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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.

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.

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.

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

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.

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.

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

DNA copy number variants (CNVs) have been reported in many human diseases including autism and schizophrenia. Primary Open Angle Glaucoma (POAG) is a complex adult-onset disorder characterized by progressive optic neuropathy and vision loss. Previous studies have identified rare CNVs in POAG; however, their low frequencies prevented formal association testing. We present here the association between POAG risk and a heterozygous deletion in the galactosylceramidase gene (GALC). This CNV was initially identified in a dataset containing 71 Caucasian POAG cases and 478 ethnically matched controls obtained from dbGAP (study accession phs000126.v1.p1.) (p = 0.017, fisher's exact test). It was validated with array comparative genomic hybridization (arrayCGH) and realtime PCR, and replicated in an independent POAG dataset containing 959 cases and 1852 controls (p = 0.021, OR (odds ratio) = 3.5, 95% CI -1.1-12.0). Evidence for association was strengthened when the discovery and replication datasets were combined (p = 0.002; OR = 5.0, 95% CI 1.6-16.4). Several deletions with different endpoints were identified by array CGH of POAG patients. Homozygous deletions that eliminate GALC enzymatic activity cause Krabbe disease, a recessive Mendelian disorder of childhood displaying bilateral optic neuropathy and vision loss. Our findings suggest that heterozygous deletions that reduce GALC activity are a novel mechanism increasing risk of POAG. This is the first report of a statistically-significant association of a CNV with POAG risk, contributing to a growing body of evidence that CNVs play an important role in complex, inherited disorders. Our findings suggest an attractive biomarker and potential therapeutic target for patients with this form of POAG.

• 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.

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.

Laser pulses were focused within 1 mm of the rhesus monkey corneal endothelium using the Coherent Model 9900® laser at energies of 3, 6, 9, and 12 mJ. Sixteen slightly off-axis pulses were applied with no contact lens on the eye. Corneal damage was studied clinically and by scanning electron microscopy. Q-switched pulses of 12 mJ or less are not likely to damage the cornea if focused more than 0.75 mm from the endothelium. The retrocorneal focal distance for a 50% incidence of endothelial damage for 6, 9, and 12 mJ pulses was found to be less than 0.5 mm. For 3 mJ pulses, it was less than 0.25 mm. The severe early effect of suprathreshold pulses is edema of endothelial cells in a 0.2- to 0.6-mm diameter circular zone surrounding a small central pit through Descemet's membrane. At two months, irregular enlargement of endothelial cells surrounding and partially covering the persistent pit exists at sites of severe damage. The extent of the longer-term change is proportional to the severity of the original insult, but in no case was there clinically significant, persistent damage in the healed corneas.

• Ciliochoroidal detachments were produced in rhesus monkeys by injecting glutathione bicarbonate Ringer's solution, autologous serum, or silicone oil into the anterior suprachoroidal space. Silicone oil detachments, like sham operations, caused a transient 2 mm Hg reduction in intraocular pressure. Detachments with glutathione bicarbonate Ringer's solution or serum caused a 6 mm Hg reduction in intraocular pressure, which normalized in three weeks. Aqueous humor flow in serum-detached eyes was normal, indicating that the hypotonia does not result from reduced aqueous humor formation. Blood was present in Schlemm's canal in most eyes with hypotonia, which suggests that hypotonia is not the result of enhanced conventional aqueous humor outflow. Therefore, it is postulated that hypotonia might result from enhanced aqueous humor outflow from the anterior chamber into the suprachoroidal space and out of the eye through the emissarial channels of the sclera (uveoscleral outflow).

A 37-year-old, white woman with xeroderma pigmentosum had reduced vision for many years because of primary and secondary corneal epithelial edema and stromal haze. Corneal grafting was required, but was not successful. Numerous primary dermal tumors of various types involving the lids of both eyes had been excised surgically or treated by freezing with liquid nitrogen. Squamous cell carcinomas involving the limbal area of the globe and adjacent tissues were excised from the left eye at age 12, the right eye at age 32, and the left eye (again) at age 36. The right limbal tumor soon recurred and invaded the orbit despite radiation treatment; this required right orbital exenteration. The second left limbal tumor recurred one year later, soon after the recurrence of a left lower lid basal cell carcinoma. Left orbital exenteration was required. Corneal graft failures and recurrent ocular squamous cell carcinoma involving the eye in xeroderma pigmentosum can be difficult management problems.

Parameters of aqueous dynamics have been evaluated for both eyes of each member of a group of young normal volunteers and of a group of old normal volunteers. In the old volunteers, the observed lower total facility is comprised of a lower true facility of outflow and a lower pseudofacility. The reduced outflow facility is partly counterbalanced by a lower aqueous flow. Also, in the older eyes, ocular rigidity is higher. Mean episcleral venous pressure is the same for the two groups. The major effect of age seen in this study is alteration of the function of the outflow pathways of the eye, with simultaneous, partially counter-balancing, decrease of aqueous production associated with decreased pseudofacility.

