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Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.Exposures: Genetic variants associated with primary open-angle glaucoma.Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10−8 in the discovery stage and in the meta-analysis of combined discovery and validation data.Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10−8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10−13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - “response to fluid shear stress” and “abnormal retina morphology” - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.

© 2016, Association for Research in Vision and Ophthalmology Inc. All rights reserved. PURPOSE. Recent studies indicate that mitochondrial proteins may contribute to the pathogenesis of primary open-angle glaucoma (POAG). In this study, we examined the association between POAG and common variations in gene-encoding mitochondrial proteins. METHODS. We examined genetic data from 3430 POAG cases and 3108 controls derived from the combination of the GLAUGEN and NEIGHBOR studies. We constructed biological-system coherent mitochondrial nuclear-encoded protein gene-sets by intersecting the MitoCarta database with the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We examined the mitochondrial gene-sets for association with POAG and with normal-tension glaucoma (NTG) and high-tension glaucoma (HTG) subsets using Pathway Analysis by Randomization Incorporating Structure. RESULTS. We identified 22 KEGG pathways with significant mitochondrial protein-encoding gene enrichment, belonging to six general biological classes. Among the pathway classes, mitochondrial lipid metabolism was associated with POAG overall (P = 0.013) and with NTG (P = 0.0006), and mitochondrial carbohydrate metabolism was associated with NTG (P = 0.030). Examining the individual KEGG pathway mitochondrial gene-sets, fatty acid elongation and synthesis and degradation of ketone bodies, both lipid metabolism pathways, were significantly associated with POAG (P = 0.005 and P = 0.002, respectively) and NTG (P = 0.0004 and P < 0.0001, respectively). Butanoate metabolism, a carbohydrate metabolism pathway, was significantly associated with POAG (P = 0.004), NTG (P = 0.001), and HTG (P = 0.010). CONCLUSIONS. We present an effective approach for assessing the contributions of mitochondrial genetic variation to open-angle glaucoma. Our findings support a role for mitochondria in POAG pathogenesis and specifically point to lipid and carbohydrate metabolism pathways as being important.

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets., Elevated intraocular pressure (IOP) is a heritable risk factor for primary open angle glaucoma. Using forward mouse genetics, cell biology, pharmacology and human genetic data, the authors identify CACNA2D1 as an IOP risk gene that can be therapeutically targeted by the drug pregabalin in animal models.

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p&nbsp

IMPORTANCE: Genetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations. OBJECTIVE: To investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018. MAIN OUTCOMES AND MEASURES: Association of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression. RESULTS: The GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10(−66)). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (β = −0.36; 95% CI, −0.56 to −0.16; P = 4.0 × 10(−4)). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10(−4)). CONCLUSIONS AND RELEVANCE: A higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.

International audience; Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.

PURPOSE: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. METHODS: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. RESULTS: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval CI: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. CONCLUSIONS: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.

Author(s): Liu, Yutao; Bailey, Jessica Cooke; Helwa, Inas; Dismuke, W Michael; Cai, Jingwen; Drewry, Michelle; Brilliant, Murray H; Budenz, Donald L; Christen, William G; Chasman, Daniel I; Fingert, John H; Gaasterland, Douglas; Gaasterland, Terry; Gordon, Mae O; Igo, Robert P; Kang, Jae H; Kass, Michael A; Kraft, Peter; Lee, Richard K; Lichter, Paul; Moroi, Sayoko E; Realini, Anthony; Richards, Julia E; Ritch, Robert; Schuman, Joel S; Scott, William K; Singh, Kuldev; Sit, Arthur J; Song, Yeunjoo E; Vollrath, Douglas; Weinreb, Robert; Medeiros, Felipe; Wollstein, Gadi; Zack, Donald J; Zhang, Kang; Pericak-Vance, Margaret A; Gonzalez, Pedro; Stamer, W Daniel; Kuchtey, John; Kuchtey, Rachel W; Allingham, R Rand; Hauser, Michael A; Pasquale, Louis R; Haines, Jonathan L; Wiggs, Janey L | Abstract: PurposeNoncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG).MethodsUsing the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR-182 expression in AH between five HTG cases and five controls.ResultsOnly rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.11-1.42, P = 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR = 1.26, 95% CI: 1.08-1.47, P = 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P = 0.03) without controlling for medication treatment.ConclusionsOur integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.

Purpose The Ocular Hypertension Treatment Study (OHTS) seeks to evaluate the safety and efficacy of topical ocular hypotensive medication in preventing or delaying the onset of visual field loss and/or optic nerve damage in ocular hypertensive subjects at risk for developing primary open-angle glaucoma. This study evaluates the baseline visual field test characteristics (visual field status, reliability properties, etc.) of patients who underwent eligibility visual field testing for entry to the OHTS. Design Cross-sectional study of baseline data as part of a longitudinal randomized clinical trial. Participants Two thousand eight hundred nineteen ocular hypertensive individuals, aged 40 to 80 (mean age, 55). Methods Subjects underwent at least two Humphrey Field Analyzer Program 30-2 Full Threshold visual field examinations in both eyes for study eligibility. A third examination was performed if a prior test was abnormal, questionable, or unreliable. For final eligibility, two sets of visual field examinations had to meet OHTS criteria for reliability and had to be classified as "normal." All OHTS visual field tests of potential subjects were submitted for eligibility assessment to the OHTS Visual Field Reading Center. Main Outcome Measures The percentage of visual fields that were normal and reliable according to OHTS criteria. Results Of the subset of 2304 subjects who completed the eligibility assessments, 1828 (79%) were OHTS-eligible based on visual field test requirements. A third eligibility test was required for 11% of all eyes because of unreliable, questionable, or abnormal test results. With the 33% fixation loss cutoff in the OHTS, 97% of all eligibility visual field examinations were reliable and 3% were unreliable. The most frequent cause (69.5%) of unreliability was excessive fixation losses. Conclusions Permitting one repeat test after an abnormal or unreliable test allowed an extra 560 patients to be "eligible" for the study based on visual field tests. A clinical screening review of otherwise normal and reliable tests was not restrictive. The adoption of a 33% fixation loss cutoff significantly reduced the number of required retests and prevented study rejection of 89 patients.

