Nailfold capillary morphology in exfoliation syndrome.

PurposeThe purpose of the study was to investigate nailfold microvascular morphology in exfoliation syndrome with or without glaucoma (XFS/XFG) compared with primary open-angle glaucoma (POAG) and control subjects using nailfold capillary videomicroscopy.Patients and methodsWe used a JH-1004 capillaroscope to perform nailfold capillary videomicroscopy on the fourth and fifth digit of the non-dominant hand. We enrolled 56 XFS/XFG patients, 87 POAG patients, and 75 control subjects. Masked observers graded the videos for hemorrhages, avascular zones ≥200 microns (µm), and degree of microvascular tortuosity on a four-point subjective scale. Multivariable odds ratios, 95% confidence intervals and P-for trends for assessing the relation between morphological changes and POAG or XFS/XFG were obtained from logistic regression analyses. We also assessed this relation with XFS/XFG compared with POAG in multivariable models.ResultsAfter adjusting for multiple covariates, nailfold hemorrhages, avascular zones ≥200 µm, and higher degree of vascular tortuosity were more common in XFS/XFG vs controls (P-for trend ≤0.0001) and in POAG vs controls (P-for trend ≤0.01). For each 100 capillaries, the number of hemorrhages was similar (P-for trend=0.91) between XFS/XFG and POAG patients; however, there were more avascular zones per 100 capillaries with borderline significance (P-for trend=0.04) in the XFS/XFG group. XFS/XFG patients had more tortuosity than POAG patients; specifically, having a tortuosity score ≥1.5 was associated with a 4.4-fold increased odds of XFS/XFG (95% confidence interval: 1.5-13.3) relative to a tortuosity score <1.0 (P-for trend=0.005).ConclusionA high degree of nailfold capillary tortuosity is a distinct non-ocular feature associated with XFS/XFG compared with either POAG or controls.

Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma.

AIMS: Vascular 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. METHODS: We 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. RESULTS: The 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<0.001: PRKAA1, CAV1, ITPR3, EDNRB, GNB2, DNM2, HFE, and MYL9. Notably, six of these eight (the first six listed) code for factors involved in the endothelial nitric oxide synthase activity, and three of these six (CAV1, ITPR3, and EDNRB) were also associated with early paracentral loss at P<0.001, whereas none of the six genes reached P<0.001 for peripheral loss only. DISCUSSION: Although the assembled vascular tone SNP set was not associated with POAG, genes that code for local factors involved in setting vascular tone were associated with POAG.

Variations in COL15A1 and COL18A1 influence age of onset of primary open angle glaucoma.

Primary open angle glaucoma (POAG) is a genetically and phenotypically complex disease that is a leading cause of blindness worldwide. Previously we completed a genome-wide scan for early-onset POAG that identified a locus on 9q22 (GLC1J). To identify potential causative variants underlying GLC1J, we used targeted DNA capture followed by high throughput sequencing of individuals from four GLC1J pedigrees, followed by Sanger sequencing to screen candidate variants in additional pedigrees. A mutation likely to cause early-onset glaucoma was not identified, however COL15A1 variants were found in the youngest affected members of 7 of 15 pedigrees with variable disease onset. In addition, the most common COL15A1 variant, R163H, influenced the age of onset in adult POAG cases. RNA in situ hybridization of mouse eyes shows that Col15a1 is expressed in the multiple ocular structures including ciliary body, astrocytes of the optic nerve and cells in the ganglion cell layer. Sanger sequencing of COL18A1, a related multiplexin collagen, identified a rare variant, A1381T, in members of three additional pedigrees with early-onset disease. These results suggest genetic variation in COL15A1 and COL18A1 can modify the age of onset of both early and late onset POAG.

Effects of caffeinated coffee consumption on intraocular pressure, ocular perfusion pressure, and ocular pulse amplitude: a randomized controlled trial.

