Homocysteine and Glaucoma.

Elevated levels of homocysteine (Hcy), a non-proteinogenic amino acid, may lead to a host of manifestations across the biological systems, particularly the nervous system. Defects in Hcy metabolism have been associated with many neurodegenerative diseases including glaucoma, i.e., the leading cause of blindness. However, the pathophysiology of elevated Hcy and its eligibility as a risk factor for glaucoma remain unclear. We aimed to provide a comprehensive review of the relationship between elevated Hcy levels and glaucoma. Through a systemic search of the PubMed and Google Scholar databases, we found that elevated Hcy might play an important role in the pathogenesis of glaucoma. Further research will be necessary to help clarify the specific contribution of elevated Hcy in the pathogenesis of glaucoma. A discovery and conceptual understanding of Hcy-associated glaucoma could be the keys to providing better therapeutic treatment, if not prophylactic treatment, for this disease.

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.

Exome-based investigation of the genetic basis of human pigmentary glaucoma.

BACKGROUND: Glaucoma is a leading cause of visual disability and blindness. Release of iris pigment within the eye, pigment dispersion syndrome (PDS), can lead to one type of glaucoma known as pigmentary glaucoma. PDS has a genetic component, however, the genes involved with this condition are largely unknown. We sought to discover genes that cause PDS by testing cohorts of patients and controls for mutations using a tiered analysis of exome data. RESULTS: Our primary analysis evaluated melanosome-related genes that cause dispersion of iris pigment in mice (TYRP1, GPNMB, LYST, DCT, and MITF). We identified rare mutations, but they were not statistically enriched in PDS patients. Our secondary analyses examined PMEL (previously linked with PDS), MRAP, and 19 other genes. Four MRAP mutations were identified in PDS cases but not in controls (p = 0.016). Immunohistochemical analysis of human donor eyes revealed abundant MRAP protein in the iris, the source of pigment in PDS. However, analysis of MRAP in additional cohorts (415 cases and 1645 controls) did not support an association with PDS. We also did not confirm a link between PMEL and PDS in our cohorts due to lack of reported mutations and similar frequency of the variants in PDS patients as in control subjects. CONCLUSIONS: We did not detect a statistical enrichment of mutations in melanosome-related genes in human PDS patients and we found conflicting data about the likely pathogenicity of MRAP mutations. PDS may have a complex genetic basis that is not easily unraveled with exome analyses.

Non-Synonymous variants in premelanosome protein (PMEL) cause ocular pigment dispersion and pigmentary glaucoma.

Pigmentary glaucoma (PG) is a common glaucoma subtype that results from release of pigment from the iris, called pigment dispersion syndrome (PDS), and its deposition throughout the anterior chamber of the eye. Although PG has a substantial heritable component, no causative genes have yet been identified. We used whole exome sequencing of two independent pedigrees to identify two premelanosome protein (PMEL) variants associated with heritable PDS/PG. PMEL encodes a key component of the melanosome, the organelle essential for melanin synthesis, storage and transport. Targeted screening of PMEL in three independent cohorts (n = 394) identified seven additional PDS/PG-associated non-synonymous variants. Five of the nine variants exhibited defective processing of the PMEL protein. In addition, analysis of PDS/PG-associated PMEL variants expressed in HeLa cells revealed structural changes to pseudomelanosomes indicating altered amyloid fibril formation in five of the nine variants. Introduction of 11-base pair deletions to the homologous pmela in zebrafish by the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 method caused profound pigmentation defects and enlarged anterior segments in the eye, further supporting PMEL's role in ocular pigmentation and function. Taken together, these data support a model in which missense PMEL variants represent dominant negative mutations that impair the ability of PMEL to form functional amyloid fibrils. While PMEL mutations have previously been shown to cause pigmentation and ocular defects in animals, this research is the first report of mutations in PMEL causing human disease.

Artificial Intelligence Classification of Central Visual Field Patterns in Glaucoma.