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

PURPOSE We examined the role of DNA copy number variants (CNVs) of known glaucoma genes in relation to primary open angle glaucoma (POAG). METHODS Our study included DNA samples from two studies (NEIGHBOR and GLAUGEN). All the samples were genotyped with the Illumina Human660W_Quad_v1 BeadChip. After removing non-blood-derived and amplified DNA samples, we applied quality control steps based on the mean Log R Ratio and the mean B allele frequency. Subsequently, data from 3057 DNA samples (1599 cases and 1458 controls) were analyzed with PennCNV software. We defined CNVs as those ≥5 kilobases (kb) in size and interrogated by ≥5 consecutive probes. We further limited our investigation to CNVs in known POAG-related genes, including CDKN2B-AS1, TMCO1, SIX1/SIX6, CAV1/CAV2, the LRP12-ZFPM2 region, GAS7, ATOH7, FNDC3B, CYP1B1, MYOC, OPTN, WDR36, SRBD1, TBK1, and GALC. RESULTS Genomic duplications of CDKN2B-AS1 and TMCO1 were each found in a single case. Two cases carried duplications in the GAS7 region. Genomic deletions of SIX6 and ATOH7 were each identified in one case. One case carried a TBK1 deletion and another case carried a TBK1 duplication. No controls had duplications or deletions in these six genes. A single control had a duplication in the MYOC region. Deletions of GALC were observed in five cases and two controls. CONCLUSIONS The CNV analysis of a large set of cases and controls revealed the presence of rare CNVs in known POAG susceptibility genes. Our data suggest that these rare CNVs may contribute to POAG pathogenesis and merit functional evaluation.

PURPOSE: To investigate the association between control of intraocular pressure after surgical intervention for glaucoma and visual field deterioration. METHODS: In the Advanced Glaucoma Intervention Study, eyes were randomly assigned to one of two sequences of glaucoma surgery, one beginning with argon laser trabeculoplasty and the other trabeculectomy. In the present article we examine the relationship between intraocular pressure and progression of visual field damage over 6 or more years of follow-up. In the first analysis, designated Predictive Analysis, we categorize 738 eyes into three groups based on intraocular pressure determinations over the first three 6-month follow-up visits. In the second analysis, designated Associative Analysis, we categorize 586 eyes into four groups based on the percent of 6-month visits over the first 6 follow-up years in which eyes presented with intraocular pressure less than 18 mm Hg. The outcome measure in both analyses is change from baseline in follow-up visual field defect score (range, 0 to 20 units). RESULTS: In the Predictive Analysis, eyes with early average intraocular pressure greater than 17.5 mm Hg had an estimated worsening during subsequent follow-up that was 1 unit of visual field defect score greater than eyes with average intraocular pressure less than 14 mm Hg (P = .002). This amount of worsening was greater at 7 years (1.89 units; P CONCLUSIONS: In both analyses low intraocular pressure is associated with reduced progression of visual field defect, supporting evidence from earlier studies of a protective role for low intraocular pressure in visual field deterioration.

Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10−11). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10−10) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss., Author Summary Primary open angle glaucoma is a blinding disease for which there is currently no cure, only treatments that may slow its progress. To help understand the mechanisms of this disease and to design more effective treatments, we identified previously a locus, SIX6, that increases the risk of glaucoma. This gene is involved in early eye development and helps to form the retina. In this paper, we test specific sequence variants in SIX6 that are found in glaucoma patients. We show that these variants have a reduced function that interferes with their ability to direct proper formation of the retina. One variant in particular is common, and may be the main reason that this gene is important in the glaucoma disease process. Patients who have two copies of this sequence variant show a change in the structure of their eye consistent with fewer neurons that carry the visual signal to the brain. These neurons typically die as people age, and people who begin life with fewer visual neurons may have an increased risk of glaucoma. Additional research in this topic may lead to new treatments that preserve sight.

