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Risk factors for progression to blindness in high tension primary open angle glaucoma: Comparison of blind and nonblind subjects.

Aims To determine which risk factors for blindness were most critical in patients diagnosed with high tension primary open angle glaucoma (POAG) in a large ethnically diverse population managed with a uniform treatment strategy. Methods A longitudinal observational study was designed to follow 487 patients (974 eyes) with POAG for an average of 5.5 ± 3.6 years. Detailed ocular and systemic information was collected on each patient and updated every six months. For this study, blindness was defined as visual acuity of 20/200 or worse and/or visual field less than 20° in either eye. Known risk factors were compared between patients with blindness in at least one eye versus nonblind patients. Results The patients with blindness had on average: higher intraocular pressure (IOP, mmHg): (24.2 ± 11.2 vs. 22.1 ± 7.7, p = 0.03), wide variation of IOP in the follow-up period (5.9 vs. 4.1 mmHg, p = 0.031), late detection (p = 0.006), poor control of IOP (p < 0.0001), and noncompliance (p < 0.0003). Other known risk factors such as race, age, myopia, family history of glaucoma, history of ocular trauma, hypertension, diabetes, vascular disease, smoking, alcohol abuse, dysthyoidism, and steroid use were not significant. Conclusions The most critical factors associated with the development of blindness among our patients were: elevated initial IOP, wide variations and poor control of IOP, late detection of glaucoma, and noncompliance with therapy.


Introduction
The multifactorial and progressive nature of primary open angle glaucoma (POAG) is well established in regard to optic nerve damage and visual fi eld (VF) loss (Wilson et al 1982;O'Brien et al 1991;Hart et al 1997). Over time, 25% to 38% of patients exhibit signs of progression and ultimately blindness in one or both eyes (Wilson et al 1982;O'Brien et al 1991;Hart et al 1997). A number of known risk factors associated with progression of vision loss and blindness in glaucoma patients is shown in Table 1 ( Reese and McGavic 1942;Harrington 1959;Spaeth 1971;Hiller and Kahn 1975;Harbin et al 1976;Kolker 1977;Drance et al 1978Drance et al , 1981Perkins 1978;Grant and Burke 1982;Leske 1983;Anderson 1989;O' Brien et al 1991;Sommer et al 1991aSommer et al , 1991bAraie et al 1994;Quigley et al 1994;Hattenhauer et al 1998;Gherghel et al 2000;King et al 2000;Stewart et al 2000;The AGIS Investigators 2000;Kwan et al 2001;Oliver et al 2002;Chen 2003).
However, it is not clear which of these factors are most important and which are infl uenced by variables such as fewer patients, short follow up, and ethnically nondiverse patient population. To determine risk factors for progression to blindness, we followed a large ethnically diverse patient population with high tension glaucoma over a long time frame. The primary outcome variable was the average percent of eyes that developed glaucoma-related blindness in either eye. Secondary outcome variables include sustained decrease of vision, progression of the disease, poor control, noncompliance, late detection, and level of intraocular pressure (IOP). Features of patients who developed blindness were compared with those who did not. The underlying hypothesis was that certain risk factors in such a diverse study population were not signifi cant over the long term allowing us to identify the most critical clinical factors.

Materials and methods
Our cohort was selected from the patient population at an academic center, a county hospital, and a Veterans Affairs Hospital.
Legal blindness is defi ned in the US as visual acuity of 20/200 or worse and/or visual fi eld less than 20° in the better eye (Social Security Act 2006). Since this study was designed to follow individual eyes, this defi nition of blindness was modifi ed to refer to either eye rather than the better eye. The diagnosis of POAG included glaucomatous optic nerve cupping with corresponding VF defects, IOP Ն21 mmHg and open irido-corneal angle (Klein et al 1992;Dielemans et al 1994). Nine patients were blind in one eye at the start of the study. They were included because adequate long term information on the study variables were available. The exclusion criteria were: normal tension glaucoma (IOP Ͻ 21 mmHg), secondary glaucoma, inability to maintain follow up for 3 months, eye conditions such as opaque media, macular degeneration, and vascular accidents that preclude diagnosis of glaucoma, and patients who were unable to perform ocular tests reliably. All eligible patients were examined and treated by the fi rst author or by the eye residents and glaucoma fellows under direct supervision. Measured continuous and categorical variables at the conclusion of the study are summarized in Table 2.
program 30-2 full threshold strategy were a cluster of two or more adjacent points of 5-decibels (dB) or greater loss, and at least one of the points showing more than 10 dB loss according to the age corrected total deviation values. Every patient received one or more VF tests yearly. Optic nerve cupping was noted and drawn at baseline exam and at each visit. No photographs were taken. Any progression was fl agged and reconfi rmed by KSK or the glaucoma fellow. Features of optic disk progression were; progression of C/D ratio by Ն0.2, rim notching and thinning from baseline, and disk hemorrhage. Noncompliance was based on documented nonadherance to therapy/surgery or from two or more missed clinic appointments during the observation period. Poor control of glaucoma was based on the following features: use of three or more medications, requirement of laser or incisional surgery, progression of C/D ratio by Ն0.2, or progression of VF from one stage to the next. Late detection was defi ned as C/D disparity of Ն0.2 or VF loss of stage Ն3 in one or both eyes at initial presentation.
Categorical variables (such as gender, procedures, medications) of blindness and no-blindness groups were compared with the Fisher's Exact Test or Chi-square statistics. Continuous variables (such as age, C/D ratio) were compared between groups with two-sample t-tests or Wilcoxon Rank Sum tests if normality assumptions were not met. Logistic regression models were used to assess multiple risk factors simultaneously. Data management was performed using Microsoft Access 97 and 2000 (Microsoft Corp. Redmond, WA). For statistical analysis, SAS version 8.0 (SAS Institute, Cary, NC) was used.

