Risk factors for development and progression of glaucoma

The decision to treat a patient with ocular hypertension to prevent the development of glaucoma and the decision to intensify or advance treatment for patients with glaucoma depend upon an ophthalmologist’s assessment of the patient’s risk for glaucomatous development and/or progression.

This article reviews risk factors for glaucoma development and progression based on clinical data and suggests practical implications for patient management based on risk factors.

Simplified approach

The Ocular Hypertension Treatment Study (OHTS) emphasized the predictive value of central corneal thickness (CCT), particularly coupled with IOP or vertical cup:disc ratio. ¹

In a population of patients with preperimetric glaucomatous optic neuropathy, Medeiros and colleagues confirmed that the following factors were predictive of visual field loss: thinner CCT (adjusted hazard ratio = 1.62/40 µm thinner CCT); baseline IOP (adjusted HR = 1.07/increase in mm Hg); and baseline vertical cup:disc ratio (1.63/0.1 larger ratio) (Figure 1). ²

Figure 1. A large cup:disc ratio (such as this moderately large cup in a 76 year-old patient with ocular hypertension (central corneal thickness of 576 µm) with normal white-on-white perimetry) is often predictive of visual field loss and glaucomatous progression, reiterating the importance of thorough disc examination. Source: Heuer DK.

Clinical data have not yet produced a single risk calculator for both glaucoma development and progression. However, Medeiros and colleagues again validated the predictive findings from OHTS in another patient population. Combined with the OHTS results, their findings served as the basis for developing a scoring system for estimating the 5-year risk for developing glaucoma among ocular hypertensives.³

It is important to emphasize, however, that OHTS¹ and both Medeiros’ studies^2,3 had strictly defined populations, and the findings are not applicable to patients who already have manifest glaucoma, thus creating a need for a better understanding of individual risk factors.

Central corneal thickness and IOP

Changes in CCT should alert ophthalmologists to a greater risk of conversion to glaucoma among patients with ocular hypertension.

One study found that thinner CCT is associated with more advanced glaucoma.⁴ However, this was in the setting of a glaucoma specialist’s practice, so that thinner CCT as a risk factor for progression among patients with manifest glaucoma is as yet an unproven hypothesis.

CCT allows ophthalmologists to qualitatively adjust IOP, as thick corneas may lead ophthalmologists to overestimate IOP and thin corneas may lead ophthalmologists to underestimate IOP.

Figure 2. Filtering surgery’s role in minimizing IOP fluctuation is demonstrated by this mature filtering bleb. Source: Heuer DK.

Ophthalmologists should resist the temptation to adjust tonometric readings with strict IOP-correction nomograms based only on CCT, because tonometric error is related not only to CCT but also to factors such as corneal curvature, corneal elasticity, corneal hydration and hysteresis.

IOP is the only modifiable risk factor for patients with glaucoma and an increasing IOP should alert ophthalmologists to a greater risk of glaucomatous development or progression.

In the Advanced Glaucoma Intervention Study (AGIS), which evaluated 586 eyes through visits every 6 months for at least 6 years, the more consistently patients achieved IOPs below 18 mm Hg, the less likely they were to progress.⁵

Multiple studies have suggested that reducing variation in IOP may be as important as how low ophthalmologists can reduce IOP.^6-8

A recent analysis of 401 patients from AGIS confirmed this suggestion, finding that the visual field scores remained stable in eyes with IOP fluctuation (as measured by the standard deviation of the IOPs taken at visits every 6 months) less than 3 mm Hg, whereas eyes with greater IOP fluctuation had statistically significant visual field score progression. ⁹

Filtering surgery to increase the flow of aqueous humor out of the eye is likely the most effective method to reduce IOP fluctuation (Figure 2), and therapy with selective beta-blockers is probably the least effective at affecting fluctuation.

Disc hemorrhage

IOP remains an important risk factor and the only modifiable risk factor for the development and progression of glaucoma. — Dale K. Heuer, MD

Disc hemorrhages are another risk factor for glaucoma development and progression. Eyes with hemorrhage in OHTS were approximately four times more likely to develop glaucoma as eyes without hemorrhage.¹⁰ The median time from hemorrhage to glaucoma was 16.3 months. The researchers excluded patients with hemorrhages at baseline, and therefore the findings may be an underestimate.

