Antitumor Activity of Novel Signal Transducer and Activator of Transcription 3 Inhibitors on Retinoblastoma.

Signal transducer and activator of transcription 3 (STAT3) is a plausible therapeutic target in the treatment of retinoblastoma, the most common intraocular malignant tumor in children. STAT3, a transcription factor of several genes related to tumorigenesis, is activated in retinoblastoma tumors as well as other cancers. In this study, we investigated the structure-activity relationship of a library of STAT3 inhibitors, including a novel series of derivatives of the previously reported compound with a Michael acceptor (compound 1). We chose two novel STAT3 inhibitors, compounds 11 and 15, from the library based on their inhibitory effects on the phosphorylation and transcription activity of STAT3. These STAT3 inhibitors effectively suppressed the phosphorylation of STAT3 and inhibited the expression of STAT3-related genes CCND1, CDKN1A, BCL2, BCL2L1, BIRC5, MYC, MMP1, MMP9, and VEGFA Intraocularly administered STAT3 inhibitors decreased the degree of tumor formation in the vitreous cavity of BALB/c nude mice of an orthotopic transplantation model. It is noteworthy that compounds 11 and 15 did not induce in vitro and in vivo toxicity on retinal constituent cells and retinal tissues, respectively, despite their potent antitumor effects. We suggest that these novel STAT3 inhibitors be used in the treatment of retinoblastoma. SIGNIFICANCE STATEMENT: The current study suggests the novel STAT3 inhibitors with Michael acceptors possess antitumor activity on retinoblastoma, the most common intraocular cancer in children. Based on detailed structure-activity relationship studies, we found a 4-fluoro and 3-trifluoro analog (compound 11) and a monochloro analog (compound 15) of the parental compound (compound 1) inhibited STAT3 phosphorylation, leading to suppressed retinoblastoma in vitro and in vivo.

Explaining the Rationale of Deep Learning Glaucoma Decisions with Adversarial Examples.

PURPOSE: To illustrate what is inside the so-called black box of deep learning models (DLMs) so that clinicians can have greater confidence in the conclusions of artificial intelligence by evaluating adversarial explanation on its ability to explain the rationale of DLM decisions for glaucoma and glaucoma-related findings. Adversarial explanation generates adversarial examples (AEs), or images that have been changed to gain or lose pathologic characteristic-specific traits, to explain the DLM's rationale. DESIGN: Evaluation of explanation methods for DLMs. PARTICIPANTS: Health screening participants (n = 1653) at the Seoul National University Hospital Health Promotion Center, Seoul, Republic of Korea. METHODS: We trained DLMs for referable glaucoma (RG), increased cup-to-disc ratio (ICDR), disc rim narrowing (DRN), and retinal nerve fiber layer defect (RNFLD) using 6430 retinal fundus images. Surveys consisting of explanations using AE and gradient-weighted class activation mapping (GradCAM), a conventional heatmap-based explanation method, were generated for 400 pathologic and healthy patient eyes. For each method, board-trained glaucoma specialists rated location explainability, the ability to pinpoint decision-relevant areas in the image, and rationale explainability, the ability to inform the user on the model's reasoning for the decision based on pathologic features. Scores were compared by paired Wilcoxon signed-rank test. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUC), sensitivities, and specificities of DLMs; visualization of clinical pathologic changes of AEs; and survey scores for locational and rationale explainability. RESULTS: The AUCs were 0.90, 0.99, 0.95, and 0.79 and sensitivities were 0.79, 1.00, 0.82, and 0.55 at 0.90 specificity for RG, ICDR, DRN, and RNFLD DLMs, respectively. Generated AEs showed valid clinical feature changes, and survey results for location explainability were 3.94 ± 1.33 and 2.55 ± 1.24 using AEs and GradCAMs, respectively, of a possible maximum score of 5 points. The scores for rationale explainability were 3.97 ± 1.31 and 2.10 ± 1.25 for AEs and GradCAM, respectively. Adversarial example provided significantly better explainability than GradCAM. CONCLUSIONS: Adversarial explanation increased the explainability over GradCAM, a conventional heatmap-based explanation method. Adversarial explanation may help medical professionals understand more clearly the rationale of DLMs when using them for clinical decisions.

Ten Years and Beyond Longitudinal Change of ß-Zone Parapapillary Atrophy: Comparison of Primary Open-Angle Glaucoma with Normal Eyes.

