Genome-Wide Association Study Identifies Two Common Loci Associated with Pigment Dispersion Syndrome/Pigmentary Glaucoma and Implicates Myopia in its Development.

PURPOSE: To identify genetic variants associated with pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG) in unrelated patients and to further understand the genetic and potentially causal relationships between PDS and associated risk factors. DESIGN: A 2-stage genome-wide association meta-analysis with replication and subsequent in silico analyses including Mendelian randomization. PARTICIPANTS: A total of 574 cases with PG or PDS and 52 627 controls of European descent. METHODS: Genome-wide association analyses were performed in 4 cohorts and meta-analyzed in 3 stages: (1) a discovery meta-analysis was performed in 3 cohorts, (2) replication was performed in the fourth cohort, and (3) all 4 cohorts were meta-analyzed to increase statistical power. Two-sample Mendelian randomization was used to determine whether refractive error and intraocular pressure exert causal effects over PDS. MAIN OUTCOME MEASURES: The association of genetic variants with PDS and whether myopia exerts causal effects over PDS. RESULTS: Significant association was present at 2 novel loci for PDS/PG. These loci and follow-up analyses implicate the genes gamma secretase activator protein (GSAP) (lead single nucleotide polymorphism [SNP]: rs9641220, P = 6.0×10-10) and glutamate metabotropic receptor 5 (GRM5)/TYR (lead SNP: rs661177, P = 3.9×10-9) as important factors in disease risk. Mendelian randomization showed significant evidence that negative refractive error (myopia) exerts a direct causal effect over PDS (P = 8.86×10-7). CONCLUSIONS: Common SNPs relating to the GSAP and GRM5/TYR genes are associated risk factors for the development of PDS and PG. Although myopia is a known risk factor, this study uses genetic data to demonstrate that myopia is, in part, a cause of PDS and PG.

Mutations in SPATA13/ASEF2 cause primary angle closure glaucoma.

Current estimates suggest 50% of glaucoma blindness worldwide is caused by primary angle-closure glaucoma (PACG) but the causative gene is not known. We used genetic linkage and whole genome sequencing to identify Spermatogenesis Associated Protein 13, SPATA13 (NM_001166271; NP_001159743, SPATA13 isoform I), also known as ASEF2 (Adenomatous polyposis coli-stimulated guanine nucleotide exchange factor 2), as the causal gene for PACG in a large seven-generation white British family showing variable expression and incomplete penetrance. The 9 bp deletion, c.1432_1440del; p.478_480del was present in all affected individuals with angle-closure disease. We show ubiquitous expression of this transcript in cell lines derived from human tissues and in iris, retina, retinal pigment and ciliary epithelia, cornea and lens. We also identified eight additional mutations in SPATA13 in a cohort of 189 unrelated PACS/PAC/PACG samples. This gene encodes a 1277 residue protein which localises to the nucleus with partial co-localisation with nuclear speckles. In cells undergoing mitosis SPATA13 isoform I becomes part of the kinetochore complex co-localising with two kinetochore markers, polo like kinase 1 (PLK-1) and centrosome-associated protein E (CENP-E). The 9 bp deletion reported in this study increases the RAC1-dependent guanine nucleotide exchange factors (GEF) activity. The increase in GEF activity was also observed in three other variants identified in this study. Taken together, our data suggest that SPATA13 is involved in the regulation of mitosis and the mutations dysregulate GEF activity affecting homeostasis in tissues where it is highly expressed, influencing PACG pathogenesis.

Mydriasert pupillary dilation for cataract surgery: an economic and clinical study.

BACKGROUND: Mydriasert is an insoluble ophthalmic insert indicated for mydriasis prior to cataract surgery, which gradually releases the active ingredients: tropicamide (0.25 mg) and phenylephrine (5.38 mg). This study aimed to evaluate the cost of Mydriasert compared with conventional mydriatic eye drops to induce pupil dilation prior to cataract surgery using a budget impact model. METHODS: A cohort-based, decision tree, budget impact model was developed to estimate the drug, consumable and staff costs for achieving mydriasis with Mydriasert compared to mydriatic eye drops (tropicamide [1%] plus phenylephrine [10%]). Insights from structured interviews with clinicians (n = 5) experienced in using both Mydriasert and mydriatic eye drops and results from the current clinical study of patients undergoing cataract surgery (n = 144) at a Greater London district general hospital were used to obtain key input parameters for the model, and to validate the model approach. RESULTS: The base case analysis in a cohort of 1763 patients undergoing cataract surgery showed that when Mydriasert substituted mydriatic eye drops, annual total costs decreased by 18% and annual total nurse time decreased from 235.1 hours to 44.1 hours over one year (2012-2013). CONCLUSIONS: This study demonstrated that despite its higher unit cost than mydriatic eye drops, Mydriasert resulted in overall savings in health-care costs, mainly associated with reduced nursing time. The economic model developed could assist National Health Service managers and local payers to estimate the budget impact of the introduction of Mydriasert into different clinical settings.

Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial.

BACKGROUND: Treatments for open-angle glaucoma aim to prevent vision loss through lowering of intraocular pressure, but to our knowledge no placebo-controlled trials have assessed visual function preservation, and the observation periods of previous (unmasked) trials have typically been at least 5 years. We assessed vision preservation in patients given latanoprost compared with those given placebo. METHODS: In this randomised, triple-masked, placebo-controlled trial, we enrolled patients with newly diagnosed open-angle glaucoma at ten UK centres (tertiary referral centres, teaching hospitals, and district general hospitals). Eligible patients were randomly allocated (1:1) with a website-generated randomisation schedule, stratified by centre and with a permuted block design, to receive either latanoprost 0·005% (intervention group) or placebo (control group) eye drops. Drops were administered from identical bottles, once a day, to both eyes. The primary outcome was time to visual field deterioration within 24 months. Analyses were done in all individuals with follow-up data. The Data and Safety Monitoring Committee (DSMC) recommended stopping the trial on Jan 6, 2011 (last patient visit July, 2011), after an interim analysis, and suggested a change in primary outcome from the difference in proportions of patients with incident progression between groups to time to visual field deterioration within 24 months. This trial is registered, number ISRCTN96423140. FINDINGS: We enrolled 516 individuals between Dec 1, 2006, and March 16, 2010. Baseline mean intraocular pressure was 19·6 mm Hg (SD 4·6) in 258 patients in the latanoprost group and 20·1 mm Hg (4·8) in 258 controls. At 24 months, mean reduction in intraocular pressure was 3·8 mm Hg (4·0) in 231 patients assessed in the latanoprost group and 0·9 mm Hg (3·8) in 230 patients assessed in the placebo group. Visual field preservation was significantly longer in the latanoprost group than in the placebo group: adjusted hazard ratio (HR) 0·44 (95% CI 0·28-0·69; p=0·0003). We noted 18 serious adverse events, none attributable to the study drug. INTERPRETATION: This is the first randomised placebo-controlled trial to show preservation of the visual field with an intraocular-pressure-lowering drug in patients with open-angle glaucoma. The study design enabled significant differences in vision to be assessed in a relatively short observation period. FUNDING: Pfizer, UK National Institute for Health Research Biomedical Research Centre.

Longitudinal study of iris concavity, corneal biomechanics, and correlations to ocular biometry in a cohort of 10- to 12-year-old UK schoolboys: 2-year follow-up data.

PURPOSE: To explore changes in iris curvature over a 2-year period. To investigate associations between iris curvature and ocular biometric parameters. To explore relationships between a number of nonocular measurements and ocular biometric parameters. METHODS: Schoolboys enrolled 2 years previously were invited to return for anterior segment optical coherence tomography, corneal hysteresis (CH), corneal resistance factor (CRF), and axial biometric measurements. Refractive error was assessed and measures of height, weight, waist circumference, digit ratio, and percentage body fat taken. RESULTS: Mean spherical equivalent refraction reduced by 0.76 diopters and mean iris concavity, defined as a measurement of less than or equal to -0.1 mm, increased by 0.018 mm at distance fixation and 0.04 mm on accommodation. Compared with 2 years previously, the prevalence of iris concavity increased from 24% to 32% on distance fixation and from 65% to 84% on accommodation. Variables significantly associated with nonaccommodating iris curvature were anterior chamber depth (ACD, P = 0.029) and mean scleral spur angle (P = 0.0001). Variables significantly associated with accommodating iris curvature were ACD (P = 0.02), lens vault (P = 0.047), and scleral spur angle (P < 0.0001). Significant association was again found between CH and accommodating spur-to-spur distance (R(2) = 0.13, P = 0.007). CONCLUSIONS: Iris concavity was more prevalent in this cohort of schoolboys than 2 years earlier. The degree of concavity remains related to ACD and lens vault. The association between spur-to-spur distance and CH was similar at baseline and after 2 years.

