Pathophysiology and management of glaucoma associated with phakomatoses.

The phakomatoses, encephalotrigeminal angiomatosis (ETA; Sturge-Weber Syndrome), neurofibromatosis type 1 (NF1 or von Recklinghausen disease), Von Hippel-Lindau (VHL) disease, tuberous sclerosis (TSC), oculodermal melanocytosis (ODM), and phakomatosis pigmentovascularis are a group of neurocutaneous disorders that have characteristic systemic and ocular manifestations. Through many different mechanisms, they may cause glaucomatous damage of the optic nerve and subsequent vision loss varying from mild to severe. Glaucoma commonly affects patients with ETA (43-72%), orbito-facial NF1 (23-50%), and ODM (10%). Rarely, it may present as neovascular glaucoma in VHL and TSC. In ETA, glaucoma typically occurs ipsilateral to the port-wine stain, which is caused by a mutation in the GNAQ gene. Specifically, mechanical malformation of the anterior chamber angle and elevated episcleral venous pressure has been implicated as causes of glaucoma in ETA. In NF1, which is caused by a mutation in the NF1 tumor suppressor gene, glaucoma commonly occurs ipsilateral to lid plexiform neurofibromas. Histological studies of eyes with NF1 have revealed direct anterior chamber infiltration by neurofibromas, secondary angle closure, fibrovascularization, and developmental angle abnormalities as mechanisms of glaucoma. Lastly, phakomatosis pigmentovascularis is a rare combination of ODM and port-wine stain. Affected patients are at very high risk of developing glaucoma. Despite the many different mechanisms of glaucomatous damage, management follows similar principles as that for congenital glaucoma and primary open angle glaucoma. First-line therapy is topical intraocular pressure-lowering eye drops. Surgical management, including goniotomy, trabeculotomy, trabeculectomy, and tube shunt placement may be required for more severe cases.

COMPARISON OF VISUAL AND ANATOMICAL OUTCOMES OF EYES UNDERGOING TYPE I BOSTON KERATOPROSTHESIS WITH COMBINATION PARS PLANA VITRECTOMY WITH EYES WITHOUT COMBINATION VITRECTOMY.

PURPOSE: To determine whether 1-year visual and anatomical results after surgery combining pars plana vitrectomy, Boston keratoprosthesis, and a glaucoma drainage device as needed are similar, better, or worse than Boston keratoprosthesis initial implantation alone. METHODS: We performed a retrospective review of adult patients undergoing Boston keratoprosthesis at our institution. Visual acuity outcomes, anatomical results, and complication rates of patients undergoing combination surgery (including pars plana vitrectomy and a posterior glaucoma drainage device) were compared with those undergoing keratoprosthesis placement alone. RESULTS: There were 70 eyes in the keratoprosthesis alone group and 55 eyes in the keratoprosthesis with pars plana vitrectomy group. Mean follow-up durations were 54.67 months in the keratoprosthesis alone group and 48.41 months in the combination group. Baseline mean Snellen equivalent visual acuities were worse for the combination group compared with the keratoprosthesis alone group (P = 0.027). Visual acuities improved postoperatively by 1 month after keratoprosthesis implantation for both groups and improved three or more lines of Snellen acuity in the majority of eyes for both groups (≥72% by 12 months). Eyes undergoing pars plana vitrectomy had lower rates of de novo (P = 0.015) and significantly lower rates of secondary procedures (P = 0.002) at 1 year. One year complications rates for retroprosthetic membrane formation, retinal detachment, hypotony, cystoid macular edema, epiretinal membrane formation, endophthalmitis, and corneal melting were similar for both groups. CONCLUSION: Compared with keratoprosthesis alone, combining keratoprosthesis with pars plana vitrectomy and a glaucoma drainage device as needed, resulted in lower rates of de novo glaucoma, lower rates of additional surgical procedures, similar visual acuity outcomes at 1 year, and did not result in higher complication rates.

Association of macular pigment optical density with retinal layer thicknesses in eyes with and without manifest primary open-angle glaucoma.

