It is proven that the presence of a thicker cornea can cause overestimation of actual intraocular pressure (IOP) by applanation methods, whereas a thinner cornea can cause underestimation.1 Besides its effects on the accuracy of IOP measurements, corneal properties might have some effect on the optic nerve head (ONH) resistance.2,3 It has been reported that central corneal thickness (CCT) has correlation with ONH parameters and that eyes with thin corneas are more susceptible to IOP-dependent glaucomatous optic nerve damage.4–7
Patients with keratoconus have corneal thinning and are usually myopic. Several studies documented reduced corneal hysteresis in eyes with keratoconus.8–10 The corneal tissue characteristics themselves, such as the ability to resist deformation, might reflect the constitution of the extracellular matrix. Cornea and sclera are the continuous segments of the collagen coat of an eye, and they are essentially made from similar extracellular matrix constituents. So it can be speculated that their biomechanical characteristics might be similar. Because considerable evidence now supports that corneal features have a major role in glaucomatous optic nerve degeneration, weakness of the ONH in eyes with weak corneas (eg, keratoconus) could be possible.
Low corneal hysteresis is proposed to be a risk factor for glaucoma.11,12 If so, patients with keratoconus could be considered at increased risk for glaucoma. In reality, patients with keratoconus can develop normal-tension glaucoma.13 Because patients with keratoconus have difficulties in visual field examination due to high refractive error and corneal opacities and inaccuracies in IOP measurement, quantification of the ONH morphology and retinal nerve fiber layer (RNFL) thickness in eyes with keratoconus can thus be helpful in diagnosis and follow-up of glaucoma. However, there is currently no accepted database of normal values for ONH and RNFL parameters for keratoconic eyes.
The aims of the current study was to evaluate the parameters generated by confocal scanning laser ophthalmoscopy and optical coherence tomography (OCT) in patients with keratoconus and compare them with healthy subjects and to determine the ONH and RNFL parameters in patients with low corneal hysteresis.
Patients and Methods
This was a prospective, observational, cross-sectional study. The study population consisted of patients with documented keratoconus who were observed at the Cornea Division, Ulucanlar Eye Research Hospital. Keratoconus was diagnosed by the cornea specialist (DI) by slit-lamp biomicroscopy findings of localized corneal thinning and ectasia and confirmed by corneal topography. Age- and gender-matched individuals with good general and ocular health were recruited from the outpatient clinic as the control group. Only one eye per subject was randomly selected if both were eligible. Informed consent was obtained from every patient at the beginning of the study. The local medical ethics committee approved the study.
During a 10-month period, a population of 68 patients with keratoconus and 85 healthy subjects were examined. Contact lens wearers were instructed not to use their lenses for a minimum of 24 hours before examination. Each study participant underwent a complete ophthalmic examination that included automated keratometry with Huvitz HRK 7000A Auto Ref-Keratometer (Huvitz Co., Ltd., Gunposi, Korea) refraction, slit-lamp biomicroscopy, fundus examination, and gonioscopy. IOP was measured by both ocular response analyzer and Goldmann applanation tonometry.
Inclusion criteria were open angle and best-corrected Snellen visual acuity of better than 20/40. Glaucoma and ocular hypertension were ruled out by glaucoma specialists on the basis of IOP less than 21 mm Hg and normal optic nerve appearance with nonglaucomatous standard automated perimetry visual field examination. Evidence of secondary causes of elevated IOP (eg, iridocyclitis or trauma) presence of any retinal disease, neurologic diseases affecting the optic disc or visual field, and history of any surgery or laser procedures were exclusion criteria. Patients with tilted discs, nonglaucomatous optic disc atrophy, or any significant media opacity in which the fundus was not visible were also excluded.
