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1.  Factors Associated with Intraocular Pressure Prior to and during Nine Years of Treatment in the Collaborative Initial Glaucoma Treatment Study 
Ophthalmology  2007;115(6):927-933.
Purpose
To evaluate, both at initial glaucoma diagnosis and during treatment, the role of demographic and clinical factors on intraocular pressure (IOP).
Design
Cohort study of patients enrolled in a randomized clinical trial.
Participants
607 patients with newly diagnosed, open-angle glaucoma (OAG) were enrolled at 14 U.S. centers.
Methods
After randomization to initial surgery or medications, patients were followed at six-month intervals. IOP was measured by Goldmann applanation tonometry. Predictive factors for IOP at baseline and during follow-up were analyzed using linear mixed models.
Main Outcome Measure
IOP at baseline and during follow-up.
Results
The mean baseline IOP was 27.5 mmHg (standard deviation, 5.6 mmHg). Predictive factors for higher baseline IOP included younger age (0.7 mmHg per 10 years), male sex (2.4 mmHg higher than females), pseudoexfoliative glaucoma (5.4 mmHg higher than primary OAG), and pupillary defect (2.2 mmHg higher than those without a defect). During nine years of follow-up, both surgery and medications dramatically reduced IOP from baseline levels, but the extent of IOP reduction was consistently greater in the surgery group. Over follow-up years 2–9, mean IOP was 15.0 vs. 17.2 mmHg for surgery vs. medicine, respectively. Predictive associations with higher IOP during follow-up included higher baseline IOP (P<0.0001), worse baseline visual field (mean deviation; P<0.0001), and lower level of education (P=0.0019). Treatment effect was modified by smoking status: non-smokers treated surgically had lower IOP than smokers treated surgically (14.6 vs. 16.7 mmHg, respectively; P=0.0013). Clinical center effects were significant (P<0.0001) in both the baseline and follow-up models.
Conclusions
In this large cohort of newly diagnosed glaucoma patients, predictors of pre-treatment IOP and IOP measurements over nine years of follow-up were identified. Our findings lend credence to the postulate that sociodemographic, economic, compliance, or other environmental influences play a role in IOP control during treatment.
doi:10.1016/j.ophtha.2007.08.010
PMCID: PMC2758572  PMID: 17964655
2.  Longitudinal Trends in Resource Utilization in an Incident Cohort of Open Angle Glaucoma Patients 
American journal of ophthalmology  2012;154(3):452-459.e2.
Purpose
To characterize the costs of caring for patients with open-angle glaucoma (OAG) in the United States (US) over time and to identify factors that influence these costs.
Design
Longitudinal cohort study.
Methods
Claims data from 19,927 newly-diagnosed OAG patients enrolled in a large US managed care network were reviewed to identify glaucoma-related charges for all incident OAG patients from 2001–2009. Average glaucoma-related charges for enrollees with OAG were characterized in six month blocks from the date of initial OAG diagnosis through the following 5 years. Factors associated with being an enrollee in the costliest 5% for glaucoma-related charges (accruing ≥$5810 in charges in the first 2 years) were identified using logistic regression.
Results
The costliest 5% of enrollees were responsible for $10,202,871 (24%) of all glaucoma-related charges. By comparison, those whose costs fell within the lower 50% of the cost distribution collectively amassed only $7,986,582 (19%) of all glaucoma-related charges. A spike in glaucoma-related charges occurred in the 6 month period around the time of OAG diagnosis, stabilized by 1 year following diagnosis, and remained relatively constant over time. Risk factors associated with being in the costliest 5% for glaucoma-related care included younger age, Northeastern US state residence, undergoing cataract surgery, and possessing ocular co-morbidities.(p<0.006 for all comparisons).
Conclusions
A small subset of enrollees account for a large proportion of all glaucoma-related charges. Understanding the characteristics of these individuals and finding ways to reduce disease burden and costs associated with their care can result in substantial cost savings.
doi:10.1016/j.ajo.2012.03.032
PMCID: PMC3422396  PMID: 22789564
3.  Neuroprotection for treatment of glaucoma in adults 
Background
Glaucoma is a heterogeneous group of conditions involving progressive damage to the optic nerve, deterioration of retinal ganglion cells and ultimately visual field loss. It is a leading cause of blindness worldwide. Open angle glaucoma (OAG), the commonest form of glaucoma, is a chronic condition that may or may not present with increased intraocular pressure (IOP). Neuroprotection for glaucoma refers to any intervention intended to prevent optic nerve damage or cell death.
Objectives
The objective of this review was to systematically examine the evidence regarding the effectiveness of neuroprotective agents for slowing the progression of OAG in adults.
Search methods
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 9), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to October 2012), EMBASE (January 1980 to October 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to October 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 16 October 2012.
Selection criteria
We included randomized controlled trials (RCTs) in which topical or oral treatments were used for neuroprotection in adults with OAG. Minimum follow up time was four years.
Data collection and analysis
Two review authors independently reviewed titles and abstracts from the literature searches. Full-text copies of potentially relevant studies were obtained and re-evaluated for inclusion. Two review authors independently extracted data related study characteristics, risk of bias, and outcome data. One trial was identified for this review, thus we performed no meta-analysis. Two studies comparing memantine to placebo are currently awaiting classification until additional study details are provided. We documented reasons for excluding studies from the review.
Main results
We included one multi-center RCT of adults with low-pressure glaucoma (Low-pressure Glaucoma Treatment Study, LoGTS) conducted in the USA. The primary outcome was visual field progression after four years of treatment with either brimonidine or timolol. Of the 190 adults enrolled in the study, 12 (6.3%) were excluded after randomization and 77 (40.5%) did not complete four years of follow up. The rate of attrition was unbalanced between groups with more participants dropping out of the brimonidine group (55%) than the timolol group (29%). Of those remaining in the study at four years, participants assigned to brimonidine showed less visual field progression than participants assigned to timolol (5/45 participants in the brimonidine group compared with 18/56 participants in the timolol group). Since no information was available for the 12 participants excluded from the study, or the 77 participants who dropped out of the study, we cannot draw any conclusions from these results as the participants for whom data are missing may or may not have progressed. The mean IOP was similar in both groups at the four-year follow up among those for whom data were available: 14.2 mmHg (standard deviation (SD) = 1.9) among the 43 participants in the brimonidine group and 14.0 mmHg (SD = 2.6) among the 48 participants in the timolol group. Among the participants who developed progressive visual field loss, IOP reduction of 20% or greater was not significantly different between groups: 4/9 participants in the brimonidine group and 12/31 participants in the timolol group. The study authors did not report data for visual acuity or vertical cup-disc ratio. The most frequent adverse event was ocular allergy to study drug, which occurred more frequently in the brimonidine group (20/99 participants) than the timolol group (3/79 participants).