PURPOSE: To quantify the central visual field (VF) loss patterns in glaucoma using artificial intelligence. DESIGN: Retrospective study. PARTICIPANTS: VFs of 8712 patients with 13 951 Humphrey 10-2 test results from 13 951 eyes for cross-sectional analyses, and 824 patients with at least 5 reliable 10-2 test results at 6-month intervals or more from 1191 eyes for longitudinal analyses. METHODS: Total deviation values were used to determine the central VF patterns using the most recent 10-2 test results. A 24-2 VF within a 3-month window of the 10-2 tests was used to stage eyes into mild, moderate, or severe functional loss using the Hodapp-Anderson-Parrish scale at baseline. Archetypal analysis was applied to determine the central VF patterns. Cross-validation was performed to determine the optimal number of patterns. Stepwise regression was applied to select the optimal feature combination of global indices, average baseline decomposition coefficients from central VFs archetypes, and other factors to predict central VF mean deviation (MD) slope based on the Bayesian information criterion (BIC). MAIN OUTCOME MEASURES: The central VF patterns stratified by severity stage based on 24-2 test results and a model to predict the central VF MD change over time using baseline test results. RESULTS: From cross-sectional analysis, 17 distinct central VF patterns were determined for the 13 951 eyes across the spectrum of disease severity. These central VF patterns could be divided into isolated superior loss, isolated inferior loss, diffuse loss, and other loss patterns. Notably, 4 of the 5 patterns of diffuse VF loss preserved the less vulnerable inferotemporal zone, whereas they lost most of the remaining more vulnerable zone described by the Hood model. Inclusion of coefficients from central VF archetypical patterns strongly improved the prediction of central VF MD slope (BIC decrease, 35; BIC decrease of >6 indicating strong prediction improvement) than using only the global indices of 2 baseline VF results. Eyes with baseline VF results with more superonasal and inferonasal loss were more likely to show worsening MD over time. CONCLUSIONS: We quantified central VF patterns in glaucoma, which were used to improve the prediction of central VF worsening compared with using only global indices.

Mutations of conserved non-coding elements of PITX2 in patients with ocular dysgenesis and developmental glaucoma.

Mutations in FOXC1 and PITX2 constitute the most common causes of ocular anterior segment dysgenesis (ASD), and confer a high risk for secondary glaucoma. The genetic causes underlying ASD in approximately half of patients remain unknown, despite many of them being screened by whole exome sequencing. Here, we performed whole genome sequencing on DNA from two affected individuals from a family with dominantly inherited ASD and glaucoma to identify a 748-kb deletion in a gene desert that contains conserved putative PITX2 regulatory elements. We used CRISPR/Cas9 to delete the orthologous region in zebrafish in order to test the pathogenicity of this structural variant. Deletion in zebrafish reduced pitx2 expression during development and resulted in shallow anterior chambers. We screened additional patients for copy number variation of the putative regulatory elements and found an overlapping deletion in a second family and in a potentially-ancestrally-related index patient with ASD and glaucoma. These data suggest that mutations affecting conserved non-coding elements of PITX2 may constitute an important class of mutations in patients with ASD for whom the molecular cause of their disease have not yet been identified. Improved functional annotation of the human genome and transition to sequencing of patient genomes instead of exomes will be required before the magnitude of this class of mutations is fully understood.

The African Descent and Glaucoma Evaluation Study (ADAGES) III: Contribution of Genotype to Glaucoma Phenotype in African Americans: Study Design and Baseline Data.

PURPOSE: To describe the study protocol and baseline characteristics of the African Descent and Glaucoma Evaluation Study (ADAGES) III. DESIGN: Cross-sectional, case-control study. PARTICIPANTS: Three thousand two hundred sixty-six glaucoma patients and control participants without glaucoma of African or European descent were recruited from 5 study centers in different regions of the United States. METHODS: Individuals of African descent (AD) and European descent (ED) with primary open-angle glaucoma (POAG) and control participants completed a detailed demographic and medical history interview. Standardized height, weight, and blood pressure measurements were obtained. Saliva and blood samples to provide serum, plasma, DNA, and RNA were collected for standardized processing. Visual fields, stereoscopic disc photographs, and details of the ophthalmic examination were obtained and transferred to the University of California, San Diego, Data Coordinating Center for standardized processing and quality review. MAIN OUTCOME MEASURES: Participant gender, age, race, body mass index, blood pressure, history of smoking and alcohol use in POAG patients and control participants were described. Ophthalmic measures included intraocular pressure, visual field mean deviation, central corneal thickness, glaucoma medication use, or past glaucoma surgery. Ocular conditions, including diabetic retinopathy, age-related macular degeneration, and past cataract surgery, were recorded. RESULTS: The 3266 ADAGES III study participants in this report include 2146 AD POAG patients, 695 ED POAG patients, 198 AD control participants, and 227 ED control participants. The AD POAG patients and control participants were significantly younger (both, 67.4 years) than ED POAG patients and control participants (73.4 and 70.2 years, respectively). After adjusting for age, AD POAG patients had different phenotypic characteristics compared with ED POAG patients, including higher intraocular pressure, worse visual acuity and visual field mean deviation, and thinner corneas (all P < 0.001). Family history of glaucoma did not differ between AD and ED POAG patients. CONCLUSIONS: With its large sample size, extensive specimen collection, and deep phenotyping of AD and ED glaucoma patients and control participants from different regions in the United States, the ADAGES III genomics study will address gaps in our knowledge of the genetics of POAG in this high-risk population.