Results
At the end of the study, there were 282 (57.9%) nonblind patients and 205 (42.1%) blind patients. Of the total number of patients, 195 were diagnosed initially at one of the three study clinics. In the blind group, 120 (58.5%) had bilateral blindness while 85 (41.5%) had unilateral blindness. Table 2 lists the main characteristics of the groups. At baseline, the blind group had statistically signifi cant higher IOP than the nonblind group (24.2 vs. 22.1 mmHg; p = 0.03). They also showed wide fl uctuations (maximum to minimum IOP) over the course of the study (5.9 mmHg vs. 4.1 mmHg, p = 0.031). The mean IOP for each patient in both groups is shown in Figure 1.
At pressure of 17 mmHg or less, 54 (26.3%) patients were blind. Pressure levels gradually decreased in both groups over time, but the standard deviation of individual IOP was still higher in the blind group (4.8 vs. 2.4 mmHg, p = 0.02).
As expected, optic nerve appearance was worse in the blind group at fi rst visit, with 154 (75%) of patients showing C/D of Ͼ0.7 compared with 102 (36.2%) in the nonblind group. This fi gure reached 175 (85.4%) and 132 (46.8%) at the last visit, respectively. Both groups exhibited deterioration of optic nerve features. Similarly, noncompliance, inadequate control and late detection were higher in blind subjects. Baseline IOP, female gender, and baseline VF were signifi cant risk factors for blindness (Table 3).
Other risk factors such as race, age, history of hypertension, diabetes, vascular disease, family history of glaucoma, smoking, alcohol abuse, systemic or topical steroids dysthyroidism, ocular trauma (all variables obtained by history) and myopia, were not signifi cant.

Discussion
Our fi ndings support the widely held belief that IOP is still of paramount importance in management of glaucoma (Harbin et al 1976;Kolker 1977;Anderson 1989 Risk factors for progression to blindness in high tension POAG our study had higher level of initial IOP, more fl uctuations in pressure, and were diffi cult to control. Blindness and progression of glaucoma was evident at all pressure levels ( Figure 1). This fi nding is in contrast to the Advanced Glaucoma Intervention Study (AGIS) where progression was minimal in patients with IOP less than 18 mmHg. The AGIS investigators found that VF progression was less if a patient maintained IOP of less than 18 mmHg at each visit, but their patients had advanced glaucoma based on medical therapy where as this study had patients in all stages of the disease (The AGIS Investigators 2000). At the fi nal visit 116 (57%) patients had IOP Ͼ21 mmHg. Why did so many patients have elevated mean IOP? There may be several explanations. First, some patients become noncompliant or exhibit poor response to therapy. Second, after an eye shows advanced VF loss such as split fi xation, there is hesitancy to reduce IOP surgically for fear of "snuffi ng out" the remaining fi bers (Kolker 1977). Third, when the visual acuity drops to HM or worse, IOP reduction becomes less of a priority compared with keeping the patient comfortable.
Similar to the fi ndings of Kwan and colleagues (2001) our blind patients also required multiple medications and more laser and incisional surgeries. Subjects with blindness also presented with advanced visual acuity loss, VF loss, and optic nerve damage. Therefore, late detection was a signifi cant risk factor. Moreover, a multivariate analysis using logistic regression to model the probability of blindness demonstrated that baseline elevated IOP and advanced VF damage were signifi cant risk factors. Of those who were initially diagnosed with POAG at one of the three study clinics, blindness was detected at the fi rst visit in 21.7%, which was similar to other studies (Perkins 1978;Grant and Burke 1982;Konstas et al 2000). Several investigators have pointed out the role played by advanced VF damage at diagnosis (Harrington 1959;Harbin et al 1976;Kolker 1977;Quigley et al 1994;King et al 2000;Oliver et al 2002;Chen 2003), degree of VF loss in the worst eye (King et al 2000), and vascular insuffi ciency (Reese and McGavic 1942;Spaeth 1971;Drance et al 1978;Gherghel et al 2000). The progressive nature of POAG was evidenced by VF deterioration. Both noncompliance to treatment and inadequate control were more prevalent in blind patients. The signifi cance of noncompliance with treatment has been stressed by several investigators (Drance et al 1978;Kostas et al 2000). One weakness of the study is that the central corneal thickness was not measured because of the unavailability of measuring devices at the three centers. The authors understand the pivotal role central corneal thickness may play in the development and progression of glaucoma (Gordon et al 2002).
In conclusion, we followed 487 ethnically diverse patients with high tension POAG in a single metropolitan area and with a uniform management strategy for over 5 years. Risk factors for blindness were mainly pressure-elated: elevated initial IOP, wide variations and poor control of IOP, late detection of glaucoma, and noncompliance with therapy. Other known factors such as older age (Quigley et al 1994;Hattenhauer et al 1998;Stewart et al 2000), black American (Sommer et al 1991a;Hiller and Kahn 1975), vascular insuffi ciency (Reese and McGavic 1942;Spaeth 1971;Drance et al 1978;Grant and Burke 1982;Gherghel et al 2000), or family history of glaucoma (Drance et al 1978) were not signifi cant. Our results suggest that further studies with larger diverse populations and longer follow are required to verify these fi ndings and to better understand the dynamics of glaucoma progression.