Glaucoma is an acquired optic neuropathy in which destruction of ganglion cells and fibers leads to irreversible visual field loss. This is a highly prevalent disease, so it has been estimated that, by 2010, roughly 2% of the population older than 50 years will be affected by primary open-angle glaucoma (POAG).1
Increased intraocular pressure (IOP) is a major and well-known risk factor for glaucoma. Different studies have provided evidence supporting that reducing the IOP decreases the risk of progression to glaucoma in patients with ocular hypertension (OHT),2 and that achieving low levels of IOP slows down the progression of glaucomatous optic neuropathy in normal-tension,3 early, and advanced glaucomas.4
Some studies have reported that central corneal thickness (CCT) is an important risk factor for the development and the severity of glaucoma. A thin central cornea has been linked to the development of glaucoma among patients with OHT2 and to the severity of both OHT5 and POAG.6 The importance of the CCT in patients with glaucoma seems to depend not only on its effect as a source of error in IOP measurement7 but also because it seems to be a significant risk factor, independent of IOP, for the development of glaucomatous damage in patients with OHT and for POAG in the general population.6
In addition, there is some evidence suggesting that changes in the IOP level induce changes in the biomechanical behavior of the cornea,8 and that glaucomatous damage may correlate with the deformability of several ocular tissues, including the cornea.9
Ultrasound-based devices are the most widely used for measuring the corneal thickness10; however, this technology offers limited information about the overall corneal morphology. Optical pachymetry, such as that performed by the Orbscan scanning slit topographer (Bausch & Lomb, Rochester, NY), can provide a complete analysis of the anterior and posterior corneal topography in the form of elevation maps, and it measures the thickness of numerous points over the entire cornea not only at the central area. Indeed, this instrument has been shown to provide precise corneal elevation measurements.11 Using the Orbscan II, Dada et al.12 found a significant decrease in the posterior corneal elevation after lowering the IOP in eyes with steroid-induced glaucoma; but to the best of our knowledge, no previous study has analyzed the anterior and posterior corneal curvatures of POAG patients using this device.
This was a prospective observer-masked study that included consecutive patients who fulfilled all the inclusion criteria and agreed to participate. Patients were recruited from the Glaucoma Unit, Vissum Madrid, Madrid, Spain. This research adhered to the tenets of the Declaration of Helsinki, and the approval of our institution’s investigational review board was obtained before the onset of the study. The nature and purpose of the study were explained in detail to all participants, who provided informed consent before entering the study.
All patients met the following inclusion criteria: myopia lower than −6.00 diopters (D), astigmatism lower than −3.00 D, and hyperopia lower than +3.00 D. In addition, patients had to have a normal anterior segment evaluation using the slit lamp, and patients with a history of previous ocular surgery, angle closure, inflammation, ocular infection, or previous corneal pathology were excluded. The study population was composed of patients with newly diagnosed POAG or POAG eyes already under treatment with any topical ocular hypotensive drug, except carbonic anhydrase inhibitors, either topical or systemic, for at least 3 months before entering the study. Primary open-angle glaucoma was defined as having an untreated IOP of 22 or higher, with the presence of typical glaucomatous visual field loss associated with glaucomatous optic nerve head damage, without any evidence of pigment dispersion, pseudoexfoliative material deposition, or any other cause of secondary IOP elevation. The control group included healthy volunteers, with normal IOP and no evidence of glaucomatous optic nerve head damage. These subjects were selected to be matched with study patients regarding age and ultrasonic CCT value (±5 μm). When both eyes of the same patient met the inclusion criteria, one eye was randomly chosen, so only one eye per patient was analyzed.
In addition to a routine ophthalmic examination, all eyes were examined with the Orbscan II (3.10 version); the CCT was also measured using ultrasonic pachymetry (DGH 1000; Technology Inc., Exton, PA). Three consecutive Orbscan measurements were obtained between 4:00 and 8:00 pm for every patient by the same examiner; the patients were instructed to fixate on a central blinking red light. The Orbscan II system is a combined scanning-slit and Placido disc corneal topographer with a multidimensional analyzer that performs a complete study of all corneal structures. The optical acquisition head scans the ocular surface using 40 light slits projected sequentially at a 45-degree angle. Internal software calculates the curvature of the anterior and posterior corneal surfaces and the elevation of the anterior and posterior corneal surfaces (taking the best-fit sphere as the reference plane). This device also determines the thickness of the entire cornea based on the difference in elevation between the anterior and posterior surfaces. For the current study, the anterior and posterior elevation maps were analyzed in the central 7-mm diameter area. The elevation parameters recorded for the analysis were the maximum and minimum elevation readings and the difference between them (highest minus lowest values) for both anterior and posterior corneal surfaces in the analyzed area (Fig. 1). Floating best-fit sphere alignment was used for obtaining such elevation measurements.
