CLINICAL SCIENCE
Topographic, Corneal Wavefront, and Refractive Outcomes 2 Years After Collagen Crosslinking for Progressive Keratoconus Ramon C. Ghanem, MD, PhD,*† Marcony R. Santhiago, MD, PhD,†‡ Thais Berti, MD,* Marcelo V. Netto, MD, PhD,† and Vinícius C. Ghanem, MD, PhD*†
Purpose: The aim was to report the corneal higher-order aberrations (HOA), the topographic metrics, and the visual and refractive outcomes 2 years after performing collagen crosslinking (CXL) for progressive keratoconus. The correlation among corneal HOAs, topographic metrics, and visual acuity changes was also investigated.
Methods: This is a prospective case series involving 42 eyes from 32 patients with progressive keratoconus treated with CXL. The main outcomes measured at baseline and 6, 12, and 24 months after treatment were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), refractive changes, topographic data, and corneal aberrations. Results: Two years after CXL treatment, the UDVA (P , 0.001), CDVA (P , 0.001), and spherical equivalent (P = 0.048) improved significantly. The corneal topographic data revealed significant decreases in apical keratometry (P , 0.001), differential keratometry (P = 0.031), and central keratometry (P = 0.003) compared with the baseline measurements. Aberration analyses revealed a significant reduction in coma (P = 0.016), trefoil (P = 0.018), secondary astigmatism (P , 0.001), quatrefoil (P = 0.031), secondary coma (P , 0.001), and secondary trefoil (P = 0.001). Corneal HOA (except quatrefoil) demonstrated a significant correlation with postoperative CDVA; the highest correlations were for coma (rho = 0.703, P , 0.001), secondary astigmatism (rho = 0.519, P = 0.001), and total HOA (rho = 0.487, P = 0.001). However, the corneal HOA changes were not statistically associated with improved visual acuity. After treatment, the reduction in apical keratometry was the only variable that correlated with the improvement in the CDVA (rho = 0.319, P = 0.042). Conclusions: After 2 years, CXL was found to be effective in improving the UDVA, CDVA, topographic metrics, and most Received for publication February 12, 2013; revision received August 19, 2013; accepted August 23, 2013. Published online ahead of print October 24, 2013. From the *Sadalla Amin Ghanem Eye Hospital, Joinville, Santa Catarina, Brazil; †Department of Ophthalmology, University of São Paulo, São Paulo, Brazil; and ‡Department of Ophthalmology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. The authors have no funding or conflicts of interest to disclose. Reprints: Marcony R. Santhiago, Department of Ophthalmology, Federal University of Rio de Janeiro, 3100 Av Abelardo Bueno 3100/ Apto 604, Barra da Tijuca, Rio de Janeiro 22775-040, Brazil (e-mail: [email protected]). Copyright © 2013 by Lippincott Williams & Wilkins
Cornea Volume 33, Number 1, January 2014
corneal HOAs in eyes with progressive keratoconus. A significant reduction was observed in apical keratometry, and this reduction directly correlated with an improvement in visual acuity. Key Words: keratoconus, crosslinking (Cornea 2014;33:43–48)
K
eratoconus is a noninflammatory disease that is characterized by a progressive corneal steepening and thinning, and it results in irregular astigmatism, increased corneal higher-order aberrations (HOAs), progressive myopia, and impaired visual acuity.1,2 Intrinsic changes in the orthogonal lamellar matrix of highly aligned collagen lead to biomechanical instability, which progresses to a severe deterioration of the corneal elasticity and rigidity and tends to subsequently weaken the cornea.3–6 These features are marked by an asymmetry in presentation and unpredictable progression, which is associated with a wide variety of abnormal topographic findings.1,2 Because mechanical corneal stability plays an important role in the progressive protrusion of the keratoconic cornea, collagen crosslinking (CXL) has emerged as a promising technique that can theoretically increase the cornea’s biomechanical strength,7 thereby halting, or at least slowing down, the progression of keratoconus.8,9 In this procedure, riboflavin (vitamin B2) is administered in conjunction with ultraviolet A (UVA, 370 nm). The interaction between a photosensitizing substance (riboflavin) with the UV light from a solid-state UVA source produces reactive oxygen species so as to induce new covalent bonds across the adjacent collagen strands in the stromal layer of the cornea that significantly increases its biomechanical strength. Topography and more recently corneal aberrometric analysis have been identified as effective instruments to detect and grade keratoconic eyes.10–14 To understand the optical quality changes that occur after CXL, it would be useful to study the long-term changes in corneal HOAs after CXL. The purpose of this prospective study was to investigate the aberrometric and topographic outcomes that occur 24 months after CXL is performed in eyes with progressive keratoconus and also to determine whether these results correlate with any visual acuity changes. www.corneajrnl.com |
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METHODS Forty-two eyes diagnosed with progressive keratoconus were enrolled in this prospective nonrandomized study. All the patients underwent standard CXL. The study was approved by the internal review boards of the University of São Paulo and Sadalla Amin Ghanem Eye Hospital, and it was conducted according to the Declaration of Helsinki principles. All the patients or their parents provided informed consent before enrollment in the study. Patients were included in the study if they were at least 14 years of age and had an apical (maximum) keratometry (K) reading of ,65 diopters (D), a central corneal thickness (CCT, measured with an ultrasound pachymeter), and a minimum corneal thickness (measured with a corneal tomography) of at least 400 mm and a diagnosis of progressive keratoconus based on axial topography patterns. Progressive keratoconus was defined as an increase of 0.5 D or more in the apical K over a 6-month period or 1.0 D in over a 1-year period. Patients were excluded if they had a history of corneal surgery, connective tissue disease, apical corneal scarring, or actual or intended pregnancy. All the patients underwent complete preoperative ophthalmologic evaluations. The preoperative data collection included age, gender, the date of the keratoconus diagnosis, the surgery date, dynamic refraction, visual acuity (refracted using a best potential vision of 20/20), ultrasound pachymetry (AccuPach V; Accutome, Malvern, EUA), corneal tomography using the Orbscan