1040-5488/14/9102-0178/0 VOL. 91, NO. 2, PP. 178Y186 OPTOMETRY AND VISION SCIENCE Copyright * 2014 American Academy of Optometry
ORIGINAL ARTICLE
Anterior and Posterior Corneal Changes after Crosslinking for Keratoconus Johannes Steinberg*, Mariam Ahmadiyar, Anika Rost†, Andreas Frings*, Filip Filev*, Toam Katz*, and Stephan J. Linke‡
ABSTRACT Purpose. To evaluate anterior and posterior changes in corneal topography and tomography after corneal crosslinking (CXL) in eyes with progressive keratoconus. Methods. Scheimpflug analyses (Pentacam, Oculus) of 20 eyes with keratoconus performed before and after corneal CXL were included into retrospective analysis. Mean follow-up was 2 years. Changes in topographic, tomographic, and pachymetric values were statistically analyzed applying analysis of variance. Further, the distance and direction between the anterior maximum keratometry (Kmax) and the apex as well as the distance and direction between the thinnest point in corneal thickness (TPCT) and the corneal apex before and after CXL were studied. Results. Two years after CXL, a statistically significant reduction of the keratometry at the flat meridian (j0.8 D, p G 0.05), the steep meridian (j0.5 D, p G 0.05), the ‘‘index of surface variance’’ (j5.3, p G 0.05), and the ‘‘index of highest decentration’’ (j0.05, p G 0.05) could be demonstrated. While the elevation of the front surface at the apex decreased (j1.5 Km, p G 0.05), the back elevation at the apex (+2 Km, p G 0.05) increased. Although not reaching statistical significance, the maximum front and back elevation demonstrated the same trend; while maximum front elevation data remained stable (j0.3 Km, p = 0.961), maximum back elevation data increased (+6.7 Km, p = 0.122). The corneal thickness at the apex (j22.0 Km, p G 0.001) and the TPCT (j20.0 Km, p G 0.001) decreased, leading to an increase of the corneal thickness progression from the corneal apex to the periphery. The position of Kmax and TPCT remained stable. Conclusions. Corneal topography proved to be useful in the follow-up for CXL because of significant changes in the keratometry. Increasing posterior elevation values, despite a stabilized anterior corneal surface, might be a sign of ongoing ectatic changes in the posterior corneal surface. (Optom Vis Sci 2014;91:178Y186) Key Words: keratoconus, corneal crosslinking, topography, tomography, Pentacam
K
eratoconus is a corneal degeneration characterized by stromal thinning and conical ectasia.1,2 Because of the progressive course of the disease, the increasing keratometry and the irregular astigmatism often result in a decreased visual acuity. In advanced stages, because of corneal scarring and contact lens intolerability, corneal grafting may be necessary for visual rehabilitation. For the last few years, corneal collagen crosslinking (CXL) has been established by study groups all over the world as an effective and safe treatment for keratoconus and other ectatic corneal
*MD † BSc(Optom) ‡ MD, PhD Department of Ophthalmology, UKE - University Medical Center HamburgEppendorf, Hamburg (JS, MA, AF, FF, TK, SJL); Fielmann Academy ‘Schloss Plo¨n’, Plo¨n (AR); and Care-Vision Germany, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (TK, SJL).
disorders.3Y7 Crosslinking is based on a photo-oxidative reaction, catalyzed by riboflavin, which induces an increase in corneal stiffness, and a biomechanical response that decreases the progression of the disease.8 Because CXL may stop, but not necessarily reverse the corneal ectasia, early treatment is important. In particular, corneal tomography based on the Scheimpflug technique has proved to be highly sensitive for the early detection of keratoconus9,10 because this technique analyzes both the anterior and the posterior corneal surfaces with high precision and repeatability.11 Despite slightly reduced repeatability after CXL, the Pentacam still provides accurate and reliable in vivo analysis during follow-up.12,13 Most of the existing clinical studies on follow-up after CXL focus on corneal topography and visual acuity changes.3,6,7,14 We, therefore, decided to analyze the effect of CXL on the anterior and posterior corneal surfaces by using Scheimpflug topography and tomographic parameters. While a potential stabilization of the anterior corneal
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Corneal Changes after Crosslinking for KeratoconusVSteinberg et al.