After the Orbscan analysis, one drop of proparacaine hydrochloride was instilled to anesthetize the cornea, and an ultrasound probe was applied as perpendicular as possible to the central cornea by the same examiner to obtain three measurements of CCT. The mean of the three values recorded was considered as the CCT. After obtaining the pachymetric measurements, Goldmann applanation tonometry was performed by the same examiner, who obtained three consecutive readings of each eye, and the average was recorded.
SPSS statistics software package version 15.0 for Windows (SPSS, Chicago, IL) was used for statistical analysis. Normality of all data samples was initially checked by means of the Kolmogorov-Smirnov test. When parametric analysis was possible, the Student t test for unpaired data was performed for visual acuity comparison between groups. On the contrary, when parametric analysis was not possible, the Mann-Whitney U test was applied to assess the significance of differences in some clinical parameters between groups using, in all cases, the same level of significance (p < 0.05). Correlations between visual outcomes and other clinical data were also investigated (Pearson or Spearman correlation coefficients depending if normality condition could be assumed or not).
A total of 138 eyes of 138 subjects fulfilled the inclusion criteria for the study. They were equally distributed between the study (n = 69) and control (n = 69) groups. The demographic characteristics of the subjects in the study (POAG) and control (healthy) groups are summarized in Table 1. The mean ultrasound CCT values were 547.88 ± 37.95 μm (range, 472 to 620 μm) and 548.89 ± 35.89 μm (range, 476 to 615 μm) in the POAG and control groups, respectively. There was no significant difference in CCT between groups because they were matched for this parameter (p = 0.87, unpaired Student t test). Mean IOP was 17.1 ± 4.5 mm Hg (range, 11 to 34 mm Hg) and 14.0 ± 2.7 mm Hg (range, 8 to 19 mm Hg) in the POAG and control groups, respectively; this difference was statistically significant (p = 0.001, Mann-Whitney U test). We found a significant positive correlation between the CCT and IOP in the POAG (p = 0.03, r = 0.26, Spearman correlation coefficient) and in healthy eyes (p = 0.001, r = 0.43, Spearman correlation coefficient).
In the study group (POAG eyes), 10 eyes were newly diagnosed glaucoma patients, so they were not receiving any hypotensive treatment. On the other hand, 35 eyes were treated with one hypotensive drug, and 24 eyes were treated with two different drugs. From the 59 POAG eyes under hypotensive treatment, 45 eyes (76.27%) were receiving a prostaglandin analog; 33 (55.93%), a beta-blocker; and in five eyes (8.47%), a topical alpha-2 agonist was used.
When elevation data from both corneal surfaces were compared in the study and control groups, a statistically significant difference (p = 0.001, Mann-Whitney U test) in the posterior maximum elevation was found (POAG, 0.052 ± 0.047 mm vs. control, 0.033 ± 0.011 mm). However, no significant differences between groups were found in the minimum elevation of the posterior corneal surface (POAG −0.048 ± 0.029 mm vs. control, −0.041 ± 0.014 mm, p = 0.66, Mann-Whitney U test). Regarding the anterior corneal surface, significant differences among groups were found in the maximum (POAG, 0.016 ± 0.011 mm vs. control, 0.018 ± 0.006 mm, p = 0.001, Mann-Whitney U test) and minimum elevation (POAG, −0.022 ± 0.012 mm vs. control, −0.029 ± 0.013 mm, p = 0.001, Mann-Whitney U test). Significant differences between groups were found in the difference between the maximum and minimum elevation reading for the anterior (POAG, 0.038 ± 0.018 mm vs. control, 0.047 ± 0.017 mm, p = 0.001, Mann-Whitney U test) and posterior corneal surface (POAG, 0.100 ± 0.070 mm vs. control, 0.074 ± 0.022 mm, p = 0.001 Mann-Whitney U test).