Purpose The CAV1/CAV2 (caveolin 1 and caveolin 2) genomic region previously was associated with primary open-angle glaucoma (POAG), although replication among independent studies has been variable. The aim of this study was to assess the association between CAV1/CAV2 single nucleotide polymorphisms (SNPs) and POAG in a large case-control dataset and to explore associations by gender and pattern of visual field (VF) loss further. Design Case-control study. Participants We analyzed 2 large POAG data sets: the Glaucoma Genes and Environment (GLAUGEN) study (976 cases, 1140 controls) and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium (2132 cases, 2290 controls). Methods We studied the association between 70 SNPs located within the CAV1/CAV2 genomic region in the GLAUGEN and NEIGHBOR studies, both genotyped on the Illumina Human 660WQuadv1C BeadChip array and imputed with the Markov Chain Haplotyping algorithm using the HapMap 3 reference panel. We used logistic regression models of POAG in the overall population and separated by gender, as well as by POAG subtypes defined by type of VF defect (peripheral or paracentral). Results from GLAUGEN and NEIGHBOR were meta-analyzed, and a Bonferroni-corrected significance level of 7.7×10 −4 was used to account for multiple comparisons. Main Outcome Measures Overall POAG, overall POAG by gender, and POAG subtypes defined by pattern of early VF loss. Results We found significant associations between 10 CAV1/CAV2 SNPs and POAG (top SNP, rs4236601; pooled P = 2.61×10 −7 ). Of these, 9 were significant only in women (top SNP, rs4236601; pooled P = 1.59×10 −5 ). Five of the 10 CAV1/CAV2 SNPs were associated with POAG with early paracentral VF (top SNP, rs17588172; pooled P = 1.07×10 −4 ), and none of the 10 were associated with POAG with peripheral VF loss only or POAG among men. Conclusions CAV1/CAV2 SNPs were associated significantly with POAG overall, particularly among women. Furthermore, we found an association between CAV1/CAV2 SNPs and POAG with paracentral VF defects. These data support a role for caveolin 1, caveolin 2, or both in POAG and suggest that the caveolins particularly may affect POAG pathogenesis in women and in patients with early paracentral VF defects.

AimsVascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG.MethodsWe used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG.ResultsThe vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P≥0.20). In gene-based analyses, eight were associated with POAG overall at permuted P

Laser systems designed for eye treatment provide the surgeon tools and methods to meet the therapeutic goal for glaucoma management of reducing the level of intraocular pressure toward a target deemed appropriate for the safety of a patient and eye. Just as glaucoma takes many forms, so do the available laser treatment strategies. The appropriate laser strategy varies with the diagnosis and extent of the clinical problem. Use of laser systems also often provides help in managing ancillary challenges that arise during glaucoma management; to name a few, examples include miosis hampering the view of the posterior pole of the eye or small bleeders that threaten sight and ocular integrity. This chapter provides history and details of a number of laser procedures for ophthalmic surgeons managing glaucoma. The surgeon will find laser modalities, tissue effects, patient preparation, laser system choice and setup, procedure detail, patient management, and expected outcomes for the various forms of laser interventions in the various forms of glaucoma.

Primary open-angle glaucoma (POAG) is a common disease with complex inheritance. The identification of genes predisposing to POAG is an important step toward the development of novel gene-based methods of diagnosis and treatment. Genome-wide association studies (GWAS) have successfully identified genes contributing to complex traits such as POAG however, such studies frequently require very large sample sizes, and thus, collaborations and consortia have been of critical importance for the GWAS approach. In this report we describe the formation of the NEIGHBOR consortium, the harmonized case control definitions used for a POAG GWAS, the clinical features of the cases and controls, and the rationale for the GWAS study design.

Multiple genes have been associated with primary open angle glaucoma (POAG) in Caucasian populations. We now examine the association of these loci in populations of African ancestry, populations at particularly high risk for POAG.We genotyped DNA samples from two populations: African American (1150 cases and 999 controls) and those from Ghana, West Africa (483 cases and 593 controls). Our analysis included 57 single nucleotide polymorphisms (SNPs) in five loci previously associated with POAG at the genome-wide level, including CDKN2B-AS1, TMCO1, CAV1/CAV2, chromosome 8q22 intergenic region, and SIX1/SIX6. We evaluated association in the full datasets, as well as subgroups with normal pressure glaucoma (NPG, maximum IOP ≤21 mm Hg) and high pressure glaucoma (HPG, IOP21 mm Hg).In African Americans, we identified an association of rs10120688 in the CDNK2B-AS1 region with POAG (P = 0.0020). Several other SNPs were nominally associated, but did not survive correction for multiple testing. In the subgroup analyses, significant associations were identified for rs10965245 (P = 0.0005) in the CDKN2B-AS1 region with HPG and rs11849906 in the SIX1/SIX6 region with NPG (P = 0.006). No significant association was identified with any loci in the Ghanaian samples.POAG genetic susceptibility alleles associated in Caucasians appear to play a greatly reduced role in populations of African ancestry. Thus, the major genetic components of POAG of African origin remain to be identified. This finding underscores the critical need to pursue large-scale genome-wide association studies in this understudied, yet disproportionately affected population.