PURPOSE: To investigate the difference in longitudinal change of ß-zone parapapillary atrophy (PPA) between eyes with primary open-angle glaucoma (POAG) and normal eyes. DESIGN: Longitudinal, observation study. PARTICIPANTS: A total of 153 eyes with POAG and 105 normal eyes. METHODS: Participants were followed for 10 years or more, with disc photography performed every year. The topographic parameters of ß-zone PPA (area, maximal radial extent, angular extent around disc) were measured. The factors associated with the enlargement of ß-zone PPA parameters were assessed by odds ratio (OR) using multivariable logistic regression. MAIN OUTCOME MEASURES: Enlargement of ß-zone PPA parameters and associated factors. RESULTS: Over the course of the average 11.6±1.3-year follow-up period, enlargement of ß-zone PPA was detected in 66.7% of POAG eyes and in 26.7% of normal eyes. Increment of all PPA parameters was significantly more common in cases of POAG than in normal eyes (all P < 0.001). The spatial distribution of maximal radial extent at baseline and final examination was significantly different between the 2 groups: POAG eyes; inferotemporal versus normal eyes; temporal (chi-square = 26.549, P < 0.001, chi-square = 19.320, P = 0.004, respectively). The widening of radial extent was significantly associated with older age (OR, 1.036; P = 0.010) and the presence of glaucoma (OR, 2.599; P = 0.002). The increment of angular extent was associated with the presence of glaucoma (OR, 12.167; P = 0.017) and optic disc hemorrhage (OR, 3.266; P = 0.019). CONCLUSIONS: The pattern of ß-zone PPA change differed between POAG and normal eyes during a follow-up of 10 years or more. The enlargement of PPA occurred more frequently in POAG than in normal eyes. The widening of radial extent was associated with older age and glaucoma, whereas the increment of angular extent was associated with glaucomatous damage.

Case Series: Herpes Zoster Ophthalmicus with Acute Orbital Inflammation.

SIGNIFICANCE: Herpes zoster ophthalmicus (HZO) has variable initial manifestations, and acute orbital inflammation may be the first sign without apparent zoster rash. This case series is significant for presenting diverse clinical features and treatment options of HZO with acute orbital inflammation. PURPOSE: To report a case series of patients diagnosed as HZO with acute orbital inflammation including two cases with unique presentations. CASE REPORTS: Medical records of four patients of HZO with acute orbital inflammation were reviewed. Two men and two women with a median age of 57 years (range, 32 to 69 years) were diagnosed as having HZO with acute orbital inflammation. Initial presentations included two cases of zoster rash and two cases of orbital pain preceding vesicles. Clinical orbital findings included proptosis, ptosis, ophthalmoplegia, and decreased visual acuity. Orbital magnetic resonance image showed enlarged extraocular muscle with enhancement and optic nerve sheath enhancement in all four patients, and unilateral dacryoadenitis in one patient. All four patients were administered with systemic steroid, three patients received intravenous acyclovir, and one patient received oral acyclovir. Orbital signs improved in all patients over several months. CONCLUSIONS: Herpes zoster ophthalmicus may initially present with orbital inflammatory signs, such as acute orbital myositis, perioptic neuritis, or dacryoadenitis, without zoster rash. Physicians should be aware of acute orbital inflammation as a presenting sign of HZO.

Optic Neuropathy Associated with Primary Sjögren's Syndrome: A Case Series.

PURPOSE: To determine the diverse clinical features of optic neuropathy associated with primary Sjögren's syndrome in Korean patients. METHODS: Five women with acute and/or chronic optic neuropathy who were diagnosed as primary Sjögren's syndrome were retrospectively evaluated. Primary Sjögren's syndrome was diagnosed by signs and symptoms of keratoconjunctivitis sicca, positive serum anti-Ro/SSA and/or anti-La/SSB antibodies, and/or minor salivary gland biopsy. All patients underwent a complete ophthalmologic examination. RESULTS: Among the five patients diagnosed as optic neuropathy related to primary Sjögren's syndrome, four patients had bilateral optic neuropathy and one patient was unilateral. The clinical course was chronic in three patients and one of them showed acute exacerbation and was finally diagnosed with neuromyelitis optica spectrum disorder. The other two patients presented as acute optic neuritis and one was diagnosed with neuromyelitis optica spectrum disorder. Sicca symptoms were present in four patients, but only two patients reported these symptoms before the onset of optic neuropathy. Patients showed minimal response to systemic corticosteroids or steroid dependence, requiring plasmapheresis in the acute phase and immunosuppressive agents for maintenance therapy. CONCLUSIONS: Optic neuropathy associated with primary Sjögren's syndrome may show variable clinical courses, including acute optic neuritis, insidious progression of chronic optic atrophy, or in the context of neuromyelitis optica spectrum disorders. Optic neuropathy may be the initial manifestation of primary Sjögren's syndrome without apparent sicca symptoms, which makes the diagnosis often difficult. The presence of specific antibodies including anti-Ro/SSA, anti-La/SSB, and anti-aquaporin-4 antibodies are supportive for the diagnosis and treatment in atypical cases of optic neuropathy.