IIz (Bausch & Lomb, Rochester, NY), and corneal topography using the Medmont E300 (Medmont International, Vermont, Australia) and the Keratron Scout (OPTIKON 2000, Rome, Italy). The apical K values, central K values, mean K values at the 3.0-mm zones (mean simulated keratometry), and the topographic astigmatism (differential keratometry) were recorded from the Medmont E300, because this has been found to be a highly accurate and repeatable topographer.15 The corneal anterior surface HOAs were calculated using the topography maps that were generated with the Keratron Scout, software version 4.0. Wavefront errors were analyzed over 6-mm-diameter pupils and decomposed into Zernike polynomials to the sixth order. The main outcome measures were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), refractive sphere and cylinder, topography, and corneal HOA. These measures were evaluated at baseline and then at 6, 12, and 24 months after treatment. The CXL was performed according to a protocol published by Wollensak et al.9 The treatment was performed using topical anesthesia, and it included central 9.0-mm corneal debridement and subsequent instillation of riboflavin 0.1% with dextran 20% for 30 minutes. Subsequently, a circular beam of 9.0-mm-diameter UVA irradiation was applied to the cornea for 30 minutes. A CBM X-Linker (Compagnia Strumenti Oftalmici) was used as the UVA radiation source. This device delivers UVA light at a 370-nm wavelength 5 cm from the apex of the cornea. A therapeutic contact lens was placed after the surgery and maintained for 7 days. Postoperative evaluations were performed on the seventh day to evaluate epithelial healing and remove the contact
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lenses; complete evaluations were performed after 1, 6, 12, and 24 months. No patients were lost to follow-up. The patients who used rigid contact lenses were asked to refrain from using the lenses for 1 week before the preoperative examination and for 3 months after the treatment. The lenses were also removed 1 week before each follow-up examination. The visual acuity measurements were converted from Snellen values to the logarithm of the minimum angle of resolution (logMAR) units. For those patients who did not correctly read all the letters on a single line, the conversion was made by interpolating between the logMAR acuity values using the fraction of the correctly read letters on a visual acuity line. The data are presented as mean 6 SD. Normality was assessed using the Kolmogorov–Smirnov test with the Lilliefors significance correction. Paired analyses were performed using the Student t test for the variables with a normal distribution, that is, age, sphere, cylinder, and spherical equivalent. The Wilcoxon test was used for the variables without a normal distribution, that is, the UDVA and CDVA measurements, CCT, K, and corneal HOA. Bivariate correlations were assessed using the Spearman test for nonparametric correlations. The data were analyzed using Microsoft Excel 2007 (Microsoft Corp, Redmond, WA) and IBM SPSS Statistics 20 software (IBM, Armonk, NY). A P value of ,0.05 was considered statistically significant.
RESULTS Forty-two eyes from 32 consecutive patients, 29 men and 13 women, with a mean age of 22.4 6 5.6 years (range, 14–34) were included in the study. Eleven patients underwent a bilateral procedure. The mean interval between the keratoconus diagnosis and the CXL was 2.2 6 2.4 years. Most of the patients reported experiencing minor to moderate ocular pain, which decreased over the first 2 to 3 days after the procedure was carried out. The contact lens was removed 1 week after the treatment. No postoperative complications were observed, except for 1 eye that had a small peripheral sterile infiltrate. Four eyes from 3 patients missed the 6-month visit, and 8 eyes from 6 patients missed being followed up at the 6-month visit. All the eyes were evaluated 24 months after the CXL was performed. The mean preoperative CCT measured with ultrasound pachymetry was 487 6 46 mm. The CCT was 471 6 49 mm 6 months after the procedure, 494 6 34 mm at 12 months, and 501 6 34 mm at 24 months.
Visual Acuity and Refraction Outcomes Table 1 shows the postoperative visual and refractive results. One and 2 years after the treatment, the mean UDVA, CDVA, and spherical equivalent were all improved significantly compared with baseline measurements. At 2 years, 29.3% of the eyes gained at least 2 lines of the CDVA; 34.1% gained 1 line; 24.4% had no change; 9.8% lost 1 line; and 2.4% lost 2 lines. A mean gain of 1.1 line of the CDVA was observed 2 years after the surgery was performed. Ó 2013 Lippincott Williams & Wilkins
Cornea Volume 33, Number 1, January 2014
Collagen Crosslinking in Progressive Keratoconus
TABLE 1. Paired Analysis Comparing the Preoperative and Postoperative Visual and Refractive Results (n = 42) at 6, 12, and 24 Months Parameter UDVA (logMAR) Mean 6 SD Range CDVA (logMAR) Mean 6 SD Range Sphere Mean 6 SD Range Cylinder Mean 6 SD Range SE Mean 6 SD Range
Preoperative
6 mos
12 mos
P
24 mos
0.67 6 0.37 0.00–1.48
0.51 6 0.34* 0.00–1.30
0.48 6 0.38* 0.00–1.30
0.43 6 0.33*† 0.00–1.30
,0.001
0.26 6 0.19 0.00–0.70
0.18 6 0.18* 0.00–0.70
0.14 6 0.13* 0.00–0.44
0.14 6 0.15* 0.00–0.70
,0.001
20.89 6 2.35 29.00 to 6.00
20.98 6 2.24 28.5 to 2.0
20.43 6 2.11*† 26.75 to 2.50
20.73 6 2.10 27.00 to 2.50
0.199
22.45 6 1.80 26.25 to 0.00
22.15 6 1.73 27.00 to 0.00
22.03 6 1.59 25.50 to 0.00
21.99 6 1.57 25.75 to 0.00
0.141
22.12 6 2.43 210.00 to 2.90
22.03 6 2.52 29.50 to 1.10
21.42 6 2.31*† 28.80 to 1.30
21.73 6 2.33* 29.00 to 1.30
0.048
*Statistically significant change compared with baseline measurements. †Statistically significant change compared with previous measurement. SE = spherical equivalent.
Corneal Topography
Corneal Wavefront
Two years after the CXL treatment, analyses of the corneal topographic measurements revealed a significant decrease in the apical K, differential K, and central K compared with the baseline measurements (Table 2). The mean K values demonstrated stability throughout the analysis period (Figure 1). At the 2-year follow-up, 22 eyes (52.4%) had a stable apical K (61.0 D of the preoperative measurement); 8 eyes (19.0%) had a decreased K between 1.1 and 2.0 D; 9 eyes (21.4%) had a decreased K between 2.1 and 3.0 D, and 2 eyes (4.8%) had a decreased K by .3.0 D. In 1 eye (2.4%), the apical K increased by 1.1 D. No other eyes showed an increase in the apical K. The apical K reduction was the only variable that significantly correlated with an improved CDVA 2 years after treatment (rho = 0.319, P = 0.042).