Iris concavity, corneal biomechanics, and their correlations with ocular biometry in a cohort of 10- to 12-year-old UK school boys: baseline data.

PURPOSE: Pigment dispersion syndrome is associated with iris concavity. This study investigated the prevalence of iris concavity, defined as a measurement of ≤-0.1 mm, in a cohort of 10- to 12-year-old boys, and explored the relationship between iris curvature and anterior segment biometry. Associations with corneal biomechanical parameters also were explored. METHODS: A cohort of school boys (n = 96) was recruited from a local school. Anterior segment optical coherence tomography (AS-OCT) was performed under accommodative and nonaccommodative conditions, and iris curvature quantified. Corneal hysteresis (CH) and corneal resistance factor (CRF) were measured with the ocular response analyzer (ORA). Noncontact axial biometry was performed using laser interferometry. RESULTS: The prevalence of iris concavity was 24% on distance fixation, increasing to 65% on accommodation. Variables significantly associated with nonaccommodating iris curvature were lens vault (P = 0.02) and mean keratometry (P = 0.02). For both variables acting jointly, R(2) = 0.30. Variables associated significantly with accommodating iris curvature were anterior chamber depth (P = 0.009), lens vault (P = 0.049), and mean scleral spur angle (P < 0.0001). For these three variables acting jointly, R(2) = 0.33. Significant association was found between CH and spur-to-spur distance (R(2) = 0.07, P = 0.025). CONCLUSIONS: Iris concavity was a common finding in this cohort and related to anterior segment biometric parameters. Further work is required to clarify whether anatomical differences exist between iris concavity seen in the adolescent eye and that found in adults with pigment dispersion syndrome.

The United Kingdom Glaucoma Treatment Study: a multicenter, randomized, double-masked, placebo-controlled trial: baseline characteristics.

OBJECTIVE: The United Kingdom Glaucoma Treatment Study (UKGTS) tests the hypothesis that treatment with a topical prostaglandin analog, compared with placebo, reduces the frequency of visual field (VF) deterioration events in patients with open-angle glaucoma (OAG) by 50% over a 2-year period. Additional goals are to evaluate study power with novel clinical trial outcomes: (1) VF deterioration velocity and (2) VF and quantitative imaging measurements modeled as joint outcomes. DESIGN: The UKGTS is a randomized, double-masked, placebo-controlled, multicenter treatment trial for OAG. PARTICIPANTS: A total of 516 patients with newly diagnosed (previously untreated) OAG were prospectively recruited at 10 UK centers between 2007 and 2010. METHODS: Eligible patients were randomly assigned to treatment with latanoprost 0.005% or placebo. The observation period was 2 years, with subjects monitored by VF testing, quantitative imaging, optic disc photography, and tonometry at 11 visits. MAIN OUTCOME MEASURES: The primary outcome measure is time to VF deterioration within 24 months. Secondary outcomes include the deterioration velocity of VF and quantitative imaging measures. RESULTS: The main source of referrals was optometrists (88%). A total of 777 subjects were assessed for eligibility, and 261 were excluded because they did not meet the inclusion criteria or declined to participate. The mean age of the 516 participants was 66 years, and 52.9% were male; 90.1% of the participants were white, and approximately one third (32.2%) reported a family history of glaucoma. A total of 777 eyes were eligible at initial assessment. Both eyes were eligible for 265 participants. Mean (standard deviation) intraocular pressure (IOP) at baseline for the eyes with better versus worse mean deviation (MD) was 18.9 (4.1) and 19.9 (4.7) mmHg, respectively (P = 0.0053). Some 56.1% of all eligible eyes had IOP <20 mmHg at baseline. The median (interquartile range) VF MD for all eligible eyes was -2.9 dB (-1.6 to -4.8 dB). CONCLUSIONS: This is the first randomized, placebo-controlled trial to evaluate the efficacy of medical treatment in reducing VF deterioration in OAG. The baseline characteristics for eligible patients and eyes from this cohort are presented and compared with those of previous trials. The baseline characteristics are similar to those of the largely population-based Early Manifest Glaucoma Trial. The early stage of the glaucoma and relatively low IOP at diagnosis suggest remarkably sensitive case findings by community optometrists in the United Kingdom.

The United Kingdom Glaucoma Treatment Study: a multicenter, randomized, placebo-controlled clinical trial: design and methodology.