surface after CXL is essential for the visual acuity, potential changes in the posterior surface could indicate an ongoing ectatic process or CXL-related changes. To the best of our knowledge, the effect of CXL on posterior elevation data is not well established. To verify the stabilizing effect of the CXL, we also studied the potential changes in the position of the thinnest point in corneal thickness (TPCT) and the position of maximum keratometry of the anterior corneal surface (Kmax) after CXL.
METHODS This retrospective study was performed at the Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Germany. Pentacam analyses of 20 patients with keratoconus (mean age = 30 T 11 yr; range = 13Y50 yr) were included into this study. Measurements were performed with a rotating Scheimpflug imaging system (Pentacam HR; Oculus, Inc., Dudenhofen, Germany). The patients were instructed to keep both eyes open and fixated on the black target in the center of the blue fixation beam. After attaining perfect alignment, the instrument automatically took a single scan containing 25 Scheimpflug images within 2 seconds. If, on examination, the scan obtained an ‘OK’ quality specification grade, it was saved if not, it was repeated. A diagnosis of keratoconus was made if the Pentacam analyses (setting, best-fit sphere; float, 8 mm) demonstrated a posterior elevation of 20 Km or greater and a locally corresponding elevation of the anterior surface of 15 Km or greater and/or a locally corresponding TPCT of less than 500 Km in at least one eye of the patient. These criteria are recommended by the Pentacam interpretation guideline and coincide with our clinical experience. In addition, a topographic keratoconus classification (TKC) of 1 or higher and a Belin/Ambrosio Enhanced Ectasia Display greater than 2.5 verified the keratoconus diagnosis in the affected eye. The TKC is calculated by the Pentacam software, including a variety of topographic parameters of the anterior corneal surface.15 The Belin/Ambrosio Enhanced Ectasia Display combines an elevation-based and a pachymetric corneal evaluation in one comprehensive display to give the clinician a global view of the tomographic structure of the cornea. Normal deviation values were implemented for the front- and back-enhanced elevations, pachymetric distribution, and vertical displacement of the thinnest point in relation to the apex. The final display showed less than 5% false-positives or false-negatives.16 Only patients with a documented preoperative progression of keratoconus (second Pentacam analysis obtained after approximately 3Y6 mo) were included in the study. Ectatic progression was diagnosed on the basis of corneal tomography and topographic changes, including progressive elevation of the posterior and/or anterior surface, progressive corneal thinning at the thinnest point, and an increase in corneal anterior keratometry steepening combined with an irregular astigmatism in the cone area. All eyes investigated in this study received standard 0.1% riboflavinYultraviolet A (UVA) CXL treatment according to the methodology described by Wollensak et al.17 Postoperatively, antibiotic, nonsteroidal anti-inflammatory eyedrops, and hyaluronic acid drops were administered, and a bandage soft contact lens was fitted. The contact lens was removed after the epithelial defect had healed. After epithelial closure, only corticosteroid