Table 3 shows the mean preoperative corneal aberration values 1 and 2 years after performing the CXL. Analyses of the corneal HOA 2 years after the CXL revealed that significant changes had occurred for coma (P = 0.016), trefoil (P = 0.018), secondary astigmatism (P , 0.001), quatrefoil (P = 0.031), secondary coma (P , 0.001), and secondary trefoil (P = 0.001) compared with the preoperative values (Table 3). The preoperative corneal HOA correlated with the preoperative CDVA [rho = 0.636, P , 0.001 (coma); rho = 0.427, P = 0.005 (secondary coma); rho = 0.424, P = 0.005 (secondary astigmatism); rho = 0.337, P = 0.029 (secondary trefoil)]. Two years after the CXL, all the corneal lower and HOAs (except quatrefoil) significantly correlated with the postoperative CDVA, with the highest correlations found for
TABLE 2. Paired Analysis Comparing the Preoperative and the Postoperative Topographic Measurements (n = 42) at 6, 12, and 24 Months Parameter Apical K Mean 6 SD Range Mean K Mean 6 SD Range Differential K Mean 6 SD Range Central K Mean 6 SD Range
Preoperative
6 mos
12 mos
24 mos
P
54.2 6 4.2 46.3–64.7
53.9 6 4.0 46.1–65.3
53.4 6 3.6 47.7–59.6
53.3 6 4.1*† 46.8–65.0
,0.001
48.0 6 3.3 41.5–61.6
48.0 6 3.0 42.1–58.2
47.5 6 2.6† 42.2–51.8
47.8 6 3.3† 41.3–61.0
0.306
4.0 6 1.9 0.9–7.8
4.1 6 2.0 0.9–8.7
3.9 6 1.8 1.0–8.0
3.8 6 2.0* 0.3–7.6
0.031
49.3 6 4.6 39.5–64.1
48.7 6 3.7* 40.6–57.6
48.3 6 3.7* 40.7–54.0
48.7 6 4.4*† 40.6–61.3
0.003
*Statistically significant change compared with baseline measurements. †Statistically significant change compared with previous measurement. Apical K, maximum keratometric measurement on topography; mean K = (K1 + K2)/2; differential K = K2 2 K1.
Ó 2013 Lippincott Williams & Wilkins
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FIGURE 1. The mean values of apical K (A), central K (B), mean K (C), and differential K (D) 6 months, 1 year, and 2 years after crosslinking. The analyses of the corneal topographic measurements 2 years after the CXL revealed a significant decrease in apical K, differential K, and central K compared with the baseline measurements. The mean K values demonstrated stability throughout the analysis period. The bars represent the SD. Apical K, maximum keratometric measurement on the topography, mean K (K1 + K2)/2, differential K, K2 2 K1; and *statistically significant change compared with the baseline measurements.
coma (rho = 0.703, P , 0.001), secondary astigmatism (rho = 0.519, P = 0.001), total HOA (rho = 0.487, P = 0.001), and secondary coma (rho = 0.453, P = 0.003). No correlation, however, was found between the changes in individual corneal aberrations and the changes in visual acuity after the CXL.
DISCUSSION Corneal CXL with riboflavin was recently developed to increase the corneal resistance in patients diagnosed with progressive ectasia.8,9 Theoretically, the CXL treatment strengthens the biomechanical properties of the corneal stroma and, consequently, halts the progression of keratoconus and ectasia. In this study, we investigated the impact of corneal stiffness changes on aberrometric, topographic, and visual outcomes 24 months after performing a CXL. Our main findings were that CXL was effective in improving the UDVA and the CDVA in eyes with progressive keratoconus and that the corneal curvature stabilized or improved 24 months after the procedure was carried out. We also found a significant improvement in the corneal HOA, such as coma, trefoil, secondary astigmatism, quatrefoil, secondary coma, and secondary trefoil, after CXL treatment.
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A correlation analysis revealed that most corneal HOAs that were measured 2 years after the CXL, particularly coma, presented a moderately to highly significant correlation with the postoperative CDVA. No individual aberration, however, was correlated or responsible for the improvement in the CDVA. The reduction in apical K was the only variable significantly associated with CDVA improvement after CXL. Thus, this study provides clinical evidence that the improvements in visual and refractive outcomes are somehow related to the combination of flattening the cone apex and a steepening symmetrically opposite, which is reflected in the coma reduction, along with a decrease in most corneal HOAs. This finding corroborates the importance of evaluating coma-like aberrations as a meaningful parameter of the optical quality in patients with ectatic disease and indicates that it should be considered a tool for monitoring the treatment efficacy. Alió et al16 demonstrated that the increase in corneal aberrometry values, particularly in primary coma, has a direct role in limiting the visual quality. In addition, primary coma has been shown to have a significant negative impact on visual acuity because of the type of blur that it induces.17 Our results are consistent with that of previous work that has shown the significance of coma aberrations in Ó 2013 Lippincott Williams & Wilkins
Cornea Volume 33, Number 1, January 2014
Collagen Crosslinking in Progressive Keratoconus
TABLE 3. Paired Analysis Comparing the RMS, P-V, Low- and Higher-order Corneal Aberrations Before and After Surgery (n = 42) Corneal Aberration*
Preoperative
RMS P-V§ Defocus Astigmatism Coma Trefoil Spherical aberration Secondary astigmatism Quatrefoil Secondary coma Secondary trefoil Pentafoil
4.87 2.52 0.04 3.48 2.79 0.99 20.07 0.76 0.28 0.43 0.24 0.09
6 6 6 6 6 6 6 6 6 6 6 6
2.08 1.03 2.05 1.70 1.53 0.46 0.68 0.37 0.15 0.24 0.14 0.07
12 mos 4.97 2.61 20.45 3.43 2.72 1.00 20.14 0.68 0.29 0.40 0.22 0.12
6 6 6 6 6 6 6 6 6 6 6 6
2.10 0.95 2.42 1.80 1.22 0.45 0.77 0.33† 0.21 0.27† 0.12 0.19
24 mos
P
6 6 6 6 6 6 6 6 6 6 6 6
,0.001 0.001 0.553 0.135 0.016 0.018 0.530 ,0.001 0.031 ,0.001 0.001 0.123
4.06 2.13 20.08 3.33 2.48 0.91 20.08 0.65 0.26 0.35 0.20 0.08
2.01†‡ 0.96†‡ 1.82 1.68 1.23† 0.39† 0.64‡ 0.33† 0.17† 0.21† 0.11† 0.06
*Corneal aberrations reported in microns. †Statistically significant change compared with baseline measurements. ‡Statistically significant change compared with previous measurement. §The peak-to-valley value was divided by 10 to facilitate the analysis. P-V, peak to valley; RMS, root mean square.