OBJECTIVE: Elevated intraocular pressure (IOP) is a major risk factor for the deterioration of open-angle glaucoma (OAG); medical IOP reduction is the standard treatment, yet no randomized placebo-controlled study of medical IOP reduction has been undertaken previously. The United Kingdom Glaucoma Treatment Study (UKGTS) tests the hypothesis that treatment with a topical prostaglandin analog, compared with placebo, reduces the frequency of visual field (VF) deterioration events in OAG patients by 50% over a 2-year period. DESIGN: The UKGTS is a randomized, double-masked, placebo-controlled, multicenter treatment trial for OAG. PARTICIPANTS: Five hundred sixteen newly diagnosed (previously untreated) patients with OAG were recruited prospectively at 10 centers between 2007 and 2010. METHODS: Patients were assigned by concealed telephone allocation to treatment with a prostaglandin analog (latanoprost 0.005%) or placebo. The observation period was 2 years, with subjects monitored by VF testing, quantitative imaging, optic disc photography, and tonometry at 11 visits. Data were acquired according to novel protocols optimized for the analysis of deterioration velocity. The sample size was determined for a 2-sided error of α=0.05 to detect the difference between 24% and 11% in incident deterioration over a 24-month follow-up at 90% power and assuming a 25% attrition rate. MAIN OUTCOME MEASURES: The primary outcome was time to VF deterioration within 24 months. Secondary outcomes included the deterioration velocity of VF and quantitative imaging measures and the relationship between these velocities and risk factors for deterioration. RESULTS: The study design enabled a short trial with a 2-year observation period and provided data that can be used to assess the feasibility of further shortening trial duration with the progression velocity of VF and structural imaging measurements as outcomes. CONCLUSIONS: The UKGTS is the first randomized, placebo-controlled trial to evaluate the efficacy of medical treatment in reducing VF deterioration in OAG. The measurement of deterioration velocity and inclusion of quantitative imaging has the potential to reduce the number of patients and duration required for subsequent clinical trials. This trial also will quantify risk factors for deterioration, enabling more precise risk profiling of patients and the development of patient management protocols. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The genetics of pigment dispersion syndrome and pigmentary glaucoma.

We review the inheritance patterns and recent genetic advances in the study of pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG). Both conditions may result from combinations of mutations in more than one gene or from common variants in many genes, each contributing small effects. We discuss the currently known genetic loci that may be related with PDS/PG in humans, the role of animal models in expanding our understanding of the genetic basis of PDS, the genetic factors underlying the risk for conversion from PDS to PG and the relationship between genetic and environmental--as well as anatomical--risk factors.

Testing an aetiological model of visual hallucinations in Parkinson's disease.

The exact pathogenesis of visual hallucinations in Parkinson's disease is not known but an integrated model has been proposed that includes impaired visual input and central visual processing, impaired brainstem regulation of sleep-wake cycle with fluctuating vigilance, intrusion of rapid eye movement dream imagery into wakefulness and emergence of internally generated imagery, cognitive dysfunction and influence of dopaminergic drugs. In a clinical study, we assessed motor and non-motor function, including sleep, mood, autonomic and global, frontal and visuoperceptive cognitive function in patients with and without visual hallucinations. A subgroup of patients underwent detailed ophthalmological assessment. In a separate pathological study, histological specimens were obtained from cases of pathologically proven Parkinson's disease and a retrospective case notes review was made for reporting of persistent formed visual hallucinations. An assessment of Lewy body and Lewy neurite pathology was carried out in five cortical regions as recommended by diagnostic criteria for dementia with Lewy Bodies and in brainstem nuclei. Ninety-four patients (mean age 67.5 ± 9.5 years) participated in the clinical study of whom 32% experienced visual hallucinations. When corrected for multiple comparisons, patients with visual hallucinations had significantly greater disease duration, treatment duration, motor severity and complications, sleep disturbances, in particular excessive daytime somnolence and rapid eye movement sleep behavioural disorder, disorders of mood, autonomic dysfunction and global, frontal and visuoperceptive cognitive dysfunction. Of the 94 patients, 50 (53%) underwent ophthalmological assessment. There were no differences in ocular pathology between the visual hallucination and non-visual hallucination groups. In a logistic regression model the four independent determinants of visual hallucinations were rapid eye movement sleep behavioural disorder (P = 0.026), autonomic function (P = 0.004), frontal cognitive function (P = 0.020) and a test of visuoperceptive function (object decision; P = 0.031). In a separate study, post-mortem analysis was performed in 91 subjects (mean age at death 75.5 ± 8.0 years) and persistent visual hallucinations were documented in 63%. Patients in the visual hallucinations group had similar disease duration but had significantly higher Lewy body densities in the middle frontal (P = 0.002) and middle temporal gyri (P = 0.033) and transentorhinal (P = 0.005) and anterior cingulate (P = 0.020) cortices but not parietal cortex (P = 0.22). Using a comprehensive assessment of the clinical, demographic and ophthalmological correlates of visual hallucinations in Parkinson's disease, the combined data support the hypothesized model of impaired visual processing, sleep-wake dysregulation and brainstem dysfunction, and cognitive, particularly frontal, impairment all independently contributing to the pathogenesis of visual hallucinations in Parkinson's disease. These clinical data are supported by the pathological study, in which higher overall cortical Lewy body counts, and in particular areas implicated in visuoperception and executive function, were associated with visual hallucinations.