OBJECTIVE: To investigate associations between baseline macular pigment optical density (MPOD) and retinal layer thicknesses in eyes with and without manifest primary open-angle glaucoma (POAG) in the Carotenoids in Age-Related Eye Disease Study 2 (CAREDS2). METHODS AND ANALYSIS: MPOD was measured at CAREDS baseline (2001-2004) via heterochromatic flicker photometry (0.5° from foveal centre). Peripapillary retinal nerve fibre layer (RNFL), macular ganglion cell complex (GCC), ganglion cell layer (GCL), inner plexiform layer (IPL), and RNFL thicknesses were measured at CAREDS2 (2016-2019) via spectral-domain optical coherence tomography. Associations between MPOD and retinal thickness were assessed using multivariable linear regression. RESULTS: Among 742 eyes (379 participants), manifest POAG was identified in 50 eyes (32 participants). In eyes without manifest POAG, MPOD was positively associated with macular GCC, GCL and IPL thicknesses in the central subfield (P-trend ≤0.01), but not the inner or outer subfields. Among eyes with manifest POAG, MPOD was positively associated with macular GCC, GCL, IPL and RNFL in the central subfield (P-trend ≤0.03), but not the inner or outer subfields, and was positively associated with peripapillary RNFL thickness in the superior and temporal quadrants (P-trend≤0.006). CONCLUSION: We observed a positive association between MPOD and central subfield GCC thickness 15 years later. MPOD was positively associated with peripapillary RNFL superior and temporal quadrant thicknesses among eyes with manifest POAG. Our results linking low MPOD to retinal layers that are structural indicators of early glaucoma provide further evidence that carotenoids may be protective against manifest POAG.

Glaucoma Care of Incarcerated Patients at an Academic Institution: A Case-Control Study.

PURPOSE: To evaluate medication and follow-up adherence in incarcerated patients examined at an academic glaucoma clinic, in comparison to nonincarcerated controls. METHODS: Retrospective, case-control study. Consecutive prisoners presenting for initial visits in the Glaucoma Clinic at the Illinois Eye and Ear Infirmary between December 2015 and December 2017 were included in the study. Nonincarcerated patients seen in the same Glaucoma Clinic with similar initial visit dates, age, race, sex, and disease severity were selected as controls. Glaucoma Clinic visits from each patient were reviewed until December 2018. Examination information, surgical intervention, follow-up and treatment recommendations, and patient-reported medication usage were recorded for each visit. Number of visits, loss to follow-up, follow-up delays, and medication nonadherence were studied as primary outcome measures. RESULTS: Twenty-four prisoners and 24 nonincarcerated controls were included. Prisoners had an average of 2.46 ± 2.38 visits during the study period, compared to 5.04 ± 3.25 for controls (P = 0.001). Follow-up visits occurred more than 30 days after the recommended follow-up time in 57.4% (95% confidence interval [CI]: 44.2%-70.6%) of prisoners, compared to 17.9% (95% CI: 10.2%-25.6%) of controls (P < 0.00001). 70.8% of prisoners (95% CI: 66.3-74.5%) were lost to follow-up, compared to 29.2% of controls (95% CI: 25.5%-32.9%; P < 0.01). Medication nonadherence rates were similar between prisoners (13.6%; 95% CI: 12.1%-15.2%) and controls (12.0%; 95% CI: 11.4%-12.6%; P = 0.78). CONCLUSIONS: Glaucoma follow-up adherence was significantly worse in prisoners compared to a nonincarcerated control population. Further study into causative factors is needed.

Gender and glaucoma: what we know and what we need to know.

PURPOSE OF REVIEW: With growing aging populations and an increase in cases of glaucoma and glaucoma blindness worldwide, aging populations are particularly at higher risk of glaucoma and glaucoma blindness. Awareness of the gender differences might increase attention toward populations at risk. RECENT FINDINGS: Women not only outlive men, but also outnumber men in glaucoma cases worldwide. Women are at higher risks for angle closure glaucoma, but there is no clear gender predilection for open angle glaucoma. Of interest, there is some evidence suggesting that female sex hormones might be protective of the optic nerve. In addition, it is hypothesized that decreased estrogen exposure is associated with increased risk for open angle glaucoma, yet population-based studies present inconsistent results. Presently, there is insufficient evidence to support hormonal replacement therapy use in glaucoma prevention. In addition, it appears that women carry a larger burden of glaucoma blindness due to longevity and disadvantages in socioeconomic/health beliefs. SUMMARY: Current evidence suggests that older women are at risk for glaucoma and glaucoma blindness. Further interdisciplinary research involving investigators, specialized in glaucoma, women's health and health disparities, will lead to better understanding of gender health disparities in glaucoma and better targeting populations at risk.