Genetic Architecture of Primary Open-Angle Glaucoma in Individuals of African Descent: The African Descent and Glaucoma Evaluation Study III.

PURPOSE: To find genetic contributions to glaucoma in African Americans. DESIGN: Cross-sectional, case-control study. PARTICIPANTS: One thousand eight hundred seventy-five primary open-angle glaucoma (POAG) patients and 1709 controls, self-identified as being of African descent (AD), from the African Descent and Glaucoma Evaluation Study (ADAGES) III and Wake Forest School of Medicine. METHODS: MegaChip genotypes were imputed to Thousand Genomes data. Association of single nucleotide polymorphisms (SNPs) with POAG and advanced POAG was tested by linear mixed model correcting for relatedness and population stratification. Genetic risk scores were tested by receiver operator characteristic curves (ROC-AUCs). MAIN OUTCOME MEASURES: Primary open-angle glaucoma defined by visual field loss without other nonocular conditions (n = 1875). Advanced POAG was defined by age-based mean deviation of visual field (n = 946). RESULTS: Eighteen million two hundred eighty-one thousand nine hundred twenty SNPs met imputation quality of r2 > 0.7 and minor allele frequency > 0.005. Association of a novel locus, EN04, was observed for advanced POAG (rs185815146 ß, 0.36; standard error, 0.065; P < 3×10-8). For POAG, an AD signal was observed at the 9p21 European descent (ED) POAG signal (rs79721419; P < 6.5×10-5) independent of the previously observed 9p21 ED signal (rs2383204; P < 2.3×10-5) by conditional analyses. An association with POAG in FNDC3B (rs111698934; P < 3.9×10-5) was observed, not in linkage disequilibrium (LD) with the previously reported ED SNP. Additional previously identified loci associated with POAG in persons of AD were: 8q22, AFAP1, and TMC01. An AUC of 0.62 was observed with an unweighted genetic risk score comprising 11 SNPs in candidate genes. Two additional risk scores were studied by using a penalized matrix decomposition with cross-validation; risk scores of 50 and 400 SNPs were identified with ROC of AUC = 0.74 and AUC = 0.94, respectively. CONCLUSIONS: A novel association with advanced POAG in the EN04 locus was identified putatively in persons of AD. In addition to this finding, this genome-wide association study in POAG patients of AD contributes to POAG genetics by identification of novel signals in prior loci (9p21), as well as advancing the fine mapping of regions because of shorter average LD (FNDC3B). Although not useful without confirmation and clinical trials, the use of genetic risk scores demonstrated that considerable AD-specific genetic information remains in these data.

Quantitative assessment of changes in anterior segment morphology after argon laser peripheral iridoplasty: findings from the EARL study group.

