PURPOSE: To compare diagnostic performance and structure-function correlations of multifocal electroretinogram (mfERG), full-field flash ERG (ff-ERG) photopic negative response (PhNR) and transient pattern-reversal ERG (PERG) in a non-human primate (NHP) model of experimental glaucoma (EG). METHODS: At baseline and after induction of chronic unilateral IOP elevation, 43 NHP had alternating weekly recordings of retinal nerve fiber layer thickness (RNFLT) by spectral domain OCT (Spectralis) and retinal function by mfERG (7F slow-sequence stimulus, VERIS), ff-ERG (red 0.42 log cd-s/m(2) flashes on blue 30 scotopic cd/m(2) background, LKC UTAS-E3000), and PERG (0.8° checks, 99% contrast, 100 cd/m(2) mean, 5 reversals/s, VERIS). All NHP were followed at least until HRT-confirmed optic nerve head posterior deformation, most to later stages. mfERG responses were filtered into low- and high-frequency components (LFC, HFC, >75 Hz). Peak-to-trough amplitudes of LFC features (N1, P1, N2) and HFC RMS amplitudes were measured and ratios calculated for HFC:P1 and N2:P1. ff-ERG parameters included A-wave (at 10 ms), B-wave (trough-to-peak) and PhNR (baseline-to-trough) amplitudes as well as PhNR:B-wave ratio. PERG parameters included P50 and N95 amplitudes as well as N95:P50 ratio and N95 slope. Diagnostic performance of retinal function parameters was compared using the area under the receiver operating characteristic curve (A-ROC) to discriminate between EG and control eyes. Correlations to RNFLT were compared using Steiger's test. RESULTS: Study duration was 15 ± 8 months. At final follow-up, structural damage in EG eyes measured by RNFLT ranged from 9% above baseline (BL) to 58% below BL; 29/43 EG eyes (67%) and 0/43 of the fellow control eyes exhibited significant (>7%) loss of RNFLT from BL. Using raw parameter values, the largest A-ROC findings for mfERG were: HFC (0.82) and HFC:P1 (0.90); for ff-ERG: PhNR (0.90) and PhNR:B-wave (0.88) and for PERG: P50 (0.64) and N95 (0.61). A-ROC increased when data were expressed as % change from BL, but the pattern of results persisted. At 95% specificity, the diagnostic sensitivity of mfERG HFC:P1 ratio was best, followed by PhNR and PERG. The correlation to RNFLT was stronger for mfERG HFC (R = 0.65) than for PhNR (R = 0.59) or PERG N95 (R = 0.36), (p = 0.20, p = 0.0006, respectively). The PhNR flagged a few EG eyes at the final time point that had not been flagged by mfERG HFC or PERG. CONCLUSIONS: Diagnostic performance and structure-function correlation were strongest for mfERG HFC as compared with ff-ERG PhNR or PERG in NHP EG.

Posner-Schlossman syndrome (PSS) shares some clinical features with uveitis and open angle glaucoma. Cytokines and autoantibodies have been associated with uveitis and open angle glaucoma. However, the role of serum cytokines and autoantibodies in the pathogenesis of PSS remains unknown. This study aimed to evaluate the associations of type 1 T helper (Th1) and Th17 related cytokines and autoantibodies with PSS. Peripheral blood serum samples were collected from 81 patients with PSS and 97 gender- and age-matched healthy blood donors. Th1 and Th17 related cytokines, including interleukin-1β (IL-1β), IL-12, tumor necrosis factor-α (TNF-α), interferon- γ (IFN-γ), IL-6 and IL-17, and glucose-6-phosphate isomerase (GPI) were determined by double antibody sandwich ELISA. Anti-nuclear antibody (ANA), anti-keratin antibody (AKA) and anti-neutrophil cytoplasmic antibody (ANCA) were detected by indirect immunofluorescence assay. Anti-cardiolipin antibody (ACA)-IgG, ACA-IgM, ACA-IgA, anti-double stranded DNA (anti-dsDNA) and anti-cyclic citrullinated peptide antibody (anti-CCP) were detected by indirect ELISA. Serum levels of IL-1β, IL-12 and IL-6 in PSS patients were significantly lower than those in controls (P < 0.003), and these associations survived the Bonferroni correction (Pc < 0.018). There was no significant difference in serum levels of TNF-α, IFN-γ and IL-17 between the PSS and control groups (Pc > 0.12). Positive rate of serum anti-dsDNA in PSS patients was significantly higher than that in the control group (P = 0.002, Pc = 0.018), while positive rates of serum ANA, AKA, ANCA, ACA-IgG, ACA-IgM, ACA-IgA, GPI and anti-CCP in the PSS group were not significantly different from those in the control group (Pc > 0.09). These results suggest that anti-dsDNA may contribute to the pathogenesis of PSS, while Th1 and Th17 related cytokines and other autoantibodies may not be major contributors to PSS.