patients suspected to have keratoconus. Maeda et al14 demonstrated that spherical- and coma-like aberrations increased in eyes with keratoconus compared with that in normal controls. Alió and Shabayek12 investigated the anterior corneal aberrations as a tool to detect and grade keratoconus and showed that coma-like aberrations were significantly higher in eyes with keratoconus than in normal eyes. Although the visual degradation that is observed in keratoconus is classically and consistently represented by the changes in K values, a steep cornea with a centered cone and even deteriorated biomechanical properties could have a satisfactory CDVA if the anterior HOA level is low because of the symmetric geometric profile of the anterior corneal profile, as Alió et al16 have demonstrated. Our findings differed from those of previous work conducted by Vinciguerra et al18 They investigated the aberrometric outcomes 12 months after the CXL in eyes with progressive advanced keratoconus. Their analysis of total (whole eye) aberrations showed a significant reduction in astigmatism, coma, and spherical aberrations. Interestingly, however, the corneal surface aberrometric analysis did not reveal any coma improvement. The authors hypothesized that a significant change in the posterior surface of the cornea might occur to explain these findings. Our results support those of Caporossi et al,19 who found a statistically significant reduction in the total corneal HOA and coma aberration, starting early after treatment and increasing for up to 24 months in 44 eyes. No change was observed in the spherical aberration. Other HOAs were not studied. Greenstein et al20 showed a significant reduction in the coma, spherical aberration, and trefoil 1 year after a CXL was performed in patients diagnosed with progressive ectasia. In their study, as in ours, the changes in HOAs were not statistically correlated with improvements in visual acuity. Because a moderate to high positive correlation has been previously demonstrated between corneal HOAs and CDVA in keratoconic patients, the role of the anterior corneal Ó 2013 Lippincott Williams & Wilkins
HOAs in the visual degradation of such patients has been established.4,12 However, because other factors, such as corneal scattering or the optical degradation of the posterior corneal surface,21 likely play significant roles in the final visual outcomes and in visual degradation, we questioned whether the collagen fiber changes that follow the CXL would allow the anterior corneal HOA to impact the spherocylindrical correction (after the procedure) to significantly improve visual acuity. Our 2-year results also corroborate the findings of previous publications that showed a significant improvement in apical and central K.17,19–23 We found a moderate to high correlation between the corneal topographic measurement changes and visual acuity. These findings, together with significant changes in corneal aberrations, provide a reasonable explanation for the improvements in the CDVA and UDVA. In a different approach, using indices that were obtained from Pentacam, Greenstein et al24 investigated the changes after CXL in patients diagnosed with keratoconus and corneal ectasia, and they analyzed the associations between these changes and visual acuity. Although they found a significant improvement in 4 of 7 topography indices 1 year after performing the CXL, no significant correlation was found between the changes in individual topography indices and the visual acuity changes after the CXL. We believe that absolute values may be more accurate and sensitive to corneal changes after CXL rather than the index generated from Placido-disk corneal topography. This may explain why apical keratometric values in our study were significantly correlated to the CDVA. In conclusion, CXL was effective in improving the UDVA and the CDVA in eyes with progressive keratoconus 2 years after the procedure was carried out in our patient population, with a concomitant improvement in topographic metrics and most corneal aberrations. A significant reduction in apical K was observed and correlated with visual acuity improvements. www.corneajrnl.com |
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REFERENCES 1. Rabinowitz YS. Keratoconus. Surv Ophthalmol. 1998;42:297–319. 2. Wilson SE, Lin DT, Klyce SD. Corneal topography of keratoconus. Cornea. 1991;10:2–8. 3. Shah S, Laiquzzaman M, Bhojwani R, et al. 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. 4. Piñero DP, Alio JL, Barraquer RI, et al. Corneal biomechanics, refraction, and corneal aberrometry in keratoconus: an integrated study. Invest Ophthalmol Vis Sci. 2010;51:1948–1955. 5. Ortiz D, Piñero D, Shabayek MH, et al. Corneal biomechanical properties in normal, post-laser in situ keratomileusis, and keratoconic eyes. J Cataract Refract Surg. 2007;33:1371–1375. 6. Meek KM, Tuft SJ, Huang Y, et al. Changes in collagen orientation and distribution in keratoconus corneas. Invest Ophthalmol Vis Sci. 2005;46: 1948–1956. 7. Wollensak G, Spoerl E, Seiler T. Stress–strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced cross-linking. J Cataract Refract Surg. 2003;29:1780–1785. 8. Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol. 2006;17:356–360. 9. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620–627. 10. Piñero DP, Alió JL, Alesón A, et al. Pentacam posterior and anterior corneal aberrations in normal and keratoconic eyes. Clin Exp Optom. 2009;92:297–303. 11. Bühren J, Kühne C, Kohnen T. Defining subclinical keratoconus using corneal first-surface higher-order aberrations. Am J Ophthalmol. 2007; 143:381–389. 12. Alió JL, Shabayek MH. Corneal higher order aberrations: a method to grade keratoconus. J Refract Surg. 2006;22:539–545. 13. Barbero S, Marcos S, Merayo-Lloves J, et al. Validation of the estimation of corneal aberrations from videokeratography in keratoconus. J Refract Surg. 2002;18:263–270.
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14. Maeda N, Fujikado T, Kuroda T, et al. Wavefront aberrations measured with Hartmann–Shack sensor in patients with keratoconus. Ophthalmology. 2002;109:1996–2003. 15. Tang W, Collins MJ, Carney L, et al. The accuracy and precision performance of four videokeratoscopes in measuring test surfaces. Optom Vis Sci. 2000;77:483–491. 16. Alió JL, Piñero DP, Alesón A, et al. Keratoconus-integrated characterization considering anterior corneal aberrations, internal astigmatism, and corneal biomechanics. J Cataract Refract Surg. 2011;37: 552–568. 17. Applegate RA, Sarver EJ, Khemsara V. Are all aberrations equal? J Refract Surg. 2002;18:S556–S562. 18. Vinciguerra P, Albè E, Trazza S, et al. Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology. 2009;116:369–378. 19. Caporossi A, Mazzotta C, Baiocchi S, et al. Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Am J Ophthalmol. 2010;149: 585–593. 20. Greenstein SA, Fry KL, Hersh MJ, et al. Higher-order aberrations after corneal collagen crosslinking for keratoconus and corneal ectasia. J Cataract Refract Surg. 2012;38:292–302. 21. Nakagawa T, Maeda N, Kosaki R, et al. Higher-order aberrations due to the posterior corneal surface in patients with keratoconus. Invest Ophthalmol Vis Sci. 2009;50:2660–2665. 22. Grewal DS, Brar GS, Jain R, et al. Corneal collagen crosslinking using riboflavin and ultraviolet-A light for keratoconus: one-year analysis using Scheimpflug imaging. J Cataract Refract Surg. 2009; 35:425–432. 23. Raiskup-Wolf F, Hoyer A, Spoerl E, et al. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008;34:796–801. 24. Greenstein SA, Fry KL, Hersh PS. Corneal topography indices after corneal collagen crosslinking for keratoconus and corneal ectasia: oneyear results. J Cataract Refract Surg. 2011;37:1282–1290.