Validity of the Worth 4 Dot Test in Patients with Red-Green Color Vision Defect.

PURPOSE: The Worth four dot test uses red and green glasses for binocular dissociation, and although it has been believed that patients with red-green color vision defects cannot accurately perform the Worth four dot test, this has not been validated. Therefore, the purpose of this study was to demonstrate the validity of the Worth four dot test in patients with congenital red-green color vision defects who have normal or abnormal binocular vision. METHODS: A retrospective review of medical records was performed on 30 consecutive congenital red-green color vision defect patients who underwent the Worth four dot test. The type of color vision anomaly was determined by the Hardy Rand and Rittler (HRR) pseudoisochromatic plate test, Ishihara color test, anomaloscope, and/or the 100 hue test. All patients underwent a complete ophthalmologic examination. Binocular sensory status was evaluated with the Worth four dot test and Randot stereotest. The results were interpreted according to the presence of strabismus or amblyopia. RESULTS: Among the 30 patients, 24 had normal visual acuity without strabismus nor amblyopia and 6 patients had strabismus and/or amblyopia. The 24 patients without strabismus nor amblyopia all showed binocular fusional responses by seeing four dots of the Worth four dot test. Meanwhile, the six patients with strabismus or amblyopia showed various results of fusion, suppression, and diplopia. CONCLUSIONS: Congenital red-green color vision defect patients of different types and variable degree of binocularity could successfully perform the Worth four dot test. They showed reliable results that were in accordance with their estimated binocular sensory status.

Optic nerve head factors associated with initial central visual field defect in primary open-angle glaucoma.

We investigated optic nerve head factors associated with initial parafoveal scotoma (IPFS) in primary open-angle glaucoma. Eighty (80) patients with an IPFS and 84 patients with an initial nasal step (INS) were compared. Central retinal vascular trunk (CRVT) deviation from the Bruch's membrane opening (BMO) center was measured as a surrogate of lamina cribrosa (LC)/BMO offset, and its obliqueness was defined as the absolute value of angular deviation from the fovea-BMO axis. Proximity of retinal nerve fiber layer defect (RNFLD) was defined as the angular deviation of the inner RNFLD margin from the fovea-BMO axis. Microvasculature dropout (MvD) was defined as a focal sectoral capillary dropout with no visible microvascular network identified in the choroidal layer. Factors associated with IPFS, as compared with INS, were assessed using logistic regression analyses and conditional inference tree analysis. The IPFS group had more oblique CRVT offset (P < 0.001), RNFLD closer to the fovea (P < 0.001), more MvD (P < 0.001), and more LC defects (P < 0.001) compared to the INS group. In logistic regression analyses, obliqueness of CRVT offset (P = 0.002), RNFLD proximity (P < 0.001), and MvD (P = 0.001) were significant factors influencing the presence of IPFS. Conditional inference tree analysis showed that RNFLD closer to the fovea (P < 0.001) in the upper level, more oblique CRVT offset (P = 0.013) and presence of MvD (P = 0.001) in the lower level were associated with the probability of having IPFS. IPFS was associated with closer RNFLD location to the fovea when assessed from the BMO. Oblique LC/BMO offset may not only mask RNFLD proximity to the fovea due to a deviated funduscopic disc appearance, but also potentiate IPFS via focal LC defect and MvD.

Clinical Significance of Optic Disc Hemorrhage Size in Visual Field Progression in Glaucoma.