Disc hemorrhages may also predict progression of glaucoma. The Collaborative Normal-Tension Glaucoma Study reported a nearly threefold greater risk of glaucoma development among patients with disc hemorrhage at baseline.¹¹ Rasker and colleagues found that normal-pressure glaucoma patients with a disc hemorrhage were more than five times as likely to show progression and patients with primary open-angle glaucoma were almost four times more likely to show progression compared with patients who did not have a disc hemorrhage.¹²

Other factors

Nerve fiber layer imaging may detect early damage and serve as a predictor for the development of glaucoma in ocular hypertensives. The risk of later visual field loss was four times to five times higher for patients with ocular hypertension and moderate or severe nerve fiber layer atrophy in one study.¹³

Nerve fiber layer imaging may detect early damage and serve as a predictor for the development of glaucoma and ocular hypertension. — Dale K. Heuer, MD

Ethnicity and family history are also important risk factors. A univariate model found a 59% increase in risk of glaucoma among black patients in OHTS, but a multivariate model found no association between race and incidence of glaucoma, presumably because the increased risk of glaucoma development among black OHTS subjects was attributed to their having thinner corneas and larger cups than the rest of the OHTS subjects.¹ The Baltimore Eye Survey found nearly a fourfold increase in risk of glaucoma among patients with a sibling with glaucoma.¹⁴

IOP remains an important risk factor and the only modifiable risk factor for the development and progression of glaucoma.

Although many other important risk factors such as CCT, disc hemorrhage, nerve fiber layer defects, patient demographics and family history cannot be modified, an ophthalmologist must be aware of how they affect risk for glaucoma development and progression. Risk factors (Table) should be considered in the decision to treat and in setting target IOP when treatment is decided upon.

Risk Factors for the Progression of Glaucoma Thinner central corneal thickness High baseline IOP Large cup:disc ratio Increasing IOP Fluctuation in IOP Disc hemorrhage Nerve fiber layer atrophy African-American ethnicity Family history Table. Risk factors should be carefully considered for each patient in the decision to treat.

References

1. Gordon MO, Beiser JA, Brandt JD, et al. The Ocular Hypertension Treatment Study: Baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:714-720.
2. Medeiros FA, Sample PA, Zangwill LM, et al. Corneal thickness as a risk factor for visual field loss in patients with preperimetric glaucomatous optic neuropathy. Am J Ophthalmol. 2003;136:805-813.
3. Medeiros FA, Weinreb RN, Sample PA, et al. Validation of a predictive model to estimate the risk of conversion from ocular hypertension to glaucoma. Arch Ophthalmol. 2005;123:1351-1360.
4. Herndon LW, Weizer JS, Stinnett SS. Central corneal thickness as a risk factor for advanced glaucoma damage. Arch Ophthalmol. 2004;122:17-21.
5. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130:429-440.
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7. Asrani S, Zeimer R, Wilensky J, et al. Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma. 2000;9:134-142.
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10. Budenz DL, Beiser JA, Piltz JR, et al. Detection and predictive value of optic disc hemorrhages in the Ocular Hypertensive Treatment Study. Poster #B913. Presented at the 2004 meeting of the Association for Research in Vision and Ophthalmology. April 25-29, 2004. Fort Lauderdale, Fla.
11. Drance S, Anderson DR, Schulzer M. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol. 2001;131:699-708.
12. Rasker MT, van den Enden A, Bakker D, Hoyng PF. Deterioration of visual fields in patients with glaucoma with and without optic disc hemorrhages. Arch Ophthalmol. 1997;115:1257-1262.
13. Quigley HA, Enger C, Katz J. Risk factors for the development of glaucomatous visual field loss in ocular hypertension. Arch Ophthalmol. 1994;112:644-649.
14. Tielsch JM, Katz J, Sommer A, et al. Family history and risk of primary open angle glaucoma: The Baltimore Eye Survey. Arch Ophthalmol. 1994;112:69-73.