Glaucoma Care of Prison Inmates at an Academic Hospital.

Importance: Glaucoma care for prison inmates is underrepresented in the literature even though managing the treatment of such patients may provide unique challenges. Objectives: To evaluate the glaucoma profile of prison inmates treated at an academic ophthalmology center and to report on the medical and surgical management and follow-up metrics. Design, Setting, and Participants: This retrospective cohort study assessed data from 82 incarcerated patients treated at the glaucoma clinic, an academic referral center at the University of Illinois at Chicago, between January 2013 and December 2017. Main Outcomes and Measures: Diagnosis, glaucoma severity, medical and surgical interventions, and patient-reported medication adherence were recorded for each visit. Recommended and actual follow-up times were recorded and compared. Data analyses were conducted from January 2013 to December 2018. Results: In total, 82 patients (161 eyes) had 375 visits during the study period. All patients were male and ranged from 20 to 75 years of age (mean [SD] age, 50.8 [11.9] years). Most participants were black patients (65 [79.3%]). The most common diagnoses were primary open-angle glaucoma (POAG; 53 eyes [32.9%]) and POAG suspect (52 eyes [32.3%]). Glaucoma severity ranged from mild (25 of 77 eyes [32.5%]) to advanced (41 of 77 eyes [53.2%]). Overall, 59 patients (73.2%) were treated medically with up to 4 topical agents (40.0%). Of those treated, 70.0% of patients (95% CI, 57.7%-81.2%) reported medication nonadherence during at least 1 visit. Medication nonadherence was more common among those taking 4 different topical medications (21 of 24 [87.5%]) compared with others taking fewer medications (20 of 35 [57.1%]), for a difference of 30.4% (95% CI, 7.0%-53.6%; P = .02), and among those with advanced disease (22 of 26 [84.6%]) compared with glaucoma suspect (6 of 13 [46.2%]), for a difference of 38.4% (95% CI, 9.3%-67.5%; P = .02). Nineteen office procedures, including laser peripheral iridotomy and laser trabeculoplasty, were performed on 14 eyes. Seventeen incisional glaucoma procedures were performed on 15 eyes, including glaucoma drainage device implant (11 procedures [64.7%]) and trabeculectomy (3 procedures [17.6%]). Only 26.6% of return office visits (95% CI, 21.3%-32.3%) occurred within the recommended follow-up time frame. Furthermore, 93 patients (34.8%; 95% CI, 28.2%-40.0%) were seen more than 1 month after the recommended follow-up. Conclusions and Relevance: Despite incarceration in prison, where medication administration and appointment attendance are theoretically controlled, the results of this study suggested that substantial medication and follow-up nonadherence exists among inmates.

Visual acuity and intraocular pressure after Descemet's stripping endothelial keratoplasty in eyes with and without preexisting glaucoma.