IMPORTANCE: Argon laser peripheral iridoplasty (ALPI) could be effective in widening residual angle closure following laser peripheral iridotomy (LPI). BACKGROUND: We investigated changes in angle parameters following ALPI and its safety profile in this study. DESIGN: Retrospective, observational case series. PARTICIPANTS: The records from a single centre, of 36 patients (60 eyes) who underwent ALPI, for residual angle closure following LPI, were reviewed. METHODS: We analysed anterior chamber parameters in anterior segment optical coherence tomography (ASOCT) images using customized software pre- and post-ALPI. Paired t-test was used to compare changes. MAIN OUTCOME MEASURES: ASOCT parameters analysed included angle opening distance (AOD 500 and 750), trabecular iris surface area (TISA 500 and 750), anterior chamber width (ACW), anterior chamber volume (ACV), angle recess area (ARA), anterior chamber area (ACA), anterior chamber depth (ACD) and lens vault (LV). RESULTS: There was a mean increase in AOD 500 (0.05 vs. 0.16 mm, P < 0.001), AOD 750 (0.15 vs. 0.27 mm, P < 0.001), TISA 500 (0.010 vs. 0.038 mm2 , P < 0.001), TISA 750 (0.039 vs. 0.102 mm2 , P < 0.001), ACV (89.76 vs. 102.25 mm3 , P = 0.01), ARA 500 (0.015 vs. 0.033 mm2 , P < 0.001) and ARA 750 (0.044 vs. 0.088 mm2 , P < 0.001). There was no significant change in ACW, ACD, ACA and LV. Mean intraocular pressure (IOP) decreased post-ALPI (17.2 vs. 15.7 mmHg, P = 0.002). The mean follow-up duration was 2.1 years (range 0.5-5 years). CONCLUSIONS AND RELEVANCE: ALPI results in changes to the angle morphology and lowered IOP in eyes with residual angle closure. Our findings suggest a possible role for ALPI in eyes with residual angle closure following peripheral iridotomy.

Glaucoma.

Glaucoma is a heterogeneous group of diseases characterised by cupping of the optic nerve head and visual-field damage. It is the most frequent cause of irreversible blindness worldwide. Progression usually stops if the intraocular pressure is lowered by 30-50% from baseline. Its worldwide age-standardised prevalence in the population aged 40 years or older is about 3·5%. Chronic forms of glaucoma are painless and symptomatic visual-field defects occur late. Early detection by ophthalmological examination is mandatory. Risk factors for primary open-angle glaucoma-the most common form of glaucoma-include older age, elevated intraocular pressure, sub-Saharan African ethnic origin, positive family history, and high myopia. Older age, hyperopia, and east Asian ethnic origin are the main risk factors for primary angle-closure glaucoma. Glaucoma is diagnosed using ophthalmoscopy, tonometry, and perimetry. Treatment to lower intraocular pressure is based on topical drugs, laser therapy, and surgical intervention if other therapeutic modalities fail to prevent progression.

Optic Nerve Head Drusen Prevalence and Associated Factors in Clinically Normal Subjects Measured Using Optical Coherence Tomography.

OBJECTIVE: To investigate the prevalence of optic nerve head drusen (ONHD) in clinically normal subjects using enhanced depth imaging (EDI) optical coherence tomography (OCT) and to evaluate associated factors. DESIGN: Prospective, cross-sectional, observational study. PARTICIPANTS: Total of 130 clinically normal subjects. METHODS: Serial horizontal and vertical EDI OCT B-scans (interval between scans, ∼30 µm) of the optic nerve head (ONH) were obtained in both eyes of clinically normal subjects. Signs of ONHD were defined as horizontal hyperreflective bands perpendicular to the OCT beam with or without a signal-poor core. The minimum length of isolated hyperreflective bands was determined based on analysis of 34 eyes with clinically definite ONHD. Age, gender, ONH diameter, and axial length were obtained from participants. MAIN OUTCOME MEASURES: Prevalence of ONHD in clinically normal subjects and its association with age, gender, ONH diameter, and axial length. RESULTS: Based on the measurements of 94 isolated hyperreflective bands in the 34 eyes with clinically definite ONHD, the minimum length of isolated hyperreflective ONHD bands in clinically normal subjects was set as 45 µm (mean minus 2 standard deviations). Among 260 clinically normal eyes (130 subjects; 68 women; mean age, 40±17 years), EDI OCT was positive for horizontal hyperreflective ONHD bands in 28 eyes (10.8%) of 19 subjects (14.6%). Of these 28 eyes, 25 eyes (9.6% of total 260 eyes) of 16 subjects (12.3% of total 130 subjects) showed isolated hyperreflective bands with no signal-poor core, and 3 eyes (1.2% of total 260 eyes) of 3 subjects (2.3% of total 130 subjects) showed a signal-poor core surrounded by hyperreflective bands. No significant differences were found in mean age (44 vs. 39 years; P = 0.121) or gender distribution (56% vs. 52% female; P = 0.766) between clinically normal subjects with hyperreflective ONHD bands and those without. Logistic regression analysis showed that a decrease in ONH diameter by 100 µm and axial length by 1 mm increased the odds of ONHD presence by 1.5-fold (odds ratio [OR] = 1.56 [confidence interval (CI), 1.22-2.00]; P < 0.001) and 2-fold (OR = 2.00 [CI, 1.15-3.49]; P = 0.015), respectively. CONCLUSIONS: Subclinical ONHD may be more prevalent than previously believed. Significant associations of subclinical ONHD with smaller ONH and shorter axial length were found.