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eyedrops (one drop four times daily during the first 4 weeks, reducing by one drop every 2 wk) and hyaluronic acid drops (every 2 hr for at least 4 wk) were administered. Pentacam imaging before CXL (T0; median = 2 mo, range = 1Y3 mo), within 6 months after CXL (T1; median = 3 mo, range = 2Y6 mo), and from the last available examination (T2; median = 24 mo, range = 12Y40 mo) were included into the statistical analysis. Data were exported to a Microsoft Excel spreadsheet and included the parameters displayed in Table 1. The Pentacam centers its scan (topography map center) on the most forward-protruding corneal spot (corneal apex). We identified the position of the maximum keratometry value of the front surface (Kmax) applying x and y coordinates derived from the Pentacam analysis (the x and y values mark the distance of Kmax from the apex on the x and y axis). We then analyzed the distance and direction (vector length) between the Kmax and the apex, as well as the vector length between TPCT and the apex before and after CXL. Results were displayed on bar charts as relative change in the initial vector length before CXL. Informed consent for retrospective data analysis was obtained from patients with keratoconus, and the local ethics committee Hamburg, Germany, approved the study. For patients using contact lenses, a minimum of 14 days (hard lenses) or 4 days (soft lenses) of contact lens abstinence was maintained. To avoid a potential bias attributed to diurnal variations of the corneal thickness and the anterior and posterior corneal surface, Pentacam analyses were performed within a total timeframe of 3 hours (between 12:00 and 15:00 h).18
Statistical Analysis We used the Shapiro-Wilk test for normality to test for normal distribution of the analyzed parameters. To test the equality of matched pairs of observations between specific time intervals, a parametric repeated-measures analysis of variance (ANOVA) was applied when the data were normally distributed (and the assumption of sphericity was satisfied), and a nonparametric alternative Friedman ANOVA if this was not the case. To follow up the omnibus tests of both methods, we compared the mean (or median) differences by applying a planned contrast after the repeated measures ANOVA and a Wilcoxon signed rank test after the Friedman ANOVA. Both were adjusted with the Bonferroni method for multiple comparisons. To analyze the relative change in Kmax and the TPCT between before and after CXL, we applied the Bonett-Price method and the Bonett-Price standard error.19 To examine the effect of age, we calculated the mean differences between T0 and T2 and compared them between the age groups defined as 30 years and younger and older than 30 years.
RESULTS Topography-, Pachymetry-, and Tomography-Related Changes After CXL Table 2 displays the considered topographic and tomographic parameters at T0, T1, and T2. A significant reduction in the flat meridian ([K1]; j0.8 D, p G 0.05) was demonstrated between T0 and T2 (long-term effect after
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180 Corneal Changes after Crosslinking for KeratoconusVSteinberg et al. TABLE 1.
Analyzed topographic and tomographic parameters Parameter Unit Topography
K1 K2 Astig. Kmax ISV IVA
D§ D§ D§ D§
IHA IHD Elevation
Ele_f_AP Km|| Ele_f_TP Km|| Ele_f_max Km|| Ele_b_AP Km|| Ele_b_TP Km|| Ele_b_max Km||
Pachymetry
TPCT CCT RPI_avg
ART_avg
Km|| Km||
Definition/explanation Flat meridian of the anterior corneal surface Steep meridian of the anterior corneal surface Astigmatism (K1 j K2) Corneal dioptric power in the steepest meridian of the anterior corneal surface Index of surface variance; the ISV gives deviation of individual corneal radii from mean values* Index of vertical asymmetry; the IVA gives degree of asymmetry of corneal radii with respect to horizontal meridian as axis of reflection* Index of highest asymmetry; the IHA displays the degree of asymmetry of height data across horizontal meridian (analogous to IVA) Index of highest decentration; the IHD gives the degree of decentration of height data in vertical direction* Front surface elevation at the corneal apex† Front surface elevation at the thinnest point† Front surface elevation at the point with highest value within the 4-mm (diameter) zone centered at the apex† Back surface elevation at the corneal apex‡ Back surface elevation at the thinnest point‡ Back surface elevation at the point with highest value within the 4-mm (diameter) zone centered at the apex‡ Corneal thickness at the thinnest point Central corneal thickness (corneal thickness at the apex) Average pachymetric progression index. The RPI is calculated for every 1- meridian along the complete 360-, starting at the thinnest point. The RPI_avg displays the average of all meridians.14 RPI will be higher if the cornea gets thicker in a more accentuated pattern from the thinnest point out to the periphery Ambro´sio relational thickness average. ART_avg is calculated as the ratio of the TPCT and the RPI_avg. Because the ART_avg displays the thickness progression in relation to the TPCT, the thickness progression results are less biased by differences in baseline corneal thickness.14
*Pentacam-derived topographic asymmetry index. †Reference surface is the best-fit sphere of the central 8 mm (diameter) of the corneal front surface centered at the corneal apex. ‡Reference surface is the best-fit sphere of the central 8 mm (diameter) of the corneal back surface centered at the corneal apex. §Diopters. ||Micrometer. ART_avg, Ambro´sio relational thickness average; Astig., topometric astigmatism; CCT, corneal thickness at the apex; Ele_b_Ap, back surface elevation at the apex using the 8-mm best-fit sphere; Ele_b_max, back surface elevation at the point with highest value within the 4-mm (diameter) zone centered at the apex using the 8-mm best-fit sphere; Ele_b_TP, back surface elevation at the thinnest point using the 8-mm best-fit sphere; Ele_f_Ap, front surface elevation at the apex using the 8-mm best-fit sphere; Ele_f_max, front surface elevation at the point with highest value within the 4-mm (diameter) zone centered at the apex using the 8-mm best-fit sphere; Ele_f_TP, front surface elevation at the thinnest point using the 8-mm best-fit sphere; IHA, index of highest asymmetry; IHD, index of highest decentration; ISV, index of surface variance; IVA, index of vertical asymmetry; K1, flat meridian of the anterior surface; K2, steep meridian of the anterior surface; Kmax, steepest keratometry of the anterior surface; RPI_avg, average pachymetric progression index; TPCT, corneal thickness at the thinnest point.
CXL). In parallel, the steepest keratometry (Kmax) also decreased, but this tendency was statistically not significant (j2.7 D, p = 0.082). Analysis of variance revealed an overall significant decrease after CXL of the steep meridian ([K2]; j0.5 D, p G 0.05) and the asymmetry indices ISV (index of surface variance, j5.3, p G 0.05) and IHD (index of highest decentration, j0.05, p G 0.05). None of the analyzed topographic parameters indicated signs of aggravation of the ectasia as a long-term effect of CXL. Analyzing the posterior surface of the cornea after CXL, we demonstrated an overall statistically significant increase of the back elevation at the apex ([Ele_b_Ap]; +2 Km, p G 0.05). In contrast, the front elevation at the apex (Ele_f_Ap) decreased on a significant level (Y1.5 Km, p G 0.05). The maximum front
(Ele_f_max) and back elevation (Ele_b_max) demonstrated the same trend as apex elevation data, although statistical significance was not reached: while maximum front elevation data (Ele_f_max) remained stable (j0.3 Km, p = 0.961), maximum back elevation data (Ele_b_max) increased (+6.7 Km, p = 0.122) as a long-term effect of CXL. We further analyzed changes in the pachymetry and pachymetry progression from the thinnest point to the corneal periphery. Regarding pachymetry, we could demonstrate a statistically significant decrease in the TPCT and the central corneal thickness (CCT) within the first 3 month after CXL, as well as 2 years after CXL (TPCT: T0 j T1= j24.0 Km, p G 0.001; T0 j T2: j20.0 Km, p G 0.001; CCT: T0 j T1: j34.0 Km, p G 0.001; T0 j T2: j22.0 Km, p G 0.001).
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Corneal Changes after Crosslinking for KeratoconusVSteinberg et al.
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TABLE 2.
