Effect of topical prostaglandin analogues on corneal hysteresis

Introduction

Glaucomatous optic neuropathy (GON) is a leading cause of visual impairment and blindness worldwide (Schacknow & Samples 2010). The intraocular pressure (IOP) level is commonly used to establish the diagnosis and for disease management and monitoring of the response to medical and surgical therapies, thus making accurate IOP measurement extremely important. Goldmann applanation tonometry (GAT) is considered the gold standard for measuring IOP in vivo (Doughty & Zaman 2000).

The GAT IOP is obtained indirectly and is based on a number of assumptions about corneal deformability and thickness, among others. The corneal mix of collagen types, corneal hydration, density of collagen fibrils, extracellular matrix and other factors undoubtedly vary among individuals, and these factors are believed to affect the accuracy of IOP estimation using GAT (Schacknow & Samples 2010).

The corneal hysteresis (CH) reflects some corneal viscoelastic properties and provides some information about the corneal biomechanical behaviour. Briefly, CH results from viscous damping of the corneal tissue exposed to the stress induced by an air pulse from the ocular response analyzer (ORA) (Reichert Technologies, Depew, NY, USA) (Tettai et al. 2012). Decreased CH is associated with progressive visual field worsening in primary open-angle glaucoma (POAG) (Congdon et al. 2006; De Moraes et al. 2012), and in asymmetric POAG, the eye with the worse visual field defect had lower CH than the fellow eye (Anand et al. 2010). Moreover, a number of studies have reported that CH increases after medically and surgically induced reductions in IOP (Sun et al. 2009; Iordanidou et al. 2010; Agarwald et al. 2012).

On the other hand, some ocular hypotensive drugs induce mild changes in the central corneal thickness (CCT); for instance, treatment with topical carbonic anhydrase inhibitors slightly increases the CCT (Wilkerson et al. 1993; Inoue et al. 2003), whereas topical F2α-prostaglandin (PG) analogues induce a mild decrease in the CCT (Viestenz et al. 2004; Harasymowycz et al. 2007; Panos et al. 2013). The reason for this effect of the PG analogues on the cornea is unknown, but it is widely accepted that these drugs induce an extracellular matrix remodelling due to the PG F-receptor-mediated increased synthesis of matrix metalloproteinases in several locations of the anterior segment of the eye (Weinreb et al. 1997; Gutierrez-Ortiz et al. 2006). In addition, treatment with PG analogues increases the keratocyte density in the corneal stroma, which might result from changes in the extracellular matrix (Bergonzi et al. 2012).

We conducted this study because these corneal changes might affect the corneal biomechanical behaviour and because, to the best of our knowledge, no prospective study has evaluated the effect of PG analogues on the corneal viscoelastic properties (CH).

Materials and Methods

This was a prospective, single-masked, observational study that included 68 eyes of 68 patients. The patients were consecutive patients newly diagnosed with POAG or ocular hypertension (OHT) in the Glaucoma Unit of our institution. No eye had been treated previously with antiglaucoma drops, and the patients were candidates for treatment with PG analogue monotherapy in at least one eye. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the local Institutional Review Board (Comité de Ética en Investigación Clínica del Hospital Universitario Príncipe de Asturias).

Glaucoma was defined based on the typical GON appearance and the corresponding visual field defects. The visual fields were analysed using the Humphrey Visual Field Analyzer (Carl Zeiss Meditec, Oberkochen, Germany), using the white-on-white 24-2 Swedish Interactive Threshold Algorithm (SITA) standard strategy. The IOP value was not used as a criterion for glaucoma diagnosis; therefore, in some patients, the IOP level was within normal limits.

OHT was defined as an IOP exceeding 24 mmHg on at least two different measurements performed on two different days without any sign of GON and normal findings in a white-on-white 24-2 SITA standard visual field test. The exclusion criteria were the presence of any corneal disease, a history of an ocular surgery and an IOP exceeding 35 mmHg without treatment or severe visual field defects. Only patients with newly diagnosed POAG or OHT were included to ensure that no eye had been treated with antiglaucoma drugs before entry into the study. Patients taking systemic medications that could affect the IOP, that is steroids, beta blockers, etc., were excluded.

At the baseline visit, a masked examiner measured the visual acuity and the IOP measured by GAT and performed an ORA examination, ultrasound pachymetry and a complete clinical ocular examination. After 6 months of treatment with latanoprost (Xalatan 0.005%, Pfizer Inc., New York, NY, USA), monotherapy applied one drop, once daily at night. The same masked examiner recorded again the GAT IOP and the ORA measurements. When both eyes of the same patient fulfilled the inclusion criteria, the data from the eye with lower GAT IOP were analysed, and if both eyes had the same GAT IOP (<3 mmHg interocular difference), the data obtained from the eye with the worse visual field defect (measured as the mean deviation) were analysed.

Statistical analyses were conducted using the Student's unpaired t-test and linear regression analysis. The normality of the analysed parameters was checked using the Kolmogorov–Smirnov test. Multiple stepwise regression analysis was used to analyse the correlations between the basal GAT IOP, basal CH, the drug-induced increase in CH and the decrease in the GAT IOP. p < 0.05 was considered statistically significant.

Results

Sixty-eight eyes of 68 patients with POAG or OHT underwent initial treatment with latanoprost, a PG analogue. The mean patient age was 68.35 ± 9.42 years (range, 48–82).

The CH value increased significantly (p = 0.0001) from 8.96 ± 2.3 mmHg to 9.79 ± 1.97 mmHg (Table 1).