The Clinical Spectrum and a New Theory of Pathogenesis of True Exfoliation Syndrome.

PURPOSE: To describe the clinical spectrum and a new theory of pathogenesis of true exfoliation syndrome. DESIGN: Cross-sectional and prospective, observational case series. PARTICIPANTS: Consecutive patients with characteristic peeling of the anterior lens capsule. METHODS: After maximal mydriasis, slit-lamp biomicroscopy, and photography, imaging of the anterior capsule and zonules was performed. The condition was classified into 4 clinical stages: annular anterior capsule thickening with a distinct splitting margin (stage 1), an inward detached crescentic flap lying on the anterior lens (stage 2), a floating and folding translucent membrane behind the iris (stage 3), and a broad membrane within the pupil (stage 4). Serial photography was performed at each 3-month follow-up visit. Ultrastructural examination of dislocated lenses and excised anterior capsules was performed. MAIN OUTCOME MEASURES: Detached membrane morphologic features, zonular defects, pigment deposition, glaucoma, phacodonesis, and cataract. RESULTS: We enrolled 259 patients (424 eyes). Ages ranged from 52 to 97 years (mean age, 75.2±7.1 years). Eleven patients were associated with trauma (n = 1) or intense heat (n = 10), whereas 248 were idiopathic. Two hundred ten patients were followed up every 3 months, with a mean follow-up of 9.6±6.1 months (range, 3-50 months). The detachment started along the anterior zonular insertions in association with zonular disruption. It progressed centrally to higher stages, manifesting a spectrum of disease. Several stages coexisted in a single eye. At the final visit, including 49 patients who were examined once, there were 70, 87, 85, and 17 patients in stages 1, 2, 3, and 4, respectively. All stages shared common histologic findings consisting of diffuse capsular lamellar separation and anterior zonular disruption. All developed cataract. Pigment deposition on the membrane was present in 178 patients (68.7%). Twenty-six patients (10%) had spontaneous phacodonesis. Eighteen eyes (4.2%) demonstrated secondary delamination. CONCLUSIONS: Capsular lamellar separation and anterior zonular disruption are characteristic findings. Aging, heat exposure, and trauma are risk factors. Initial capsular splits occur along the insertions of disrupted anterior zonules. The peeling progresses centrally in association with iris movement and aqueous flow. A second detachment can occur.

Visual Field Change and 24-Hour IOP-Related Profile with a Contact Lens Sensor in Treated Glaucoma Patients.

PURPOSE: To test the hypothesis that a 24-hour recording of intraocular pressure (IOP)-related measurements derived from a contact lens sensor (CLS) correlates to the rate of visual field progression in treated glaucomatous eyes. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Forty treated glaucomatous patients with 8 or more 24-2 visual field tests. METHODS: Twenty-four-hour recording with a CLS that provides IOP-related measurements. MAIN OUTCOME MEASURES: Rates of visual field mean deviation (MD) change before and at the time of CLS recording and CLS parameters, namely number of large peaks, mean peak ratio, wake-to-sleep slope, amplitude and area under the cosine curve, and variability from the mean. RESULTS: When comparing the rate of MD change before and at the time of CLS recording of all patients, the average slope was -0.05 dB/year faster in the beginning compared with the end (P = 0.087), suggesting a deceleration of progression by the time of CLS recording. The number of long peaks and the mean peak ratio when patients were awake were the best predictors of faster progression. The combination of CLS parameters provided better measures of goodness of fit than Goldmann IOP parameters (mean, peak, and fluctuation) in the same period. CONCLUSIONS: Intraocular pressure-related parameters obtained with 24-hour recording with a CLS were associated with the rate of visual field progression in treated glaucomatous eyes. This technology may be useful in detecting eyes at higher risk of glaucoma progression while receiving treatment.