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Topographic, Corneal Wavefront, and Refractive Outcomes 2 Years After Collagen Crosslinking for Progressive Keratoconus Ramon C. Ghanem, MD, PhD,*† Marcony R. Santhiago, MD, PhD,†‡ Thais Berti, MD,* Marcelo V. Netto, MD, PhD,† and Vinícius C. Ghanem, MD, PhD*†
Purpose: The aim was to report the corneal higher-order aberrations (HOA), the topographic metrics, and the visual and refractive outcomes 2 years after performing collagen crosslinking (CXL) for progressive keratoconus. The correlation among corneal HOAs, topographic metrics, and visual acuity changes was also investigated.
Methods: This is a prospective case series involving 42 eyes from 32 patients with progressive keratoconus treated with CXL. The main outcomes measured at baseline and 6, 12, and 24 months after treatment were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), refractive changes, topographic data, and corneal aberrations. Results: Two years after CXL treatment, the UDVA (P , 0.001), CDVA (P , 0.001), and spherical equivalent (P = 0.048) improved significantly. The corneal topographic data revealed significant decreases in apical keratometry (P , 0.001), differential keratometry (P = 0.031), and central keratometry (P = 0.003) compared with the baseline measurements. Aberration analyses revealed a significant reduction in coma (P = 0.016), trefoil (P = 0.018), secondary astigmatism (P , 0.001), quatrefoil (P = 0.031), secondary coma (P , 0.001), and secondary trefoil (P = 0.001). Corneal HOA (except quatrefoil) demonstrated a significant correlation with postoperative CDVA; the highest correlations were for coma (rho = 0.703, P , 0.001), secondary astigmatism (rho = 0.519, P = 0.001), and total HOA (rho = 0.487, P = 0.001). However, the corneal HOA changes were not statistically associated with improved visual acuity. After treatment, the reduction in apical keratometry was the only variable that correlated with the improvement in the CDVA (rho = 0.319, P = 0.042). Conclusions: After 2 years, CXL was found to be effective in improving the UDVA, CDVA, topographic metrics, and most Received for publication February 12, 2013; revision received August 19, 2013; accepted August 23, 2013. Published online ahead of print October 24, 2013. From the *Sadalla Amin Ghanem Eye Hospital, Joinville, Santa Catarina, Brazil; †Department of Ophthalmology, University of São Paulo, São Paulo, Brazil; and ‡Department of Ophthalmology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. The authors have no funding or conflicts of interest to disclose. Reprints: Marcony R. Santhiago, Department of Ophthalmology, Federal University of Rio de Janeiro, 3100 Av Abelardo Bueno 3100/ Apto 604, Barra da Tijuca, Rio de Janeiro 22775-040, Brazil (e-mail: [email protected]). Copyright © 2013 by Lippincott Williams & Wilkins
Cornea Volume 33, Number 1, January 2014
corneal HOAs in eyes with progressive keratoconus. A significant reduction was observed in apical keratometry, and this reduction directly correlated with an improvement in visual acuity. Key Words: keratoconus, crosslinking (Cornea 2014;33:43–48)
K
eratoconus is a noninflammatory disease that is characterized by a progressive corneal steepening and thinning, and it results in irregular astigmatism, increased corneal higher-order aberrations (HOAs), progressive myopia, and impaired visual acuity.1,2 Intrinsic changes in the orthogonal lamellar matrix of highly aligned collagen lead to biomechanical instability, which progresses to a severe deterioration of the corneal elasticity and rigidity and tends to subsequently weaken the cornea.3–6 These features are marked by an asymmetry in presentation and unpredictable progression, which is associated with a wide variety of abnormal topographic findings.1,2 Because mechanical corneal stability plays an important role in the progressive protrusion of the keratoconic cornea, collagen crosslinking (CXL) has emerged as a promising technique that can theoretically increase the cornea’s biomechanical strength,7 thereby halting, or at least slowing down, the progression of keratoconus.8,9 In this procedure, riboflavin (vitamin B2) is administered in conjunction with ultraviolet A (UVA, 370 nm). The interaction between a photosensitizing substance (riboflavin) with the UV light from a solid-state UVA source produces reactive oxygen species so as to induce new covalent bonds across the adjacent collagen strands in the stromal layer of the cornea that significantly increases its biomechanical strength. Topography and more recently corneal aberrometric analysis have been identified as effective instruments to detect and grade keratoconic eyes.10–14 To understand the optical quality changes that occur after CXL, it would be useful to study the long-term changes in corneal HOAs after CXL. The purpose of this prospective study was to investigate the aberrometric and topographic outcomes that occur 24 months after CXL is performed in eyes with progressive keratoconus and also to determine whether these results correlate with any visual acuity changes. www.corneajrnl.com |
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METHODS Forty-two eyes diagnosed with progressive keratoconus were enrolled in this prospective nonrandomized study. All the patients underwent standard CXL. The study was approved by the internal review boards of the University of São Paulo and Sadalla Amin Ghanem Eye Hospital, and it was conducted according to the Declaration of Helsinki principles. All the patients or their parents provided informed consent before enrollment in the study. Patients were included in the study if they were at least 14 years of age and had an apical (maximum) keratometry (K) reading of ,65 diopters (D), a central corneal thickness (CCT, measured with an ultrasound pachymeter), and a minimum corneal thickness (measured with a corneal tomography) of at least 400 mm and a diagnosis of progressive keratoconus based on axial topography patterns. Progressive keratoconus was defined as an increase of 0.5 D or more in the apical K over a 6-month period or 1.0 D in over a 1-year period. Patients were excluded if they had a history of corneal surgery, connective tissue disease, apical corneal scarring, or actual or intended pregnancy. All the patients underwent complete preoperative ophthalmologic evaluations. The preoperative data collection included age, gender, the date of the keratoconus diagnosis, the surgery date, dynamic refraction, visual acuity (refracted using a best potential vision of 20/20), ultrasound pachymetry (AccuPach V; Accutome, Malvern, EUA), corneal tomography