living longer with glaucoma. The major risk factors for going blind from glaucoma are poor compliance with treatment and severity of glaucoma at diagnosis [23, 54, 12]. The more advanced the glaucoma is at the time of diagnosis, the more likely that it is to lead to blindness during a patient’s lifetime [23, 57].

Summary for the Clinician

››The risk of progression to bilateral blindness in treated POAG is fairly low. Estimates from 2001 and 2003 place the risk at about 6% at 15 years.

››The risk of progression to unilateral blindness in treated POAG from these same studies is about 15% at 15 years.

››In most patients glaucoma has been diagnosed within 15 years of death, so the risk of going blind from glaucoma past 15 years may be less relevant to our patients. However, as longevity increases this may change.

››The risk factors for progression to blindness include poor compliance with treatment and more advanced glaucoma at diagnosis.

22.2  What are the Main Risk Factors for Primary Open-Angle Glaucoma?

A risk factor is something that increases a person’s chances of developing a disease. Different risk fac­ tors are sometimes detected by different study designs (cross-sectional vs. incidence studies). Knowledge of POAG risk factors is important and practical in two settings: (a) for screening purposes; money and efforts are best relegated to screening people in higher risk categories, and (b) because each patient encounter in a general ophthalmology or glaucoma specialty clinic is a chance for risk stratification. For example, risk stratification can be used to dismiss the shortand intermediate-term risks of glaucoma in a 15-year-old teenager seeking an eye exam for astigmatism correction. On the other hand, risk stratification would cause one to spend more time examining the nerve and performing visual field testing in a 70-year-old diabetic woman with a family history of glaucoma, borderline

pressures, and possible early signs of pseudoexfoliation syndrome.

Something to keep in mind when thinking about risk factors is that they can be divided into various categories. There are modifiable and nonmodifiable risk factors. For example, intraocular pressure (IOP) is the only known modifiable risk factor for POAG. Also, some risk factors, such as disc hemorrhages or cup-to-disc asymmetry, can be conceptually thought of as early signs of the disease, which can confuse matters. Some risk factors are so common that they do not automatically lead to a diagnosis of “glaucoma suspect” per se. These are risk factors detected in population-based studies (age, gender, race, myopia, central corneal thickness (CCT), and possibly systemic risk factors, such as diabetes and systemic hypertension) and are so frequent in people without glaucoma that they do not have strong discriminating power. Others, such as a positive family history, portend probable genetic predisposition.

Findings from the Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS) have provided a practical framework for risk estimation in eyes with ocular hypertension[53]. However, in eyes without elevated IOP, our knowledge of the prognostic significance of the various risk factors identified by OHTS and EGPS remains inadequate so that a quantitative estimation of the probability of development of glaucoma is not yet possible. In these cases, clinicians commonly use some kind of intuitive extrapolation to sum up the risk factor profile for a particular patient. However, in a recent study, despite adequate training in the results of OHTS, general ophthalmologists were quite variable in their intuitive estimation of the risk of progression in ocular hypertensive eyes [41].

22.2.1  Intraocular Pressure:

The Sole Treatable Risk Factor for Glaucoma

Almost all population-based studies of prevalence and incidence have identified IOP as a risk factor for the presence or development of glaucoma [5]. Long-term follow-up of patients with ocular hypertension (OHT) in clinical trials, such as OHTS and EGPS, has shown IOP to be a major risk factor for progression to glaucoma

[22, 17]. Other long-term studies of glaucomatous populations have established the definitive role of IOP reduction in decreasing the risk of glaucoma progression [1, 29].

In the Barbados glaucoma incidence study, a consistent increase in relative risk (RR) for incident glaucoma was observed with increasing baseline IOP [50]. Compared to eyes with a baseline IOP < 12 mmHg, the unadjusted RR increased to 1.4 for those with baseline IOPs between 12 and 17 mmHg, to 7.4 for those with IOPs between 21 and 23 mmHg, and to 18.0 for participants with baseline IOPs of 25 mmHg or more. Also, when IOP was evaluated as a continuous variable, the risk of open-angle glaucoma (OAG) increased by 12% with each 1 mmHg increase in IOP (RR = 1.12; 95% CI, 1.08–1.16; p < 0.0001). The 4-year incidence of OAG among persons with OHT in the Barbados Eye Study was about 5% [39]. Interestingly, the 9-year incidence in the same cohort was 11%, on average 1% per year, which suggests a linear rate of progression to glaucoma in eyes with elevated IOP [40]. Preliminary analysis of the incidence data from the Rotterdam Eye Study found that the risk of incident OAG increased by 16% per each millimeter of mercury increment in the highest IOP of either eye [14]. Ocular hypertension at baseline, defined as IOP > 21mmHg or use of glaucoma drops, led to a threefold higher risk for incident OAG (odds ratio 3.3). Similarly, The Visual Impairment Study in Australia found that every millimeter of mercury increase in the baseline IOP increased the risk of progression to possible or probable glaucoma by about 10% [49].

Findings from the OHTS and EGPS have recently provided us with a framework that can be used to estimate the 5-year risk of developing glaucoma in a given patient. A prognostic study by the OHTS group showed that the main predictors for glaucoma development were advancing age, higher IOP, thinner CCT, a higher visual field pattern standard deviation, and a higher cup- to-disc ratio [22]. Specifically, the hazard ratio for conversion to glaucoma was shown to increase by 10% for each mmHg increment in the baseline IOP. This finding has been confirmed by the EGPS. Higher baseline IOP increased the risk of progression to glaucoma by 7–18% in that study [17].

Higher IOP fluctuation has been suggested as another risk factor for glaucoma progression, although this issue remains controversial [4, 10, 52]. The ­available evidence at this time does not support IOP

fluctuation as a risk factor for progression of OHT to glaucoma [3, 46].

22.2.2  Demographic Factors

• Age and gender

Most studies have demonstrated increasing prevalence and incidence of glaucoma with advancing age. This is likely a function of longer disease duration in older individuals, although other factors may also be involved [5]. Gender has not been found to be a clear-cut risk factor for OAG; however, in a recent meta-analysis, men were found to be at higher risk of having OAG (odds ratio 1.37) [65].

• Ethnicity

African-American and Hispanic ancestry have been shown to be associated with a higher incidence of glaucoma compared to white or Caucasian ethnicity [68, 35, 61, 74]. In a meta-analysis of 46 published studies, glaucoma prevalence was calculated to be at least two times higher in African–Americans (average of 4.2%) compared to Caucasians (2.1%) and Asians (1.4%) [68]. A higher incidence of glaucoma has also has been found in other populations of African descent [9, 64]. People of African–American ancestry tend to be affected earlier (by almost a decade compared to whites) and are also more likely to go blind from glaucoma [35, 71]. This susceptibility is multifactorial and likely has both anatomic and socioeconomic causes [62]. African– Americans have thinner corneas and larger optic discs, and tended to have larger baseline cup-to-disc ratios in OHTS [73, 22]. They are also less likely to have access to appropriate care.

• Family history

It has been shown that patients often inaccurately report a positive family history of glaucoma [70]. Despite this fact, the available evidence suggests that positive family history is a strong risk factor for glaucoma. In the Rotterdam Eye Study, all relatives of glaucoma cases were examined [78]. The RR for having glaucoma was 10 times higher in first-degree relatives of glaucoma cases. In the Barbados Family Study of Open-Angle Glaucoma, family members of a subgroup of 230 OAG cases were examined [37]. The