Efficacy of the Amsler Grid Test in Evaluating Glaucomatous Central Visual Field Defects.

PURPOSE: To investigate the efficacy of the Amsler grid test in detecting central visual field (VF) defects in glaucoma. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Patients with glaucoma with reliable Humphrey 10-2 Swedish Interactive Threshold Algorithm standard VF on the date of enrollment or within the previous 3 months. METHODS: Amsler grid tests were performed for each eye and were considered "abnormal" if there was any perceived scotoma with missing or blurry grid lines within the central 10 degrees ("Amsler grid scotoma"). An abnormal 10-2 VF was defined as ≥3 adjacent points at P < 0.01 with at least 1 point at P < 0.005 in the same hemifield on the pattern deviation plot. Sensitivity, specificity, and positive and negative predictive values of the Amsler grid scotoma area were calculated with the 10-2 VF as the clinical reference standard. Among eyes with an abnormal 10-2 VF, regression analyses were performed between the Amsler grid scotoma area and the 10-2 VF parameters (mean deviation [MD], scotoma extent [number of test points with P < 0.01 in total deviation map] and scotoma mean depth [mean sensitivity of test points with P < 0.01 in total deviation map]). MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values of the Amsler grid scotoma area. RESULTS: A total of 106 eyes (53 patients) were included (mean ± standard deviation age, 24-2 MD and 10-2 MD = 66±12 years, -9.61±8.64 decibels [dB] and -9.75±9.00 dB, respectively). Sensitivity, specificity, and positive and negative predictive values of the Amsler grid test were 68%, 92%, 97%, and 46%, respectively. Sensitivity was 40% in eyes with 10-2 MD better than -6 dB, 58% in eyes with 10-2 MD between -12 and -6 dB, and 92% in eyes with 10-2 MD worse than -12 dB. The area under the receiver operating characteristic curve of the Amsler grid scotoma area was 0.810 (95% confidence interval, 0.723-0.880, P < 0.001). The Amsler grid scotoma area had the strongest relationship with 10-2 MD (quadratic R(2)=0.681), followed by 10-2 scotoma extent (quadratic R(2)=0.611) and 10-2 scotoma mean depth (quadratic R(2)=0.299) (all P < 0.001). CONCLUSIONS: The Amsler grid can be used to screen for moderate to severe central vision loss from glaucoma.

African Descent and Glaucoma Evaluation Study (ADAGES): Racial Differences in Optic Disc Hemorrhage and Beta-Zone Parapapillary Atrophy.

PURPOSE: To investigate the differences in the frequency of optic disc hemorrhage (DH) and prevalence of beta-zone parapapillary atrophy (ßPPA) between individuals of African descent (AD) and European descent (ED). DESIGN: Prospective, multicenter, observational cohort. PARTICIPANTS: A total of 1950 eyes of 1172 participants of the African Descent and Glaucoma Evaluation Study (ADAGES). METHODS: Stereoscopic disc photographs of subjects with and without glaucomatous optic neuropathy (GON) followed during the first 13 years of the ADAGES underwent masked review searching for DH and ßPPA. A total of 928 eyes (non-GON, 581; GON, 347) of 551 AD patients (non-GON, 334; GON, 217) and 1022 eyes (non-GON, 568; GON, 454) of 611 ED patients (non-GON, 334; GON, 277) were included. We compared the number of eyes with detected DH at any time during follow-up and eyes with ßPPA between the AD and ED groups. The analyses were then adjusted for clinical parameters using multivariable logistic regression. MAIN OUTCOME MEASURES: Differences in frequency of DH and prevalence of ßPPA. RESULTS: A total of 9395 stereoscopic disc photographs were reviewed. More ED eyes experience DH than AD eyes (49/1022 [4.8%] vs. 10/928 eyes [1.1%], respectively; P < 0.001), whereas ßPPA had higher prevalence in AD eyes (675 eyes [72%] vs. 659 eyes [64%]; P < 0.001). In the final multivariable model, after controlling for confounders, AD eyes were less likely to have at least 1 detected DH than ED eyes (odds ratio [OR], 0.21; 95% CI, 0.10-0.45; P < 0.001) but were more likely to have ßPPA than ED eyes (OR, 1.55; 95% CI, 1.12-2.14; P = 0.008). CONCLUSIONS: Subjects of ED are at higher risk for developing DH compared with AD subjects, whereas AD subjects have greater prevalence of ßPPA. These findings suggest that there are structural differences within the optic nerve complex between these groups. Further research is needed to determine whether racial differences in the frequency of DH and prevalence of ßPPA affect the likelihood of glaucomatous progression.

