Effect of Latanoprost on Central Corneal Thickness in Unilateral Normal-Tension Glaucoma

Introduction

Normal-tension glaucoma (NTG) is a clinical entity defined as a chronic progressive optic neuropathy, resulting in characteristic optic nerve head changes, retinal nerve fiber layer defects, and visual field (VF) defects. In NTG, the intraocular pressure (IOP) values are lower than 22 mm Hg, which differentiates it from primary open-angle glaucoma (POAG).^1,2 Despite many controversies regarding the origin and pathogenesis of NTG, major treatment modalities for NTG are directed toward IOP reduction.

Currently, latanoprost is being prescribed frequently for the management of NTG. Before the introduction of latanoprost, the proper lowering of IOP in NTG was not easy because the IOP-lowering effects of previous agents were not as potent as those of latanoprost. Latanoprost is a prostaglandin analog and reduces IOP by stimulating uveoscleral outflow. ³ Although the exact cellular mechanism for this effect is not clarified, it is well known that these drugs are associated with a reduction of collagen fibers within the uveoscleral outflow pathway.

Considering the fact that the cornea is mainly composed of collagen fibers, many previous studies of prostaglandin analogs have been shown to decrease the central corneal thickness (CCT) values in patients with various types of glaucoma. Due to the influence of CCT on IOP measured by Goldmann applanation tonometer, ⁴ it is important to determine the CCT values serially, during the follow-up of glaucoma, especially NTG patients who were medicated with prostaglandin analogs. Thus, this study was performed to evaluate the effect of latanoprost on the CCT in patients with unilateral NTG during 24-month follow-up period.

Methods

The study was approved by the institutional review board of Konkuk University Medical Center, and conformed to the Declaration of Helsinki. We retrospectively reviewed the records of all the patients, who were newly diagnosed with unilateral NTG and were medicated with latanoprost 0.005% monotherapy over 24 months. Unilateral NTG was defined as open angle detected by gonioscopy; an IOP consistently ≤21 mm Hg; characteristic glaucomatous optic nerve head damage, such as notch and neuroretinal rim thinning in only one eye; glaucomatous VF loss in only one eye; and no neurologic disorder that could affect the optic nerve. Patients with ocular diseases other than glaucoma, contact lens users, and patients who had undergone refractive surgery, intraocular surgery, or laser photocoagulation treatment were excluded. Also, patients with myopia or hypermetropia greater than 3D or astigmatism more than 1D that could potentially affect our measurements were excluded. An unaffected eye in the unilateral NTG patients was evaluated for the control group.

The CCT was measured with an ultrasound pachymeter (AL-2000; Bio & Pachymeter) in the upright position by the same physician. We obtained an average value from 5 consecutive measurements. CCT measurements before treatment, and 3, 6, 9, 12, and 24 months after treatment were analyzed. To evaluate the variation in CCT values, at different time intervals within the group, a paired-sample t-test was used. Comparison of changes in CCT measures between the groups was undertaken using the repeated measures analysis of variance (ANOVA). An independent sample t-test was used to compare the baseline IOP, and baseline CCT between the groups. A P value<0.05 was considered statistically significant. All the statistical analyses were carried out using SPSS 17.0 for Windows (SPSS, Inc.).

Results

Patients' demographics are shown in Table 1. Thirty-eight patients with unilateral NTG were included. The mean age of the patients was 55.31±11.13 years. There were no significant differences between the latanoprost group (affected eyes) and the control group (unaffected eyes) for the baseline IOP and CCT. The intraclass correlation coefficient for repeatability of CCT measurements was calculated and found to be 0.985 (P<0.001). The mean difference between the repeated CCT measurements was 0.49 μm.

The mean CCT in both groups, from the baseline to 24 months, is shown in Table 2. During the follow-up, the mean CCT of the latanoprost group decreased, except at 9 months after treatment, but only statistically significant after 24 months of treatment (544.6±38.4 vs. 540.3±37.8 μm, P=0.013) by using a paired-sample t-test. However, with repeated measures ANOVA, there were no significant differences between 2 groups for CCT change (P=0.635).

Discussion

Prostaglandins have been advocated recently in the management of NTG because they have the potential to lower IOP within the statistically normal range seen in NTG. Pressure reductions of 15%–30% have been seen in NTG, in response to the prostaglandin therapy.^5,6 Further, prostaglandins have been knwon to increase pulsatile ocular blood flow to the optic nerve, thus, possibly enhancing the perfusion in what may be an ischemic-perfusion poor disease.^7,8 However, prostaglandin analogs were found to decrease the CCT values in some studies.^9–11 Viestenz and coworkers ¹⁰ have demonstrated a reduction of CCT in patients under the treatment with topical prostaglandin analogs, when compared with those with topical carbonic anhydrase inhibitors. Stefan and colleagues ¹¹ also described equivalent CCT thinning in patients receiving either travoprost or latanoprost over a period of 3 months. Sen et al. ¹² found a percent CCT reduction rate of 1.9%±2.4% and 2.8%±1.8% in a 24-month-period use of latanoprost and bimatoprost, respectively. Thus, we determined the long-term effect of latanoprost on CCT values with a longitudinal follow-up of 24 months in patients with unilateral NTG.