PURPOSE: (1) To characterize the pattern of intraocular pressure (IOP) changes after Descemet's stripping endothelial keratoplasty (DSEK) in patients without preexisting glaucoma and in those with preexisting glaucoma, with and without prior glaucoma surgery. (2) To compare vision and IOP outcomes among the 3 groups. DESIGN: A retrospective chart review. PARTICIPANTS: A total of 805 DSEK cases performed in 641 patients by a single surgeon from December 2003 to August 2007 were available in the database. Only the first-treated eye of each patient with at least 1-year follow-up was included. Four hundred cases qualified: 315 eyes had no glaucoma (C); 64 eyes had glaucoma with no previous glaucoma surgery (G); and 21 eyes had prior glaucoma surgery (GS). Eyes with preexisting retinal problems were included in the analysis. METHODS: Data analysis included calculation of incidence of postoperative IOP elevation. The study criteria for postoperative IOP elevation were IOP > or =24 mmHg or IOP increase > or =10 mmHg from baseline. Kruskal-Wallis test was used to compare visual acuity (VA) and IOP among the 3 groups preoperatively and at 1-, 3-, 6-, and 12-month postoperative visits. MAIN OUTCOME MEASURES: Visual acuity (Snellen) and IOP (millimeters of mercury). RESULTS: The incidence of postoperative IOP elevation by the study criteria was 35%, 45%, and 43% for groups C, G, and GS, respectively. Elevated IOP was medically managed by initiating or increasing glaucoma medications or reducing steroids in 27%, 44%, and 38% of the patients in groups C, G, and GS, respectively. A subsequent glaucoma procedure was performed in 0.3%, 5%, and 19% of patients in groups C, G, and GS, respectively. Only the control group had statistically significant IOP elevation at 12 months (median increase of 2 mmHg) when compared with baseline (P<0.0001). All 3 groups had statistically significant improvement in vision at 12 months when compared with baseline (12-month median VA = 20/40 for C and G; and 20/50 for GS, P<0.0001). CONCLUSIONS: All groups had a substantial incidence of IOP elevation after DSEK. Close monitoring of IOP is warranted. In this cohort, preexisting glaucoma did not seem to have a negative effect on VA after DSEK. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Dietary Antioxidants, Macular Pigment, and Glaucomatous Neurodegeneration: A Review of the Evidence.

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide, and the prevalence is projected to increase to 112 million worldwide by 2040. Intraocular pressure is currently the only proven modifiable risk factor to treat POAG, but recent evidence suggests a link between antioxidant levels and risk for prevalent glaucoma. Studies have found that antioxidant levels are lower in the serum and aqueous humor of glaucoma patients. In this review, we provide a brief overview of the evidence linking oxidative stress to glaucomatous pathology, followed by an in-depth discussion of epidemiological studies and clinical trials of antioxidant consumption and glaucomatous visual field loss. Lastly, we highlight a possible role for antioxidant carotenoids lutein and zeaxanthin, which accumulate in the retina to form macular pigment, as evidence has emerged supporting an association between macular pigment levels and age-related eye disease, including glaucoma. We conclude that the evidence base is inconsistent in showing causal links between dietary antioxidants and glaucoma risk, and that prospective studies are needed to further investigate the possible relationship between macular pigment levels and glaucoma risk specifically.

Brimonidine tartrate for the treatment of glaucoma.

INTRODUCTION: Brimonidine tartrate is a commonly used eyedrop for short- and long-term lowering of intraocular pressure. Its use has been popularized due to its effects on aqueous suppression and uveoscleral outflow, as well as the suggestion of neuroprotection. Although available with alternative preservative vehicles, brimonidine is associated with high rates of local allergy and is contraindicated in breastfeeding women, neonates, young children, and the elderly due to risk of central nervous system depression. Other topical agents with differing advantages have challenged brimonidine's role in the treatment algorithm of ocular hypertension and glaucoma. Areas covered: The authors review the development of topical alpha-adrenergic agonists, with particular attention to the currently available formulations of brimonidine tartrate. Its mechanism of action, pharmacodynamics and safety, and clinical efficacy are analyzed. Expert opinion: Despite clinical familiarity with brimonidine after two decades of use, agents that offer daily dosing, nocturnal effect, and more favorable ocular and systemic side effect profiles have ultimately led to brimonidine's adjunctive use in patients with elevated intraocular pressure or high- or low-tension glaucomas. Still, brimonidine may be advantageous in patients undergoing laser trabeculoplasty or iridotomy, in certain forms of glaucoma, or in pregnant individuals prior to the last trimester, underscoring its clinical importance.

Longitudinal Study of Peripapillary Thinning in Sickle Cell Hemoglobinopathies.