Different hypotensive drugs have been found to be implicated in changes of the corneal properties, mainly, topical carbonic anhydrase inhibitors (excluded from this study) and prostaglandin analogs. As prostaglandin analogs are the predominant hypotensive agents in our study sample, we decided to subdivide the POAG group in two: eyes treated with prostaglandin (PG) analogs (PG group, 45 eyes) or eyes not treated with prostaglandin (PG-free group, 24 eyes) (Table 2). No significant differences in visual acuity, refraction, keratometry, CCT, and IOP were found between these two subgroups (p ≥ 0.34, Mann-Whitney U test) (Table 2). Regarding the anterior elevation data, no statistically significant differences in the maximum (PG-free, 0.016 ± 0.014 mm vs. PG, 0.016 ± 0.010 mm, p = 0.44, Mann-Whitney U test) and in the minimum values (PG-free, −0.021 ± 0.009 mm vs. PG, −0.023 ± 0.014 mm, p = 0.52, Mann-Whitney U test) were found. A similar trend was found for the maximum (PG-free, 0.057 ± 0.058 mm vs. PG, 0.050 ± 0.040 mm, p = 0.33, Mann-Whitney U test) and minimum (PG-free, −0.044 ± 0.034 mm vs. PG, −0.050 ± 0.032 mm, p = 0.56, Mann-Whitney U test) elevation of the posterior corneal surface. Finally, no significant differences between PG-free and PG subgroups were found in the difference between the maximum and minimum elevation reading for the anterior (PG-free, 0.037 ± 0.018 mm vs. PG, 0.039 ± 0.019 mm, p = 0.40, Mann-Whitney U test) and posterior corneal surface (PG-free, 0.101 ± 0.082 mm vs. PG, 0.100 ± 0.022 mm, p = 0.65, Mann-Whitney U test).
Measuring the CCT is an important component of proper management of OHT and glaucoma. Underestimation of the IOP with Goldmann applanation tonometry partly explains the significance between thin corneas and increased glaucoma risk.13 The CCT also may be an independent risk factor for glaucoma.2,6 Most studies on the relationship between glaucoma and CCT were designed to compare the CCT in patients with different types of glaucoma,14 the effect of the corneal thickness on Goldmann applanation tonometry, or the impact of corneal thickness on different types of tonometers.7 However, to the best of our knowledge, no study has analyzed the overall corneal thickness and the corneal topography in patients with glaucoma.
The corneal thickness and the anterior corneal curvature are thought to be independent of each other.15 Some studies have established that the central cornea is thinner than the more peripheral cornea in normal subjects16; the difference between the central and peripheral corneal thickness seems not to be a fixed characteristic among individuals because substantial interindividual differences have been reported.10 One factor in this difference could be the age of the subjects because the difference between the central and peripheral corneal thickness seems to become progressively less with aging.17 Interestingly, some authors also have observed slight differences when comparing central and peripheral corneal thicknesses between normal subjects and patients with POAG, normal-tension glaucoma, and pseudoexfoliation glaucoma.14
Although optical pachymeters were the first to be used to measure corneal thickness, ultrasound-based pachymetry is the most widely used method for this purpose nowadays.10 As it is well known, the Orbscan scanning-slit topographer is a device with the ability of providing a complete analysis of the anterior and posterior corneal topography in the form of elevation maps and of mapping the entire corneal thickness. It is recognized that Orbscan II has some limitations when evaluating the posterior surface after surface ablation18 or after LASIK.19–21 Nevertheless, it has been shown that the evaluation of both the anterior and the posterior corneal surfaces using this device in nonoperated “virgin” corneas is very accurate and reproducible.11,22,23 For this reason, this device has been used in the current series for evaluating and comparing the anterior and posterior corneal elevation data in eyes with POAG and healthy control subjects. We found that POAG eyes have a posterior corneal surface that is more elevated than in healthy subjects even though both groups were matched for age and central pachymetry values. In addition, there were also significant differences, although minimal in magnitude, between glaucomatous and healthy corneas regarding anterior surface elevation. These differences in corneal topography between glaucomatous and CCT-matched healthy subjects and the significant correlation between the IOP level and the posterior corneal elevation we found in the POAG group suggest that they are somehow related to the glaucomatous disease. Future studies evaluating other corneal parameters such as the corneal volume should be performed in the future to confirm this finding.