Geographic variations in microbial keratitis: an analysis of the peer-reviewed literature.

The epidemiology of microbial keratitis has been investigated in several studies by analysis of organisms cultured from corneal scrapes. However, a comparison of the frequency of different organisms causing keratitis in different parts of the world is lacking. The authors present a review incorporating an analysis of data from studies worldwide. The data provide a comparison of the frequency of culture-positive organisms found in different parts of the world. Associations between a country's gross national income and types of causative organism are explored. The highest proportion of bacterial corneal ulcers was reported in studies from North America, Australia, The Netherlands and Singapore. The highest proportion of staphylococcal ulcers was found in a study from Paraguay, while the highest proportion of pseudomonas ulcers was reported in a study from Bangkok. The highest proportions of fungal infections were found in studies from India and Nepal. The Spearman correlation coefficient demonstrated statistically significant correlations between gross national income and percentages of bacterial (0.85 (95% CI 0.68 to 0.91, p<0.0001)), fungal (-0.81 (95% CI -0.90 to -0.66, p<0.0001)) and streptococcal (-0.43 (95% CI -0.66 to -0.12, p=0.009)) isolates.

Prevalence of at-risk drinking among a national sample of medical students.

As limited research exists on medical students' substance use patterns, including over-consumption of alcohol, the objective of this study was to determine prevalence and correlates of at-risk drinking among a national sample of medical students, using a cross-sectional, anonymous, Web-based survey. A total of 2710 medical students from 36 U.S. medical schools (1st to 4th year) completed the survey. Included in the instruments was a 10-item scale (AUDIT) to assess at-risk drinking behaviors within the last 12 months. Over 15% of the subjects (n = 412) scored positive for at-risk drinking (>/= 8). Multivariate analysis of the data revealed the following independent predictors were statistically significant (P

Successful treatment of a serous retinal pigment epithelial detachment by coiling of a carotid-cavernous fistula.

PURPOSE: To report a patient presenting with a symptomatic retinal pigment epithelial detachment (RPED) that resolved after successful treatment of a slow flow dural carotid cavernous fistula (CCF). Possible pathophysiological mechanisms are discussed. METHODS: Interventional case report. RESULTS: A 69-year-old female presented with left uniocular distortion, confirmed on fluorescein and indocyanine green angiography to be secondary to a non-vascularised serous RPED. Further examination revealed a long standing left VI nerve palsy, mild proptosis and conjunctival injection. Magnetic resonance and cranial angiography confirmed the presence of a dural CCF. Surgical closure of the CCF resulted in a rapid resolution of the clinical signs and improvement in visual symptoms. CONCLUSIONS: Patients with serous RPED and other signs or symptoms of a CCF may warrant neuroimaging of the orbit and/or angiography to evaluate for CCF, as correct diagnosis may lead to an excellent visual outcome.

External ophthalmoplegia as the presenting feature of systemic amyloidosis.

INTRODUCTION: Amyloidosis is a multi-system disease characterised by the intracellular deposition of beta-pleated sheets of amyloid. It can involve the eye, orbit and ocular adnexae. METHOD: We describe a case of a 58-year-old woman presenting to the eye department with external ophthalmoplegia, including the findings of various investigations. The spectrum of ocular amyloidosis is discussed. CONCLUSION: Amyloidosis may be the underlying diagnosis in some cases of external ophthalmoplegia with findings atypical to other systemic disease.