Although the exact mechanism of action of prostaglandin analogs is still not fully understood, it has been theorized that they act primarily through the activation of matrix metalloproteinases (MMPs). MMPs are proteases that degrade collagen—a basement membrane constituent—and other components in the extracellular matrix. ¹³ The predominant IOP effect of prostaglandin analogs is known to be caused by MMP-1 activation in the smooth muscle of the ciliary body. ¹⁴ It is known that MMPs are found in the cornea; thus, it is possible that through direct activation of the corneal MMPs, prostaglandin analogs induce physical changes to the corneal architecture. Bergonzi et al. ¹⁵ suggested that prolonged treatment with prostaglandin analogs was associated with an increase in the keratocyte density in the corneal stroma, which could be the result of collagen degradation in the stromal extracellular matrix, owing to the activation of MMPs and the inhibition of tissue inhibitors of metalloproteinases. A long-lasting consequence of this alteration could be the reduction of CCT.

CCT has become an important subject of glaucoma practice after understanding its influence on IOP measurements. Doughty and Zaman ¹⁶ have demonstrated that higher CCT values are related to higher IOP levels, which may explain the relationship between thicker corneas and ocular hypertension, and thinner corneas and NTG.^17,18 Several studies have noted that CCT is less in NTG, when compared with that of POAG and normal control patients.^19–21 Because the force, which is required to applanate, is influenced by the CCT, this feature could give artificially low IOP readings. The importance of CCT in the management of glaucoma was also demonstrated by the Ocular Hypertension Treatment Study (OHTS), where it was shown that CCT has a strong predictive value for the risk of glaucoma development in ocular hypertensive patients. ²² Therefore, CCT has recently been shown to be an important risk factor for the development and severity of glaucoma.^22,23

In this study, a 4.3 μm statistically significant reduction in CCT was observed in the latanoprost group at 24 months after treatment by using paired-sample t-test. This result is consistent with other previous studies. In the latanoprost group, the mean CCT tends to decrease during the follow-up period, except at 9 months after treatment, in spite of the lack of statistical significance. Through a retrospective chart review, we found that after 6 months of treatment, 17 patients, who had dry eye symptoms, such as ocular irritation and foreign body sensation, were prescribed the artificial tears consistently. That might be the reason why the mean CCT was not decreased at 9 months. Karadayi et al. ²⁴ showed that CCT in dry eyes increases rapidly and significantly compared with those of normal eyes after the application of artificial tears.

Chronic exposure to a hyperosmotic tear film, which could be induced by topical anti-glaucoma medication, has been reported to be capable of inducing general corneal thinning. ²⁵ Terai et al. ²⁶ has demonstrated a significant reduction in tear break-up time under latanoprost application in healthy subjects. There lacks an exact mechanism of CCT reduction in prostaglandin analogs; yet a previous study reported that the short-term effect of prostaglandin analogs on CCT could not exclude the reason of CCT reduction, due to dry eye caused by hyperosmotic tear film.

However, in our study, the mean CCT decreased with statistical significance at 24 months after treatment by using paired-sample t-test, despite the 17 patients who applicated the artificial tears consistently after 6 months. It could reconfirm the CCT reduction theory in prostaglandin analogs by MMP activation. However, by using repeated measures ANOVA, there was no statistical significance for CCT reduction between the groups. It might be due to small sample size and minimal changes of CCT by prostaglandin analogs. Aging and using artificial tears could also affect this result. The small amount of corneal thinning may not be clinically significant and may not influence IOP measurements. However, the prostaglandin analogs are the first line of choice in POAG and NTG patients and could be for lifelong use. Thus, the corneal thinning might increase more for the long-term follow-up. Even though it was a small reduction of CCT—this study included only NTG patients who have thinner baseline CCT than that of past studies that included mainly POAG patients—it could be meaningful in NTG patients.

The strength of this study was the inclusion of a group of unilateral NTG patients with an unaffected eye as the control group, which allowed us to show that the prostaglandin group and the control group had similar corneal parameter physiologically. However, this was a retrospective study and has a small sample size.

In conclusion, long-term use of latanoprost may decrease the CCT in patients with NTG. Because of the thinner cornea in NTG than other glaucoma, this data should be taken into consideration for a long-standing latanoprost treatment of NTG.