 5.1 ± 0.1 dB; and for slow progressors with HTG, losses were 0.55 ± 0.06, 1.04 ± 0.08, and 1.59 ± 0.10 dB. Fast progressors with NTG had greater MD decline than fast progressors with HTG at each target IOP (P ≤ 0.007 for all). The MD decline for slow progressors with HTG and NTG were similar (P ≥ 0.24 for all target IOPs). Fast progressors with HTG had greater MD loss than those with NTG with 0%-10% IOP reduction since baseline (P ≤ 0.01 for all), but not 25% (P = 0.07) or 50% (P = 0.76) reduction since baseline. CONCLUSIONS: Machine learning algorithms using Kalman filtering techniques demonstrate promise at forecasting future MD values at different target IOPs for patients with NTG and HTG.

Stratification-Based Investigation of Adjunctive Brimonidine or Timolol to a Prostaglandin Analogue in Japanese Patients with Normal-Tension Glaucoma.

PURPOSE: 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 ß-blockers for glaucoma treatment.

Ocular and Systemic Factors Affecting Laser Speckle Flowgraphy Measurements in the Optic Nerve Head.

Purpose: To investigate the ocular and systemic factors related to glaucoma and to be adjusted for interindividual comparison of ocular blood flow measurement results by laser speckle flowgraphy (LSFG) obtained from the optic nerve head (ONH) in normal Japanese individuals. Methods: A multicenter, prospective cross-sectional study was conducted. The ONH tissue-area and vessel-area mean blur rate (MT and MV) were evaluated using LSFG and ONH structural parameters using planimetric methods. Multivariate linear mixed-effects modeled regression analysis was used to identify the contributing factors to the MT and MV. The explanatory variables were age; gender; smoking history; body mass index; mean arterial pressure (MAP); heart rate; intraocular pressure; axial length (AL); disc, rim, cup, and ß-peripapillary atrophy (ß-PPA) areas; and central retinal artery and vein equivalents. Results: In total, 195 eyes of 126 healthy individuals with an average age of 48.1 years were included. Multivariate analysis showed that MAP and disc area had a negative (P < 0.001) correlation, whereas ß-PPA area had a positive correlation with MT (P = 0.010). Age and AL had a negative correlation (P = 0.001 and P = 0.011, respectively), whereas cup area had a positive correlation (P = 0.012) with MV. Conclusions: Interindividual comparison of MT or MV must be adjusted for both systemic factors (blood pressure or age) and local ocular factors (AL and disc, cup, or ß-PPA area). Translational Relevance: Our results provided reference data on the LSFG measurement and are important in comparing ocular blood flow between individuals using LSFG.

Comparisons between retinal vessel calibers and various optic disc morphologic parameters with different optic disc appearances: The Glaucoma Stereo Analysis Study.

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.

iStent Trabecular Micro-Bypass Stent Implantation with Cataract Surgery in a Japanese Glaucoma Population.

INTRODUCTION: This study assesses two-year efficacy and safety following implantation of a single trabecular micro-bypass stent (iStent®) with concomitant phacoemulsification cataract surgery in Japanese patients with open-angle glaucoma (OAG). MATERIALS AND METHODS: This retrospective, consecutive case series included eyes that underwent iStent implantation with phacoemulsification and were followed for 24 months postoperative. Efficacy and safety measures included intraocular pressure (IOP), number of glaucoma medications, adverse events, secondary surgeries, visual fields, and endothelial cell counts. RESULTS: Of 73 operated eyes, 53 eyes had 24 months of follow-up and are analyzed. Diagnoses included primary open-angle glaucoma (POAG, n=25), normal-tension glaucoma (NTG, n=16), and pseudoexfoliative glaucoma (PXG, n=12). At 24 months, mean IOP reduced by 18% to 13.6±3.0 mmHg versus 16.5±3.4 mmHg preoperatively (p<0.0001), and mean medication number reduced by 81% to 0.37±0.74 versus 1.96±0.98 preoperatively (p<0.0001). The percentage of medication-free eyes was 77% versus 0% preoperatively, and 81% of eyes had IOP ≤15 mmHg versus 42% preoperatively. Results were similarly favorable across glaucoma subtypes (POAG, NTG, PXG). Notably, mean IOP in NTG eyes decreased to 12.8±1.4 mmHg from 14.4±3.0 mmHg preoperatively (p=0.03), and medications decreased by 87% to 0.31±0.70 versus 2.38±0.72 preoperatively (p<0.0001). At 24 months, 81% of NTG eyes were medication-free (versus 0% preoperatively); 2 NTG eyes (13%) were on ≥2 medications (versus 100% preoperatively). Throughout the follow-up, visual fields and endothelial cell counts remained stable; 1 eye (1.9%) underwent filtration surgery. DISCUSSION: Favorable safety and significant IOP and mediation reductions were achieved through two years following iStent implantation with phacoemulsification in a Japanese population. These gains were achieved across all glaucoma subtypes (including POAG, NTG, PXG). CONCLUSION: This real-world study supports the viability of iStent implantation to treat Japanese patients with glaucoma and shows that the benefits extend to those with NTG or PXG in addition to POAG.