Analyzed topographic and tomographic parameter and their changes after CXL T0 Pentacam parameter Topometry
Elevation
Pachy
Mean/ median
K1 K2 Astig. Kmax ISV IVA IHA IHD Ele_f_Ap Ele_f_TP Ele_f_max Ele_b_Ap Ele_b_TP Ele_b_max TPCT CCT RPI_avg ART_avg
T2
47.2 51.4 4.2 57.3 106.0 1.1 28.4 0.105 T1 12.0 26.1 35.8 28 T2 61.5 66.8 467 T1.T2 480 T1.T2 2.24 T1.T2 202.0
T1
SD/ Q25YQ75 Min
Max
4.0 39.3 5.0 43.8 2.2 1.5 53.1Y61.7 50.5 36.3 53.0 0.5 0.4 22.8Y50.1 13.6 0.1 0.0 8Y17 j2.0 16.3 j20.0 10.9 18.0 17Y38 j10.0 39Y78 22.0 25.9 30.0 50.9 386.0 448Y505 396.0 1.1 0.0 144Y284 0.0
55.6 63.9 9.7 90.0 187.0 1.8 116.0 0.2 36.0 55.0 57.0 100.0 181.0 135.0 605.0 618.0 4.6 649.0
Mean/ SD/ median Q25YQ75 47.3 51.7 4.4 57.5 107.0 1.1 28.3 0.1 14.0 29.5 35.6 31.0 65.5 69.4 443.0 446.0 2.7 172.5
T2 Min
Max
Mean/ SD/ median Q25YQ75
4.7 39.3 58.6 5.3 43.9 64.5 2.5 0.8 10.1 51.7Y61.9 48.2 81.8 35.9 52.0 183.0 0.4 0.5 1.7 14Y44.3 4.9 115.2 0.1 0.0 0.2 8.5Y21 j3.0 34.0 11.1 11.0 50.0 10.5 17.0 52.0 22.5Y48.5 j8.0 64.0 49.5Y81 22.0 106.0 18.8 38.0 108.0 50.4 368.0 570.0 427Y482 373.0 582.0 1.0 1.2 5.1 124Y220 82.0 469.0
46.4 50.7 4.2 54.6 100.7 1.1 20.1 0.1 10.5 28.1 35.5 30.0 64.5 73.5 447.0 458.0 2.6 173.0
4.7 4.9 2.3 51.5Y62.1 36.2 0.4 11.1Y39 0.1 5.5/17.5 11.9 12.8 24Y44.5 51.5Y78 19.8 49.2 433Y478 0.9 143Y210
Min 38.9 43.4 1.0 48.7 48.0 0.4 0.1 0.0 j2.0 10.0 14.0 j6.0 22.0 47.0 355.0 391.0 1.1 78.0
Max
p
58.4 0.011 60.8 0.015 10.3 0.692 77.8 0.082* 180.0 0.029 1.9 0.607 102.0 0.91* 0.2 0.032 46.0 0.025* 62.0 0.458 63.0 0.961 97.0 0.015* 124.0 0.331* 125.0 0.122 589.0 G0.001 601.0 G0.001* 4.7 0.019 547.0 0.037*
Superscripts indicate the significant simple contrast (p G 0.05) between T0 and T1 or between T0 and T2. All contrast were adjusted using the Bonferroni method. Tested with repeated-measures ANOVA or, if the assumption of normality is not satisfied, its nonparametric alternative Friedman ANOVA. *Tested with nonparametric Friedman ANOVA. ANOVA, analysis of variance; ART_avg, Ambro´sio relational thickness average; Astig, topometric astigmatism; CCT, corneal thickness at the apex; CXL, corneal cross-linking; Ele_b_Ap, back surface elevation at the apex using the 8-mm best-fit sphere; Ele_b_max, back surface elevation at the point with highest value within the 4-mm (diameter) zone centered at the apex using the 8-mm best-fit sphere; Ele_b_TP, back surface elevation at the thinnest point using the 8-mm best-fit sphere; Ele_f_Ap, front surface elevation at the apex using the 8-mm best-fit sphere; Ele_f_max, front surface elevation at the point with highest value within the 4-mm (diameter) zone centered at the apex using the 8-mm best-fit sphere; Ele_f_TP, front surface elevation at the thinnest point using the 8-mm best-fit sphere; IHA, index of highest asymmetry; IHD, index of highest decentration; ISV, index of surface variance; IVA, index of vertical asymmetry; K1, flat meridian of the anterior surface; K2, steep meridian of the anterior surface; Kmax, steepest keratometry of the anterior surface; RPI_avg, average pachymetric progression index; TPCT, corneal thickness at the thinnest point.