PURPOSE: To investigate the correlation between optic disc hemorrhage (DH) size and glaucoma progression. DESIGN: A retrospective observational cohort study METHODS:   SETTING: A single tertiary hospital in South Korea STUDY POPULATION: Two hundred and fifty (250) open-angle glaucoma (OAG) patients with DH. Participants were followed for 5 years or longer, with a minimum of 5 visual field (VF) tests. OBSERVATION PROCEDURE: The DH area was calculated by comparing the pixel numbers of the DH area with the disc area based on optical coherence tomography (OCT). For recurrent DH cases, we calculated the average DH area. DH size was classified as large or small based on the median value. Rates of mean deviation (MD) loss were determined using guided progression analysis (GPA). Univariable and multivariable regression analyses were performed to identify significant predictors of MD loss. MAIN OUTCOME MEASURES: DH size and longitudinal VF progression RESULTS: The mean follow-up period was 11.1 ± 3.6 years. The group with large DH showed faster global MD loss relative to the group with small DH (-0.51±0.48 dB/y vs -0.36 ± 0.42 dB/y, P = .01). In the multivariable model, mean DH size, maximum DH size, and initial MD were all significantly associated with the overall rate of MD loss (all P < .05). CONCLUSIONS: DH size was associated with the rate of VF deterioration. Eyes with larger DH showed more pronounced VF progression.

Comparison of Patterns of Structural Progression in Primary Open Angle Glaucoma and Pseudoexfoliation Glaucoma.

PRCIS: Primary open angle glaucoma and pseudoexfoliation glaucoma showed different progression patterns of the retinal nerve fiber layer and ganglion cell-inner plexiform layer thinning in OCT-guided progression analysis. PURPOSE: To compare the patterns of progression of retinal nerve fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thinning by guided progression analysis (GPA) of optical coherence tomography (OCT) in primary open angle glaucoma (POAG) and pseudoexfoliation glaucoma (PXG). MATERIALS AND METHODS: The progression of RNFL and GCIPL thinning was assessed by the GPA of Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA). By overlaying the acquired images of the RNFL and GCIPL thickness-change maps, the topographic patterns of progressive RNFL and GCIPL thinning were evaluated. The rates of progression of RNFL and GCIPL thinning were analyzed and compared between patients with POAG and those with PXG. RESULTS: Of the 248 eyes of 248 patients with POAG (175 eyes of 175 patients) or PXG (73 eyes of 73 patients) enrolled, 156 POAG eyes and 48 PXG eyes were included. Progressive RNFL thinning was significantly more common in PXG than in POAG ( P =0.005). According to the RNFL progression-frequency maps, progression appeared mainly in the superotemporal and inferotemporal areas in POAG, whereas it had invaded more into the temporal area in PXG. According to the GCIPL maps, progression was most common in the inferotemporal area in both POAG and PXG. The average progression rate of GCIPL thinning was faster in PXG than in POAG ( P =0.013), and when analyzed in 2 halves (superior/inferior), the progression rate of the inferior half was faster in PXG than in POAG ( P =0.011). CONCLUSIONS: OCT GPA showed progression patterns of RNFL and GCIPL thinning in POAG and PXG. Understanding the specific patterns of progressive RNFL and GCIPL thinning according to glaucoma type may prove helpful to glaucoma-patient treatment and monitoring.

Structure-function relationship in glaucoma: Optical coherence tomography en face imaging vs. red-free fundus photography.

BACKGROUND/OBJECTIVES: To analyse retinal nerve fibre layer (RNFL) defect measurements obtained from red-free fundus photography and optical coherence tomography (OCT) en face imaging, respectively, and to compare them for the strength of the structure-function association. SUBJECTS/METHODS: Two hundred and fifty-six glaucomatous eyes of 256 patients with localized RNFL defect on red-free fundus photography were enrolled. A subgroup analysis included 81 highly myopic eyes (≤ -6.0 dioptres). Angular width of RNFL defect was compared between red-free fundus photography (i.e., red-free RNFL defect) and OCT en face imaging (i.e., en face RNFL defect). The correlation between angular width of each RNFL defect and functional outcomes, reported as mean deviation (MD) and pattern standard deviation (PSD), were assessed and compared. RESULTS: The angular width of en face RNFL defect was measured smaller than that of red-free RNFL defect in 91.0% eyes (mean difference, 19.98°). The association of en face RNFL defect with MD and PSD was stronger (R2 = 0.311 and R2 = 0.372, respectively) than that of red-free RNFL defect with MD and PSD (R2 = 0.162 and R2 = 0.137, respectively) (P < 0.05 for all). Especially in highly myopic eyes, the association of en face RNFL defect with MD and PSD was much stronger (R2 = 0.503 and R2 = 0.555, respectively) than that of red-free RNFL defect with MD and PSD (R2 = 0.216 and R2 = 0.166, respectively) (P < 0.05 for all). CONCLUSIONS: En face RNFL defect showed a higher correlation with severity of visual field loss than did red-free RNFL defect. The same dynamic was observed for highly myopic eyes.