The ocular response analyzer was then used to measure corneal hysteresis, corneal resistance factor, Goldmann correlated IOP, and cornea compensated IOP by one of the authors (ABC). The principles of the ocular response analyzer have been described elsewhere.8 Ocular response analyzer measurements were performed before any contact procedures to eliminate the possible effect that applanation may have on the hysteresis value. No eye drops were used before ocular response analyzer measurements and time between measurements was approximately 10 to 15 seconds. A minimum of three and a maximum of four ocular response analyzer readings of good quality were obtained consecutively and only good-quality readings were analyzed. CCT was measured with a handheld ultrasonic pachymeter attached to the ocular response analyzer. The instrument takes multiple measurements for each corneal contact, and it reports a standard deviation to aid interpretation of measurement repeatability/reliability. Axial length measurement and gonioscopy were performed using an A-mode ultrasound device (Cine Scan; Quantel Medical SA, Clermont-Ferrand, France) and a Goldmann three-mirror lens, respectively. There was a resting interval of approximately 15 minutes between contact procedures.
All subjects’ visual fields were assessed by the Humphrey field analyzer 750i (Carl Zeiss Meditec, Dublin, CA), program 24-2 using Swedish Interactive Thresholding Algorithm. Patients who wore contact lenses reinserted them prior to visual field testing. The visual field reliability criteria included less than 20% fixation loss and less than 20% false-negative and false-positive rates. All participants had a normal Glaucoma Hemifield Test, mean and pattern standard deviations within normal limits, and no characteristic glaucomatous visual field defects.
All confocal scanning laser ophthalmoscopy scans were performed with the Heidelberg Retinal Tomo-graph III (software version 3.1; Heidelberg Engineering, GmbH, Dossenheim, Germany) by a trained technician. The principles of confocal scanning laser ophthalmoscopy have been described elsewhere.14 A 15-degree angle view was used under the same intensity as dim room light. Subjective refraction results were used to set initial scan focus. Three scans centered on the optic disc were automatically obtained for each test eye, and a mean topography was created. The disc margin was outlined on the mean topography image by a technician while he viewed simultaneous stereoscopic photographs of the optic disc. The accuracy in defining ONH circumference was ensured using a minimum of six points for drawing the contour line. Keratometry values were used for correction of magnification errors. Scans with a standard deviation of less than 30 μm were accepted for analysis. The stereometric parameters compared between the control and keratoconus groups were the disc area (mm2), cup area (mm2), rim area (mm2), cup volume (mm3), rim volume (mm3), cup–disc area ratio, linear cup–disc ratio, mean cup depth (mm), maximum cup depth (mm), cup shape measure, height variation contour (mm), and mean RNFL thickness (mm).
The latest version of OCT, Spectralis OCT (Heidelberg Engineering), was used to image the peripapillary RNFL. Details of this technique have been described.15 During OCT imaging, a scan circle with a diameter of 3.45 mm was manually positioned at the center of the optic disc while the eye-tracking system was activated. Only good quality OCT data (signal quality more than 20 dB) were used for further analysis. The parameters calculated by the Spectralis OCT software and evaluated in this study were global and regional RNFL thickness measurements. In this evaluation, RNFL thickness around the optic disc is divided into six sectors: temporal, superotemporal, superonasal, nasal, inferonasal, and inferotemporal. In the analysis printout, global RNFL measurement is indicated by a categorical classification as “within normal limits" (within 95% normal distribution), “borderline" (between the lower 95.0% and the lower 99% of normal distribution), or “outside normal limits" (below the lower 99% of normal distribution).
Data were processed using the statistical software Statistical Package for the Social Sciences 15.0 (SPSS, Inc., Chicago, IL). Results are expressed as mean ± standard deviation. Normality was tested with the Kolmogorov–Smirnov test. Comparison of continuous variables was performed with the unpaired t test. Categorical data were analyzed with the chi-square test. The Bonferroni correction was used for secondary multiple comparison analysis. A P value of less than .05 was accepted as statistically significant.
Sixty-eight eyes from 68 patients with keratoconus and 85 eyes from 85 normal subjects involved in the study. Thirteen patients with keratoconus were excluded from the analysis because they had suboptimal Heidelberg Retinal Tomograph III or OCT scans. None of the eyes were excluded because of poor image in control eyes. Reliable visual field tests could not be obtained from 11 healthy eyes and 9 eyes with keratoconus. As a result, 46 patients with keratoconus and 74 normal subjects were recruited in the data analysis, excluding those with suboptimal measurements.