Purpose: To learn the long-term outcome of ciliary ablation with diode laser contact transscleral cyclophotocoagulation (TSCPC) in eyes with recalcitrant, severe glaucoma. Methods: Twenty-seven eyes of 27 patients with medically and surgically uncontrollable glaucoma and no previous ciliary ablation enrolled in this study. After baseline measurements and informed consent, the authors performed contact TSCPC. There were 14 pseudophakic, 7 aphakic, and 6 phakic eyes; 15 of these had primary openangle glaucoma and the remainder had various secondary or open- or closed-angle glaucomas. Median follow-up was 19 months (range, 6 weeks to 27 months). Initially after laser surgery, glaucoma medications were continued, except for a 2-week interruption of miotics; the ophthalmologist later adjusted medications in accordance with the patient's status. The authors define failure of TSCPC in two ways, based on IOP measurements during two consecutive study examinations 6 weeks or more after intervention or at the final examination: (1) less than 20% intraocular pressure (IOP) reduction from baseline, and (2) either less than 20% reduction of IOP from baseline or IOP greater than 22 mmHg. Results: For 27 eyes, the baseline IOP (mean ± standard deviation) was 36.4 ± 12.4 mmHg (range, 20-70 mmHg). The mean IOP at last examination was 20.3 ± 8.7 mmHg. With failure definition 1, the cumulative probability of success was 84% at 1 year and 62% at 2 years. With failure definition 2 the cumulative probability of success was 72% at 1 year and 52% at 2 years. At the last examination, 19 eyes (70%) had visual acuity improved within one line of visual acuity at eligibility. One of these eyes, with light perception vision at entry, declined to no light perception. Three eyes (11 %) lost two lines of vision and five (19%)lost three or more lines. Conclusions: Contact diode laser TSCPC yields long-term improvement of IOP and preservation of visual acuity in a substantial proportion of eyes with severe, medically uncontrolled glaucoma.

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma., Author Summary Loss of vision from glaucoma, a common cause of blindness worldwide, is due to irreversible damage to the optic nerve. Current therapies cannot prevent glaucoma-related optic nerve disease and very little is known about the underlying responsible molecular events. Glaucoma patients affected by the “normal-pressure” subtype of glaucoma (NPG) have increased susceptibility to optic nerve degeneration. Although NPG has a high heritability, common predisposing genetic variants have not been identified. Therefore, we performed a meta-analysis of two independent genome-wide association studies for a common form of glaucoma, primary open angle glaucoma (POAG), followed by NPG subgroup analysis. We found that SNPs in the CDKN2BAS gene region on 9p21 and a highly conserved region with a probable regulatory function on 8q22 were associated with NPG and with optic nerve disease in a second type of glaucoma, exfoliation glaucoma. Both genomic regions are predicted to influence TGF-beta activity, and using whole-genome data we showed that the TGF-beta signaling pathway overall is associated with NPG. These results reveal new insights into the molecular pathogenesis of optic nerve disease in glaucoma and are an important step toward the development of preventative and protective therapies.

Medical therapy has been the standard initial treatment for open-angle glaucoma. When some visual field has been lost and maximum tolerated and effective medical therapy does not succeed in controlling the disease, the patient is considered to have advanced glaucoma, and the first of a potential sequence of surgical treatments is usually indicated. Little is known about the long-term course and prognosis of advanced glaucoma or about the long-term effectiveness of sequential surgical treatments in controlling the disease and preventing vision loss and blindness. The Advanced Glaucoma Intervention Study was designed to study, in advanced glaucoma, the long-term clinical course and prognosis, and, in a randomized trial, the comparative outcomes of two sequences of surgical treatments. Toward these goals, 789 eyes in 591 patients were enrolled at 11 clinical centers between 1988 and 1992. Follow-up will continue until 1996. Eyes were randomly assigned to one of two sequences of surgical treatments. One sequence begins with argon laser trabeculoplasty (ALT), is followed by trabeculectomy, an incisional surgical filtering procedure, should ALT fail to control the disease, and by a second trabeculectomy should the first trabeculectomy fail. The other sequence begins with trabeculectomy, is followed by ALT should the trabeculectomy fail, and by a second trabeculectomy should ALT fail. The main outcome of interest is visual function (visual field and visual acuity). Other important outcomes are intraocular pressure, complications of surgery, time to treatment failure, and extent of need for additional medical therapy. We present in this paper the rationale, objectives, design and methods of the study, and the baseline characteristics of study patients and eyes.

PURPOSE To determine the probability of future glaucomatous visual field (VF) progression with clinical and perimetric data. METHODS One hundred sixty-one eyes of patients (161) enrolled in the Advanced Glaucoma Intervention Study (AGIS) with >or=8 years of follow-up and a baseline VF score

To test the hypothesis that cataract extraction in glaucomatous eyes improves overall sensitivity of visual function without affecting the size or depth of glaucomatous scotomas.Experimental study with no control group.One hundred fifty-eight eyes (of 140 patients) from the Advanced Glaucoma Intervention Study with at least two reliable visual fields within a year both before and after cataract surgery were included. Average mean deviation (MD), pattern standard deviation (PSD), and corrected pattern standard deviation (CPSD) were compared before and after cataract extraction. To evaluate changes in scotoma size, the number of abnormal points (P.05) on the pattern deviation plot was compared before and after surgery. We described an index ("scotoma depth index") to investigate changes of scotoma depth after surgery.Mean values for MD, PSD, and CPSD were -13.2, 6.4, and 5.9 dB before and -11.9, 6.8, and 6.2 dB after cataract surgery (Por = .001 for all comparisons). Mean (+/- SD) number of abnormal points on pattern deviation plot was 26.7 +/- 9.4 and 27.5 +/- 9.0 before and after cataract surgery, respectively (P = .02). Scotoma depth index did not change after cataract extraction (-19.3 vs -19.2 dB, P = .90).Cataract extraction caused generalized improvement of the visual field, which was most marked in eyes with less advanced glaucomatous damage. Although the enlargement of scotomas was statistically significant, it was not clinically meaningful. No improvement of sensitivity was observed in the deepest part of the scotomas.