using the Orbscan IIz (Bausch & Lomb, Rochester, NY), and corneal topography using the Medmont E300 (Medmont International, Vermont, Australia) and the Keratron Scout (OPTIKON 2000, Rome, Italy). The apical K values, central K values, mean K values at the 3.0-mm zones (mean simulated keratometry), and the topographic astigmatism (differential keratometry) were recorded from the Medmont E300, because this has been found to be a highly accurate and repeatable topographer.15 The corneal anterior surface HOAs were calculated using the topography maps that were generated with the Keratron Scout, software version 4.0. Wavefront errors were analyzed over 6-mm-diameter pupils and decomposed into Zernike polynomials to the sixth order. The main outcome measures were uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), refractive sphere and cylinder, topography, and corneal HOA. These measures were evaluated at baseline and then at 6, 12, and 24 months after treatment. The CXL was performed according to a protocol published by Wollensak et al.9 The treatment was performed using topical anesthesia, and it included central 9.0-mm corneal debridement and subsequent instillation of riboflavin 0.1% with dextran 20% for 30 minutes. Subsequently, a circular beam of 9.0-mm-diameter UVA irradiation was applied to the cornea for 30 minutes. A CBM X-Linker (Compagnia Strumenti Oftalmici) was used as the UVA radiation source. This device delivers UVA light at a 370-nm wavelength 5 cm from the apex of the cornea. A therapeutic contact lens was placed after the surgery and maintained for 7 days. Postoperative evaluations were performed on the seventh day to evaluate epithelial healing and remove the contact
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lenses; complete evaluations were performed after 1, 6, 12, and 24 months. No patients were lost to follow-up. The patients who used rigid contact lenses were asked to refrain from using the lenses for 1 week before the preoperative examination and for 3 months after the treatment. The lenses were also removed 1 week before each follow-up examination. The visual acuity measurements were converted from Snellen values to the logarithm of the minimum angle of resolution (logMAR) units. For those patients who did not correctly read all the letters on a single line, the conversion was made by interpolating between the logMAR acuity values using the fraction of the correctly read letters on a visual acuity line. The data are presented as mean 6 SD. Normality was assessed using the Kolmogorov–Smirnov test with the Lilliefors significance correction. Paired analyses were performed using the Student t test for the variables with a normal distribution, that is, age, sphere, cylinder, and spherical equivalent. The Wilcoxon test was used for the variables without a normal distribution, that is, the UDVA and CDVA measurements, CCT, K, and corneal HOA. Bivariate correlations were assessed using the Spearman test for nonparametric correlations. The data were analyzed using Microsoft Excel 2007 (Microsoft Corp, Redmond, WA) and IBM SPSS Statistics 20 software (IBM, Armonk, NY). A P value of ,0.05 was considered statistically significant.
RESULTS Forty-two eyes from 32 consecutive patients, 29 men and 13 women, with a mean age of 22.4 6 5.6 years (range, 14–34) were included in the study. Eleven patients underwent a bilateral procedure. The mean interval between the keratoconus diagnosis and the CXL was 2.2 6 2.4 years. Most of the patients reported experiencing minor to moderate ocular pain, which decreased over the first 2 to 3 days after the procedure was carried out. The contact lens was removed 1 week after the treatment. No postoperative complications were observed, except for 1 eye that had a small peripheral sterile infiltrate. Four eyes from 3 patients missed the 6-month visit, and 8 eyes from 6 patients missed being followed up at the 6-month visit. All the eyes were evaluated 24 months after the CXL was performed. The mean preoperative CCT measured with ultrasound pachymetry was 487 6 46 mm. The CCT was 471 6 49 mm 6 months after the procedure, 494 6 34 mm at 12 months, and 501 6 34 mm at 24 months.
Visual Acuity and Refraction Outcomes Table 1 shows the postoperative visual and refractive results. One and 2 years after the treatment, the mean UDVA, CDVA, and spherical equivalent were all improved significantly compared with baseline measurements. At 2 years, 29.3% of the eyes gained at least 2 lines of the CDVA; 34.1% gained 1 line; 24.4% had no change; 9.8% lost 1 line; and 2.4% lost 2 lines. A mean gain of 1.1 line of the CDVA was observed 2 years after the surgery was performed. Ó 2013 Lippincott Williams & Wilkins
Cornea Volume 33, Number 1, January 2014
Collagen Crosslinking in Progressive Keratoconus
TABLE 1. Paired Analysis Comparing the Preoperative and Postoperative Visual and Refractive Results (n = 42) at 6, 12, and 24 Months Parameter UDVA (logMAR) Mean 6 SD Range CDVA (logMAR) Mean 6 SD Range Sphere Mean 6 SD Range Cylinder Mean 6 SD Range SE Mean 6 SD Range
Preoperative
6 mos
12 mos
P
24 mos
0.67 6 0.37 0.00–1.48
0.51 6 0.34* 0.00–1.30
0.48 6 0.38* 0.00–1.30
0.43 6 0.33*† 0.00–1.30
,0.001
0.26 6 0.19 0.00–0.70
0.18 6 0.18* 0.00–0.70
0.14 6 0.13* 0.00–0.44
0.14 6 0.15* 0.00–0.70
,0.001
20.89 6 2.35 29.00 to 6.00
20.98 6 2.24 28.5 to 2.0
20.43 6 2.11*† 26.75 to 2.50
20.73 6 2.10 27.00 to 2.50
0.199
22.45 6 1.80 26.25 to 0.00
22.15 6 1.73 27.00 to 0.00
22.03 6 1.59 25.50 to 0.00
21.99 6 1.57 25.75 to 0.00
0.141
22.12 6 2.43 210.00 to 2.90
22.03 6 2.52 29.50 to 1.10
21.42 6 2.31*† 28.80 to 1.30
21.73 6 2.33* 29.00 to 1.30
0.048
*Statistically significant change compared with baseline measurements. †Statistically significant change compared with previous measurement. SE = spherical equivalent.
Corneal Topography
Corneal Wavefront
Two years after the CXL treatment, analyses of the corneal topographic measurements revealed a significant decrease in the apical K, differential K, and central K compared with the baseline measurements (Table 2). The mean K values demonstrated stability throughout the analysis period (Figure 1). At the 2-year follow-up, 22 eyes (52.4%) had a stable apical K (61.0 D of the preoperative measurement); 8 eyes (19.0%) had a decreased K between 1.1 and 2.0 D; 9 eyes (21.4%) had a decreased K between 2.1 and 3.0 D, and 2 eyes (4.8%) had a decreased K by .3.0 D. In 1 eye (2.4%), the apical K increased by 1.1 D. No other eyes showed an increase in the apical K. The apical K reduction was the only variable that significantly correlated with an improved CDVA 2 years after treatment (rho = 0.319, P = 0.042).