We found significant correlations between the reduction of the GAT IOP and basal CH (p = 0.01, r = 0.24, r² = 0.06), and also with IOP measured by the ORA (p = 0.0001, r = 0.51 and r² = 0.26) and the corneal compensated IOP measured by the ORA (p = 0.0001, r = 0.056 and r² = 0.31), between the CH increase and the basal CH (p = 0.0001, r = 0.64, r² = 0.41), between the CH increase and the basal GAT IOP (p = 0.001, r = 0.32, r² = 0.10), and between the CH increase and the GAT IOP decrease (p = 0.0007, r = 0.34, r² = 0.11). We did not find a significant (p = 0.5) correlation between the CH increase and the basal CCT.

Because several of the parameters studied are interrelated and to determine the extent to which the response of CH to topical latanoprost was correlated with the basal CH, the basal GAT IOP and/or the GAT IOP decrease, we conducted multiple stepwise regression analysis and found that the drug-induced change in CH was correlated significantly (p = 0.001) only with the basal GAT IOP, and the correlation with the GAT IOP decrease and basal CH was no longer significant.

Discussion

We found a decrease in the GAT IOP and an increase in CH after topical treatment with latanoprost for 6 months in eyes that were newly diagnosed with POAG and OHT. Previous studies have reported that a therapeutic decrease in the GAT IOP may induce an increase in CH, which has been observed in eyes that underwent different surgical procedures, such as deep sclerectomy (Iordanidou et al. 2010) and trabeculectomy (Sun et al. 2009), and in those treated medically (Agarwald et al. 2012) to reduce the IOP. The results of the current study agree with them.

The relationship between the IOP and corneal biomechanical properties is not well understood. Sun and colleagues (Sun et al. 2009) postulated that high IOP itself can alter the corneal biomechanics, because the CH increased after the IOP decreased in response to various therapeutic methods, including trabeculectomy and instillation of topical drugs, and that the degree of the increase in CH was significantly correlated with the amount of the IOP decrease. Nevertheless, because those investigators analysed the corneal and IOP changes induced by a variety of methods, it was difficult to determine whether all methods affected the CH in the same way.

Iordanidou and colleagues (Iordanidou et al. 2010) also reported an increase in CH after the therapeutically induced IOP decrease. In that study, the decrease in the GAT IOP was achieved surgically with deep sclerectomy, and the authors found that filtering surgery induced a change in CH that seemed to be correlated with the decrease in the GAT IOP.

In addition, in a retrospective study that analysed CH and the changes in the IOP measured by ORA induced by topical PG analogues, other authors (Agarwald et al. 2012) found that CH was correlated significantly with the IOP measured by ORA, so the lower that IOP measurement was, the higher the CH. Interestingly, those authors also reported that the baseline CH was associated with the magnitude of the decrease in the IOP measured by ORA, so a lower CH value might predict a greater PG analogue-induced IOP reduction. Their results agreed with ours, because we found that a higher basal CH was related to a lower latanoprost-induced IOP reduction. Nevertheless, Agarwald and colleagues (Agarwald et al. 2012) analysed only the correlation between CH and IOP measured by ORA, which differs from the IOP measured using GAT. We found that the relationship differed if we evaluated the decrease in the IOP measured by ORA (p = 0.0001, r = 0.51, r² = 0.26) rather than by GAT (p = 0.01, r = 0.24, r² = 0.06). Thus, we believe that the true predictive effect of the basal CH on the decrease in the GAT IOP induced by topical PG analogues is low.

Because many variables analysed in the current study are interrelated, and to better understand the correlations among them, we performed multiple stepwise regression analysis and found that the latanoprost-induced increase in CH was unrelated to the magnitude of the GAT IOP decrease or to the basal CH and was only significantly correlated with the basal GAT IOP.

This finding suggests that latanoprost therapy induces a change in the CH not directly correlated with its GAT IOP lowering effect, that is the drug seems to have a direct effect on the CH in addition to the indirect effect due to the latanoprost-induced IOP decrease on the corneal viscoelastic properties.

Different topical antiglaucoma medications can modify some corneal properties, and these changes may be unrelated to the drug-induced changes in IOP. For instance, topical carbonic anhydrase inhibitors can induce corneal oedema in predisposed eyes (Adamson 1999; Konowal et al. 1999), and these drugs reduce the negative intrastromal corneal pressure created by the endothelial pump function (Teus et al. 2009).

On the other hand, PG analogues seem to induce extracellular matrix remodelling due to the PG F-receptor-mediated increased synthesis of some matrix metalloproteinases (Lindsey et al. 2007; Honda et al. 2010) in several locations of the anterior segment (Weinreb et al. 1997; Gaton et al. 2001; Wierzbowska & Stankiewicz 2006; Lindsey et al. 2007). In addition, PG analogues slightly decrease the CCT in human eyes (Viestenz et al. 2004) and may increase the keratocyte density in the corneal stroma, both of which may be due to drug-induced changes in the extracellular matrix (Bergonzi et al. 2012). Furthermore, these changes may be responsible for the PG analogue-induced change in the normal corneal strain response to acute increases in IOP (Bolívar et al. 2011).

Thus, a plausible explanation for the latanoprost-induced increase in CH may be the combination of a direct effect of the drug on the cornea and the effect that lowering the IOP seems to have on CH.

However, we do not know exactly why the therapeutically induced IOP decrease increases CH. A possible explanation forwarded by Shimmyo (Shimmyo 2009) was that at high IOP levels, corneal collagen fibres may be stretched to the mechanical extreme and may not yield further; thus, the difference between the ORA parameters P1 and P2, which is CH, may become low. When the IOP returns to the normal range, the CH also recovers normal values.

In conclusion, topical treatment with a PG analogue increases the CH, and this increase is not related to the amount of the decrease in the GAT IOP induced by the therapy. More studies are clearly needed to confirm these findings and increase our knowledge about the relationship between the corneal biomechanical properties and glaucoma therapy.