Purpose To investigate the risk factors associated with visual field (VF) progression in the Advanced Glaucoma Intervention Study (AGIS) with pointwise linear regression (PLR) analysis of serial VFs. Design Prospective, multicenter, randomized clinical trial. Participants Five hundred nine eyes of 401 patients from the AGIS with a baseline VF score of ≤16, ≥7 VF examinations, and ≥3 years of follow-up were selected. Main outcome measure Visual field progression. Methods This is a cohort study of patients enrolled in a prospective randomized clinical trial (AGIS). Worsening of a test location on PLR analysis was defined as a change of threshold sensitivity of ≥1.00 decibels a year, with P ≤0.01. Visual field progression was defined as worsening of at least 2 test locations within a Glaucoma Hemifield Test cluster with PLR analysis. Multivariate logistic regression was used to determine risk factors associated with VF worsening. Intraocular pressure (IOP) fluctuation was defined as standard deviation of the IOP at all visits after the initial surgery. Results The mean (± standard deviation) follow-up time and baseline AGIS score were 7.4 (±1.7) years and 7.7 (±4.4), respectively. Visual field progression was detected with PLR analysis in 151 eyes (30%). Older age at the initial intervention ( P = 0.0012; odds ratio [OR], 1.30; 95% confidence interval [CI], 1.11–1.50), larger IOP fluctuation ( P = 0.0013; OR, 1.31; 95% CI, 1.12–1.54), increasing number of glaucoma interventions ( P = 0.01; OR, 1.74; 95% CI, 1.14–2.64), and longer follow-up ( P = 0.02; OR, 1.19; 95% CI, 1.03–1.38) were associated with increased odds of VF progression. When regression analyses were repeated in eyes with and without a history of cataract extraction, IOP fluctuation was the only variable to be consistently associated with VF progression. Conclusion Both increasing age and greater IOP fluctuation increase the odds of VF progression by 30% (for each 5-year increment in age and 1-mmHg increase in IOP fluctuation). The higher risk conferred by IOP fluctuation was consistently observed in eyes with and without a history of cataract extraction.

Purpose To describe a method to determine progression of glaucoma based on visual field thresholds. Design Observational retrospective longitudinal cohort study. Methods A back propagation neural network with three hidden layers was developed with commercial software. Visual field data from 80 patients who participated in the Advanced Glaucoma Intervention Study (AGIS) were used. Glaucomatous visual field progression was defined as a change of 4 or more units in the AGIS score, confirmed by at least two sequential subsequent tests. Inputs to the neural network consisted of threshold measurements from 55 visual field locations from the baseline examination and each follow-up examination. The data set was randomized so the sequence of examinations would not influence the training or testing of the neural network. Two thirds of the randomized data were used for training and the remaining one third for testing. Results The mean age of 80 patients enrolled in AGIS at initial examination was 67.4 (± 7.3 standard deviation [SD]) years. The average follow-up period was 7.2 (±2.3 SD) years and the mean duration between examinations was 0.46 (± 0.39 SD) years. The neural network estimated the probability of progression for each baseline and follow-up comparison with an average sensitivity of 86% and specificity of 88%. The area under the receiver operating characteristic (ROC) curve was 0.92, with a sensitivity of 86% at the 80% specificity level and a sensitivity of 91% at the 90% specificity level. Conclusions From analysis of AGIS data, progression of glaucoma could be detected from visual field thresholds with a neural network.

PURPOSE: To compare the incidence of encapsulated bleb after trabeculectomy in eyes with and without previous argon laser trabeculoplasty and to assess other risk factors for encapsulated bleb development. METHODS: After medical treatment failure, eyes enrolled in the Advanced Glaucoma Intervention Study (AGIS) were randomly assigned to sequences of interventions starting with either argon laser trabeculoplasty or trabeculectomy. In the present study we compared the clinical course for 1 year after trabeculectomy in 119 eyes with failed argon laser trabeculoplasty with that of 379 eyes without previous argon laser trabeculoplasty. Data on bleb encapsulation were collected at the time that the encapsulation was diagnosed, and 3 and 6 months later. RESULTS: Of multiple factors examined in the AGIS data for the risk of developing encapsulated bleb, only male gender and high school graduation without further formal education were statistically significant. Encapsulation occurred in 18.5% of eyes with previous argon laser trabeculoplasty failure and 14.5% of eyes without previous argon laser trabeculoplasty (unadjusted relative risk, 1.27; 95% confidence limits = 0.81, 2.00; P = .23). After adjusting for age, gender, educational achievement, prescribed systemic β-blockers, diabetes, visual field score, and years since glaucoma diagnosis, this difference remains statistically not significant. Four weeks after trabeculectomy, mean intraocular pressure was 7.5 mm Hg higher in eyes with (22.5 mm Hg) than without (15.0 mm Hg) encapsulated bleb; at 1 year after trabeculectomy and the resumption of medical therapy when needed, this excess was reduced to 1.4 mm Hg. CONCLUSIONS: This study, as did two previous studies, found male gender to be a risk factor for bleb encapsulation. Four studies, including the present study, have reported a higher rate of encapsulation in eyes with previous argon laser trabeculoplasty; in two of the studies, one of which was the present study, the rate was not statistically significantly higher; in the other two studies the rate was significantly higher. The 4-week postoperative mean intraocular pressure was higher in eyes with than without encapsulated bleb; with the resumption of medical treatment the two means converged after 1 year.