The pachymetric progression index is calculated for every 1- meridian along the complete 360-, starting at the thinnest point. The average pachymetric progression index (RPI_avg) displays the average of all meridians.16 The pachymetric index will be higher if the cornea gets thicker in a more accentuated pattern from the thinnest point to the periphery. Our data demonstrated an increased thickness progression at T1 and T2 compared to T0. We also analyzed the relational thickness parameter (ART_avg), which is calculated as the ratio of the TPCT and the RPI_avg. Because the ART_avg displays the thickness progression in relation to the TPCT, the thickness progression results are less biased by differences in baseline corneal thickness.9 Higher values indicate a limited increase in the thickness from the thinnest point to the periphery. The analysis including ART_avg confirmed the results of the RPI_avg analysis: The pachymetric increase from the TPCT to the corneal periphery was more pronounced after CXL. To control for the effect of age, we calculated the mean differences between T0 and T2 for every parameter and compared them between the age groups defined as 30 years or younger and older than 30 years. The mean age of these groups were 22 T 4 and 40 T 6 years, respectively. None of the parameters demonstrated a significant difference between the age groups.
Decentration of the Front Surface Kmax and TPCT Location We further analyzed the TPCT and Kmax position in the right (Fig. 1A) and left (Fig. 1B) keratoconus eyes before CXL. Figure 2 displays the relative change in the distance between TPCT and the apex (A) as well as between Kmax and the apex (B) before (T0) and a median of 2 years (T2) after CXL. The TPCT median vector length at 2 years after CXL (T2) increased by 5.8% compared to the preoperative state (T0). This change in vector length was not statistically significant. The median Kmax vector length at T2 increased by 9.5% compared to that at T0. This change in vector length was also not statistically significant.
DISCUSSION This retrospective study analyzed the topographic and tomographic changes after CXL using riboflavin and UVA irradiation. We demonstrated a statistically significant reduction of the flat and steep meridian and of the topographic asymmetry parameters (ISV and IHD) as long-term effects after CXL. In agreement with other reports,3,5,20,21 corneal pachymetry (TPCT and CCT) decreased after CXL, leading to an increased pachymetric progression from
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182 Corneal Changes after Crosslinking for KeratoconusVSteinberg et al.
FIGURE 1. Position of the thinnest point in corneal thickness (TPCT; -) and the maximum keratometry (Kmax, +) in the right (A) and left (B) eyes before crosslinking. Optometry and Vision Science, Vol. 91, No. 2, February 2014
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Corneal Changes after Crosslinking for KeratoconusVSteinberg et al.
183
FIGURE 2. Relative changes in the vector length before and a median of 2 years after crosslinking between the corneal apex and the thinnest point in corneal thickness (A) and Kmax (B).
the thinnest point to the corneal periphery. To the best of our knowledge, the current study is the first to reveal an increased back surface elevation after CXL, whereas the typically decentered position of the TPCT and Kmax did not shift significantly after CXL. To study the natural course of the keratoconus, the collaborative longitudinal evaluation of keratoconus (CLEK) study was initiated in 1996.22 CLEK study included 1209 patients with clinical manifest keratoconus and performed an annual follow-up for 8 years. Corneal curvature was measured by manual keratometry. The flat corneal meridian increased with an annual rate of 0.20 D T 0.80 D/yr, leading to an overall 8-year increase of 1.60 D. Above, 24% of patients demonstrated an increase of 3.00 D or more. These (and other) changes led to a significant decrease in high- and lowcontrast and best-corrected visual acuity.22 We did not analyze visual acuity changes but, other than the natural course of the ectatic disease, we could demonstrate a significantly decrease of the flat (K1) and steep (K2) meridian within 2 years after CXL (K1: j0.8 D,
p G 0.05; K2: j0.7 D, p G 0.05). Further topographic or tomographic parameters like Kmax and front or back elevation values were not analyzed within the CLEK study. The first study analyzing the clinical effect of CXL in keratoconus eyes was performed by Wollensak et al.17 and included 23 eyes. The study group demonstrated a mean decrease of the anterior maximum keratometry (Kmax) of 2.01 D after a mean follow-up of 3 to 4 years. Other study groups23Y25 have described similar results. Recently, Raiskup-Wolf et al.26 studied the long-term effect of CXL (follow-up of 4Y6 yr) and demonstrated a Kmax reduction of 1.46 D after 1 year, 1.91 D after 2 years, and 2.66 D after 4 years. Our results are in line with these results by demonstrating a Kmax decrease of 2.7 D after a mean follow-up of 2 years. Despite including almost the same number of eyes in our analysis as Wollensak et al.,17 our results did not reach statistical significance. Wollensak et al.17 used the t test for their statistical analysis. We had to apply the nonparametric Friedman ANOVA because our Kmax data were
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184 Corneal Changes after Crosslinking for KeratoconusVSteinberg et al.