Purpose: Optic nerve head astrocytes, a subtype of white-matter astrocytes, become reactive early in the course of glaucoma. It was shown recently that in the DBA/2J mouse model of inherited glaucoma optic nerve astrocytes extend new longitudinal processes into the axon bundles before ganglion cell loss becomes apparent. The present study aims at testing whether this behavior of astrocytes is typical of early glaucomatous damage. Methods: Mice expressing green fluorescent protein in individual astrocytes were used to evaluate the early response of astrocytes in the glial lamina of the optic nerve head after increasing the IOP using the microbead occlusion method. Tissue sections from the glial lamina were imaged consecutively by confocal and electron microscopy. Results: Confocal and electron microscope images show that astrocytes close to the myelination transition zone in the hypertensive nerve heads extend new processes that follow the longitudinal axis of the optic nerve and invade axon bundles in the nerve head. Ultrastructurally, the longitudinal processes were largely devoid of subcellular organelles except for degenerating mitochondria. Conclusions: The longitudinal processes are a common feature of glaucomatous optic nerve astrocytes, whereas they are not observed after traumatic nerve injury. Thus, astrocytes appear to fine-tune their responses to the nature and/or timing of the injury to the neurons that they surround.

PURPOSE: To investigate the association between exercise and glaucoma in a South Korean population-based sample. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 11,246 subjects, 40 years and older who underwent health care assessment as part of the 2008-2011 Korean National Health and Nutrition Examination Survey. METHODS: Variables regarding the duration (total minutes per week), frequency (days per week), and intensity of exercise (vigorous, moderate exercise and walking) as well as glaucoma prevalence were ascertained for 11,246 survey participants. Demographic, comorbidity, and health-related behavior information was obtained via interview. Multivariable logistic regression analyses were performed to determine the association between the exercise-related parameters and odds of a glaucoma diagnosis. MAIN OUTCOME MEASURE(S): Glaucoma defined by International Society for Geographical and Epidemiological Ophthalmology criteria. RESULTS: Overall, 336 (2.7%) subjects met diagnostic criteria for glaucomatous disease. After adjustment for potential confounding variables, subjects engaged in vigorous exercise 7 days per week had higher odds of having glaucoma compared with those exercising 3 days per week (Odds Ratio [OR] 3.33, 95% confidence interval [CI] 1.16-9.54). High intensity of exercise, as categorized by the guidelines of the American College of Sports Medicine (ACSM), was also associated with greater glaucoma prevalence compared with moderate intensity of exercise (OR 1.55, 95% CI 1.03-2.33). There was no association between other exercise parameters including frequency of moderate exercise, walking, muscle strength exercise, flexibility training, or total minutes of exercise per week, and the prevalence of glaucoma. In sub-analyses stratifying by gender, the association between frequency of vigorous exercise 7 days per week and glaucoma diagnosis remained significant in men (OR 6.05, 95% CI 1.67-21.94) but not in women (OR 0.96 95% CI: 0.23-3.97). A U-shaped association between exercise intensity and glaucoma prevalence was noted in men (OR 1.71, 95% CI 1.09-2.69 for low intensity versus moderate intensity; OR 2.19, 95% CI 1.25-3.85 for high intensity versus moderate intensity). CONCLUSION: In a South Korean population sample, daily vigorous exercise was associated with higher glaucoma prevalence. In addition, the intensity of exercise was positively associated with glaucoma diagnosis in men but not women.

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increase risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

We describe the surgical technique of endoscopic cyclophotocoagulation in a Boston keratoprosthesis type II patient. This patient with ocular cicatricial pemphigoid had pars plana endoscopic cyclophotocoagula through wounds created in the eyelids.