Purpose: To examine the effect of digital ocular pressure (DOP) on the intraocular pressure (IOP) of eyes 3 months or longer after successful glaucoma filtering surgery. Methods: Fifteen patients participated in this study. Each had one eye with a successful filtering operation (IOP ≤ 21 mmHg without medications) and a fellow eye that was not operated on, which served as a control. The authors measured IOP in both eyes before and serially after DOP until return to baseline or for 3 hours to determine the amounts and durations of reductions. The authors monitored changes of bleb morphology and searched for complications. Results: Digital ocular pressure 3 months or more after successful filtering surgery reduced IOP by approximately 50% of baseline. The time after DOP for 50% of eyes to have intraocular pressure return to within 2 mmHg of baseline was 95 minutes; 40% recovered within 20 minutes and 30% had not recovered by 3 hours. Eyes with localized blebs recovered faster than did eyes with diffuse blebs. Transient shallowing of the anterior chamber developed in one eye. Otherwise, there were no adverse effects. Time since surgery and baseline IOP were not correlated with response. Fellow eyes had minimal response to DOP and recovered within 30 minutes. Conclusion: This study shows that a substantial, transient decrease of IOP after DOP occurs in glaucomatous eyes with a well-functioning bleb 3 months to 6 years after filtering surgery. The duration exceeds 90 minutes in more than 50% of the eyes tested and 180 minutes in more than 30% of the eyes tested.

Purpose To assess the association between single nucleotide polymorphisms (SNPs) of the gene region containing cyclin-dependent kinase inhibitor 2B antisense noncoding RNA ( CDKN2B-AS1 ) and glaucoma features among primary open-angle glaucoma (POAG) patients. Design Retrospective observational case series. Methods We studied associations between 10 CDKN2B-AS1 SNPs and glaucoma features among 976 POAG cases from the Glaucoma Genes and Environment (GLAUGEN) study and 1971 cases from the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium. For each patient, we chose the feature from the eye with the higher value. We created cohort-specific multivariable models for glaucoma features and then meta-analyzed the results. Results For 9 of the 10 protective CDKN2B-AS1 SNPs with minor alleles associated with reduced disease risk (eg, the G allele at rs2157719), POAG patients carrying these minor alleles had smaller cup-to-disc ratio (0.05 units smaller per G allele at diagnosis; 95% CI: −0.08, −0.03; P = 6.23E-05) despite having higher intraocular pressure (IOP) (0.70 mm Hg higher per G allele at DNA collection; 95% CI: 0.40, 1.00; P = 5.45E-06). For the 1 adverse rs3217992 SNP with minor allele A associated with increased disease risk, POAG patients with A alleles had larger cup-to-disc ratio (0.05 units larger per A allele at diagnosis; 95% CI: 0.02, 0.07; P = 4.74E-04) despite having lower IOP (−0.57 mm Hg per A allele at DNA collection; 95% CI: −0.84, −0.29; P = 6.55E-05). Conclusion Alleles of CDKN2B-AS1 SNPs, which influence risk of developing POAG, also modulate optic nerve degeneration among POAG patients, underscoring the role of CDKN2B-AS1 in POAG.

PURPOSE. To investigate the effects of central corneal thickness (CCT)-associated variants on primary open-angle glaucoma (POAG) risk using single nucleotide polymorphisms (SNP) data from the Glaucoma Genes and Environment (GLAUGEN) and National Eye Institute (NEI) Glaucoma Human Genetics Collaboration (NEIGHBOR) consortia. METHODS. A replication analysis of previously reported CCT SNPs was performed in a CCT dataset (n ¼ 1117) and these SNPs were then tested for association with POAG using a larger POAG dataset (n ¼6470). Then a CCT genome-wide association study (GWAS) was performed. Top SNPs from this analysis were selected and tested for association with POAG. cDNA libraries from fetal and adult brain and ocular tissue samples were generated and used for candidate gene expression analysis. RESULTS. Association with one of 20 previously published CCT SNPs was replicated: rs12447690, near the ZNF469 gene (P ¼ 0.001; b ¼� 5.08 lm/allele). None of these SNPs were significantly associated with POAG. In the CCT GWAS, no SNPs reached genome-wide significance. After testing 50 candidate SNPs for association with POAG, one SNP was identified, rs7481514 within the neurotrimin (NTM) gene, that was significantly associated with POAG in a low-tension subset (P ¼ 0.00099; Odds Ratio [OR] ¼ 1.28). Additionally, SNPs in the CNTNAP4 gene showed suggestive association with POAG (top SNP ¼ rs1428758; P ¼ 0.018; OR ¼ 0.84). NTM and CNTNAP4 were shown to be expressed in ocular tissues. CONCLUSIONS. The results suggest previously reported CCT loci are not significantly associated with POAG susceptibility. By performing a quantitative analysis of CCT and a subsequent analysis of POAG, SNPs in two cell adhesion molecules, NTM and CNTNAP4, were identified and may increase POAG susceptibility in a subset of cases. (Invest Ophthalmol Vis

• Endocapsular hematoma, to our knowledge, is a previously unreported type of postoperative hemorrhage. In this condition, blood collects in the narrow space between the anterior surface of the posterior capsule and the posterior optic surface of a posterior chamber intraocular lens. Endocapsular hematoma differs from anterior chamber hyphema in several ways: the location of the blood is in the endocapsular space, a small amount of endocapsular blood can cause visually disabling symptoms, the blood in the endocapsular space often fails to reabsorb, and neodymium-YAG laser capsulotomy can be used to drain the endocapsular blood into the vitreous cavity. We present six cases of endocapsular hematoma. Neodymium-YAG laser capsulotomy was successfully used to drain the endocapsular hematoma in three of these cases.