Table 3 shows the mean preoperative corneal aberration values 1 and 2 years after performing the CXL. Analyses of the corneal HOA 2 years after the CXL revealed that significant changes had occurred for coma (P = 0.016), trefoil (P = 0.018), secondary astigmatism (P , 0.001), quatrefoil (P = 0.031), secondary coma (P , 0.001), and secondary trefoil (P = 0.001) compared with the preoperative values (Table 3). The preoperative corneal HOA correlated with the preoperative CDVA [rho = 0.636, P , 0.001 (coma); rho = 0.427, P = 0.005 (secondary coma); rho = 0.424, P = 0.005 (secondary astigmatism); rho = 0.337, P = 0.029 (secondary trefoil)]. Two years after the CXL, all the corneal lower and HOAs (except quatrefoil) significantly correlated with the postoperative CDVA, with the highest correlations found for
TABLE 2. Paired Analysis Comparing the Preoperative and the Postoperative Topographic Measurements (n = 42) at 6, 12, and 24 Months Parameter Apical K Mean 6 SD Range Mean K Mean 6 SD Range Differential K Mean 6 SD Range Central K Mean 6 SD Range
Preoperative
6 mos
12 mos
24 mos
P
54.2 6 4.2 46.3–64.7
53.9 6 4.0 46.1–65.3
53.4 6 3.6 47.7–59.6
53.3 6 4.1*† 46.8–65.0
,0.001
48.0 6 3.3 41.5–61.6
48.0 6 3.0 42.1–58.2
47.5 6 2.6† 42.2–51.8
47.8 6 3.3† 41.3–61.0
0.306
4.0 6 1.9 0.9–7.8
4.1 6 2.0 0.9–8.7
3.9 6 1.8 1.0–8.0
3.8 6 2.0* 0.3–7.6
0.031
49.3 6 4.6 39.5–64.1
48.7 6 3.7* 40.6–57.6
48.3 6 3.7* 40.7–54.0
48.7 6 4.4*† 40.6–61.3
0.003
*Statistically significant change compared with baseline measurements. †Statistically significant change compared with previous measurement. Apical K, maximum keratometric measurement on topography; mean K = (K1 + K2)/2; differential K = K2 2 K1.
Ó 2013 Lippincott Williams & Wilkins
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FIGURE 1. The mean values of apical K (A), central K (B), mean K (C), and differential K (D) 6 months, 1 year, and 2 years after crosslinking. The analyses of the corneal topographic measurements 2 years after the CXL revealed a significant decrease in apical K, differential K, and central K compared with the baseline measurements. The mean K values demonstrated stability throughout the analysis period. The bars represent the SD. Apical K, maximum keratometric measurement on the topography, mean K (K1 + K2)/2, differential K, K2 2 K1; and *statistically significant change compared with the baseline measurements.
coma (rho = 0.703, P , 0.001), secondary astigmatism (rho = 0.519, P = 0.001), total HOA (rho = 0.487, P = 0.001), and secondary coma (rho = 0.453, P = 0.003). No correlation, however, was found between the changes in individual corneal aberrations and the changes in visual acuity after the CXL.
DISCUSSION Corneal CXL with riboflavin was recently developed to increase the corneal resistance in patients diagnosed with progressive ectasia.8,9 Theoretically, the CXL treatment strengthens the biomechanical properties of the corneal stroma and, consequently, halts the progression of keratoconus and ectasia. In this study, we investigated the impact of corneal stiffness changes on aberrometric, topographic, and visual outcomes 24 months after performing a CXL. Our main findings were that CXL was effective in improving the UDVA and the CDVA in eyes with progressive keratoconus and that the corneal curvature stabilized or improved 24 months after the procedure was carried out. We also found a significant improvement in the corneal HOA, such as coma, trefoil, secondary astigmatism, quatrefoil, secondary coma, and secondary trefoil, after CXL treatment.
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A correlation analysis revealed that most corneal HOAs that were measured 2 years after the CXL, particularly coma, presented a moderately to highly significant correlation with the postoperative CDVA. No individual aberration, however, was correlated or responsible for the improvement in the CDVA. The reduction in apical K was the only variable significantly associated with CDVA improvement after CXL. Thus, this study provides clinical evidence that the improvements in visual and refractive outcomes are somehow related to the combination of flattening the cone apex and a steepening symmetrically opposite, which is reflected in the coma reduction, along with a decrease in most corneal HOAs. This finding corroborates the importance of evaluating coma-like aberrations as a meaningful parameter of the optical quality in patients with ectatic disease and indicates that it should be considered a tool for monitoring the treatment efficacy. Alió et al16 demonstrated that the increase in corneal aberrometry values, particularly in primary coma, has a direct role in limiting the visual quality. In addition, primary coma has been shown to have a significant negative impact on visual acuity because of the type of blur that it induces.17 Our results are consistent with that of previous work that has shown the significance of coma aberrations in Ó 2013 Lippincott Williams & Wilkins
Cornea Volume 33, Number 1, January 2014
Collagen Crosslinking in Progressive Keratoconus
TABLE 3. Paired Analysis Comparing the RMS, P-V, Low- and Higher-order Corneal Aberrations Before and After Surgery (n = 42) Corneal Aberration*
Preoperative
RMS P-V§ Defocus Astigmatism Coma Trefoil Spherical aberration Secondary astigmatism Quatrefoil Secondary coma Secondary trefoil Pentafoil
4.87 2.52 0.04 3.48 2.79 0.99 20.07 0.76 0.28 0.43 0.24 0.09
6 6 6 6 6 6 6 6 6 6 6 6
2.08 1.03 2.05 1.70 1.53 0.46 0.68 0.37 0.15 0.24 0.14 0.07
12 mos 4.97 2.61 20.45 3.43 2.72 1.00 20.14 0.68 0.29 0.40 0.22 0.12
6 6 6 6 6 6 6 6 6 6 6 6
2.10 0.95 2.42 1.80 1.22 0.45 0.77 0.33† 0.21 0.27† 0.12 0.19
24 mos
P
6 6 6 6 6 6 6 6 6 6 6 6
,0.001 0.001 0.553 0.135 0.016 0.018 0.530 ,0.001 0.031 ,0.001 0.001 0.123
4.06 2.13 20.08 3.33 2.48 0.91 20.08 0.65 0.26 0.35 0.20 0.08
2.01†‡ 0.96†‡ 1.82 1.68 1.23† 0.39† 0.64‡ 0.33† 0.17† 0.21† 0.11† 0.06
*Corneal aberrations reported in microns. †Statistically significant change compared with baseline measurements. ‡Statistically significant change compared with previous measurement. §The peak-to-valley value was divided by 10 to facilitate the analysis. P-V, peak to valley; RMS, root mean square.