PurposeTo report surgical outcomes of microcatheter-assisted trabeculotomy following failed angle surgeries, and compare those with no previous angle surgery, in primary congenital glaucoma (PCG).MethodsThe early postoperative (12 months) results of 42 eyes of 36 patients who underwent microcatheter-assisted trabeculotomy by single surgeon for PCG were retrospectively analyzed. Group 1, 20 eyes of 16 patients, had no previous angle surgery. Group 2, 22 eyes of 20 patients, had one or two previous failed angle surgeries. Success was defined as an intraocular pressure (IOP) <21 mm Hg with at least a 30% reduction from preoperative IOP with (qualified success) or without (complete success) the use of antiglaucoma medication.ResultsMean IOP decreased from 31.5±7.2 mm Hg on 3 (median, range: 1-5) medications in Group 1 and 34.6±7.3 mm Hg on 3 (median, range: 1-4) medications in Group 2 preoperatively to 15.6±3.1 mm Hg on 0 (median, range: 0-4) medications in Group 1 and 16.0±4.6 mm Hg on 0 (median, range: 0-2) medications in Group 2 postoperatively at 12 months (both P<0.001), respectively. The mean percentage of IOP reduction from preoperative to last postoperative visit was 46.0±20.1% in Group 1 and 45.5±25.0% in Group 2, P=0.947. Qualified and complete successes were comparable between Group 1 and Group 2 (qualified success: 90.0% vs 77.3%, P=0.294; complete success: 78.9% vs 77.3%, P=0.853). Complications were minimal.ConclusionsMicrocatheter-assisted trabeculotomy achieved significant pressure-lowering effects with a reduction in medication use in PCG, and it represents a reasonable choice of initial and repeat surgical treatment for PCG.

Interventions in the treatment of mild to moderate glaucoma have evolved to include a group of procedures collectively named "Minimally Invasive Glaucoma Surgery (MIGS)." These procedures are less invasive than traditional filtering surgery and setons and offer the benefit of an improved side-effect profile. A review of current published literature has shown that these procedures offer lower intraocular pressure, decrease reliance on topical medications, have no negative effect on refractive outcomes, and can be safely done following failed tube surgery.

AIM: To characterize whether a glaucoma model with chronic elevation of the intraocular pressure (IOP) was able to be induced by anterior chamber injection of microbeads in rabbits. METHODS: In order to screen the optimal dose of microbead injection, IOP was measured every 3d for 4wk using handheld applanation tonometer after a single intracameral injection of 10 µL, 25 µL, 50 µL or 100 µL microbeads (5×10(6) beads/mL; n=6/group) in New Zealand White rabbits. To prolong IOP elevation, two intracameral injections of 50 µL microbeads or phosphate buffer saline (PBS) were made respectively at days 0 and 21 (n=24/group). The fellow eye was not treated. At 5wk after the second injection of microbeads or PBS, bright-field microscopy and transmission electron microscopy (TEM) were used to assess the changes in the retina. The expression of glial fibrillary acidic protein (GFAP) in the retina was evaluated by immunofluorescence, quantitative real-time polymerase chain reaction and Western blot at 5wk after the second injection of microbeads. RESULTS: Following a single intracameral injection of 10 µL, 25 µL, 50 µL or 100 µL microbead, IOP levels showed a gradual increase and a later decrease over a 4wk period after a single injection of microbead into the anterior chamber of rabbits. A peak IOP was observed at day 15 after injection. No significant difference in peak value of IOP was found between 10 µL and 25 µL groups (17.13±1.25 mm Hg vs 17.63±0.74 mm Hg; P=0.346). The peak value of IOP from 50 µL group (23.25±1.16 mm Hg) was significantly higher than 10 µL and 25 µL groups (all P<0.05). Administration of 100 µL microbead solution (23.00±0.93 mm Hg) did not lead to a significant increase in IOP compared to the 50 µL group (P=0.64). A prolonged elevated IOP duration up to 8wk was achieved by administering two injections of 50 µL microbeads (20.48±1.21 mm Hg vs 13.60±0.90 mm Hg in PBS-injected group; P<0.05). The bright-field and TEM were used to assess the changes of retinal ganglion cells (RGCs). Compared with PBS-injected group, the extended IOP elevation was associated with the degeneration of optic nerve, the reduction of RGC axons (47.16%, P<0.05) and the increased GFAP expression in the retina (4.74±1.10 vs 1.00±0.46, P<0.05). CONCLUSION: Two injections of microbeads into the ocular anterior chamber of rabbits lead to a prolonged IOP elevation which results in structural abnormality as well as loss in RGCs and their axons without observable ocular structural damage or inflammatory response. We have therefore established a novel and practical model of experimental glaucoma in rabbits.