Demographic characteristics of the study population are summarized in Table 1. There was no significant difference in the age, gender, and refractive status in spherical equivalent between the two groups. On the other hand, best-corrected visual acuity (0.6 ± 0.21 vs 0.99 ± 0.07), CCT (486.8 ± 43.5 vs 558.8 ± 46.0 μm), cornea compensated IOP (15.3 ± 2.9 vs 16.7 ± 3.0 mm Hg), and corneal hysteresis (7.56 ± 1.3 vs 10.3 ± 1.6 mm Hg) values were significantly lower and average central keratometry (50.5 ± 4.2 vs 44.4 ± 1.52 diopters) was significantly higher in the keratoconus group. Although mean axial length measurement was statistically higher in the control group, 0.7 mm difference in axial length might be insignificant clinically.
Table 1: Demographic and Clinical Characteristics of Participants
Significant differences were found between control eyes and eyes with keratoconus in Heidelberg Retinal Tomograph III measurements (Table 2). The mean disc area in eyes with keratoconus (2.37 ± 0.5 mm2) was larger than that in control eyes (2.17 ± 0.36 mm2) (P = .013). Mean cup area was 0.65 ± 0.53 mm2 in eyes with keratoconus and 0.49 ± 0.28 mm2 in control group eyes (P = .035). According to our analysis, eyes with keratoconus had deeper cup depths (0.24 ± 0.09 vs 0.20 ± 0.07 mm for mean cup depth, P = .008, and 0.69 ± 0.27 vs 0.60 ± 0.17 mm for maximum cup depth, P = .037). Height variation contour (P = .007) and mean RNFL thickness (P = .004) also had different values between the two groups. No differences were found in rim area, rim volume, cup volume, cup–disc area ratio, linear cup–disc ratio, and cup shape measure between groups.
Table 2: Scanning Laser Ophthalmoscopic Parameters in Eyes With Keratoconus and Control Eyes
Table 2 also presents the proportion of eyes classified as within normal limits, borderline, or outside normal limits according to the Moorfields regression analysis. The proportion of optic nerves graded as “borderline" or “outside normal limits" according to the Moorfields regression analysis was greater in the keratoconus group (P = .004).
Table 3 summarizes the comparison of global RNFL thickness and the RNFL thickness in sectors between control eyes and the eyes with keratoconus. Differences in RNFL thickness between the keratoconus and control groups was observed only in the inferonasal sector (102.6 ± 16.9 vs 110.8 ± 19.8 μm, P = .02). As shown in Table 3, no significant difference existed for global RNFL categorical classification of spectral-domain OCT for the keratoconus group compared with the control group (P = .43).
Table 3: Comparison of RNFL Measured by Optical Coherence Tomography in Eyes With Keratoconus and Control Eyes
Since the Ocular Hypertension Treatment Study results were published, it has been recognized that reduced CCT is a risk factor for glaucoma in patients with ocular hypertension.16 It has been shown that patients with ocular hypertension with relatively thinner corneas may have encountered early psychophysical losses.17 An association of CCT and severity of primary open-angle glaucoma was reported.2 Hewitt and Franzco have reported that thicker corneas may offer a greater protective role against optic nerve damage in glaucoma cases.7
The cornea and sclera form the continuous collagenous external coat of the eye. Many investigators have focused on the role of CCT on ONH parameters. In a previous study including healthy eyes, we reported an inverse correlation between CCT and the optic disc area, showing that eyes with thin corneas have larger optic discs.4 Jonas et al. postulated a positive correlation between CCT and neuroretinal rim expressing that glaucomatous eyes with thinner corneas also have thinner neuroretinal rims.5 Moreover, Gunvant et al. reported that eyes with thin cornea had larger and deeper optic disc cups.6 However, a correlation between CCT and lamina cribrosa thickness, thickness of the peripapillary sclera, could not be proven in a histomorphometric study done on enucleated eyes.18
The rigidity or elasticity of ocular tissue has been of great interest to ophthalmologists. Corneal hysteresis is a direct measurement of an aspect of ocular biomechanics measured at the cornea. On the other hand, CCT represents only one parameter that affects the biomechanics. The results of the study by Shah et al. showed that the mean hysteresis in eyes with normal-tension glaucoma was lower compared with ocular hypertensive eyes and the difference was statistically significant.11 According to Abitbol et al., corneal hysteresis is significantly lower in patients with glaucoma than in nonglaucomatous subjects.12 If low corneal hysteresis proves to be a risk factor for glaucoma, then patients with keratoconus should be considered at increased risk.