Authors’ conclusions
Although neuroprotective agents are intended to act as pharmacological antagonists to prevent cell death, this trial did not provide evidence that they are effective in preventing retinal ganglion cell death, and thus preserving vision in people with OAG. Further clinical research is needed to determine whether neuroprotective agents may be beneficial for individuals with OAG. Such research should focus outcomes important to patients, such as preservation of vision, and how these outcomes relate to cell death and optic nerve damage. Since OAG is a chronic, progressive disease with variability in symptoms, RCTs designed to measure the effectiveness of neuroprotective agents would require long-term follow up (more than four years) in order to detect clinically meaningful effects.
doi:10.1002/14651858.CD006539.pub3
PMCID: PMC4261923  PMID: 23450569
Administration, Oral; Administration, Topical; Cell Death; Disease Progression; Glaucoma, Open-Angle [*drug therapy]; Neuroprotective Agents [*administration & dosage]; Optic Nerve; Optic Nerve Diseases [etiology, *prevention & control]; Retinal Ganglion Cells [physiology]; MeSH check words: Adult; Humans
4.  Comparison of Newly Diagnosed Ocular Hypertension and Open-Angle Glaucoma: Ocular Variables, Risk Factors, and Disease Severity 
Journal of Ophthalmology  2011;2012:757106.
Purpose. To describe the distribution of ocular variables, risk factors, and disease severity in newly diagnosed ocular hypertension (OH) or open-angle glaucoma (OAG). Methods. Eligible subjects underwent a complete history and examination. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) obtained from multiple logistic regression models were used to compare OAG to OH and advanced to early/moderate OAG. Results. 405 subjects were enrolled: 292 (72.1%) with OAG and 113 (27.9%) with OH. 51.7% had early, 27.1% moderate, and 20.9% advanced OAG. The OR for OAG versus OH was 8.19 (P < 0.0001) for disc notch, 5.36 (P < 0.0001) for abnormal visual field, 1.45 (P = 0.001) for worsening mean deviation, 1.91 (P < 0.0001) for increased cupping, 1.03 for increased age (P = 0.030), and 0.36 (P = 0.010) for smoking. Conclusions. Increased age was a risk for OAG, and smoking decreased the risk of OAG compared to OH. Almost half of the OAG subjects had moderate/advanced disease at diagnosis.
doi:10.1155/2012/757106
PMCID: PMC3159007  PMID: 21869921
5.  The Relationship Between Statin Use and Open-Angle Glaucoma 
Ophthalmology  2012;119(10):2074-2081.
Purpose
To determine whether 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) affect the risk of developing open-angle glaucoma (OAG) in persons with hyperlipidemia.
Design
Retrospective longitudinal cohort analysis.
Participants
Individuals age ≥60 with hyperlipidemia enrolled in a national United States managed care network between 2001 and 2009.
Methods
Multivariable Cox regression analyses were performed to assess the relationship between statin use and the development of OAG (from no prior OAG diagnosis), progression from a prior diagnosis of suspected glaucoma to a diagnosis of OAG, and need for medical or surgical interventions for OAG. Regression models were adjusted for sociodemographic factors, medical and ocular comorbidities.
Main Outcome Measures
Hazard ratios (HR) with 95% confidence intervals (CI).
Results
Of the 524,109 individuals with hyperlipidemia, 316,182 (60%) had at least 1 outpatient prescription for statins. The hazard of developing OAG decreased 0.3% (adjusted HR = 0.997, CI (0.994–0.999)) for every additional month of statin consumption. Individuals with hyperlipidemia who took statins continuously for 2 years had an 8% (adjusted HR = 0.922, CI (0.870–0.976) decreased OAG risk relative to those who received no statin therapy. The hazard of progressing from a diagnosis of suspected glaucoma to OAG decreased 0.4% (adjusted HR = 0.996, CI (0.993–0.999)) for every additional month of statin exposure. Individuals who took statins continuously for 2 years had a 9% (adjusted HR = 0.907, CI (0.846–0.973) decreased risk of progressing from suspected glaucoma to OAG relative to those who received no statin therapy. The hazard of requiring medical treatment for OAG decreased 0.4% (adjusted HR = 0.996, CI (0.993–0.998)) for every additional month of statin exposure. No significant differences in need for glaucoma surgery were noted among those with OAG who were and were not taking statins (adjusted HR = 1.002, CI (0.994–1.010)).
Conclusion
Statin use was associated with a significant reduction in the risk of OAG in persons with hyperlipidemia. Given the mounting evidence of statin protection against OAG including both basic science and observational clinical studies, an interventional prospective study might provide additional insights into the role of statins in the prevention of early OAG.
doi:10.1016/j.ophtha.2012.04.029
PMCID: PMC3459293  PMID: 22727176
6.  Selective laser trabeculoplasty 
The introduction of selective laser trabeculoplasty (SLT) provided a new choice for the reduction of intraocular pressure (IOP) in eyes with open angle glaucoma (OAG) and ocular hypertension (OHT). SLT was demonstrated equally as effective as topical medical therapy and argon laser trabeculoplasty (ALT) to lower IOP. It is a potentially repeatable procedure because of the lack of coagulation damage to the trabecular meshwork (TM) and also effect in patients with previously failed ALT. SLT can be used to treat patients with OAG, pseudoexfoliation glaucoma, pigmentary glaucoma, normal-tension glaucoma, OHT, juvenile glaucoma, pseudophakic and aphakic glaucoma. Furthermore, SLT can be considered as a primary treatment option in patients who cannot tolerate or are noncompliant with medications, while not interfering with the success of future surgery. Its safety profiles include mild and transient inflammation, ocular pain and a small risk of moderate IOP elevations after the procedure. SLT is a safe and effective means of IOP reduction in eyes with OAG and OHT.
doi:10.3980/j.issn.2222-3959.2012.06.17
PMCID: PMC3530819  PMID: 23275911
open angle glaucoma; intraocular pressure; selective laser trabeculoplasty
7.  A retrospective study of the association between Fuchs’ endothelial dystrophy and glaucoma 
Objective
The goal of this study was to examine a possible clinical association between Fuchs’ endothelial dystrophy (FED) and glaucoma suspect (GS)/ocular hypertension (OHT) or open angle glaucoma (OAG).