The Effect of Brimonidine 0.1% on Disc Hemorrhage in Primary Open-Angle Glaucoma Patients.

BACKGROUND: This retrospective study evaluated the effect of adjunctive administration of brimonidine 0.1% on disc hemorrhage (DH) in patients with primary open-angle glaucoma or normal-tension glaucoma who were already treated with other anti-glaucoma drugs. METHODS: Patients with DH, before adjunctive therapy with brimonidine, were enrolled. Subjects were excluded if their treatment regimen was changed within 1 year after initiation of adjunctive therapy with brimonidine. We investigated the frequency of DH and intraocular pressure (IOP). Both parameters were compared before and after adjunctive administration of brimonidine. RESULTS: The frequency of DH before and after brimonidine administration was 0.67±0.68 and 0.31±0.72 times/year, respectively, with a significant decrease (P=0.01), and the mean IOP before and after brimonidine administration was 12.5±1.9 and 11.2±2.2 mmHg, respectively, (P=0.0006) with a significant reduction after adjunctive administration. CONCLUSION: The results of this study supported the hypothesis that the frequency of DH is reduced by brimonidine alongside lowering of IOP.

Predicting Lifetime Transition Risk of Severe Visual Field Defects Using Monte Carlo Simulation in Japanese Patients with Primary Open-Angle Glaucoma.

PURPOSE: To maintain visual fields and quality of life over a lifetime, medical practice must be conducted taking into consideration not only visual field progression but also future visual field changes that occur over the patients' expected lifespan. The purpose of this study is to investigate the feasibility of establishing a model that predicts prognosis, estimating the proportion of glaucoma patients with severe visual field defects. PATIENTS AND METHODS: The data of 191 patients with primary open-angle glaucoma, with a predominance of normal-tension glaucoma, were used for this study. The model was developed based on patients' backgrounds and risk factors, using Monte Carlo simulation. A "severe visual field defect" was defined as ≤-20 dB. The mean deviation (MD) value for 10,000 virtual patients in each simulation pattern (144 patterns) was calculated using a predictive formula to estimate the MD slope, and the effects of risk factors and intraocular pressure (IOP) reduction on the proportion of patients with severe visual field defects were evaluated. RESULTS: Younger age, later-stage disease, more severe glaucomatous structural abnormalities and the presence of disc hemorrhage were associated with an increase in the progression rate of patients with severe visual field defects. Conversely, lower IOP was associated with a decrease in this rate. CONCLUSION: Combining regression analysis with Monte Carlo simulation could be a useful method for developing predictive models of prognosis in glaucoma patients.

[Two familial cases of optic nerve hypoplasia including superior segmental optic hypoplasia].