Evaluation of University of North Carolina OCT Index for Diagnosis of Early Glaucoma.

PURPOSE: To evaluate the diagnostic performance of the University of North Carolina (UNC) OCT Index based on Cirrus high-definition OCT to discriminate early glaucomatous eyes from normal eyes in clinical practice. DESIGN: Evaluation of diagnostic test or technology. PARTICIPANTS: Ninety-eight patients with early glaucoma and 98 age-matched normal subjects. METHODS: Macular ganglion cell-inner plexiform layer (GCIPL) thickness, peripapillary retinal nerve fiber layer (RNFL) thickness, and optic nerve head parameters were measured in each subject. The measurements were run through the UNC OCT algorithm to compare their diagnostic abilities. MAIN OUTCOME MEASURES: Area under the curve (AUC) of the receiver operating characteristic and sensitivity at 95% specificity. RESULTS: The AUC of the UNC OCT Index was 0.974. The best AUCs of the single parameters were those of the minimum GCIPL (0.926) of the macular GCIPL, average RNFL (0.916) of the peripapillary RNFL, and rim area (0.964) of the optic nerve head. The AUC of the UNC OCT Index was significantly greater than those of the minimum GCIPL and average RNFL (all P values < 0.05), and also outperformed the rim area. The sensitivity value of the UNC OCT Index (90.8) was greater than that of single OCT parameters (minimum GCIPL, 42.9; average RNFL, 64.3; rim area, 84.7) at 95% specificity. CONCLUSIONS: The diagnostic performance of the UNC OCT Index in discriminating early glaucomatous eyes from normal eyes is high and exceeds the best optic nerve head, peripapillary RNFL, and macular GCIPL parameters in clinical practice.

Ten-year-and-beyond longitudinal change of ß-zone parapapillary atrophy in glaucoma: association with retinal nerve fibre layer defect.

BACKGROUND: To investigate the longitudinal change of localised retinal nerve fibre layer (RNFL) defects associated with change of ß-zone parapapillary atrophy (PPA) in primary open-angle glaucoma (POAG) eyes. METHODS: POAG patients with a localised RNFL defect and ß-zone PPA who had undergone disc/RNFL photography at 1-year intervals for 10 years or longer were enrolled. The topographic parameters of ß-zone PPA (area, maximal radial extent and angular extent around disc) were measured. Progression of RNFL defect was defined as widening of defect and/or appearance of new defect. The factors associated with progression of RNFL defect were assessed by OR using multivariable logistic regression. RESULTS: A total of 209 patients (209 eyes) with POAG were included (mean: 54 years old). Over the course of 11.5±2.3-year follow-up period, progression of RNFL defect was detected in 114 eyes (54.5%). Enlargement of PPA parameters (area and angular extent) was significantly more common in patients with RNFL defect progression than in eyes without progression (all p<0.001, respectively). Widening of radial extent did not show a significant difference in both groups (p=0.61). Increment of angular extent was in the direction of RNFL defect progression in 82.1% of eyes. Progression of RNFL defect was significantly associated with disc haemorrhage (OR: 6.653, p<0.001), enlargement of PPA area (OR: 4.114, p=0.004) and angular extent (OR: 6.572, p<0.001). CONCLUSIONS: Progression of RNFL defect is associated with increment of angular extent of PPA in POAG eyes.

Patterns of Optical Coherence Tomography Imaging in Preperimetric Open Angle Glaucoma: A Comparative Study With Young-Age-Onset and Old-Age-Onset Eyes.