Glaucoma is a multifactorial disease resulting in the death of retinal ganglion cells (RGCs) and irreversible blindness. Glaucoma-associated RGC death depends on the proapoptotic and proinflammatory activity of membrane-bound Fas ligand (mFasL). In contrast to mFasL, the natural cleavage product, soluble Fas ligand (sFasL) inhibits mFasL-mediated apoptosis and inflammation and, therefore, is an mFasL antagonist. DBA/2J mice spontaneously develop glaucoma and, predictably, RGC destruction is exacerbated by expression of a mutated membrane-only FasL gene that lacks the extracellular cleavage site. Remarkably, one-time intraocular adeno-associated virus-mediated gene delivery of sFasL provides complete and sustained neuroprotection in the chronic DBA/2J and acute microbead-induced models of glaucoma, even in the presence of elevated intraocular pressure. This protection correlated with inhibition of glial activation, reduced production of TNF-α, and decreased apoptosis of RGCs and loss of axons. These data indicate that cleavage of FasL under homeostatic conditions, and the ensuing release of sFasL, normally limits the neurodestructive activity of FasL. The data further support the notion that sFasL, and not mFasL, contributes to the immune-privileged status of the eye.

PURPOSE: To study resident compliance with the American Academy of Ophthalmology (AAO) Preferred Practice Patterns (PPPs) for primary open-angle glaucoma suspect (POAGS) in a resident ophthalmology clinic. PATIENTS AND METHODS: Two hundred charts were selected for analysis of adult patients with the International Classification of Diseases diagnosis code for POAGS during their initial visit between November 2, 2010 and May 6, 2014 at the Kresge Eye Institute resident clinic. Electronic medical records of clinic visits for POAGS patients were evaluated for documentation and compliance with 17 elements of AAO PPPs. RESULTS: The overall mean compliance was 73.8% for all charts (n=200), 74.4% for first-year residents (n=53), 74.5% for second-year residents (n=38), and 73.3% for third-year residents (n=109). Documentation rates were high (>90%) for 9 elements, which included most elements of physical examination and history. Documentation of ocular history, central corneal thickness, gonioscopy, optic nerve head and retinal nerve fiber layer analysis, and visual field ranged from 40% to 80%. Documentation was lowest for patient education elements which ranged from 0% to 10%. Compliance was not significantly different (P>0.05) between residents or between different resident years for any element. CONCLUSIONS: Residents' compliance was high for most elements of the PPPs for POAGS. We identified elements with poor compliance especially regarding patient education. Adherence to AAO PPPs can be a helpful method of assessing resident performance.

Diabetes mellitus represents a growing international public health issue with a near quadrupling in its worldwide prevalence since 1980. Though it has many known microvascular complications, vision loss from diabetic retinopathy is one of the most devastating for affected individuals. In addition, there is increasing evidence to suggest that diabetic patients have a greater risk for glaucoma as well. Though the pathophysiology of glaucoma is not completely understood, both diabetes and glaucoma appear to share some common risk factors and pathophysiologic similarities with studies also reporting that the presence of diabetes and elevated fasting glucose levels are associated with elevated intraocular pressure-the primary risk factor for glaucomatous optic neuropathy. While no study has completely addressed the possibility of detection bias, most recent epidemiologic evidence suggests that diabetic populations are likely enriched with glaucoma patients. As the association between diabetes and glaucoma becomes better defined, routine evaluation for glaucoma in diabetic patients, particularly in the telemedicine setting, may become a reasonable consideration to reduce the risk of vision loss in these patients.

PURPOSE: To compare effectiveness of fornix- and limbal-based conjunctival flaps in trabeculectomy surgery. DESIGN: Systematic review. METHODS: Setting: CENTRAL, MEDLINE, LILACS, ISRCTN registry, ClinicalTrials.gov, WHO, and ICTRP were searched to identify eligible randomized controlled trials (RCTs). STUDY POPULATION: RCTs in which benefits and complications of fornix- vs limbal-based trabeculectomy for glaucoma were compared in adult glaucoma patients. OBSERVATION PROCEDURE: We followed Cochrane methodology for data extraction. MAIN OUTCOME MEASURES: Proportion of failed trabeculectomies at 24 months, defined as the need for repeat surgery or uncontrolled intraocular pressure (IOP) >22 mm Hg, despite topical/systemic medications. RESULTS: The review included 6 trials with a total of 361 participants, showing no difference in effectiveness between fornix-based vs limbal-based trabeculectomy surgery, although with a high level of uncertainty owing to low event rates. In the fornix-based and limbal-based surgery, mean IOP at 12 months was similar, with ranges of 12.5-15.5 mm Hg and 11.7-15.1 mm Hg, respectively. Mean difference was 0.44 mm Hg (95% CI -0.45 to 1.33) and 0.86 mm Hg (95% CI -0.52 to 2.24) at 12 and 24 months of follow-up, respectively. Mean number of postoperative glaucoma medications was similar between the 2 groups. Mean difference was 0.02 (95% CI -0.15 to 0.19) at 12 months. As far as postoperative complications, an increased risk of shallow anterior chamber was observed in the limbal-based group. CONCLUSION: Similar efficacy of trabeculectomy surgery with respect to bleb failure or IOP control was observed in both types of conjunctival flap incisions. A significant difference was detected in the risk of postoperative shallow anterior chamber, which was increased in the limbal-based group.