Methods
A retrospective chart review was carried out using data from electronic medical records and paper records from a private ophthalmology clinic in Kansas City, MO, USA. The review included 257 patients with FED and 584 randomly selected controls with no history of endothelial dystrophy. Binomial and multinomial regression using generalized estimating equations was used to create models to examine the correlation between FED diagnosis/severity and glaucoma diagnosis/type of glaucoma adjusted for age, sex, presence of diabetes, number of guttae, and intraocular pressure (IOP).
Results
No statistically significant increase in prevalence of either OHT or GS/OHT compared to controls was observed (P>0.3). There was a statistically significant positive correlation between increasing age and IOP with increased glaucoma prevalence (P<0.05). There was also a statistically significant positive correlation between increasing age, IOP and male sex, with increased prevalence of the more severe glaucoma subtype of OAG versus GS/OHT and controls (P<0.05). Increasing severity of FED divided into category 1 and 2 based upon number of guttae was not associated with any significant increase in glaucoma prevalence (P>0.09), and was actually significantly negatively correlated to worsening glaucoma subtype for category 2 FED patients (P<0.05). Diabetes was not associated with the prevalence of either glaucoma or its subtypes of GS/OHT or OAG.
Conclusion
The correlation between FED and glaucoma has been controversial. This study showed no statistically significant association between FED and glaucoma by prevalence or severity of FED as measured by corneal guttae. Further study is needed to determine if a connection between FED and glaucoma does exist, and if so, whether this relationship may impact earlier the detection and treatment of disease.
doi:10.2147/OPTH.S67340
PMCID: PMC4213138  PMID: 25378902
ocular hypertension; open angle glaucoma; cornea guttata; oxidative
8.  Baseline Risk Factors that Predict the Development of Open-angle Glaucoma in a Population: The Los Angeles Latino Eye Study 
Ophthalmology  2012;119(11):2245-2253.
Objective
To determine which baseline socio-demographic, lifestyle, anthropometric, clinical, and ocular risk factors predict the development of open-angle glaucoma (OAG) in an adult population.
Design
A population-based, prospective cohort study.
Participants
A total of 3,772 self-identified Latinos aged 40 years and older from Los Angeles, California who were free of OAG at baseline.
Methods
Participants from the Los Angeles Latino Eye Study had standardized study visits at baseline and 4-year follow-up with structured interviews and a comprehensive ophthalmologic examination. OAG was defined as the presence of an open angle and a glaucomatous visual field abnormality and/or evidence of glaucomatous optic nerve damage in at least one eye. Multivariate logistic regression with stepwise selection was performed to determine which potential baseline risk factors independently predict the development of OAG.
Main Outcome Measure
Odds ratios for various risk factors.
Results
Over the 4-year follow-up, 87 participants developed OAG. The baseline risk factors that predict the development of OAG include: older age (odds ratio [OR] per decade, 2.19; 95% confidence intervals [CI], 1.74-2.75; P<0.001), higher intraocular pressure (OR per mmHg, 1.18; 95% CI, 1.10-1.26; P<0.001), longer axial length (OR per mm, 1.48; 95% CI, 1.22-1.80; P<0.001), thinner central cornea (OR per 40 μm thinner, 1.30; 95% CI, 1.00-1.70; P=0.050) higher waist to hip ratio (OR per 0.05 higher, 1.21; 95% CI, 1.05-1.39; P=0.007) and lack of vision insurance (OR, 2.08; 95% CI, 1.26-3.41; P=0.004).
Conclusions
Despite a mean baseline IOP of 14 mmHg in Latinos, higher intraocular pressure is an important risk factor for developing OAG. Biometric measures suggestive of less structural support such as longer axial length and thin CCT were identified as important risk factors. Lack of health insurance reduces access to eye care and increases the burden of OAG by reducing the likelihood of early detection and treatment of OAG.
doi:10.1016/j.ophtha.2012.05.030
PMCID: PMC3474872  PMID: 22796305
9.  Predictors of additional intraocular pressure reduction in patients changed to latanoprost/timolol fixed combination 
BMC Ophthalmology  2010;10:10.
Background
Given the growing number of ocular hypotensive medications available, it is important to be able to predict a positive response to therapy. The purpose of the present study was to identify predictors of an additional 10% intraocular pressure (IOP) reduction after 12 weeks of treatment with latanoprost/timolol fixed combination (FC) in patients requiring a change in their previous ocular hypotensive medication.
Methods
This multicenter, open-label, prospective, phase IIIb study included subjects ≥18 years of age with open-angle glaucoma (OAG) or ocular hypertension (OHT). Eligible subjects had baseline IOP ≥21 mmHg and insufficient response to current beta-blocker monotherapy. The primary efficacy analysis (logistic regression) identified predictors of a positive response after 12 weeks of latanoprost/timolol FC.