PURPOSE: To examine the effects of caffeinated coffee consumption on intraocular pressure (IOP), ocular perfusion pressure (OPP), and ocular pulse amplitude (OPA) in those with or at risk for primary open-angle glaucoma (POAG). METHODS: We conducted a prospective, double-masked, crossover, randomized controlled trial with 106 subjects: 22 with high tension POAG, 18 with normal tension POAG, 20 with ocular hypertension, 21 POAG suspects, and 25 healthy participants. Subjects ingested either 237 ml of caffeinated (182 mg caffeine) or decaffeinated (4 mg caffeine) coffee for the first visit and the alternate beverage for the second visit. Blood pressure (BP) and pascal dynamic contour tonometer measurements of IOP, OPA, and heart rate were measured before and at 60 and 90 min after coffee ingestion per visit. OPP was calculated from BP and IOP measurements. Results were analysed using paired t-tests. Multivariable models assessed determinants of IOP, OPP, and OPA changes. RESULTS: There were no significant differences in baseline IOP, OPP, and OPA between the caffeinated and decaffeinated visits. After caffeinated as compared with decaffeinated coffee ingestion, mean mm Hg changes (± SD) in IOP, OPP, and OPA were as follows: 0.99 (± 1.52, P<0.0001), 1.57 (± 6.40, P=0.0129), and 0.23 (± 0.52, P<0.0001) at 60 min, respectively; and 1.06 (± 1.67, P<0.0001), 1.26 (± 6.23, P=0.0398), and 0.18 (± 0.52, P=0.0006) at 90 min, respectively. Regression analyses revealed sporadic and inconsistent associations with IOP, OPP, and OPA changes. CONCLUSION: Consuming one cup of caffeinated coffee (182 mg caffeine) statistically increases, but likely does not clinically impact, IOP and OPP in those with or at risk for POAG.

Female reproductive factors and primary open-angle glaucoma in the Nurses' Health Study.

PURPOSE: The purpose of this study was to explore the relation between age at menarche, parity, and oral contraceptive (OC) use, and primary open-angle glaucoma (POAG). METHODS: We followed 79 440 women in the Nurses' Health Study prospectively from 1980 to 2006 and identified 813 cases of incident POAG. Eligible participants were ≥40 years old, free of POAG at baseline, had information on reproductive history, and reported receiving eye examinations during follow-up. Relevant exposure data and POAG risk factors were updated using biennial questionnaires. We used proportional hazards models to calculate multivariable rate ratios (MVRRs) of POAG and 95% confidence intervals (CI). RESULTS: In multivariable analysis, there were no significant linear trends between age at menarche (P for trend=0.65) or reproductive duration defined as time between age at menarche and menopause (P for trend=0.30) and POAG. Although ever using OCs was not associated with POAG risk (MVRR=1.14; 95% CI, 0.98, 1.34), ≥5 years of OC use was associated with a modest 25% increased risk of POAG (MVRR=1.25; 95% CI, 1.02, 1.53; P for linear trend=0.04). Furthermore, among past OC users, a shorter time since stopping OC use was also associated with an increased risk of POAG (P for linear trend=0.02). Parity was not associated with POAG risk. CONCLUSION: The ≥5 years of OC use was associated with a modestly increased risk of POAG. These data add further support for a role of circulating estrogen in the pathogenesis of POAG.

Distribution of COL8A2 and COL8A1 gene variants in Caucasian primary open angle glaucoma patients with thin central corneal thickness.