Collagen matrix vs mitomycin-C in trabeculectomy and combined phacoemulsification and trabeculectomy: a randomized controlled trial.

BACKGROUND: Antifibrotic agents are commonly utilized to enhance the success rates of trabeculectomy. Novel approaches to further improve success rates and reduce the risks of complications are needed. The purpose of this study was to compare intraocular pressure (IOP)-lowering efficacy and safety of trabeculectomy or combined phacoemulsification and trabeculectomy with mitomycin-C (MMC) vs. Collagen Matrix (CM). METHODS: A prospective, multicenter, randomized controlled trial was performed. Ninety-five eyes of 94 patients with uncontrolled glaucoma despite medical therapy, without previous incisional glaucoma surgery underwent trabeculectomy (85 eyes) or combined phacoemulsification and trabeculectomy (10 eyes) and were randomized to MMC or CM. One eye of each subject was analyzed. Patients were followed for 24 months. The criteria for complete success were IOP >5 and ≤21 mmHg with at least a 20% reduction below medicated baseline without additional glaucoma surgery or medications. The main outcome measures were complete success rates at 24 months with Kaplan-Meier analysis and incidence of adverse events. RESULTS: The baseline IOPs were 20.4 ± 6.0 mmHg and 21.2 ± 6.1 (mean ± standard deviation, p = 0.49) on 3.2 ± 1.1 and 3.1 ± 1.0 medications (p = 0.53) compared to 11.8 ± 5.2 and 12.8 ± 3.7 (p = 0.36) on 0.5 ± 0.8 and 0.6 ± 1.0 medications (p = 0.63) at 2 years in the MMC and CM groups, respectively. Kaplan-Meier analysis demonstrated complete success rates were similar in both groups at 24 months: 38.4 ± 7.6% with MMC and 56.2 ± 7.9% with CM (mean ± standard error, p = 0.112, log rank test); however, a significantly higher incidence of failure due to persistent hypotony was observed with MMC (p = 0.002). CONCLUSIONS: Use of the CM implant at the time of trabeculectomy or combined phacoemulsification and trabeculectomy is associated with similar complete success rates compared to adjunctive MMC; however, the risk of persistent hypotony is higher with MMC. TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT01440751 . Registered 9/14/11.

Congenital cataracts: de novo gene conversion event in CRYBB2.

PURPOSE: To identify the cause of congenital cataracts in a consanguineous family of Ashkenazi Jewish ancestry. METHODS: We performed genome-wide linkage analysis and whole-exome sequencing for the initial discovery of variants, and we confirmed the variants using gene-specific primers and Sanger sequencing. RESULTS: We found significant evidence of linkage to chromosome 22, under an autosomal dominant inheritance model, with a maximum logarithm of the odds (LOD) score of 3.91 (16.918 to 25.641 Mb). Exome sequencing identified three nonsynonymous changes in the CRYBB2 exon 5 coding sequence that are consistent with the sequence of the corresponding region of the pseudogene CRYBB2P1. The identification of these changes was complicated by possible mismapping of some mutated CRYBB2 sequences to CRYBB2P1. Sequencing with gene-specific primers confirmed that the changes--rs2330991, c.433 C>T (p.R145W); rs2330992, c.440A>G (p.Q147R); and rs4049504, c.449C>T (p.T150M)--present in all ten affected family members are located in CRYBB2 and are not artifacts of cross-reaction with CRYBB2P1. We did not find these changes in six unaffected family members, including the unaffected grandfather who contributed the affected haplotype, nor did we find them in the 100 Ashkenazi Jewish controls. CONCLUSIONS: Our data are consistent with a de novo gene conversion event, transferring 270 base pairs at most from CRYBB2P1 to exon 5 of CRYBB2. This study highlights how linkage mapping can be complicated by de novo mutation events, as well as how sequence-analysis pipeline mapping of short reads from next-generation sequencing can be complicated by the existence of pseudogenes or other highly homologous sequences.