Results
The intent-to-treat (ITT) population included 383 subjects treated with ≥1 drop of FC and having ≥1 follow-up IOP assessment. Mean IOP was 22.19 ± 2.16 mmHg at baseline and was reduced by 5.42 ± 2.71 mmHg at study end. In all, 325 (84.9%) subjects had a positive response to latanoprost/timolol FC; the response rate was similar across groups: OAG (n = 208; 82.7%); OHT (n = 161; 87.6%); OAG+OHT (n = 14; 85.7%). Higher baseline IOP (odds ratio: 1.284; 95% confidence interval [CI]: 1.101, 1.497; p = 0.0014) and absence of adverse events (odds ratio: 0.318; 95% CI: 0.161, 0.629; p = 0.0010) were significant predictors of positive response. Age, gender, ethnic origin, diagnosis, family history of OAG/OHT, corneal thickness, and concomitant systemic beta-blocker were not significant predictors of a positive response in the ITT analysis. The FC was well tolerated. The most common adverse events were related to the eye and were consistent with known adverse events associated with latanoprost and timolol.
Conclusions
These results support the use of latanoprost/timolol FC in patients whose IOP is insufficiently controlled on beta-blocker monotherapy. Patients with higher baseline IOP levels and who do not experience adverse events while on therapy are most likely to achieve a positive response to latanoprost/timolol FC.
Trial Registration
Study registration number: NCT00230763
doi:10.1186/1471-2415-10-10
PMCID: PMC2861019  PMID: 20346127
10.  Mathematical modeling approaches in the study of glaucoma disparities among people of African and European descents 
Open angle glaucoma (OAG) is a severe ocular disease characterized by progressive and irreversible vision loss. While elevated intraocular pressure (IOP) is a well-established risk factor for OAG, the progression of OAG in many cases, despite IOP treatment, suggests that other risk factors must play significant roles in the development of the disease. For example, various structural properties of the eye, ocular blood flow properties, and systemic conditions have been identified as risk factors for OAG. Ethnicity has also been indicated as a relevant factor that affects the incidence and prevalence of OAG; in fact, OAG is the leading cause of blindness among people of African descent. Numerous clinical studies have been designed to examine the possible correlation and causation between OAG and these factors; however, these studies are met with the challenge of isolating the individual role of multiple interconnected factors. Over the last decade, various mathematical modeling approaches have been implemented in combination with clinical studies in order to provide a mechanical and hemodynamical description of the eye in relation to the entire human body and to assess the contribution of single risk factors to the development of OAG. This review provides a summary of the clinical evidence of ocular structural differences, ocular vascular differences and systemic vascular differences among people of African and European descent, describes the mathematical approaches that have been proposed to study ocular mechanics and hemodynamics while discussing how they could be used to investigate the relevance to OAG of racial disparities, and outlines possible new directions of research.
doi:10.1166/jcsmd.2013.1004
PMCID: PMC3912249  PMID: 24501718
Mathematical Modeling; Glaucoma; Blood Flow; Ocular Mechanics; Ocular Hemodynamics
11.  The Relationship Between Components of Metabolic Syndrome and Open-Angle Glaucoma 
Ophthalmology  2011;118(7):1318-1326.
Purpose
To determine whether an association exists between various components of metabolic syndrome (diabetes mellitus (DM), systemic arterial hypertension (HTN), hyperlipidemia, and obesity) and open-angle glaucoma (OAG) in a large, diverse group of individuals throughout the United States.
Design
Longitudinal cohort study.
Participants
All beneficiaries age ≥40 years continuously enrolled in a managed care network who had ≥1 visit to an eye care provider were identified from 2001–2007.
Methods
Billing codes were used to identify individuals with OAG and those with components of metabolic syndrome. Cox regression was used to determine the hazard of developing OAG in enrollees with individual components or combinations of components of metabolic syndrome, with adjustment for sociodemographic factors, systemic medical conditions, and other ocular diseases.
Main Outcome Measures
Hazard of developing OAG.
Results
Of the 2,182,315 enrollees who met inclusion criteria, 54,558 (2.5%) had OAG. After adjustment for confounding factors, those with DM (hazard ratio (HR)=1.35 [95% confidence interval (CI): 1.21–1.50]) or HTN (HR=1.17 [95% CI: 1.13–1.22]) alone, or in combination, (HR=1.48 [95% CI: 1.39–1.58]) had an increased hazard of developing OAG relative to persons with neither of these conditions. By contrast, persons with hyperlipidemia alone had a 5% decreased hazard of OAG (HR=0.95 [95% CI: 0.91–0.98]). Comorbid hyperlipidemia attenuated the increased hazard between HTN (HR=1.09 [95% CI 1.05–1.12]) or DM (HR=1.13 [95% CI 1.05–1.21]) and OAG.
Conclusion
Given the increasing prevalence of metabolic disorders in the United States, this study furthers our understanding of risk factors associated with OAG and helps identify persons who may be at risk for this condition.
doi:10.1016/j.ophtha.2010.11.022
PMCID: PMC3129406  PMID: 21481477
12.  Should Men and Women be Managed Differently in Glaucoma? 
Introduction
To assess differences in associations of ocular perfusion pressure (OPP) as well as retinal and retrobulbar blood flow between men and women with primary open angle glaucoma (OAG).
Methods
A total of 116 patients with OAG (age 66.9 ± 10.9 years, 70 females) participating in the Indianapolis Glaucoma Progression Study were assessed for OPP, retinal microcirculation, and retrobulbar blood flow. Confocal scanning laser Doppler flowmetry measured peripapillary retinal capillary blood flow. Color Doppler imaging measured peak systolic (PSV) and diastolic blood flow velocities and vascular resistance in the ophthalmic (OA), central retinal (CRA), and nasal and temporal short posterior ciliary arteries (N/T PCA). Bivariate Spearman correlation and multivariate linear regression analyses were performed.
Results
In female patients with OAG, inferior retinal capillary flow was associated with OPP (r = 0.246, P = 0.044). In men, superior and inferior sector retinal blood flow was associated with OPP (r = −0.402, P = 0.006 and r = −0.357, P = 0.016, respectively). There was no statistically significant association between OPP and retrobulbar blood vessel flow velocities in male patients with OAG but there was an association between OA and TPCA PSV and OPP in female patients with OAG (r = 0.290, P = 0.015 and r = 0.357, P = 0.002, respectively). In female patients with OAG, multivariate regression showed no statistically significant effect of any variable on the superior retinal capillary blood flow, with CRA PSV as a sole predictor to the inferior retinal sector (partial rho = 0.302, P = 0.015) and in male patients with OAG, superior sector retinal capillary blood flow was independently associated with intraocular pressure (partial rho = −0.371, P = 0.016) and OPP (partial rho = −0.456, P = 0.002) with a trend of association with OPP in the inferior retina (partial rho = −0.301, P = 0.053).