To evaluate whether baseline visual field data and asymmetries between eyes predict the onset of primary open-angle glaucoma (POAG) in Ocular Hypertension Treatment Study (OHTS) participants.A new index, mean prognosis (MP), was designed for optimal combination of visual field thresholds, to discriminate between eyes that developed POAG from eyes that did not. Baseline intraocular pressure (IOP) in fellow eyes was used to construct measures of IOP asymmetry. Age-adjusted baseline thresholds were used to develop indicators of visual field asymmetry and summary measures of visual field defects. Marginal multivariate failure time models were constructed that relate the new index MP, IOP asymmetry, and visual field asymmetry to POAG onset for OHTS participants.The marginal multivariate failure time analysis showed that the MP index is significantly related to POAG onset (P0.0001) and appears to be a more highly significant predictor of POAG onset than either mean deviation (MD; P = 0.17) or pattern standard deviation (PSD; P = 0.046). A 1-mm Hg increase in IOP asymmetry between fellow eyes is associated with a 17% increase in risk for development of POAG. When threshold asymmetry between eyes existed, the eye with lower thresholds was at a 37% greater risk of development of POAG, and this feature was more predictive of POAG onset than the visual field index MD, though not as strong a predictor as PSD.The MP index, IOP asymmetry, and binocular test point asymmetry can assist in clinical evaluation of eyes at risk of development of POAG.

Objective To investigate pointwise linear regression (PLR) for longitudinal evaluation of visual fields and to compare results with those of the Advanced Glaucoma Intervention Study (AGIS) criteria. Methods We selected 509 eyes (401 patients) from the AGIS with 3 or more years of follow-up, 7 or more visual field examinations, and an AGIS reference score of 16 or lower. Visual field change at test locations was defined as a change of threshold sensitivity of 1 dB/y or higher andP≤.01. Several sets of criteria were investigated for defining change of visual field series with PLR. Main Outcome Measures Progression or improvement of visual field series with PLR and AGIS criteria. Results Mean (SD) follow-up time and baseline AGIS score were 7.4 (1.7) years and 7.7 (4.4), respectively. Pairwise agreement between AGIS and various PLR criteria ranged from 52% to 64% with the κ statistic varying between 0.22 (95% confidence interval, 0.15-0.29) and 0.30 (95% confidence interval, 0.22-0.38). One hundred thirty-eight (27%) and 151 (30%) eyes progressed (85 eyes or 17% detected by both methods) while 72 (14%) and 11 (2%) eyes improved (5 eyes or 1% detected by both methods) based on AGIS and the most rigorous PLR criteria, respectively. Conclusions Based on rigorous, clinically relevant criteria, PLR detects progression in a similar proportion of eyes compared with AGIS criteria. Pointwise linear regression may be superior to AGIS methods since it identifies fewer visual field series as improving.

Purpose To determine the least worsening of a visual field (VF) and the least number of confirming tests needed to identify progression of glaucomatous VF defects. Design Cohort study of participants in a clinical trial. Participants Seven hundred fifty-two eyes of 565 patients with advanced glaucoma. Methods Visual field tests were quantified with the Advanced Glaucoma Intervention Study (AGIS) VF defect score and the Humphrey Field Analyzer mean deviation (MD). Follow-up was 8 to 13 years. Main outcome measures Two measures based on the AGIS VF defect score: (1) sustained decrease of VF (SDVF), a worsening from baseline by 2 (alternatively, 3 or 4) or more units and sustained for 2 (alternatively, 3) consecutive 6-month visits and (2) after the occurrence of SDVF, the average percent of eyes with worsening by 2 (alternatively, 3 or 4) or more units from baseline. Two similar measures based on MD. Results Based on the original AGIS criteria for SDVF (a worsening of 4 units in the AGIS score sustained during 3 consecutive 6-month visits), 31% of eyes had an SDVF. The percent of eyes with a sustained event increases by approximately 10% when either the minimum number of units of field loss or the minimum number of 6-month visits during which the loss is sustained decreases by 1. During 3 years of follow-up after a sustained event, a worsening of at least 2 units was found in 72% of eyes that had a 2-visit sustained event. The same worsening was found in 84% of eyes that had a 3-visit sustained event. Through the next 10 years after a sustained event, based on worsening of 2, 3, or 4 units at 2 or 3 consecutive tests, the loss reoccurred, on average, in >/=75% of study eyes. Results for MD are similar. Conclusions In patients with advanced glaucoma, a single confirmatory test 6 months after a VF worsening indicates with at least 72% probability a persistent defect when the worsening is defined by at least 2 units of AGIS score or by at least 2 decibels of MD. When the number of confirmatory tests is increased from 1 to 2, the percentage of eyes that show a persistent defect increases from 72% to 84%.