The relation between corneal biomechanical properties and optic disc features and RNFL thickness measurements has not been not fully studied in nonglaucomatous eyes. Therefore, patients with keratoconus are suitable for the purpose of investigating the ONH parameters and RNFL thickness measurements in nonglaucomatous eyes with low corneal hysteresis. To the best of our knowledge, this is the first report of comparison of ONH and RNFL parameters between keratoconic and normal eyes.
Quantitative comparisons showed a significantly larger disc area for the keratoconus group than the control group (P = .013). This was in accord with the results of previous investigations reporting that eyes with thin corneas have larger discs.4,5 Our study also showed that keratoconic eyes had thinner corneas and larger and deeper optic disc cups. The results are consistent with a previous study.6 Larger optic discs may be associated with increased vulnerability to pressure-induced deformation. It was claimed that this sensitivity might be due to qualitative characteristics of extracellular matrix.18 When the disc size gets bigger, the ratio of lamina cribrosa pores to disc area increases, and therefore the connective tissue in the optic disc becomes less supportive. Moreover, according to Laplace’s Law, the deformability of a disc with larger radius is more than that of one with smaller radius.
Mean and maximum cup depth values were higher in the keratoconus group and the differences reached statistical significance, which indicate that eyes with keratoconus have deeper optic disc cups. Wells et al. increased IOP with a modified LASIK suction ring to an average of 64 mm Hg for less than 30 seconds and mapped the optic nerve surface before and during IOP elevation by the Heidelberg Retinal Tomograph II.19 Change in mean cup depth during IOP elevation was calculated. Their analysis showed that corneal hysteresis was correlated with increased mean cup depth in patients with glaucoma. The results suggest that corneal hysteresis represents properties of the eye as a whole and not just the cornea, and that patients with glaucoma have altered ocular biomechanics.
Mean cup area was also significantly larger in eyes with keratoconus. Height variation contour and mean RNFL thickness also had different values in two groups. As a result, a significant trend existed for abnormal Moorfields regression analysis for the keratoconus versus control group. If borderline and outside normal limits results were classified as false positive, the Moorfields regression analysis specificities were 81.1% and 63% for the control and keratoconus groups, respectively.
In contrast to results of Heidelberg Retinal Tomograph III measurements, spectral-domain OCT RNFL thickness measurements did not reveal striking differences between the keratoconus and control groups. Only RNFL thickness in the inferonasal sector showed statistically different values for each of the two groups, with control group eyes having the thicker RNFL.
There are some weaknesses in this study. First, our groups were not matched for parameters other than age, gender, and refractive error. Therefore, other factors may have affected the investigated parameters in both groups. Another limitation of the study is the relatively small number of eyes included. Moreover, excluding subjects with severe keratoconus due to poor Heidelberg Retinal Tomograph III or OCT scan qualities might have effects on our results.
The results of this study suggest that optic disc parameters may have a relationship with corneal hysteresis. According to our results, eyes with keratoconus may have greater optic disc areas and deeper cups. The evaluation of ONH imaging for glaucoma diagnosis in this patient population must be made with caution. RNFL assessment with OCT seems to be better than the optic disc assessment with Heidelberg Retinal Tomograph III in patients with keratoconus. Further longitudinal studies with a larger sample size are needed to elucidate the relationship between keratoconus and development of glaucoma.
- Doughty MJ, Zaman ML. Human corneal thickness and its impact on intraocular pressure measures: a review and meta-analysis approach. Surv Ophthalmol. 2000;44:367–408. doi:10.1016/S0039-6257(00)00110-7 [CrossRef]
- Herndon LW, Weizer JS, Stinnett SS. Central corneal thickness as a risk factor for advanced glaucoma damage. Arch Ophthalmol. 2004;122:17–21. doi:10.1001/archopht.122.1.17 [CrossRef]
- Medeiros FA, Sample PA, Zangwill LM, Bowd C, Aihara M, Weinreb RN. Corneal thickness as a risk factor for visual field loss in patients with preperimetric glaucomatous optic neuropathy. Am J Ophthalmol. 2003;136:805–813. doi:10.1016/S0002-9394(03)00484-7 [CrossRef]
- Cankaya AB, Elgin U, Batman A, Acaroglu G. Relationship between central corneal thickness and parameters of optic nerve head topography in healthy subjects. Eur J Ophthalmol. 2008;18:32–38.