Conclusions
There was a positive linear association between retinal microcirculation and OPP in females and a negative association in males. Male and female patients with OAG may differ in their vascular autoregulation in response to changes in OPP.
doi:10.1007/s40123-012-0001-0
PMCID: PMC4108137  PMID: 25135581
Glaucoma; Hormone; Ocular blood flow; Ocular perfusion pressure
13.  Anterior Chamber Configuration Changes after Cataract Surgery in Eyes with Glaucoma 
Purpose
To evaluate changes in anterior chamber depth (ACD) and angle width induced by phacoemulsification and intraocular lens (IOL) implantation in eyes with glaucoma, using anterior segment optical coherence tomography (AS-OCT).
Methods
Eleven eyes of 11 patients with angle-closure glaucoma (ACG) and 12 eyes of 12 patients with open-angle glaucoma (OAG) underwent phacoemulsification and IOL implantation. Using AS-OCT, ACD and angle parameters were measured before and 2 days after surgery. Change in intraocular pressure (IOP) and number of ocular hypotensive drugs were evaluated.
Results
After surgery, central ACD and angle parameters increased significantly in eyes with glaucoma (p < 0.05). Prior to surgery, mean central ACD in the ACG group was approximately 1.0 mm smaller than that in the OAG group (p < 0.001). Post surgery, mean ACD of the ACG group was still significantly smaller than that of the OAG group. No significant differences were found in angle parameters between the ACG and OAG groups. In the ACG group, postoperative IOP at the final visit was significantly lower than preoperative IOP (p = 0.018) and there was no significant change in the number of ocular hypotensive medications used, although clinically, patients required fewer medications. In the OAG group, the IOP and number of ocular hypotensive drugs were almost unchanged after surgery.
Conclusions
The ACD and angle width in eyes with glaucoma increased significantly after phacoemulsification and IOL implantation. Postoperative ACD significantly differed between the ACG and OAG groups, whereas angle parameters did not differ.
doi:10.3341/kjo.2012.26.2.97
PMCID: PMC3325628  PMID: 22511835
Angle-closure glaucoma; Anterior chamber; Anterior eye segment; Cataract extraction; Open-angle glaucoma
14.  Genetic heterogeneity of primary open angle glaucoma and ocular hypertension: linkage to GLC1A associated with an increased risk of severe glaucomatous optic neuropathy. 
Journal of Medical Genetics  1997;34(7):546-552.
The GLC1A locus for autosomal dominant juvenile and middle age onset primary open angle glaucoma (OAG) has been mapped to chromosome 1q21-q31. OAG, however, is a heterogeneous disease. We tested linkage of OAG and ocular hypertension (OHT), a major risk factor for OAG, to GLC1A in eight French families with multiple cases of juvenile and middle age onset OAG. There was strong evidence of genetic heterogeneity, four families being linked to GLC1A and two or three others being unlinked, depending on whether the complete OAG phenotype was analysed alone or jointly with OHT. Peak intraocular pressure (IOP) did not differ significantly between the two groups of families, while linkage to GLC1A conferred a highly increased risk of developing OAG and of having severe glaucomatous optic neuropathy. Testing linkage of familial OAG to GLC1A may therefore have prognostic value too.
PMCID: PMC1050993  PMID: 9222961
15.  Trends in Utilization of Ancillary Glaucoma Tests for Patients with Open-Angle Glaucoma from 2001 to 2009 
Ophthalmology  2012;119(4):748-758.
Purpose
To assess trends in the use of ancillary diagnostic tests in the evaluation of patients with open-angle glaucoma (OAG) and glaucoma suspects over the past decade.
Design
Retrospective longitudinal cohort analysis.
Participants
169,917 individuals with OAG and 395,721 with suspected glaucoma age ≥40 enrolled in a national United States managed care network between 2001–2009.
Methods
Claims data were analyzed to assess trends in visual field (VF) testing, fundus photography (FP), and other ocular imaging (OOI) testing for patients with OAG or suspected glaucoma in 2001–2009. Repeated measures logistic regression was performed to identify differences in the odds of undergoing these procedures in 2001, 2005, and 2009 and whether differences exist for patients under the exclusive care of optometrists versus ophthalmologists.
Main Outcome Measures
Odds and annual probabilities of undergoing VF testing, FP, and OOI for OAG from 2001–2009.
Results
For patients with OAG, the odds of undergoing VF testing decreased by 36% from 2001 to 2005, 12% from 2005 to 2009, and 44% from 2001 to 2009. By comparison, the odds of having OOI increased by 100% from 2001 to 2005, 24% from 2005 to 2009, and 147% from 2001 to 2009. Probabilities of undergoing FP were relatively low (13–25%) for both provider types and remained fairly steady over the decade. For patients cared for exclusively by optometrists, the probability of VF testing decreased from 66% in 2001 to 44% in 2009. Among those seen exclusively by ophthalmologists, the probability of VF testing decreased from 65% in 2001 to 51% in 2009. The probability of undergoing OOI increased from 26% in 2001 to 47% in 2009 for patients of optometrists and from 30% in 2001 to 46% in 2009 for patients of ophthalmologists. By 2008, patients with OAG receiving care exclusively by optometrists had a higher probability of undergoing OOI than VF testing.
Conclusion
During 2001–2009 OOI rose dramatically whereas VF testing declined considerably. Since OOI has not been shown to be as effective at detecting OAG or disease progression compared to VF testing, increased reliance upon OOI technology, in lieu of VF testing, may be detrimental to patient care.
doi:10.1016/j.ophtha.2011.09.045
PMCID: PMC3319788  PMID: 22218146
16.  Differences in Rates of Glaucoma Among Asian Americans Compared With Other Races and Among Individuals of Different Asian Ethnicities 
Ophthalmology  2011;118(6):1031-1037.