The effect of an alpha adrenergic agonist, ALO 2145 (para-amino-clonidine [PAC]), was examined in a double-masked, multicenter study on the postoperative intraocular pressure (IOP) elevation after laser surgery in 165 patients (83 trabeculoplasty, 36 iridotomy, and 46 capsulotomy). One drop of 1.0% ALO 2145 or vehicle was instilled 1 hour before and immediately after laser surgery. The mean IOP increase in the ALO 2145-treated group was lower (P less than 0.05) than in the placebo group at each of the first three postoperative hours. Overall, 18% of placebo-treated eyes experienced IOP increases greater than or equal to 10 mmHg as compared with 4% of ALO 2145-treated eyes (P less than 0.003). Ocular and systemic side effects were minimal and did not differ between the treatment groups. ALO 2145 safely and effectively reduced the incidence and magnitude of potentially harmful IOP elevations after anterior segment laser surgery.

Ultrashort, Q-switched or mode-locked, neodymium-YAG laser pulses focused within 2 mm of the retina caused reproducible retinal damage in four eyes of two monkeys and in four eyes of three rabbits. The distance of the laser focus from the retina for clinically observed threshold retinal damage was characterized for pulse energies up to 9 mJ. For the 2- to 6-mJ pulse energies necessary to rupture vitreal membranes in clear media in rabbits, the high-power laser pulses could not be focused within 2 mm of the retina without substantial risk of damaging the underlying retina. These laser pulses did not rupture vitreal membranes in hazy ocular media that prevented precise focusing. The retinal damage was somewhat greater than expected for retinal absorption of 1.06-micron laser energy, suggesting that secondary effects such as self-focusing and shock waves emanating from the focus may be important.

Laser pulses were focused 0.85 to 1.60 mm from the rhesus monkey corneal endothelium using a mode-locked laser at 3.3 and 4.5 mJ. Sixteen slightly off-axis pulses were applied with no contact lens on the eye. Corneal damage was studied clinically and by scanning electron microscopy. The retrocorneal distance for a 50% incidence of endothelial damage (LD 50 = lesion distance, 50%) for 3.3 mJ mode-locked pulses was found to be 1.60 mm. All mode-locked pulses of 4.5 mJ focused 0.85 to 1.60 mJ from the endothelium caused damage. In comparison, Q-switched pulses of 12 mJ or less are not likely to damage the cornea if focused more than 0.75 mm from the endothelium. The severe, early effect of mode-locked pulses is edema of endothelial cells in a 0.2- to 0.3-mm diameter circular zone surrounding a 0.1-mm diameter denuded zone with a small central break of Descemet's membrane. By two months, mild and moderate lesions heal with little or no distortion of the endothelial mosaic. Irregular enlargement of endothelial cells surrounding and covering the previously denuded area of severe lesions is caused by both mode-locked and Q-switched treatment. In no case was there clinically significant, persistent damage in the healed monkey corneas.

THE surgical repair of retinal detachment associated with a small retinal dialysis is accomplished with a high rate of success by most retinal surgeons,1,2regardless of the specific technique employed. In contrast, detachments associated with giant dialyses have been corrected with less success, especially if the posterior edges are rolled, and in some instances attempted repair has not even been tried.1In this report, a technique is described which permitted a giant dialysis and tear with rolled edge to be successfully reattached. Report of a Case A 25-year-old male student was seen because of acute right eye pain and blurred vision. This developed immediately after he was struck in the eye by a finger while playing football. His past medical history revealed several minor shrapnel injuries to the left arm and knee, reattachment of a severed left thumb, and treatment for malaria; all occurring while he was in

• Sustained intraocular pressure elevations were induced in 15 monkey eyes by argon laser photocoagulation of the trabecular meshwork. Large fluctuations of IOP resulted. Posttreatment gonioscopy revealed an open angle with scattered low peripheral anterior synechiae. Optic disc cupping progressed during pressure elevations, manifested first as posterior bowing of the optic nerve head and peripapillary tissues. Reversal of this early phase of cupping occurred in eight eyes during spontaneous normalization of IOP. In most eyes, as cupping evolved from saucerization to a deeper cup, the cup remained round. In four eyes, focal sloping of the cup to the inferotemporal rim occurred with nerve fiber layer defects. Total cupping with undermining of the rim occurred in five eyes with prolonged IOP elevation. Laser-induced primate glaucoma has features in common with juvenile human glaucoma and is a useful model for the study of cupping of the optic nerve head.