PURPOSE: To determine the rate of retinal nerve fiber layer (RNFL) thinning in patients with sickle cell hemoglobinopathies. DESIGN: This was a prospective cohort study. METHODS: Sixty-seven patients averaging 35.8 ± 11.5 years of age at enrollment with electrophoretically confirmed sickle cell hemoglobinopathies followed by the University of Illinois at Chicago retina clinic for ≥1 year were included. Exclusion criteria included a history of diabetes, uncontrolled hypertension, glaucoma, ocular opacities, other retinopathies, and previous retinal procedures. The optic nerve head RNFL thicknesses were measured with spectral-domain optical coherence tomography (Heidelberg Engineering, Inc) at enrollment and subsequent follow-ups. Linear mixed models were used to estimate rates of thinning. RESULTS: A total of 122 eyes were followed for 3.8 ± 2.0 years (range 1-8 years). Mean global peripapillary RNFL thickness was 100.9 ± 13.0 µm at baseline. Global peripapillary RNFL thickness decreased at a rate of 0.98 µm per year (95% confidence interval [CI] 0.77-1.19 µm/year). A history of stroke was associated with a faster rate of global RNFL thinning (1.72 ± 0.20 vs 0.79 ± 0.12 µm/year, P < .001), whereas a history of hypertension was associated with a slower rate of thinning (0.33 ± 0.27 vs 1.14 ± 0.12 µm/year, P = .002). CONCLUSIONS: Peripapillary RNFL thinning in patients with sickle cell hemoglobinopathies occurred faster in patients with a history of stroke and slower in patients with controlled hypertension. Future studies will compare these rates to those of healthy age- and race-matched individuals.

Staged ocular fornix reconstruction for glaucoma drainage device under neoconjunctiva at the time of Boston type 1 Keratoprosthesis implantation.

PURPOSE: Glaucoma is the leading cause of vision loss in eyes with Boston Keratoprosthesis (KPro). Glaucoma drainage devices (GDDs) have been shown to be effective in controlling glaucoma with KPro. Cicatricial conjunctival disease with forniceal shortening is a major challenge and limitation to the use of GDD. In our series, we report the success of fornix reconstruction in cicatricial ocular surface disease as a staged procedure prior to a combined KPro/GDD surgery. METHODS: Retrospective case series involving 4 eyes with surface cicatricization. Three patients with chemical burns and one patient with Ectrodactyly Ectodermal Dysplasia-Clefting syndrome. Preoperative data, surgical interventions, and clinical outcomes were reviewed. CONCLUSION: This series represents the first report of fornix reconstruction for combined KPro/GDD surgery. Fornix reconstruction with the aid of AMT with or without OMM grafting is a relatively safe and effective way to manage complex cicatricial surface disease associated with corneal scarring and glaucoma, allowing for subsequent successful implantation of GDD and KPro in cases that were otherwise poor surgical candidates.

Detection of mosaic retinal dysfunction in choroideremia carriers electroretinographic and psychophysical testing.

PURPOSE: To test whether choroideremia carriers have a mosaic pattern of retinal dysfunction, as noted in carriers of X-linked recessive retinitis pigmentosa and X-linked retinoschisis. DESIGN: Prospective observational case series. PARTICIPANTS: Seven obligate choroideremia carriers (age range, 18-72) with visual acuity (VA) of 20/25 or better were recruited into the study. METHODS: The carriers underwent VA testing (Snellen chart), ophthalmic examination, Humphrey visual field (VF), and multifocal electroretinographic testing. The amplitude and implicit time scales were measured by the algorithm of Hood and Li. The amplitude measures (a scales) and implicit time measures (t scales) were reported abnormal when they were >2 standard deviations above the mean of age-similar normally sighted control subjects. MAIN OUTCOME MEASURES: Mapping of local 103 electroretinographic response amplitudes and implicit times. RESULTS: Only 1 of the 7 carriers showed abnormal Humphrey VF thresholds, whereas 6 of the 7 carriers showed a mosaic pattern of retinal dysfunction measured by multifocal electroretinographic testing. All 6 carriers showed statistically significant implicit time delays, whereas 4 carriers showed statistically significant amplitude reductions and implicit time delays (P<0.05 to P<0.0006). One carrier with a normal-appearing macula and normal Humphrey VF showed a cluster of statistically significant implicit time delays within the macula (P<0.05 to P<0.0006). The overall extent of local electroretinographic abnormalities corresponded to the severity of ophthalmoscopically apparent pigmentary changes. The one carrier with mild threshold elevation on Humphrey VF testing showed the most ophthalmoscopically apparent extensive fundus pigmentary changes. CONCLUSIONS: We demonstrated a mosaic pattern of retinal cone dysfunction in carriers of choroideremia. Our findings are consistent with the Lyon hypothesis of random X-chromosome inactivation. Multifocal electroretinographic testing is potentially sensitive to detect local retinal dysfunction in choroideremia carriers even in those with a normal-appearing macula and good VA.