patients suspected to have keratoconus. Maeda et al14 demonstrated that spherical- and coma-like aberrations increased in eyes with keratoconus compared with that in normal controls. Alió and Shabayek12 investigated the anterior corneal aberrations as a tool to detect and grade keratoconus and showed that coma-like aberrations were significantly higher in eyes with keratoconus than in normal eyes. Although the visual degradation that is observed in keratoconus is classically and consistently represented by the changes in K values, a steep cornea with a centered cone and even deteriorated biomechanical properties could have a satisfactory CDVA if the anterior HOA level is low because of the symmetric geometric profile of the anterior corneal profile, as Alió et al16 have demonstrated. Our findings differed from those of previous work conducted by Vinciguerra et al18 They investigated the aberrometric outcomes 12 months after the CXL in eyes with progressive advanced keratoconus. Their analysis of total (whole eye) aberrations showed a significant reduction in astigmatism, coma, and spherical aberrations. Interestingly, however, the corneal surface aberrometric analysis did not reveal any coma improvement. The authors hypothesized that a significant change in the posterior surface of the cornea might occur to explain these findings. Our results support those of Caporossi et al,19 who found a statistically significant reduction in the total corneal HOA and coma aberration, starting early after treatment and increasing for up to 24 months in 44 eyes. No change was observed in the spherical aberration. Other HOAs were not studied. Greenstein et al20 showed a significant reduction in the coma, spherical aberration, and trefoil 1 year after a CXL was performed in patients diagnosed with progressive ectasia. In their study, as in ours, the changes in HOAs were not statistically correlated with improvements in visual acuity. Because a moderate to high positive correlation has been previously demonstrated between corneal HOAs and CDVA in keratoconic patients, the role of the anterior corneal Ó 2013 Lippincott Williams & Wilkins
HOAs in the visual degradation of such patients has been established.4,12 However, because other factors, such as corneal scattering or the optical degradation of the posterior corneal surface,21 likely play significant roles in the final visual outcomes and in visual degradation, we questioned whether the collagen fiber changes that follow the CXL would allow the anterior corneal HOA to impact the spherocylindrical correction (after the procedure) to significantly improve visual acuity. Our 2-year results also corroborate the findings of previous publications that showed a significant improvement in apical and central K.17,19–23 We found a moderate to high correlation between the corneal topographic measurement changes and visual acuity. These findings, together with significant changes in corneal aberrations, provide a reasonable explanation for the improvements in the CDVA and UDVA. In a different approach, using indices that were obtained from Pentacam, Greenstein et al24 investigated the changes after CXL in patients diagnosed with keratoconus and corneal ectasia, and they analyzed the associations between these changes and visual acuity. Although they found a significant improvement in 4 of 7 topography indices 1 year after performing the CXL, no significant correlation was found between the changes in individual topography indices and the visual acuity changes after the CXL. We believe that absolute values may be more accurate and sensitive to corneal changes after CXL rather than the index generated from Placido-disk corneal topography. This may explain why apical keratometric values in our study were significantly correlated to the CDVA. In conclusion, CXL was effective in improving the UDVA and the CDVA in eyes with progressive keratoconus 2 years after the procedure was carried out in our patient population, with a concomitant improvement in topographic metrics and most corneal aberrations. A significant reduction in apical K was observed and correlated with visual acuity improvements. www.corneajrnl.com |
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REFERENCES 1. Rabinowitz YS. Keratoconus. Surv Ophthalmol. 1998;42:297–319. 2. Wilson SE, Lin DT, Klyce SD. Corneal topography of keratoconus. Cornea. 1991;10:2–8. 3. Shah S, Laiquzzaman M, Bhojwani R, et al. 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. 4. Piñero DP, Alio JL, Barraquer RI, et al. Corneal biomechanics, refraction, and corneal aberrometry in keratoconus: an integrated study. Invest Ophthalmol Vis Sci. 2010;51:1948–1955. 5. Ortiz D, Piñero D, Shabayek MH, et al. Corneal biomechanical properties in normal, post-laser in situ keratomileusis, and keratoconic eyes. J Cataract Refract Surg. 2007;33:1371–1375. 6. Meek KM, Tuft SJ, Huang Y, et al. Changes in collagen orientation and distribution in keratoconus corneas. Invest Ophthalmol Vis Sci. 2005;46: 1948–1956. 7. Wollensak G, Spoerl E, Seiler T. Stress–strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced cross-linking. J Cataract Refract Surg. 2003;29:1780–1785. 8. Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol. 2006;17:356–360. 9. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620–627. 10. Piñero DP, Alió JL, Alesón A, et al. Pentacam posterior and anterior corneal aberrations in normal and keratoconic eyes. Clin Exp Optom. 2009;92:297–303. 11. Bühren J, Kühne C, Kohnen T. Defining subclinical keratoconus using corneal first-surface higher-order aberrations. Am J Ophthalmol. 2007; 143:381–389. 12. Alió JL, Shabayek MH. Corneal higher order aberrations: a method to grade keratoconus. J Refract Surg. 2006;22:539–545. 13. Barbero S, Marcos S, Merayo-Lloves J, et al. Validation of the estimation of corneal aberrations from videokeratography in keratoconus. J Refract Surg. 2002;18:263–270.
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14. Maeda N, Fujikado T, Kuroda T, et al. Wavefront aberrations measured with Hartmann–Shack sensor in patients with keratoconus. Ophthalmology. 2002;109:1996–2003. 15. Tang W, Collins MJ, Carney L, et al. The accuracy and precision performance of four videokeratoscopes in measuring test surfaces. Optom Vis Sci. 2000;77:483–491. 16. Alió JL, Piñero DP, Alesón A, et al. Keratoconus-integrated characterization considering anterior corneal aberrations, internal astigmatism, and corneal biomechanics. J Cataract Refract Surg. 2011;37: 552–568. 17. Applegate RA, Sarver EJ, Khemsara V. Are all aberrations equal? J Refract Surg. 2002;18:S556–S562. 18. Vinciguerra P, Albè E, Trazza S, et al. Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology. 2009;116:369–378. 19. Caporossi A, Mazzotta C, Baiocchi S, et al. Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Am J Ophthalmol. 2010;149: 585–593. 20. Greenstein SA, Fry KL, Hersh MJ, et al. Higher-order aberrations after corneal collagen crosslinking for keratoconus and corneal ectasia. J Cataract Refract Surg. 2012;38:292–302. 21. Nakagawa T, Maeda N, Kosaki R, et al. Higher-order aberrations due to the posterior corneal surface in patients with keratoconus. Invest Ophthalmol Vis Sci. 2009;50:2660–2665. 22. Grewal DS, Brar GS, Jain R, et al. Corneal collagen crosslinking using riboflavin and ultraviolet-A light for keratoconus: one-year analysis using Scheimpflug imaging. J Cataract Refract Surg. 2009; 35:425–432. 23. Raiskup-Wolf F, Hoyer A, Spoerl E, et al. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008;34:796–801. 24. Greenstein SA, Fry KL, Hersh PS. Corneal topography indices after corneal collagen crosslinking for keratoconus and corneal ectasia: oneyear results. J Cataract Refract Surg. 2011;37:1282–1290.
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