PURPOSE: One approach to identify genes that contribute to common complex ocular disorders such as primary open angle glaucoma (POAG) is to study the genetic determinates of endophenotypes that are defined by underlying pre-disposing heritable quantitative traits such as central corneal thickness (CCT). Collagen VIII is a major component of Descemet's membrane and studies in mice have indicated that targeted inactivation of the genes encoding the collagen type 8 alpha1 (Col8a1) and collagen type 8 alpha2 (Col8a2) subunits (COL8A1 and COL8A2) results in thinning of the corneal stroma and of Descemet's membrane. The purpose of this study is to evaluate COL8A1 and COL8A2 as candidate genes for thin CCT in human POAG patients. METHODS: 100 Caucasian POAG patients were enrolled in this study. The entire COL8A1 and COL8A2 coding sequence was determined in 8 patients with CCT<513 µm (one standard deviation (36 microns) below the mean (550 microns) and 8 patients with CCT>586 µm (one standard deviation above the mean). Selected COL8A2 exons containing variants of interest were sequenced in the full POAG cohort. Association and quantitative trait analyses were performed. RESULTS: Three patients with CCT less than 513 µm and advanced POAG were found to have missense changes in COL8A2; two patients had a previously identified mutation, R155Q and one had a novel change, P678L (p=0.0035, Fisher's exact test). Missense changes were not found in any of the patients with CCT>513 µm and missense changes in the COL8A1 gene were not found in any patient. One common COL8A2 SNP, rs274754 was also statistically associated with CCT (p=0.018). CONCLUSIONS: In this study we have identified COL8A2 missense changes in a group of Caucasian patients with very thin CCT and advanced POAG. These results suggest that DNA sequence variants in the COL8A2 gene may be associated with thin corneas in some glaucoma patients. Further study of COL8A2 variants in other patient populations, especially those with thinner CCT such as African-Americans would provide further support for a role of COL8A2 in corneal thickness and in glaucoma.

Brimonidine 0.2% versus apraclonidine 0.5% for prevention of intraocular pressure elevations after anterior segment laser surgery.

OBJECTIVE: To compare the efficacy of brimonidine 0.2% with apraclonidine 0.5% in preventing intraocular pressure (IOP) elevations after anterior segment laser surgery. DESIGN: Double-masked, randomized clinical trial. PARTICIPANTS: Sixty-six patients underwent either laser peripheral iridotomy, argon laser trabeculoplasty, or neodymium:yttrium-aluminum-garnet laser capsulotomy. INTERVENTION: Eyes received either one drop of brimonidine 0.2% or apraclonidine 0.5% before laser surgery. MAIN OUTCOME MEASURES: Intraocular pressure, heart rate, and blood pressure were measured before laser surgery and at 1 hour, 3 hours, 24 hours, and 1 week after laser surgery. RESULTS: Before the laser treatment, 33 patients (50.0%) received brimonidine 0.2% and 33 patients (50.0%) received apraclonidine 0.5%. Eight of 33 patients (24.2%) in the brimonidine-treated group and 9 of 33 patients (27.3%) in the apraclonidine group had postoperative IOP increases of 5 mmHg or more. This was not statistically different (P = 0.80). By the time of last follow-up examination, 3 of 33 patients (9.1%) in the brimonidine-treated group and 3 of 33 patients (9.1%) in the apraclonidine group had IOP increases of 10 mmHg or more. This was also not statistically different (P > or = 0.95). The mean IOP reduction from baseline in the brimonidine group (-2.8 +/- 2.8 mmHg) was not statistically different (P = 0.55) compared with the mean IOP reduction in the apraclonidine group (-3.6 +/- 3.3 mmHg). There were no statistically significant changes in mean heart rate or blood pressure in either group except for a slight reduction in diastolic blood pressure at 1 hour (P = 0.005) in the brimonidine group (-5.2 +/- 7.4 mmHg) compared with the apraclonidine group (-0.2 +/- 6.4 mmHg). There were no clinically significant side effects noted in either group. CONCLUSIONS: A single preoperative drop of brimonidine 0.2% is as effective as apraclonidine 0.5% in preventing IOP elevation immediately after anterior segment laser surgery.

Which patients are treated for glaucoma? An observational analysis.