- Jonas JB, Stroux A, Velten I, Juenemann A, Martus P, Budde WM. Central corneal thickness correlated with glaucoma damage and rate of progression. Invest Ophthalmol Vis Sci. 2005;46:1269–1274. doi:10.1167/iovs.04-0265 [CrossRef]
- Gunvant P, Porsia L, Watkins RJ, Bayliss-Brown H, Broadway DC. Relationship between central corneal thickness and optic disc topography in eyes with glaucoma, suspicion of glaucoma, or ocular hypertension. Clin Ophthalmol. 2008;2:591–599. doi:10.2147/OPTH.S2814 [CrossRef]
- Hewitt AW, Franzco RLC. Relationship between corneal thickness and optic disc damage in glaucoma. Clin Exp Ophthalmol. 2005;33:158–163. doi:10.1111/j.1442-9071.2005.00971.x [CrossRef]
- Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg. 2005;31:156–162. doi:10.1016/j.jcrs.2004.10.044 [CrossRef]
- Shah S, Laiquzzaman M, Bhojwani R, Mantry S, Cunliffe I. Assessment of the biomechanical properties of the cornea with the ocular response analyzer in normal and keratoconic eyes. Invest Ophthalmol Vis Sci. 2007;48:3026–3031. doi:10.1167/iovs.04-0694 [CrossRef]
- Fontes BM, Ambrósio R, Jardim D, Velarde GC, Nosé W. Corneal biomechanical metrics and anterior segment parameters in mild keratoconus. Ophthalmology. 2010;117:673–679. doi:10.1016/j.ophtha.2009.09.023 [CrossRef]
- Shah S, Laiquzzaman M, Mantry S, Cunliffe I. Ocular response analyser to assess hysteresis and corneal resistance factor in low tension, open angle glaucoma and ocular hypertension. Clin Exp Ophthalmol. 2008;36:508–513. doi:10.1111/j.1442-9071.2008.01828.x [CrossRef]
- Abitbol O, Bouden J, Doan S, Hoang-Xuan T, Gatinel D. Corneal hysteresis measured with the Ocular Response Analyzer in normal and glaucomatous eyes. Acta Ophthalmol. 2010;88:116–119. doi:10.1111/j.1755-3768.2009.01554.x [CrossRef]
- Cohen EJ, Myers JS. Keratoconus and normal-tension glaucoma: a study of the possible association with abnormal biomechanical properties as measured by corneal hysteresis. Cornea. 2010;29:955–970. doi:10.1097/ICO.0b013e3181ca363c [CrossRef]
- Zangwill LM, Bowd C, Weinreb RN. Evaluating the optic disc and retinal nerve fiber layer in glaucoma: II. Optical image analysis. Semin Ophthalmol. 2000;15:206–220. doi:10.3109/08820530009037872 [CrossRef]
- Chen TC. Spectral domain optical coherence tomography in glaucoma: qualitative and quantitative analysis of the optic nerve head and retinal nerve fiber layer. Trans Am Ophthalmol Soc. 2009;107:254–281.