PRCIS: Optic coherence tomography imaging in preperimetric open angle glaucoma (OAG) differed between young-age-onset and old-age-onset eyes. Inferior and superior quadrants were thinner in young and old-age-onset eyes, respectively. Understanding the specific patterns of early glaucomatous damage based on age-at-onset may improve glaucoma diagnosis and monitoring. PURPOSE: To investigate the patterns of retinal nerve fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thinning in preperimetric OAG by optical coherence tomography based on age at onset ("young-age onset (<40 y)" vs. "old-age onset (≥40 y)". MATERIALS AND METHODS: The RNFL and GCIPL deviation images were acquired by Cirrus HD-optical coherence tomography, and overlaid, thus converted to a "deviation frequency map", respectively. The topographic thinning patterns and parameters of RNFL and GCIPL thickness measurements were compared. RESULTS: A total of 194 eyes of 194 patients with preperimetric OAG and 97 eyes of 97 age-matched normal subjects were analyzed. Young-age-onset eyes of preperimetric OAG mainly had RNFL defects inferotemporally (264-296 degrees) with GCIPL defects in the inferior region (213-357 degrees). Old-age-onset preperimetric OAG eyes had RNFL defects inferotemporally (266-294°) and superotemporally (33-67 degrees), with GCIPL defects in the inferior and superior regions (206-360 degrees, 0-22 degrees). The inferior quadrant of RNFL and GCIPL thicknesses were significantly thinner in young-age-onset eyes compared with old-age-onset eyes ( P =0.012, 0.016), while the superior quadrant of those were significantly thinner in the old-age-onset eyes ( P =0.003, 0.005). CONCLUSION: Young-age-onset and old-age-onset eyes of preperimetric OAG present different specific patterns of RNFL and GCIPL thinning.

Decision Tree Algorithm-Based Prediction of Vulnerability to Depressive and Anxiety Symptoms in Caregivers of Children With Glaucoma.

PURPOSE: Development and validation of a decision tree model (DTM) for prediction of mental health status in Korean caregivers of children with glaucoma. DESIGN: Cross-sectional study. METHODS: Caregivers of children younger than 18 years with diagnosed primary childhood glaucoma (n = 42), secondary childhood glaucoma (n = 51), and glaucoma suspect (GS; n = 36) were prospectively enrolled at Seoul National University Children's Hospital, Seoul, Korea. The participants completed 2 questionnaires, the 9-item Patient Health Questionnaire (PHQ-9) and the 7-item Generalized Anxiety Disorder (GAD-7) Assessment. A DTM analysis for discrimination of those with moderate-to-severe depressive (PHQ-9 score ≥10) and anxiety (GAD-7 score ≥11) symptoms was performed with recursive partitioning algorithms based on the obtained clinical, demographic, and socioeconomic data. RESULTS: The mean PHQ-9 and GAD-7 scores did not significantly differ among the 3 groups (P = .823 for PHQ-9 score; P = .730 for GAD-7 score). The DTM's balanced accuracies were 0.875 (95% CI = 0.778-0.972) for the PHQ-9 score and 0.880 (95% CI = 0.800-0.960) for theGAD-7 score. The DTM of the PHQ-9 revealed that in caregivers of children with glaucoma, depressive symptoms should be strongly suspected when (1) the child has undergone more than 2 glaucoma surgeries; or (2) the visual acuity (VA, converted to logarithm of minimum angle of resolution [logMAR]) in the better eye is worse than 0.4 if the child has had only 1 or no surgery. CONCLUSIONS: Evaluation of the number of glaucoma surgeries and VA in the better eye can be a useful decision support tool in predicting mental illness in caregivers of children with glaucoma.

Morphological characteristics of parapapillary atrophy and subsequent visual field progression in primary open-angle glaucoma.

BACKGROUND/AIMS: To investigate the associations between the morphological characteristics of beta-zone parapapillary atrophy (ß-zone PPA) and subsequent visual field (VF) progression in eyes with primary open-angle glaucoma (POAG). METHODS: One hundred and twenty-one POAG eyes with ß-zone PPA along with 48 normal eyes with ß-zone PPA were included. ß-zone PPA area was calculated based on the PPA pixel area/optic-disc pixel area ratio and the optical coherence tomography (OCT)-measured disc area. ß-zone PPA margin irregularity was quantified as a function of both area (A) and perimeter (P, calculated as 1/(4πA/P²)). VF progression was defined using standard automated perimetry's guided progression analysis software. RESULTS: Of the 121 POAG eyes, 49 (40.5%) showed VF progression during the 10.1±1.9 years of follow-up. The baseline ß-zone PPA area was similar among the three groups (Progressors, Non-progressors and Controls, p=0.995). However, the ß-zone PPA irregularity index was significantly higher in the Progressors (p<0.001). The cumulative probability of VF progression was greater in the higher PPA irregularity index group (p<0.001, log-rank test). A Cox proportional hazards model showed the significant influences of optic disc haemorrhage (HR: 2.661, p=0.034) and higher baseline PPA irregularity index (HR: 1.455, p=0.007) on subsequent progression. CONCLUSIONS: In POAG eyes, baseline ß-zone PPA margin regularity was significantly associated with subsequent VF progression. Irregular margin of ß-zone PPA might be the mark of vulnerability in the parapapillary area to further glaucomatous damage.