PURPOSE: More than one million patients in the United States are treated for glaucoma, although little is known about the typical clinical characteristics of this group of patients and the type of therapy they receive. This study was conducted to describe the demographic and diagnostic characteristics of patients beginning long-term drug therapy for glaucoma. METHODS: This cross-sectional study included 544 patients beginning topical glaucoma medication regimens who received care at a group model health-maintenance organization (HMO) located in central Massachusetts. The primary medical records of 544 patients beginning topical glaucoma medication between 1987 and 1990 were reviewed to ascertain the presence of three clinical findings: intraocular pressure (IOP) > or = 22 mmHg; optic disc changes including cup-to-disc ratio > or = 0.8, cup-to-disc asymmetry > or = 0.2, or morphologic disc changes consistent with glaucomatous optic neuropathy; and visual field defect consistent with glaucoma. RESULTS: A majority of the 544 patients (86%) were diagnosed as having primary open-angle glaucoma (POAG) by their physicians. Almost half (44.7%) of these patients had only an elevation in IOP without other clinical findings, and 9% met none of the above criteria for glaucoma according to information in the medical record. CONCLUSION: In this setting, most patients who were prescribed drug therapy for POAG were treated for an elevation in IOP alone in the absence of other ophthalmologic characteristics of glaucoma.

Postoperative sympathetic ophthalmia.

Although uncommon, SO is a fearful postoperative complication because of its potential to blind both eyes. It can result not only from penetrating ocular surgery but also from nonpenetrating ocular procedures. Thus, it is important to consider in any patient who has undergone ocular surgery and develops bilateral uveitis, particularly because prompt, sufficient treatment is required to maximize visual outcome. It is also important to note that the disease may present with a spectrum of clinical findings, none of which is pathognomonic. Thus, suspicion is important for making the diagnosis. Treatment should address the T-cell-mediated nature of the disease. With appropriate treatment, visual acuity of no less than 20/60 is likely. However, before the start of treatment, which consists of immunosuppressants, infection must be ruled out and potential side effects of treatments must be considered. Furthermore, any patient with a history of SO needs ample immunosuppressant coverage for ocular procedures. Better understanding of the pathogenesis of the disease may lead to safer treatments that result in improved visual outcome and a cure. Meanwhile, because of its relapsing nature, SO requires continual, close surveillance, even after many years of quiescence.

Determinants of glaucoma awareness in a general eye clinic.

PURPOSE: Heightened public awareness about glaucoma may increase the chance of identifying undetected cases. To ascertain determinants of glaucoma awareness, we surveyed a population visiting a general eye clinic. DESIGN: Cross-sectional study. PARTICIPANTS: 1197 general eye clinic patients and their companions. METHODS: We designed and administered a questionnaire about glaucoma to general eye clinic patients and their companions. We created multivariate logistic regression models to ascertain the effect of demographic and clinical features on the likelihood of being unaware of glaucoma. MAIN OUTCOME MEASURES: Adjusted odds ratio (OR) with 95% confidence intervals of survey attributes associated with self-perceived unfamiliarity with glaucoma. RESULTS: Glaucoma awareness overall (72%) approached that found in the subgroup self-reporting a diagnosis of glaucoma (80%). Survey attributes associated with an increased likelihood of being unaware of glaucoma were African American race (OR = 1.69 [1.28-2.20], Hispanic ethnicity (OR = 2.13 [1.46-3.02]), and less than a college education (OR = 1.67 [1.37-2.05]). Age was also a determinant of glaucoma awareness (for ages 50-64 years, OR = 0.60 [0.44-0.80] and for ages 65-79 years, OR = 0.56 [0.41-0.75] compared with ages less than 35 years). A self-report of glaucoma was not a determinant of glaucoma awareness (OR = 0.63 [0.33-1.17]), although there was a trend toward enhanced glaucoma awareness in this subgroup. Finally, respondents with a history of employment in the health field (OR = 0.63 [0.49-0.82]) myopia (OR = 0.68 [0.56-0.82]), glaucoma in a first-degree relative (OR = 0.68 [0.53-0.87]), and respondents who reported having a dilated eye examination (OR = 0.53 [0.42-0.66]) were less likely to be unaware of glaucoma than those who did not have these attributes. CONCLUSIONS: Although glaucoma awareness in this population was high, Hispanics, African Americans, and those with less than a college education were more likely to be unfamiliar with the disease. Interestingly, a self-report of having glaucoma was not a statistically significant determinant of glaucoma awareness.