PURPOSE: To report two familial cases of optic nerve hypoplasia including superior segmental optic hypoplasia (SSOH). CASES: In Family 1, case 1 and case 2 were sisters. In Family 2, case 3 was the mother of case 4 and the younger sister of case 5. The cases in Family 1 had SSOH in one eye, whereas Family 2 showed various patterns of SSOH, as well as nasal optic nerve hypoplasia, and a wide range of optic nerve hypoplasia. Case 1 and case 3 were diagnosed as normal tension glaucoma and treated with eye drops at a previous hospital. None of the cases had any systemic illness. The father of cases 1 and 2, and the father of Cases 3 and 5 were under treatment for type 2 diabetes mellitus. CONCLUSION: In this study, SSOH seemed to be prevalent among family members. In addition, as the cases in Family 2 illustrate, hypoplasia of the optic nerve showed various patterns in the superior segment, nasal segment, and over a wide range of the optic nerve. Therefore SSOH was just one part of the overall optic nerve hypoplasia.

The Relationship Between Interocular Asymmetry of Visual Field Defects and Optic Nerve Head Blood Flow in Patients With Glaucoma.

PURPOSE: To investigate the association between asymmetry of visual field (VF) defects and optic nerve head (ONH) blood flow in patients with glaucoma using laser speckle flowgraphy. METHODS: In total, 170 eyes of 85 patients with primary open-angle glaucoma were included. Intraocular pressure, VF (Humphrey 24-2, SITA program), mean blur rate in the tissue area (MBR-T) of the ONH measured by laser speckle flowgraphy, axial length, circumpapillary retinal nerve fiber layer thickness (cpRNFLT), disc area, cup/disc area ratio, and parapapillary atrophy (PPA) area was measured in each eye. The paired eyes were divided into better and worse eyes according to the mean deviation (MD) of VF, and intereye differences of various parameters (better MD eye minus worse MD eye) were examined. Factors associated with MD difference, MBR-T difference, or cpRNFLT difference were investigated. RESULTS: MD of the VF in better and worse eyes were -10.2±7.3 dB and -16.8±7.4 dB, respectively. In stepwise multiple regression analysis, MBR-T differences, cpRNFLT differences and sex (male) were significantly correlated with MD differences (ß, 0.26, 0.21, 0.20; P=0.01, 0.04, 0.047, respectively). MD differences were significantly associated with MBR-T differences (ß, 0.28; P=0.01). For cpRNFLT differences, differences in ß-PPA area and MD differences were identified as significant factors (ß, -0.26, 0.22; P=0.02, 0.04, respectively). CONCLUSIONS: Asymmetry of ONH blood flow is significantly associated with asymmetry of visual field defects in patients with glaucoma independently of cpRNFLT.

Using Kalman Filtering to Forecast Disease Trajectory for Patients With Normal Tension Glaucoma.

PURPOSE: To determine whether a machine learning technique called Kalman filtering (KF) can accurately forecast future values of mean deviation (MD), pattern standard deviation, and intraocular pressure for patients with normal tension glaucoma (NTG). DESIGN: Development and testing of a forecasting model for glaucoma progression. METHODS: We parameterized and validated a KF (KF-NTG) to forecast MD, pattern standard deviation, and intraocular pressure at 24 months into the future using 263 eyes of 263 Japanese patients with NTG. We determined the proportion of patients with MD forecasts within 0.5, 1.0, and 2.5 dBs of the actual values and calculated the root mean squared error (RMSE) for each forecast. We compared KF-NTG with a previously published KF model calibrated using patients with high-tension open-angle glaucoma (KF-HTG) and to 3 conventional forecasting algorithms. RESULTS: The 263 patients with NTG had mean ± standard deviation age of 63.4 ± 10.5 years. KF-NTG forecasted MD values 24 months ahead within 0.5, 1.0, and 2.5 dBs of the actual value for 78 eyes (32.2%), 122 eyes (50.4%), and 211 eyes (87.2%), respectively. The proportion of eyes with MD values forecasted within 2.5 dB of the actual value for the KF-NTG (87.2%) were similar to KF-HTG (86.0%) and the null model (86.4%), and much better than the 2 linear regression-based models (72.7-74.0%; P < .001). When forecasting MD, KF-NTG (RMSE = 2.71) and KF-HTG (RMSE = 2.68) achieved lower RMSE than the other 3 forecasting models (RMSE = 2.81-3.90), indicating better performance. CONCLUSION: As observed previously for patients with HTG, KF can also effectively forecast disease trajectory for many patients with NTG.

Validation of formula-predicted glaucomatous optic disc appearances: the Glaucoma Stereo Analysis Study.

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.