Genetic Risk and Phenotype Correlation of Primary Open-Angle Glaucoma Based on Rho-Kinase Gene Polymorphisms.

Rho-associated coiled-coil kinase (ROCK) signaling can affect glaucoma risk by regulating trabecular meshwork outflow. We investigated the effect of ROCK gene polymorphism on the risks of primary open-angle glaucoma (POAG) and POAG-related phenotypes including intraocular pressure (IOP) in a Korean population. A total of 24 single-nucleotide polymorphisms (SNPs) from ROCK1 and ROCK2 were selected and genotyped for 363 POAG patients and 213 healthy controls. Among the 363 POAG patients, 282 were normal-tension glaucoma (NTG, baseline IOP ≤ 21 mmHg) and 81 were high-tension glaucoma (HTG, baseline IOP > 21 mmHg). The SNPs rs288979, rs1006881, rs35996865, rs10083915, and rs11873284 in ROCK1 (tagged to each other, r2 = 1) were nominally associated with risk of HTG (OR = 0.52, p = 0.045). However, there were no SNPs that were significantly associated with the risk of NTG. In the genotype-phenotype correlation analysis, the SNPs rs2230773 and rs3771106 in ROCK2 were significantly correlated with central corneal thickness (CCT)-adjusted IOP (p = 0.024) and axial length (AXL; p = 0.024), respectively. The present data implicated the role of ROCK in POAG development, and as such, can serve as a good reference for upcoming Rho/ROCK-pathway-related studies on POAG.

Deep optic nerve head morphology and glaucoma progression in eyes with and without laminar dot sign: a longitudinal comparative study.

PURPOSE: To investigate the association between the laminar dot sign (LDS) and the deep optic nerve head (ONH) structure in eyes with primary-open-angle glaucoma (POAG). METHODS: Eighty-four eyes of 84 patients with POAG were prospectively included. All of the patients underwent stereo optic disc photography (SDP), red-free retinal nerve fibre layer (RNFL) photography, SS-OCT, and standard automated perimetry. By evaluating the SDP, patients were classified into laminar dot sign (LDS) and non-LDS groups. The deep structure of the ONH including the anterior prelaminar depth (APLD) and prelaminar tissue thickness (PTT) were quantitated using SS-OCT. Progression was assessed by structural or functional deterioration during the average 4.3 ± 1.2 years of follow-up. RESULTS: The LDS group had deeper APLD (405.47 ± 107.55 vs. 302.45 ± 149.51, P < 0.001) and thinner PTT (74.34 ± 24.46 vs. 137.29 ± 40.07, P = 0.001) relative to the non-LDS group. By multivariate analysis, thin PTT was significantly associated with the presence of LDS (odds ratio = 0.939, P < 0.001). Structural progression was detected in 45 eyes (84.9%) in the LDS group and 8 eyes (25.8%) in the non-LDS group. Functional progression was demonstrated in 29 eyes (34.5%) in the LDS group and 6 eyes (19.4%) in the non-LDS group. The eyes with LDS had a significantly higher risk of glaucoma progression (χ2 = 5.00, degree of freedom = 1, P = 0.033). CONCLUSIONS: In eyes with POAG, the presence of LDS was associated with thinner prelaminar tissue and faster disease progression.

Association of Intereye Visual-Sensitivity Asymmetry With Progression of Primary Open-Angle Glaucoma.

Purpose: To investigate the relationship between intereye visual field defect (VFD) asymmetry and subsequent VF progression in primary open-angle glaucoma (POAG). Methods: Moderate-stage patients with POAG (226 eyes of 113 patients) with a single hemifield defect were followed for 8.7 years. Participants were categorized into three groups by initial VF pattern: (1) unilateral VFD, (2) bilateral VFD within same hemifield (superior-superior, inferior-inferior), (3) bilateral VFD within opposite hemifield (superior-inferior). The mean deviation (MD) difference between the intereye was defined as the intereye MD asymmetry index (iMAI). Intereye visual-sensitivity difference within the same hemifield was calculated as the intereye hemifield visual-sensitivity asymmetry index. Functional progression was detected by Glaucoma Progression Analysis. The overall rate of MD change and the association between new indices were evaluated by linear regression. A Kaplan-Meier survival analysis was performed and the factors associated with glaucoma progression were evaluated by Cox proportional hazard modeling. Results: Unilateral VFD eyes and bilateral VFD eyes within opposite VF hemifield showed significant progression and faster rate of MD change compared with bilateral VFD eyes within same VF hemifield (71.1% vs. 45.9% vs. 21.1% [P = 0.001]; -1.27 dB/y vs. -0.64 dB/y vs. -0.32 dB/y [P = 0.001]). Unilateral VFD eyes showed the fastest time to VF progression compared with other groups (P = 0.002). A faster rate of MD change was associated with greater intereye MD asymmetry index (P = 0.001) and greater intereye hemifield visual-sensitivity asymmetric index (P = 0.031), which were significant risk factors for glaucoma progression (all P < 0.001). Conclusions: Among POAG eyes with comparable hemifield VFDs, eyes without a corresponding hemifield defect in the fellow eye showed faster rates of progression compared with those with a corresponding hemifield defect.