The cardiovascular, pulmonary, and ocular hypotensive effects of 0.2% brimonidine.

OBJECTIVE: To compare the cardiovascular, pulmonary, and ocular hypotensive effects of 0.2% brimonidine tartrate with those of 0.5% timolol maleate, 0.25% betaxolol suspension, and brimonidine vehicle. DESIGN AND PATIENTS: A single-center, double-masked, randomized, crossover study of 24 young, healthy men. INTERVENTIONS: Baseline heart rate, blood pressure, respiratory rate, and intraocular pressure were recorded at hour 0. At hour 2, heart rate, blood pressure, respiratory rate, and forced expiratory volume in 1 second were measured and a 15-minute treadmill test performed. Hour 0 measurements were repeated at hour 4. On four subsequent visits, we instilled one drop of a study medication into each eye after the baseline measurements at hour 0. RESULTS: Timolol reduced resting (-5.3 to -6.5 beats/min, P < or = .004) and exercise-induced heart rate (-4.3 to -13.6 beats/min; P < or = .022) compared with brimonidine, betaxolol suspension, and brimonidine vehicle. At hour 4, brimonidine reduced resting systolic blood pressure compared with all other study medications (-5.2 to -7.3 mm Hg; P < or = .024). Timolol reduced systolic blood pressure during exercise and brimonidine reduced systolic blood pressure during recovery more than betaxolol suspension and brimonidine vehicle (-5.1 to -7.7 mm Hg; P < or = .033; and -5.4 to -6.0 mm Hg; P < or = .002, respectively). Mean respiratory rate and forced expiratory volume in 1 second were not significantly altered by any study medication. At hour 4, brimonidine lowered intraocular pressure as well as timolol and better than betaxolol suspension (-1.9 mm Hg; P < .001) or brimonidine vehicle (-1.8 mm Hg; P < .001). CONCLUSIONS: The cardiopulmonary effects of 0.2% brimonidine were limited to a slight reduction in systolic blood pressure during recovery from exercise and at 4 hours after instillation. The ocular hypotensive effect of brimonidine was comparable to that of timolol and greater than that of betaxolol suspension in this patient population.

Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders.

BACKGROUND: Retinal ischemia induces intraocular neovascularization, which often leads to glaucoma, vitreous hemorrhage, and retinal detachment, presumably by stimulating the release of angiogenic molecules. Vascular endothelial growth factor (VEGF) is an endothelial-cell-specific angiogenic factor whose production is increased by hypoxia. METHODS: We measured the concentration of VEGF in 210 specimens of ocular fluid obtained from 164 patients undergoing intraocular surgery, using both radioimmuno-assays and radioreceptor assays. Vitreous proliferative potential was measured with in vitro assays of the growth of retinal endothelial cells and with VEGF-neutralizing antibody. RESULTS: VEGF was detected in 69 of 136 ocular-fluid samples from patients with diabetic retinopathy, 29 of 38 samples from patients with neovascularization of the iris, and 3 of 4 samples from patients with ischemic occlusion of the central retinal vein, as compared with 2 of 31 samples from patients with no neovascular disorders (P < 0.001, P < 0.001, and P = 0.006, respectively). The mean (+/- SD) VEGF concentration in 70 samples of ocular fluid from patients with active proliferative diabetic retinopathy (3.6 +/- 6.3 ng per milliliter) was higher than that in 25 samples from patients with nonproliferative diabetic retinopathy (0.1 +/- 0.1 ng per milliliter, P = 0.008), 41 samples from patients with quiescent proliferative diabetic retinopathy (0.2 +/- 0.6 ng per milliliter, P < 0.001), or 31 samples from nondiabetic patients (0.1 +/- 0.2 ng per milliliter, P = 0.003). Concentrations of VEGF in vitreous fluid (8.8 +/- 9.9 ng per milliliter) were higher than those in aqueous fluid (5.6 +/- 8.6 ng per milliliter, P = 0.033) in all 10 pairs of samples obtained simultaneously from the same patient; VEGF concentrations in vitreous fluid declined after successful laser photocoagulation. VEGF stimulated the growth of retinal endothelial cells in vitro, as did vitreous fluid containing measurable VEGF. Stimulation was inhibited by VEGF-neutralizing antibodies. CONCLUSIONS: Our data suggest that VEGF plays a major part in mediating active intraocular neovascularization in patients with ischemic retinal diseases, such as diabetic retinopathy and retinal-vein occlusion.