Intraocular pressure measurements following Descemet stripping endothelial keratoplasty.

PURPOSE: The effect of increased corneal thickness after Descemet stripping endothelial keratoplasty (DSEK) on intraocular pressure (IOP) measurement has not been previously studied. It is uncertain if this increase in corneal thickness would artificially elevate IOP reading by Goldmann tonometry [GAT] (Haag-Streit, Konig, Switzerland). Therefore the effect of DSEK-related thick cornea on IOP measurement was investigated using three different techniques. DESIGN: Prospective cross-sectional study. METHODS: Participants were recruited from a single tertiary referral center. Fifty eyes of 38 patients with successful DSEK at least three months prior to testing were evaluated. At the time of the study, none of the participants had clinically detectable corneal edema. IOP was measured with GAT, pneumatonometry, and dynamic contour tonometry (DCT) in an unmasked randomized sequence. Central corneal thickness (CCT) was measured by ultrasonic pachymetry. RESULTS: Mean CCT was 701 +/- 68 microm. The mean IOP +/- standard deviation (SD) was 15.9 +/- 4.9 mm Hg for GAT, 20.3 +/- 4.5 mm Hg for pneumatonometry, and 19.8 +/- 4.4 mm Hg for DCT. Pneumatonometry and DCT IOP measurements were significant higher than GAT (P < .01). In contrast, the difference between pneumatonometry and DCT readings was not statistically significant (P = .28). The correlations between IOP and corneal thickness were not significant in this cohort (P > .05). CONCLUSIONS: Falsely elevated GAT, as expected in thick corneas, was not demonstrated after DSEK. High IOP reading by GAT therefore should raise suspicion of elevated IOP in DSEK eyes.

Systemic Disease and Long-term Intraocular Pressure Mean, Peak, and Variability in Nonglaucomatous Eyes.

PURPOSE: Elevated intraocular pressure (IOP) is a well-known risk factor in glaucoma development and progression. As most glaucoma risk factors are not modifiable, IOP remains the sole focus of medical and surgical therapy. Identifying modifiable factors and their effects on IOP, such as systemic diseases, is therefore of interest. The objective is to assess the long-term, longitudinal relationship between systemic diseases and IOP mean, peak, and variability, including diabetes, hypertension, body mass index (BMI), and smoking status. DESIGN: Secondary analysis of randomized clinical trial data. METHODS: Longitudinal IOP and systemic disease data from the Age-Related Eye Disease Study (AREDS), a randomized clinical trial of high-dose antioxidants, was analyzed. STUDY POPULATION: A total of 3909 older participants without a reported diagnosis of glaucoma or glaucoma treatment during AREDS with up to 12 years of annual IOP and systemic disease data. MAIN OUTCOME MEASURES: Independent systemic disease risk factors associated with IOP. RESULTS: Univariate analysis identified numerous systemic disease factors associated with IOP mean, peak, and variability. Longitudinal adjusted models identified diabetes, obesity, and systolic hypertension as significantly associated with increased IOP, while systemic beta-blocker use was inversely associated. CONCLUSIONS: Results demonstrate a relationship between multiple systemic diseases and IOP; moreover, they demonstrate that systemic diseases influence additional parameters beyond mean IOP, such as IOP peak and variability. Although only to be taken within the context of IOP, these population-level trends reveal potentially modifiable factors in IOP control, and are particularly important in the context of increasing obesity and diabetes prevalence rates in American adults.

Three Dimensional Stimulus Source for Pattern Electroretinography in Mid- and Far-peripheral Retina.