- 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. doi:10.1001/archopht.120.6.714 [CrossRef]
- Medeiros FA, Sample PA, Weinreb RN. Corneal thickness measurements and visual function abnormalities in ocular hypertensive patients. Am J Ophthalmol. 2003;135:131–137. doi:10.1016/S0002-9394(02)01886-X [CrossRef]
- Jonas JB, Holbach L. Central corneal thickness and thickness of the lamina cribrosa in human eyes. Invest Ophthalmol Vis Sci. 2005;46:1275–1279. doi:10.1167/iovs.04-0851 [CrossRef]
- Wells AP, Garway-Heath DF, Poostchi A, Wong T, Chan KCY, Sachdev N. Corneal hysteresis but not corneal thickness correlates with optic nerve surface compliance in glaucoma patients. Invest Ophthalmol Vis Sci. 2008;49:3262–3268. doi:10.1167/iovs.07-1556 [CrossRef]
Demographic and Clinical Characteristics of Participants
||29.9 ± 6.8 (19–43)
||31.5 ± 6.8 (17–45)
|Spherical equivalent (D)
||−3.25 ± 2.1 (−7.75– 1.25)
||−3.13 ± 1.73 (−7.7– −0.5)
|Visual acuity (Snellen)
||0.6 ± 0.21(0.3–1.0)
||0.99 ± 0.07 (0.5–1.0)
|Average central keratometry (D)
||50.5 ± 4.2 (43.25–59)
||44.4 ± 1.52 (41.5–47.25)
|Central corneal thickness (μm)
||486.8 ± 43.5 (379–580)
||558.8 ± 46.0 (458–665)
|Axial length (mm)
||24.1 ± 1.3 (21.8–27.6)
||24.8 ± 1.71 (22.1–28.9)
|GAT IOP (mm Hg)
||10.9 ± 3.5 (5.0–18.0)
||16.1 ± 3.5 (9.0–21.0)
|Corneal hysteresis (mm Hg)
||7.56 ± 1.3 (5.3–10.3)
||10.3 ± 1.6 (6.6–14.2)
|IOPcc (mm Hg)
||15.3 ± 2.9 (9.1–20.9)
||16.7 ± 3.0 (9.6–21.4)
Scanning Laser Ophthalmoscopic Parameters in Eyes With Keratoconus and Control Eyes
|Disc area (mm2)
||2.37 ± 0.5 (1.60–4.09)
||2.17 ± 0.36 (1.51–3.09)
|Cup area (mm2)
||0.65 ± 0.53 (0.0–2.58)
||0.49 ± 0.28 (0.0–1.22)
|Rim area (mm2)
||1.72 ± 0.58 (0.27–3.54)
||1.68 ± 0.30 (1.10–2.34)
|Cup volume (mm3)
||0.23 ± 0.57 (0.0–0.37)
||0.10 ± 0.09 (0.0–0.38)
|Rim volume (mm3)
||0.53 ± 0.34 (0.04–1.64)
||0.47 ± 0.16 (0.22–0.96)
|Cup–disc area ratio
||0.27 ± 0.19 (0.0–0.88)
||0.22 ± 0.11 (0.0–0.50)
|Linear cup–disc ratio
||0.48 ± 0.19 (0.04–0.74)
||0.44 ± 0.12 (0.03–0.71)
|Mean cup depth (mm)
||0.24 ± 0.09 (0.08–0.48)
||0.20 ± 0.07 (0.09–0.39)
|Maximum cup depth (mm)
||0.69 ± 0.27 (0.22–1.62)
||0.60 ± 0.17 (0.27–1.01)
|Cup shape measure
||−0.24 ± 0.27 (−2.0– −0.09)
||−0.21 ± 0.10 (−0.37–0.20)
|Height variation contour (mm)
||0.65 ± 0.64 (0.19–4.64)
||0.43 ± 0.15 (0.22–1.35)
|Mean RNFL thickness (mm)
||0.16 ± 0.30 (−1.41–0.56)
||0.27 ± 0.08 (−0.09–0.47)
| Within normal limits
| Outside normal limits
Comparison of RNFL Measured by Optical Coherence Tomography in Eyes With Keratoconus and Control Eyes
||133.5 ± 16.2 (101–178)
||133.1 ± 17.7 (105–165)
||101.1 ± 15.1 (74–129)
||105.7 ± 20.6 (64–164)
||71.6 ± 13.3 (52–100)
||73.8 ± 10.5 (50–103)
||102.6 ± 16.9 (72–149)
||110.8 ± 19.8 (63–165)
||149.4 ± 15.7 (114–179)
||150.6 ± 16.9 (126–208)
||70.0 ± 8.9 (52–91)
||71.8 ± 11.4 (53–118)
||96.5 ± 7.3 (82–113)
||99.0 ± 8.7 (81–119)
| Within normal limits
| Outside normal limits