PURPOSE Contact fiberoptic laser transscleral cyclophotocoagulation (TSCPC) is an aqueous inflow-reducing surgical treatment for glaucoma. One delivery device uses a 600-microm diameter quartz glass fiberoptic with a hemispheric tip. A larger fiberoptic diameter would reduce fluence through conjunctiva and sclera. This study determined the relation of fiberoptic to ciliary body burn diameters after TSCPC with the IRIS Medical SLx diode laser system in human autopsy eyes. MATERIALS AND METHODS Laser energy was applied with two models of delivery probe that were identical except for fiberoptic diameter (600 or 800 microm). Both had hemispheric tips, each with the hemisphere radius equal to the radius of the fiberoptic. Six fresh human autopsy eyes (three pairs) were used, each receiving eight diode laser applications at 1.75 (2 eyes) or 2.0 (4 eyes) watts for 2.5 seconds-four applications per eye with the 600-microm fiberoptic and four with the 800-microm fiberoptic. Eyes were fixed in 10% formalin then opened coronally at the equator. Inner surface burn diameters were measured parallel and perpendicular to the limbus using calipers and an operating microscope at 10x magnification. RESULTS Ciliary body burns with the 600- and 800-microm fiberoptic tips had nearly the same average diameter, range of diameter, average area, and range of areas. CONCLUSION The 800-microm fiber, which has a 78% larger cross-sectional area than a 600-microm fiber, reduces fluence through ocular surface tissue during diode laser TSCPC, theoretically decreasing the risk of surface bums. In this study, the larger fiber gives essentially the same size ciliary body coagulation as obtained with the 600-microm fiberoptic. This suggests that the larger fiberoptic, compared with the standard 600-microm fiberoptic, will be more safe yet equally effective for TSCPC.

In Reply. —In preparing our article, we performed a computerized literature search of English and foreign language ophthalmology journals using several search strategies. None of them revealed the two articles cited by Nishi et al. We are all describing the same entity. We believe Thomas and co-authors, Nishi et al, and McManus are incorrect in referring to blood confined to the capsular bag as a "hyphema."Hyphemarefers to blood in the anterior chamber. We believe the more precise term is the one we used:endocapsular hematoma. Posterior capsular neovascularization due to rubeosis iridis can be added to the causes of blood within the capsular bag. It should be easily distinguishable from the cases we described. The association of glaucoma with endocapsular hematoma in some of the reported cases invites conjecture. Definite conclusions cannot be made with such a small number of cases. We do not believe that postoperative hypotony

• The sensitivity and specificity of alternate analytic strategies for recognizing glaucomatous visual field loss from automated threshold perimetry (C-30-2 test of the Humphrey Field Analyzer) were compared among one eye each of 106 patients with glaucoma and 249 normal subjects. Algorithms included commercially available global indexes and cross-meridional differences (Statpac 1 and Statpac 2), as well as cross-meridional and cluster analyses that were developed independently for natural history studies and clinical trials. The sensitivity of most algorithms was high, except for those that used only diffuse loss as an indicator of abnormality. Specificity was acceptably high for all algorithms. Subjects who failed to meet the manufacturer's standard for reliability had much reduced specificity, but sensitivity was also affected. Algorithms that were based on any of the alternate definitions of localized reduction in retinal sensitivity performed equally well, which suggests that any of these approaches is useful in searching for glaucomatous visual loss as typified by this database. Availability, familiarity, and convenience may govern the selection of any one analytic approach for use in a particular setting.

Clinical and pathologic examinations were performed after 18 iridectomies had been created in six eyes of three rhesus monkeys using increasing 0-switched neodymium (Nd):YAG laser energy, pulses per burst, and number of bursts. Treatment parameters bracketed the threshold for lens damage during iridectomy. Iridectomy with one or two bursts of one or two Qswitched pulses at 5 to 6.2 mJ per pulse was achieved without lens damage. Slight increase of pulse energy or an increase to three pulses per burst (without pulse energy increase) caused local damage to the underlying lens. Marked increase of any of the treatment parameters caused slightly larger iridectomies and slightly larger, localized damage of the underlying lens. Synechiae developed between the monkey posterior iris surface at the iridectomy and the damaged area in 80% of the lens lesions. In monkeys, the small pulsed laser iridectomies created with pulses of energies up to 6.5 mJ became occluded during the healing process.

We examined five patients with Down's syndrome and bilateral infantile glaucoma. In the first few months of life four patients had large cloudy corneas, breaks in Descemet's membrane, increased intraocular pressure, photophobia, and tearing. In one patient the diagnosis was delayed until 3 1/2 years of age because of concomitant nasolacrimal duct obstruction. Two patients developed cataracts and retinal detachment and have undergone multiple surgical procedures. The clinical course in these two older patients suggests that coexistence of congenital glaucoma, severe myopia, and cataracts in patients with trisomy 21 strongly predisposes for the development of retinal detachment and poor visual outcome.

Four of 13 patients receiving intermittent high-dose methotrexate therapy experienced recurrent symptoms of ocular irritation (burning, pruritus, "dry eyes") two to seven days after chemotherapy. Ophthalmic examination was unremarkable in symptomatic individuals except for decreased reflex production of tears in some patients. Pharmacokinetic studies of a group of these patients revealed concentrations of methotrexate in tears equivalent to those in plasma at 24 and 48 hours after treatment; these concentrations reached 1 X 10(-5) M during the infusion of methotrexate. The occurrence of acidic lacrimal secretions, pH 6.5 in one symptomatic patient, may have contributed to decreased solubility of methotrexate in the fluid of the conjunctival sac.