PURPOSE: The pattern electroretinogram (pERG) response reflects, in part, ganglion cell function. However, probing retinal ganglion cell (RGC) function in the mid- and far peripheral retina is difficult with conventional flat-panel pERG stimulus sources. A pattern stimulus source is presented for probing the peripheral retina. Peripheral pERG (ppERG) responses were evaluated versus luminance, reversal rate, and field subtended, and were compared with conventional pERG in healthy eyes. METHODS: Eleven normally-sighted subjects were recruited. A hemispherical surface was used to present a reversing checkerboard pattern to the peripheral retina, from approximately 35° to 85° of visual field, in all directions. Responses to stimuli presented to peripheral field sectors (superior, nasal, inferior, temporal) were also recorded. Conventional pERG responses were recorded on the same day. Amplitudes and implicit times of waveform peaks were evaluated. RESULTS: Robust pERG responses from peripheral retina resemble conventional pERG responses but with shorter implicit times and reduced positive component. Responses to high-luminance patterns include high-frequency components resembling flash ERG oscillatory potentials. Negative response component amplitudes increased with increasing pattern luminance, and decreased with increasing reversal rate. CONCLUSIONS: Peripheral-field pERG responses are robust and repeatable; the unique response properties reflect differences between central and peripheral retina. Field-sector response ratios can be used to probe for sectoral dysfunction associated with disease. TRANSLATIONAL RELEVANCE: The ppERG approach provides direct measurement of proximal retinal function beyond the fields probed by conventional perimetry and pERG, providing access to a relatively under studied part of the retina relevant to early stage glaucoma.

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets.

Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk. Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]). Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations. Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

Topical treatment of glaucoma: established and emerging pharmacology.

INTRODUCTION: Glaucoma is a collection of optic neuropathies consisting of retinal ganglion cell death and corresponding visual field loss. Glaucoma is the leading cause of irreversible vision loss worldwide and is forecasted to precipitously increase in prevalence in the coming decades. Current treatment options aim to lower intraocular pressure (IOP) via topical or oral therapy, laser treatment to the trabecular meshwork or ciliary body, and incisional surgery. Despite increasing use of trabecular laser therapy, topical therapy remains first-line in the treatment of most forms of glaucoma. Areas covered: Novel glaucoma therapies are a long-standing focus of investigational study. More than two decades have passed since the last United States Food and Drug Administration (FDA) approval of a topical glaucoma drug. Here, the authors review established topical glaucoma drops as well as those currently in FDA phase 2 and 3 clinical trial, nearing clinical use. Expert opinion: Current investigational glaucoma drugs lower IOP, mainly through enhanced trabecular meshwork outflow. Although few emerging therapies show evidence of retinal ganglion cell and optic nerve neuroprotection in animal models, emerging drugs are focused on lowering IOP, similar to established medicines.

Age-Related Macular Degeneration and Mortality in the Age-Related Eye Disease Study (AREDS): The Effect of Sex and Time.

PURPOSE: Age-related macular degeneration (AMD) shares similar risk factors and pathogeneses with cardiovascular diseases (CVDs). Epidemiologic studies over the past 2 decades analyzing the association between AMD and all-cause and CVD-specific mortality have failed to yield conclusive results. The purpose of this analysis is to investigate the sex-specific association between AMD and all-cause and CVD-specific mortality, and to assess whether duration of follow-up alters the strength of association. DESIGN: The database of Genotypes and Phenotypes (dbGaP) data set for the Age-Related Eye Disease Study, a randomized clinical trial of high-dose antioxidants in AMD prevention, with participants enrolled from 1992 to 1998 and followed through 2005, was used in the analysis. PARTICIPANTS: There were 4757 Age-Related Eye Disease Study participants aged 55 through 80 years (mean, 69.4 years; 44.1% male) recruited from 11 retinal specialty clinics. Participants had standard Age-Related Eye Disease Study AMD categories (category 1, n = 1117; category 2, n = 1062; category 3, n = 1621; category 4, n = 957). METHODS: The sex-specific adjusted hazard ratio (HRadj) between baseline AMD and all-cause and CVD-specific mortality was determined at multiple time points (e.g., 5, 7, 10, and all years), adjusting for age, race, diabetes, hypertension, angina, cancer, smoking, obesity, clinical trial antioxidant treatment category, and education. MAIN OUTCOME MEASURES: Sex-specific all-cause and CVD-specific mortality. RESULTS: Mean follow-up was 9.6 years (range, 0.5-12.5 years), with 1087 deaths (category 1, n = 197 [17.6%]; category 2, n = 200 [18.8%]; category 3, n = 356 [22.0%]; category 4, n = 326 [34.1%]). Sex-stratified models demonstrated sex differences; in women, a significant association between AMD category 4 and all-cause mortality existed compared with category 1 at each period (HRadj, 1.5-2.3; all P ≤ 0.005); similar category 4 findings were present with CVD-specific mortality, strengthening with shorter periods (HRadj, 1.9-4.6; all P ≤ 0.01). Among men, a significant association between all AMD stages and all-cause (HRadj, 1.5-2.3; all P ≤ 0.05) and CVD-specific mortality (HRadj, 1.6-4.0; all P ≤ 0.05) existed for nearly all periods. CONCLUSIONS: Substantial late AMD cases and deaths exceed those in previous population-based studies to better test mortality-related hypotheses. Age-related macular degeneration was significantly associated with all-cause and CVD-specific mortality. Relationships weakened over a longer duration of follow-up, and sex seems to modify the association. Future analyses are warranted to interrogate the possible clinical usefulness of these relationships.