Purpose
To determine the incidence and prevalence rates of different glaucoma types among Asian Americans, contrast glaucoma incidence and prevalence rates for Asian Americans with other races, and evaluate the hazard of developing glaucoma among different Asian ethnicities and other races.
Design
Retrospective longitudinal cohort study
Participants
2,259,061 beneficiaries aged ≥40 enrolled in a large, national managed-care network in the United States (US) in 2001–2007
Methods
Incidence and prevalence rates of open-angle glaucoma (OAG), narrow-angle glaucoma (NAG), and normal-tension glaucoma (NTG) were determined for the beneficiaries and stratified by race and Asian ethnicity. Cox regression analyses determined the hazard of developing OAG, NAG, and NTG for Asian Americans compared with other races and among different Asian ethnicities, with adjustment for confounding factors.
Main Outcome Measures
Multivariable hazard of OAG, NAG, and NTG among different races and Asian ethnicities.
Results
The OAG prevalence rate for Asian Americans of 6.52% was similar to that of Latinos (6.40%) and higher than that of non-Hispanic whites (5.59%). The NAG and NTG prevalence rates (3.01% and 0.73%, respectively) were considerably higher among Asian Americans compared with each of the other races. After adjustment for confounding factors, Asian Americans had a 51% increased hazard of OAG (Hazard ratio (HR)=1.51 (95% confidence interval (CI) 1.42–1.60), a 123% increased hazard of NAG (HR=2.23 (95% CI 2.07–2.41), and a 159% increased hazard of NTG (HR=2.59 (95% CI 2.22–3.02) compared with non-Hispanic whites. Vietnamese Americans (HR=3.78, (95% CI 3.19–4.48), Pakistani Americans (HR=2.45, 95% CI 1.50–4.01) and Chinese Americans (HR=2.31, 95% CI 2.06–2.59) had considerably higher hazards of NAG while Japanese Americans (HR=4.37, 95% CI 3.24–5.89) had a substantially higher hazard of NTG, compared with non–Asian Americans.
Conclusions
Given the rapid rise in the number of Asian Americans in the US population, resources need to be devoted to identifying and treating glaucoma among these individuals. Eye-care providers should be aware of the increased hazard of developing OAG, NAG, and NTG among Asian Americans relative to other races. When evaluating Asian Americans, inquiring about ethnicity can provide additional information on risk of specific glaucoma types.
Financial Disclosures
The authors have no proprietary or commercial interest in any materials discussed in this article.
doi:10.1016/j.ophtha.2010.10.024
PMCID: PMC3109193  PMID: 21310489
17.  Cholesterol-Lowering Drugs and Incident Open-Angle Glaucoma: A Population-Based Cohort Study 
PLoS ONE  2012;7(1):e29724.
Background
Open-angle glaucoma (OAG) is a progressive neurodegenerative disease that may lead to blindness. An elevated intraocular pressure (IOP) is its major risk factor. OAG treatment is currently exclusively directed towards the lowering of the IOP. IOP lowering does not prevent disease progression in all patients and thus other treatment modalities are needed. Earlier studies reported cholesterol-lowering drugs to have neuroprotective properties. The aim of this study was to determine the associations between the use of cholesterol-lowering drugs and incident OAG.
Methodology/Principal Findings
Participants in a prospective population-based cohort study underwent ophthalmic examinations, including IOP measurements and perimetry, at baseline and follow-up. The use of statins and non-statin cholesterol-lowering drugs was monitored continuously during the study. Associations between the use of cholesterol-lowering drugs and incident OAG were analyzed with Cox regression; associations between cholesterol-lowering drugs and IOP at follow-up were analyzed with multiple linear regression. During a mean follow-up of 9.8 years, 108 of 3939 eligible participants (2.7%) developed OAG. The hazard ratio for statin use was 0.54 (95% confidence interval 0.31–0.96; P = 0.034) and for non-statin cholesterol-lowering drugs 2.07 (0.81–5.33; P = 0.13). The effect of statins was more pronounced with prolonged use (hazard ratio 0.89 [0.41–1.94; P = 0.77] for use two years or less; 0.46 [0.23–0.94; P = 0.033] for use more than two years; P-value for trend 0.10). The analyzes were adjusted for age and gender, baseline IOP and IOP-lowering treatment, the family history of glaucoma, and myopia. There was no effect of statins on the IOP.
Conclusions/Significance
Long-term use of statins appears to be associated with a reduced risk of OAG. The observed effect was independent of the IOP. These findings are in line with the idea that statins have neuroprotective properties and may open a way to a new OAG treatment modality.
doi:10.1371/journal.pone.0029724
PMCID: PMC3251600  PMID: 22238644
18.  Longitudinal glaucoma screening for siblings of patients with primary open angle glaucoma: the Nottingham Family Glaucoma Screening Study 
Aims
To assess the prevalence and cumulative incidence of open angle glaucoma (OAG) in a cohort group of siblings of OAG probands.
Methods
Between 1994 and 2003, a group of siblings of OAG probands underwent both initial and follow up standardised ophthalmic examinations. Siblings were classified as “definite glaucoma” (primary OAG (POAG) and normal tension glaucoma (NTG)), “glaucoma suspects” (NTG suspects or ocular hypertension (OHT)), and normal. The prevalence and cumulative incidence of OAG over the follow up interval were calculated.
Results
At the initial study, 271 siblings (mean age 63.6 years; female to male ratio 1.2) from 156 probands were examined. 32 (11.8%) were classified as definite glaucoma and 15 (5.5%) as suspects. In the follow up study, 157 of the 224 “normal” siblings from the initial study were examined (mean interval from initial study 7.0 (SD 1.0) years). 11 (7%) were classified as definite glaucoma and 30 (19.1%) as suspects. There were significant trends of increasing prevalence and incidence of OAG with age and a lifetime risk estimated at approximately 20% by age 70.
Conclusion
Siblings of glaucoma patients have an increased risk of developing glaucoma and the risk increases with age. An effective and repeated screening programme should be considered for this high risk group.
doi:10.1136/bjo.2005.072751
PMCID: PMC1856884  PMID: 16361669
primary open angle glaucoma; siblings
19.  Identification of Persons with Incident Ocular Diseases Using Health Care Claims Databases 
American journal of ophthalmology  2013;156(6):10.1016/j.ajo.2013.06.035.