Angular Location of Retinal Nerve Fiber Layer Defect: Association With Myopia and Open-Angle Glaucoma.

Purpose: To compare retinal nerve fiber layer (RNFL) defects' angle measurements determined from the center of the optic disc and Bruch's membrane opening (BMO), as a function of myopia and open-angle glaucoma (OAG) subtypes. Methods: In total, 118 patients with OAG were grouped by axial length (AL; high myopia, AL >26 mm; mild to moderate myopia, 24 ≤ AL ≤26 mm; nonmyopia, AL <24 mm) and OAG subtype (normal-tension glaucoma [NTG], high-tension glaucoma [HTG]). The disc and BMO centers were determined by a merged image of red-free fundus photography and spectral-domain optical coherence tomography. The angular location of the RNFL defect close to the fovea (angle α) was measured from the disc center and BMO center, respectively (angle αdisc and angle αBMO). The difference between angle αdisc and αBMO (Δα), as well as the RNFL defect width (angle γ), was evaluated. Results: Angle αdisc was smaller in myopic eyes and correlated significantly with AL (P = 0.001), whereas it did not differ among OAG subgroups. Angle αBMO and angle γ were not different in the myopic and OAG subgroups. The Δ α was larger for eyes with higher degree of myopia and had significant correlation with AL (P < 0.001) and was larger in NTG eyes than in HTG eyes (P = 0.023). Conclusions: The angular location of the RNFL defect measured from the disc center, but not from the BMO center, was closer to the fovea for glaucomatous eyes with higher values of AL. The present study may facilitate understanding of the characteristic locational pattern of the RNFL defect in myopic glaucomatous eyes.

Interdigitation Zone Change According to Glaucoma-Stage Advancement.

Purpose: To compare the macular interdigitation zone (IZ) of normal eyes with eyes showing different normal-tension glaucoma (NTG) stages. Methods: Forty-two normal eyes (age, 56 ± 5.4 years), 45 pre-perimetric eyes (age, 59 ± 6.9 years), 51 mild-to-moderate glaucoma eyes (age, 58 ± 7.2 years; mean deviation [MD], -5.5 ± 3.0 dB), and 50 severe glaucoma eyes (age, 59 ± 6.9 years; MD, -15.1 ± 5.4 dB) were enrolled. All of the subjects underwent high-resolution spectral-domain optical coherence tomography (SD-OCT) to obtain 19 horizontal and 19 vertical macular B-scans 9 mm in length. The en face image of the scan area was divided into 589 rectangular boxes (side length of 375 µm). The IZ locations were marked on the corresponding image boxes. The IZ area was then quantified according to the number of boxes showing IZs among the 589 total boxes. Results: The IZ area in the severe glaucoma eyes was significantly smaller than in the mild-to-moderate glaucoma eyes (28.99 ± 7.88 mm2 vs. 40.79 ± 7.46 mm2; P < 0.001), was smaller in the mild-to-moderate glaucoma eyes than in the pre-perimetric glaucoma eyes (40.79 ± 7.46 mm2 vs. 49.92 ± 8.10 mm2; P < 0.001), and was smaller still in the pre-perimetric glaucoma eyes than in the normal eyes (49.92 ± 8.10 mm2 vs. 56.85 ± 7.94 mm2; P < 0.001). In the 146 NTG eyes, a statistically significant correlation was found between IZ area and MD (r = 0.64; P < 0.001). Conclusions: SD-OCT revealed a reduction in IZ area in NTG eyes, and the extent of the reduction was positively associated with glaucoma severity. These findings suggest, though tentatively, that changes in the outer retinal layer can occur in the course of glaucoma progression.