A new index to monitor central visual field progression in glaucoma.

PURPOSE: The visual field index (VFI) summarizes global visual field (VF) data and was developed to monitor glaucoma progression using 24-2 and 30-2 strategies. We applied similar principles and statistical procedures to develop a new parameter, the central field index (CFI), to monitor 10-2 VF progression. DESIGN: Retrospective cohort. PARTICIPANTS: Glaucoma patients with paracentral defects seen on 24-2 perimetry and followed up with at least 5 10-2 VF tests. METHODS: The CFI was developed by calculating age-corrected defect depth at test points obtained during 10-2 examinations. The sensitivities at these points were scored as percentages similar to the method described for the VFI: 100-[(|total deviation|/age-corrected normal threshold) × 100]. A weighting procedure was applied based on published estimates of the occipital cortical spatial magnification. For validation, we performed mixed linear model testing for the association between CFI rates of change (%/year) and known risk factors for glaucoma progression in a population with established glaucoma and at least 5 10-2 VF tests. To determine whether the CFI was affected by cataract, as is known to occur with mean deviation (MD), we conducted a pilot evaluation comparing rates of CFI change in 3 groups: (1) eyes with cataract, (2) pseudophakic eyes, and (3) eyes in which cataract surgery was performed in the middle of the series. MAIN OUTCOME MEASURES: Rates of CFI and MD change. RESULTS: Central field index values were calculated for 176 eyes of 142 patients. The mean rate of CFI change of the entire sample was -1.10%/year (95% confidence interval, -1.03 to -1.16%/year). Elevated intraocular pressure (P<0.001) was associated significantly with faster CFI change, whereas lens status did not influence CFI rates of change (P>0.100) CONCLUSIONS: We developed and validated a new index to monitor central field progression that is minimally affected by the presence or removal of cataract and that correlates significantly with an important risk factor for glaucoma progression. This new index may become useful for glaucoma management, especially when combined with conventional static perimetry strategies.

Defining 10-2 visual field progression criteria: exploratory and confirmatory factor analysis using pointwise linear regression.

PURPOSE: To test different visual field progression criteria using trend analysis in a glaucoma population followed with long sequences of 10-2 tests as a first attempt to understand and document rates of progression in the central field. DESIGN: Retrospective cohort study. PARTICIPANTS: We included 146 eyes of 146 patients with established glaucoma. METHODS: Pointwise linear regression analysis using the methods of ordinary least squares was performed on the 68 test locations of the 10-2 visual field sequences. Threshold sensitivities at each test location were plotted as the dependent variable against follow-up time as the independent variable. Statistically significant progression or improvement of a visual field test point was defined if its regression slope measured ≤-1.0 dB/year or ≥+1.0 dB/year, respectively, at P<0.01. We explored sets of criteria to define visual field progression, generating a hypothetical sensitivity (progression), specificity (improvement), and progression-to-improvement ratio (PIR) for each criterion. The criterion with the highest PIR was deemed the one with best performance. Latent class analysis (LCA) was used to determine visual field sectors with highest inter-correlation. MAIN OUTCOME MEASURES: The performance of different visual field progression criteria to detect fast rates of mean deviation (MD) change. RESULTS: Median baseline 10-2 MD value was -12.0 dB (interquartile range [IQR], -6.7 to -17.8 dB), and the median rate of 10-2 MD change over time was -0.38 dB/year (IQR, -0.07 to -0.77 dB/year). The highest PIR was obtained with the progression criterion requiring at least 3 test points located in the same LCA-derived 10-2 visual field sector progressing faster than -1.0 dB/year at P<0.01. This criterion was further validated for content and convergence. CONCLUSIONS: This is the first study to investigate progression criteria for 10-2 visual fields using rates of change and to test their performance and validity. These findings may be useful to improve the monitoring of patients with glaucoma at different levels of functional loss and to develop new perimetric algorithms that scrutinize specific visual field locations for a more accurate detection of progression.