Purpose
To assess the extent to which incidence rates calculated for common ocular diseases by using claims data may be overestimated according to the length of the disease-free, look-back period used in the analysis.
Design
Retrospective longitudinal cohort analysis.
Methods
Billing records of 2457 persons continuously enrolled for 11 years in a managed-care network were searched for International Classification of Diseases (ICD-9-CM) diagnoses of cataract, open-angle glaucoma (OAG), nonexudative age-related macular degeneration (ARMD), and nonproliferative diabetic retinopathy (NPDR) at eye-care visits in the first half of 2001, the second half of 2010, and 2011. For each condition, incidence rates calculated by using look-back periods ranging from 0.5 to 9 years were compared with best estimates from a gold-standard period of 9.5 years.
Results
With a 1-year disease-free look-back period, incidence was overestimated by 260% for cataract, 135% for OAG, 209% for ARMD, and 300% for NPDR. Expanding the disease-free “look back” period to three years resulted in a reduction of incidence overestimation to 40% for cataract, 14% for OAG, 45% for AMD, and 100% for NPDR. A 5-year look-back period yielded incidence rates overestimated by<30% for all four conditions.
Conclusions
In our claims-data analysis of four common ocular conditions, a disease-free interval ≤ 1 year insufficiently distinguished newly diagnosed from pre-existing disease, resulting in grossly overestimated incidence rates. Using look-back periods of 3–5 years, depending on the specific diagnosis, yielded considerably more accurate estimates of disease incidence.
doi:10.1016/j.ajo.2013.06.035
PMCID: PMC3836859  PMID: 23972306
20.  Association of Open-Angle Glaucoma Loci With Incident Glaucoma in the Blue Mountains Eye Study 
American Journal of Ophthalmology  2015;159(1):31-36.e1.
Purpose
To determine if open-angle glaucoma (OAG)-associated single nucleotide polymorphisms (SNPs) are associated with incident glaucoma and if such genetic information is useful in OAG risk prediction.
Design
Case-control from within a population-based longitudinal study.
Methods
study population: Individuals aged over 49 years of age living in the Blue Mountains region west of Sydney and enrolled in the Blue Mountains Eye Study. observation: Cases for this sub-study (n = 67) developed incident OAG between baseline and 10-year visits, in either eye, while controls (n = 1919) had no evidence for OAG at any visit. All participants had an ocular examination and DNA genotyped for reported OAG risk SNPs. main outcome measure: Incident OAG.
Results
Two loci also known to be associated with cup-to-disc ratio as well as OAG (9p21 near CDKN2B-AS1 and SIX1/SIX6) were both significantly associated with incident OAG in the Blue Mountains Eye Study cohort (P = .006 and P = .004, respectively). The TMCO1 locus was nominally associated (P = .012), while the CAV1/CAV2 and 8q22 loci were not associated. Multivariate logistic regression and neural network analysis both indicated that the genetic risk factors contributed positively to the predictive models incorporating traditional risk factors.
Conclusions
This study shows that previously reported genetic variations related to OAG and cup-to-disc ratio are associated with the onset of OAG and thus may become useful in risk prediction algorithms designed to target early treatment to those most at risk of developing glaucoma.
doi:10.1016/j.ajo.2014.09.020
PMCID: PMC4265734  PMID: 25242315
21.  Ocular perfusion pressure and glaucoma: clinical trial and epidemiologic findings 
Purpose of review
A possible connection between ocular perfusion pressure and open-angle glaucoma (OAG) has been hypothesized. This review summarizes the scientific rationale for the proposed relationship, presents recent data, and outlines potential implications.
Recent findings
Population-based epidemiologic studies found strong relationships between low ocular perfusion pressure and OAG prevalence, as well as OAG incidence. Clinical studies report similar associations between low perfusion pressure and OAG progression. These consistent findings suggest that altered blood flow in the optic disc increases both the risk of OAG development and the progression of established OAG. An underlying factor would be impaired vascular autoregulation, which may lead to poor perfusion in OAG. In contrast, there is conflicting evidence on the possible link of glaucoma to blood pressure/hypertension.
Summary
Current evidence supports the role of vascular factors as part of the multifactorial etiology of OAG. Since ocular perfusion pressure reflects the vascular status at the optic disc, it may be more relevant than systemic blood pressure alone. While the associations of OAG to perfusion pressure are strong, consistent and biologically plausible, they require careful interpretation. The evidence implicating a vascular etiology in OAG is mounting, but the clinical implications for patient management are still uncertain.
doi:10.1097/ICU.0b013e32831eef82
PMCID: PMC2662722  PMID: 19240538
Open-angle glaucoma; ocular perfusion pressure; glaucoma risk factors; blood pressure
22.  Filtering data from the collaborative initial glaucoma treatment study for improved identification of glaucoma progression 
Background
Open-angle glaucoma (OAG) is a prevalent, degenerate ocular disease which can lead to blindness without proper clinical management. The tests used to assess disease progression are susceptible to process and measurement noise. The aim of this study was to develop a methodology which accounts for the inherent noise in the data and improve significant disease progression identification.
Methods
Longitudinal observations from the Collaborative Initial Glaucoma Treatment Study (CIGTS) were used to parameterize and validate a Kalman filter model and logistic regression function. The Kalman filter estimates the true value of biomarkers associated with OAG and forecasts future values of these variables. We develop two logistic regression models via generalized estimating equations (GEE) for calculating the probability of experiencing significant OAG progression: one model based on the raw measurements from CIGTS and another model based on the Kalman filter estimates of the CIGTS data. Receiver operating characteristic (ROC) curves and associated area under the ROC curve (AUC) estimates are calculated using cross-fold validation.
Results
The logistic regression model developed using Kalman filter estimates as data input achieves higher sensitivity and specificity than the model developed using raw measurements. The mean AUC for the Kalman filter-based model is 0.961 while the mean AUC for the raw measurements model is 0.889. Hence, using the probability function generated via Kalman filter estimates and GEE for logistic regression, we are able to more accurately classify patients and instances as experiencing significant OAG progression.