A clinical study of peripapillary crescents of the optic disc in chronic experimental glaucoma in monkey eyes.

OBJECTIVE: We produced chronic experimental glaucoma in 41 monkey eyes and assessed the long-term effects of elevated intraocular pressure on the presence of, and changes in, peripapillary crescents. METHODS: Three readers independently plotted peripapillary crescent size and location using stereo fundus photographs before and after chronic elevation of intraocular pressure in 41 monkey eyes. RESULTS: Crescents were found in a majority of normal eyes. After chronically elevated intraocular pressure, new peripapillary crescents developed in only two eyes. Using planimetric analysis, crescent size was enlarged in five (22%) of the 23 eyes with preexisting crescents. Preexisting crescents became more apparent without change in size in a majority of eyes (reader A, 15 [68%] of 22 eyes; reader B, 17 [74%] of 23 eyes; and reader C, 13 [68%] of 19 eyes). CONCLUSIONS: We conclude that peripapillary crescents are often present in normal monkey eyes but that they do not often undergo dramatic changes in size with chronic intraocular pressure elevation. The presence of a crescent was not significantly associated with the development of optic disc cup enlargement in the experimental monkey eye.

Immunolocalization of TGF-beta 1, TGF-beta 2, and TGF-beta 3 in the anterior segment of the human eye.

PURPOSE: To determine the distribution of transforming growth factor type beta (TGF-beta) in the anterior segment of the human eye. This knowledge is important because TGF-beta may regulate various physiologic responses in the anterior segment by controlling cell proliferation and differentiation, angiogenesis, and extracellular matrix composition. METHODS: Immunohistochemical methods were used to localize the beta 1, beta 2, and beta 3 isoforms of TGF-beta in the anterior segment of the human eye. RESULTS: Eight of eight eyes (six eye bank specimens and two eyes enucleated because of choroidal melanoma) exhibited staining for at least one of the TGF-beta isoforms. TGF-beta 1 was found in superficial limbal epithelial cells (four of eight eyes) and in the stroma proximal to the ciliary processes (seven of eight eyes). TGF-beta 2 was found in superficial limbal epithelial cells (six of eight eyes), the conjunctival stroma (eight of eight eyes), in the ciliary processes (three of eight eyes), and in a diffuse distribution in the region of the radial and circular muscles of the ciliary body (eight of eight eyes). In addition, TGF-beta 2 was found in the stroma adjacent to the pigmented epithelium in the pars plana (eight of eight eyes). TGF-beta 3 was found in white blood cells in one of eight specimens; otherwise it was not found in the anterior segment. The corneal stroma, corneal endothelium, trabecular meshwork, iris, and ciliary epithelia did not exhibit immunoreactivity with the antibodies used in this study. CONCLUSION: TGF-beta 1 and TGF-beta 2 have a distinct and specific distribution in the anterior segment of the adult human eye.