The treatment paradigm in glaucoma classically starts with exhausting all medical therapy prior to proceeding with laser or incisional surgery, although laser-first and surgery-first strategies have been explored in randomized clinical trials. Although glaucoma drops are proven to work well to lower intraocular pressure, slow the conversion from ocular hypertension, and slow the progression of disease in early open angle glaucoma, adherence to treatment is likely optimum in the randomized clinical trials that support these claims. In real-world scenarios, medical therapy often fails and practitioners are forced to proceed with more invasive treatment modalities to slow the progression of this blinding disease. This review aims to take an evidence-based approach to study the risk factors for poor adherence in glaucoma patients, to determine whether poor adherence is, in fact, associated with worse outcomes, and to seek potential strategies to improve adherence in these patients.

OBJECTIVE: Several attributes of female reproductive history, including age at natural menopause (ANM), have been related to primary open-angle glaucoma (POAG). We assembled 18 previously reported common genetic variants that predict ANM to determine their association with ANM or POAG. METHODS: Using data from the Nurses' Health Study (7,143 women), we validated the ANM weighted genetic risk score in relation to self-reported ANM. Subsequently, to assess the relation with POAG, we used data from 2,160 female POAG cases and 29,110 controls in the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD), which consists of 8 datasets with imputed genotypes to 5.6+ million markers. Associations with POAG were assessed in each dataset, and site-specific results were meta-analyzed using the inverse weighted variance method. RESULTS: The genetic risk score was associated with self-reported ANM (P = 2.2 × 10) and predicted 4.8% of the variance in ANM. The ANM genetic risk score was not associated with POAG (Odds Ratio (OR) = 1.002; 95% Confidence Interval (CI): 0.998, 1.007; P = 0.28). No single genetic variant in the panel achieved nominal association with POAG (P ≥0.20). Compared to the middle 80 percent, there was also no association with the lowest 10 percentile or highest 90 percentile of genetic risk score with POAG (OR = 0.75; 95% CI: 0.47, 1.21; P = 0.23 and OR = 1.10; 95% CI: 0.72, 1.69; P = 0.65, respectively). CONCLUSIONS: A genetic risk score predicting 4.8% of ANM variation was not related to POAG; thus, genetic determinants of ANM are unlikely to explain the previously reported association between the two phenotypes.

Purpose: To describe spectral-domain optical coherence tomography (OCT) methods for quantifying neuroretinal rim tissue in glaucoma and to compare these methods to the traditional retinal nerve fiber layer thickness diagnostic parameter. Methods: Neuroretinal rim parameters derived from three-dimensional (3D) volume scans were compared with the two-dimensional (2D) Spectralis retinal nerve fiber layer (RNFL) thickness scans for diagnostic capability. This study analyzed one eye per patient of 104 glaucoma patients and 58 healthy subjects. The shortest distances between the cup surface and the OCT-based disc margin were automatically calculated to determine the thickness and area of the minimum distance band (MDB) neuroretinal rim parameter. Traditional 150-μm reference surface-based rim parameters (volume, area, and thickness) were also calculated. The diagnostic capabilities of these five parameters were compared with RNFL thickness using the area under the receiver operating characteristic (AUROC) curves. Results: The MDB thickness had significantly higher diagnostic capability than the RNFL thickness in the nasal (0.913 vs. 0.818, P = 0.004) and temporal (0.922 vs. 0.858, P = 0.026) quadrants and the inferonasal (0.950 vs. 0.897, P = 0.011) and superonasal (0.933 vs. 0.868, P = 0.012) sectors. The MDB area and the three neuroretinal rim parameters based on the 150-μm reference surface had diagnostic capabilities similar to RNFL thickness. Conclusions: The 3D MDB thickness had a high diagnostic capability for glaucoma and may be of significant clinical utility. It had higher diagnostic capability than the RNFL thickness in the nasal and temporal quadrants and the inferonasal and superonasal sectors.