Conclusion
A Kalman filter approach for estimating the true value of OAG biomarkers resulted in data input which improved the accuracy of a logistic regression classification model compared to a model using raw measurements as input. This methodology accounts for process and measurement noise to enable improved discrimination between progression and nonprogression in chronic diseases.
doi:10.1186/1472-6947-13-137
PMCID: PMC3878032  PMID: 24359562
23.  Nutrient intake and risk of open-angle glaucoma: the Rotterdam Study 
European Journal of Epidemiology  2012;27(5):385-393.
Open-angle glaucoma (OAG) is the commonest cause of irreversible blindness worldwide. Apart from an increased intraocular pressure (IOP), oxidative stress and an impaired ocular blood flow are supposed to contribute to OAG. The aim of this study was to determine whether the dietary intake of nutrients that either have anti-oxidative properties (carotenoids, vitamins, and flavonoids) or influence the blood flow (omega fatty acids and magnesium) is associated with incident OAG. We investigated this in a prospective population-based cohort, the Rotterdam Study. A total of 3502 participants aged 55 years and older for whom dietary data at baseline and ophthalmic data at baseline and follow-up were available and who did not have OAG at baseline were included. The ophthalmic examinations comprised measurements of the IOP and perimetry; dietary intake of nutrients was assessed by validated questionnaires and adjusted for energy intake. Cox proportional hazard regression analysis was applied to calculate hazard ratios of associations between the baseline intake of nutrients and incident OAG, adjusted for age, gender, IOP, IOP-lowering treatment, and body mass index. During an average follow-up of 9.7 years, 91 participants (2.6%) developed OAG. The hazard ratio for retinol equivalents (highest versus lowest tertile) was 0.45 (95% confidence interval 0.23–0.90), for vitamin B1 0.50 (0.25–0.98), and for magnesium 2.25 (1.16–4.38). The effects were stronger after the exclusion of participants taking supplements. Hence, a low intake of retinol equivalents and vitamin B1 (in line with hypothesis) and a high intake of magnesium (less unambiguous to interpret) appear to be associated with an increased risk of OAG.
doi:10.1007/s10654-012-9672-z
PMCID: PMC3374099  PMID: 22461101
Glaucoma; Nutrition; Magnesium; Vitamin A; Vitamin B1; Population-based; Dietary intake
24.  Dysfunctional regulation of ocular blood flow: A risk factor for glaucoma? 
Primary open angle glaucoma (OAG) is a multifactorial optic neuropathy characterized by progressive retinal ganglion cell death and associated visual field loss. OAG is an emerging disease with increasing costs and negative outcomes, yet its fundamental pathophysiology remains largely undetermined. A major treatable risk factor for glaucoma is elevated intraocular pressure (IOP). Despite the medical lowering of IOP, however, some glaucoma patients continue to experience disease progression and subsequent irreversible vision loss. The scientific community continues to accrue evidence suggesting that alterations in ocular blood flow play a prominent role in OAG disease processes. This article develops the thesis that dysfunctional regulation of ocular blood flow may contribute to glaucomatous optic neuropathy. Evidence suggests that impaired vascular autoregulation renders the optic nerve head susceptible to decreases in ocular perfusion pressure, increases in IOP, and/or increased local metabolic demands. Ischemic damage, which likely contributes to further impairment in autoregulation, results in changes to the optic nerve head consistent with glaucoma. Included in this review are discussions of conditions thought to contribute to vascular regulatory dysfunction in OAG, including atherosclerosis, vasospasm, and endothelial dysfunction.
PMCID: PMC2699797  PMID: 19668439
glaucoma; autoregulation; blood flow; atherosclerosis; vasospasm; endothelial dysfunction
25.  Prospective, Unmasked Evaluation of the iStent®Inject System for Open-Angle Glaucoma: Synergy Trial 
Advances in Therapy  2014;31(2):189-201.
Introduction
Micro-invasive glaucoma surgical implantation of trabecular micro-bypass stents, previously shown to be safe and effective for open-angle glaucoma (OAG) subjects during cataract surgery, was considered for evaluation as a sole procedure. The aim of this study was to evaluate the safety and intraocular pressure (IOP)-lowering efficacy after ab interno implantation of two Glaukos Trabecular Micro-Bypass iStent inject second generation devices in subjects with OAG. This study was performed at sites in France, Germany, Italy, Republic of Armenia, and Spain.
Methods
In this pan-European, multi-center prospective, post-market, unmasked study, 99 patients with OAG on at least two topical ocular hypotensive medications who required additional IOP lowering to control glaucoma disease underwent implantation of two GTS400 stents in a stand-alone procedure. Patients were qualified if they presented with preoperative mean IOP between 22 and 38 mmHg after medication washout. Postoperatively, subjects were assessed at Day 1, Months 1, 3, 6, 7, 9, and 12. IOP, medication use and safety were assessed at each visit.
Results
Sixty-six percent of subjects achieved IOP ≤18 mmHg at 12 months without medication, and 81% of subjects achieved Month 12 IOP ≤ 18 mmHg with either a single medication or no medication. Mean baseline washout IOP values decreased by 10.2 mmHg or 39.7% from 26.3 (SD 3.5) mmHg to 15.7 (SD 3.7) mmHg at Month 12. Mean IOP at 12 months was 14.7 (SD 3.1) mmHg in subjects not using ocular hypotensive medications. Reduction from preoperative medication burden was achieved in 86.9% of patients, including 15.2% with reduction of one medication and 71.7% with reduction of two or more medications. Postoperative complications occurred at a low rate and resolved without persistent effects.
Conclusion
In this series, implantation of two trabecular micro-bypass second generation stents in subjects with OAG resulted in IOP and medication reduction and favorable safety outcomes.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-014-0095-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s12325-014-0095-y
PMCID: PMC3930835  PMID: 24452726
Ab interno; Intraocular pressure; iStent inject; Open-angle glaucoma; Ophthalmology; Trabecular bypass

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