M&S Smart System Contrast Sensitivity Measurements Compared With Standard Visual Function Measurements in Primary Open-Angle Glaucoma Patients.

PURPOSE: To evaluate the nature and extent of letter contrast sensitivity (CS) deficits in glaucoma patients using a commercially available computer-based system (M&S Smart System II) and to compare the letter CS measurements to standard clinical measures of visual function. METHODS: Ninety-four subjects with primary open-angle glaucoma participated. Each subject underwent visual acuity, letter CS, and standard automated perimetry testing (Humphrey SITA 24-2). All subjects had a best-corrected visual acuity (BCVA) of 0.3 log MAR (20/40 Snellen equivalent) or better and reliable standard automated perimetry (fixation losses, false positives, and false negatives <33%). CS functions were estimated from the letter CS and BCVA measurements. The area under the CS function (AUCSF), which is a combined index of CS and BCVA, was derived and analyzed. RESULTS: The mean (± SD) BCVA was 0.08±0.10 log MAR (∼20/25 Snellen equivalent), the mean CS was 1.38±0.17, and the mean Humphrey Visual Field mean deviation (HVF MD) was -7.22±8.10 dB. Letter CS and HVF MD correlated significantly (r=0.51, P<0.001). BCVA correlated significantly with letter CS (r=-0.22, P=0.03), but not with HVF MD (r=-0.12, P=0.26). A subset of the subject sample (∼20%) had moderate to no field loss (≤-6 dB MD) and minimal to no BCVA loss (≤0.3 log MAR), but had poor letter CS. AUCSF was correlated significantly with HVF MD (r=0.46, P<0.001). CONCLUSIONS: The present study is the first to evaluate letter CS in glaucoma using the digital M&S Smart System II display. Letter CS correlated significantly with standard HVF MD measurements, suggesting that letter CS may provide a useful adjunct test of visual function for glaucoma patients. In addition, the significant correlation between HVF MD and the combined index of CS and BCVA (AUCSF) suggests that this measure may also be useful for quantifying visual dysfunction in glaucoma patients.

Evidence-Based Approaches to Glaucoma Management During Pregnancy and Lactation.

With increasing maternal age in this decade, there is a parallel rise in the number of pregnant and lactating women affected by glaucoma worldwide. Understanding the diagnosis and management of glaucoma during pregnancy and lactation is essential to preventing blindness from glaucoma in this vulnerable population. This report provides a review of the current literature and offers effective strategies that will overcome the challenges in managing glaucoma during pregnancy and lactation. Practically, glaucoma management during pregnancy and lactation presents a unique challenge for the physician, as the benefit of any treatment must be weighed against the potential risks to the fetus. Prior to initiating or continuing treatment, the physician should be familiar with the various treatment options to manage intraocular pressure during pregnancy and lactation, including the safety of various anti-glaucoma medications as supported by the existing literature and based on the food and drug administration guidelines. A collaborative team effort between the ophthalmologist, obstetrician, and neonatologist in high-risk pregnancies is recommended to optimize care for the mother and fetus.