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Addressing new risk factors could improve patient management

ByJohn R. Samples, MD

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In recent years, researchers have expanded the list of commonly known risk factors for glaucoma, and their work has added greatly to the understanding of how the disease progresses. The newest risk factors for both diagnosis and progression of glaucoma include thin cornea, diurnal IOP fluctuation, family history, blood pressure, noncompliance and chemical factors in the anterior chamber (Figure 1). Taken together, they give ophthalmologists the means to develop effective new patient management strategies.

Thin cornea

In 2002, the Ocular Hypertension Treatment Study (OHTS) found that in addition to factors such as older age, larger vertical and horizontal cup-to-disc ratio and high IOP, a thinner central corneal measurement is predictive for the development of primary open-angle glaucoma (POAG). Participants in OHTS with a corneal thickness less than or equal to 555 µm had a threefold greater risk of developing POAG than those with a corneal thickness greater than or equal to 588 µm.¹

Although it is generally accepted that a thinner cornea leads to an “under-reading” of IOP, a minority view holds that a common collagen abnormality found in both the corneal stroma and in the lamina cribrosa predisposes a patient to glaucoma. It may be more complicated than this, however, and is perhaps linked to corneal rigidity, with the relationship to corneal thickness remaining somewhat unclear.

A variety of correction formulas for corneal thinness have been proposed (Figure 2), and most studies indicate a nonlinear relationship between IOP and corneal thickness. Some estimates speculate that a range of 1 mm Hg to 7 mm Hg translates into a value of 50 µm. I believe a range of 2.1 mm Hg to 2.7 mm Hg translates into 50 µm, but the accuracy of these remains unclear.

Several outstanding questions surround the issue of corneal thickness, including whether it changes over time and how it is influenced by drugs. The latter question was addressed by the researchers behind OHTS, who found that patients with thickened corneas had less significant responses to ocular hypotensive medication than those with normal or thin corneas. ² Further study is also needed to elucidate which devices are the most promising for measuring corneal thickness.

Diurnal fluctuation

In most people, aqueous production is highest in the early morning, lower in the afternoon and halved during early sleep. It is important to note, however, that this does not mean that IOP is also at its lowest during sleep; some research has indicated that sleeping in a supine position increases pressure.³ During the day, normal flow is approximately 2.75 µL/min. Use of the beta-blocker timolol is consistent at suppressing flow during daytime hours, but has little to no effect on sleeping patients.⁴

Corticosteroids and melatonin have both been hypothesized to cause diurnal variation in IOP,^5,6 but there is a strong case that circulating catecholamines are the underlying cause.⁷ One current theory holds that melatonin from the pineal gland signals the adrenal gland to release circulating catecholamines, which in turn drive aqueous production.

The emerging importance of minimizing diurnal fluctuations in IOP supports the need to conduct diurnal curves during patient visits. In an oft-cited study from 2000, Duke University researchers correlated large fluctuations in diurnal IOP with a significantly higher risk of progression within 5 years in patients with POAG.⁸ Additionally, a study of 12 young patients with central retinal vein occlusion found that although none had an IOP of greater than 21 mm Hg during the day, when diurnal curves were eventually performed, 11 of the patients had diurnal fluctuation with pressures between 22 mm Hg and 30 mm Hg.⁹

Tracking these fluctuations may be time consuming, but the payoff can be considerable. When compared with in-office measurements, 24-hour monitoring revealed a peak IOP that was 4.9 mm Hg higher on average and was 12 mm Hg higher in four patients.¹⁰ These discoveries translated into improved patient management, including a small group of patients who were offered trabeculectomy as a result.¹⁰

The prostaglandin analogue travoprost (Travatan, Alcon Laboratories, Inc.) is a particularly promising agent for lowering IOP due to its long duration of action, a result of its high affinity and selectivity for the FP receptor. Similar to other prostaglandins, travoprost flattens the diurnal curve and may potentially have long-acting properties in this area. ¹¹

Family history

Although POAG appears to be a single disease in the clinic, from a genetic viewpoint it is actually a group of diseases. At the moment, a total of nine autosomal dominant genetic loci account for perhaps one-fourth of all cases of high-pressure POAG. Three actual genes among these loci have been identified. All of these genetic loci vary in terms of their phenotypic characteristics, such as corneal thickness, diurnal variation, age of onset and disease aggressiveness. Effective testing for these genes is most likely 5 years off, but once provided it will give us the means to select particularly at-risk patients for immediate treatment and other management strategies.

Pharmacogenetic studies are also helping to explain variations in patient response to beta-blockers, such as excessive beta-blockade following timolol use, and may one day serve as effective screening techniques. One such study analyzed patients who were coadministered topical timolol and oral quinidine, and tested for their ability to metabolize debrisoquin. Quinidine is a known inhibitor of the cytochrome P-450 enzyme CYP2D6, and thus reduces the metabolism of certain agents. The use of quinidine was found to inhibit the metabolism of timolol and increase beta-blockade.¹²

Additional risk factors

In addition to noncompliance, other health factors may put patients at risk for progression of POAG. Soluble CD44 in the anterior chamber is another risk factor for glaucoma and may be associated with visual field progression. There are some data identifying soluble CD44 in increased amounts in patients with POAG and normal-tension glaucoma, although not in those with pseudoexfoliation or pigmentary disease.¹³

Though previously thought to be less than significant, elevated blood pressure may have a considerable impact on glaucoma. Results from the Beaver Dam Eye Study published last year showed a strong correlation between IOP and systolic and diastolic blood pressures. This correlation remained even after adjustments for diabetes and medication use were made.¹⁴

Preservatives are also potentially more detrimental than once believed, particularly benzalkonium chloride, which has been linked to a series of toxic or immunoinflammatory effects.^15-17 Long-term chronic use has been proven to compromise the corneal epithelium and tear film,¹⁵ and benzalkonium chloride has been associated with increased inflammation and conjunctival cell apoptosis.¹⁷ Preservatives can also result in other ocular surface problems common in glaucoma patients. In fact, dry eye and other external disease conditions are probably much more frequent in glaucoma patients than is generally recognized.

Conclusion

As researchers continually expand their knowledge of glaucoma risk factors, both on a clinical and pharmacogenetic level, the management of patients will become increasingly specific. While we wait for the day when that research produces verifiable testing, we can assure optimal management of these at-risk patients by assessing corneal thickness, family history and diurnal curves, as well as health factors such as blood pressure and preservative use.

References

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