We do not know exactly the reason for the increased elevation of the posterior corneal surface in our patients with POAG. One possible explanation could be that this corneal morphology could have been present before the onset of the disease and might serve as a biologic marker in subjects prone to develop optic nerve glaucomatous disease. In fact, the CCT is believed to be an inherited characteristic, suggesting that it is under fine genetic control.24 Some authors have speculated that CCT could be an IOP-independent risk factor for glaucoma perhaps because of a link between the structural corneal properties and the biomechanical characteristics of the eye wall itself, in fact they have reported that patients with open-angle glaucoma or OHT have a thinner CCT, with a significantly greater shallowing of the cup, a marker for lamina cribrosa compliance, and that increased forward movement of the lamina cribrosa after IOP lowering is observed in eyes with thinner CCT values.25
In addition, corneal hysteresis may be associated with progressive worsening of the visual fields, suggesting that more elastic or distensible ocular tissues, including the cornea and the lamina cribrosa, might be associated with an increased risk of glaucoma progression.26 Thus, a thin central cornea may be a marker for differences in the biomechanical properties of the sclera and the lamina cribrosa and perhaps for the risk of developing glaucomatous optic nerve damage. On the contrary, some authors have reported that the relationship between CCT and the susceptibility to develop glaucoma could not be explained by a corresponding anatomy between corneal and lamina cribrosa thickness because they did not find a significant correlation between the thickness of both the central cornea and the lamina cribrosa in nonglaucomatous monkey and human globes.27,28
Another explanation for our findings could be that the elevation topography and the corneal thickness, in previously normal corneas, do change during the course of the glaucomatous disease, and that this change could be caused by the effect of elevated IOP on the cornea, which may cause mechanical distortion12 similarly to the IOP-induced mechanical stress observed at the level of the lamina cribrosa.29 Ang et al.9 recently reported that the corneal biomechanical properties seem to be related to the IOP level, suggesting that changes in the corneal tissue may be caused by the chronically increased IOP seen in POAG; in addition, partial recovery of these biomechanical properties has been observed after successful IOP-lowering therapy.8 Furthermore, the corneal hysteresis values in patients with glaucoma have been associated with an increased deformation of the optic nerve surface during transient IOP elevations,30 and a thinner central cornea in patients with OHT and POAG has been related to greater forward displacement of the base of the cup, considered a surrogate marker for the biomechanical properties of the lamina cribrosa, after IOP reduction.25 Reports of transient keratectasia with evident posterior corneal surface elevation after episodes of acute IOP elevation have suggested that high IOP could compress fluid out of the corneal stroma,12 causing an inverse relationship between the IOP and corneal thickness.31
Although few longitudinal studies analyzing the changes in CCT over time in glaucomatous populations have been published, some authors have suggested that the CCT may decrease more markedly over time in patients with POAG than in the normal population.32 In addition, it is also possible that a decrease in the CCT during glaucoma could be related to the effect of certain ocular hypotensive drugs on the ocular surface.
It has been suggested that topical PGs may induce an increase in the metalloproteinases activity in the anterior segment of the eye33; in fact, there is a report of a case of a keratoconus progression presumably triggered by a topical PG analog treatment.34 Although the current study was not designed to analyze the influence of treatment with PGs in the cornea, we found no difference in the Orbscan parameters between POAG patients under therapy with PG analogs and those not using these agents.
In conclusion, eyes with POAG have a higher posterior corneal elevation than controls, suggesting that mechanical compression of the corneal stroma has occurred in these eyes. We do not know the role that increased IOP, the biomechanical effect on the cornea of the antiglaucomatous drugs, or a predisposition of these corneas to a pressure-induced deformation, may play in the changes in the posterior corneal elevation we found. It is clear that further research is needed to increase our knowledge about the relationship between the cornea and the glaucomatous disease.
Novovision Clínica Oftalmológica
Paseo de la Castellana, 54
None of the authors have conflicts of interest with the submission. No financial support was received for this submission.
This research adhered to the tenets of the Declaration of Helsinki, and the approval of our institution’s investigational review board was obtained before the onset of the study. The nature and purpose of the study were explained in detail to all participants who provided informed consent before entering the study.
Received March 11, 2013; accepted May 29, 2013.
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