not normally distributed. Koller et al.27 showed that the baseline Kmax value (Kmax before CXL) is an important predictor for the amount of the Kmax decrease after CXL. They found that a Kmax 9 54.0 D was the main risk factor for a limited reduction of Kmax after CXL (odds ratio = 1.88). Vinciguerra et al.7 demonstrated an optimized morphological and clinical outcome after CXL for patients between 18 and 39 years. In our cohort with a mean age of 30 T 11 years (range = 13Y50 years) and a mean Kmax of 59.3 D before CXL, we demonstrated a marked reduction of Kmax (j2.7 D at 2 yr after the procedure), which was, however, not statistically significant. The most probable reason for the lack of statistical significance is the high variation of this value within our patient cohort (see Q25YQ75 and min/max in Table 2) and the low number of included subjects (n = 20). When controlling for the effect of age, no statistical significance was demonstrated for the analyzed parameters between the two age groups (e30 vs. 930 yr). However, because of the small sample size (n = 9 vs. n = 11), the application of the statistical tests for differences between age groups lacks power. Thus, it is difficult to estimate the real impact of age in our study, and the age effect remains an issue for further research. Besides the marked but not statistically significant reduction of Kmax, we demonstrated a statistically significant decrease in the steep and flat meridian and in the asymmetry parameters ISV and IHD. Hassan et al.,28 analyzing corneal topography changes 3 years after CXL, could not demonstrate significant changes in the analyzed asymmetry or keratometry parameters. They included 38 eyes and used the TMS-4 (Tomey) topography device. On the one hand, Hassan et al. provided a larger study population; on the other, the TMS-4 uses a different optical technique, acquiring significantly less measurement points per eye (8000 [TMS-4] vs. 138,000 [Pentacam HR]) and calculating different asymmetry indices. Nevertheless, their results and ours could demonstrate that CXL at least stops the progression of topographic asymmetry in progressive keratoconus. We demonstrated a statistically significant increase in the posterior elevation at the apex 2 years after CXL ([Ele_b_Ap]; +2 Km) accompanied by a trend of increasing posterior elevation values at the thinnest point ([Ele_b_TP]; + 3 Km) and the point of maximum posterior elevation ([Ele_b_max]); + 6.7 Km). Grewal et al.29 and Henriquez et al.,5 also analyzing corneal changes after CXL with Scheimpflug imaging, found no significant changes in the posterior elevation. The progressive increase in the posterior elevation, despite a CXL-induced flattening effect on values for the front surface keratometry, is surprising and has not been shown before. At present, it is unclear whether this opposite trend for front surface flattening and progressive back surface elevation is due to an ongoing ectatic change within the deeper layers of the cornea (although stabilization of the anterior part of the cornea was successful)30,31 or whether it is a secondary effect induced by the observed corneal thinning after CXL. We and others29,32Y34 have found decreasing pachymetric values at the apex (1 yr after CXL: j34.0 Km, p G 0.001; 2 yr after CXL: j22.0 Km, p G 0.001) and at the TPCT (1 yr after CXL: j24.0 Km, p G 0.001; 2 yr after CXL: j20.0 Km, p G 0.001). Greenstein et al.,33 who included 53 keratoconus eyes and used Scheimpflug pachymetry, found a significant reduction of the pachymetry at the apex (j20.4 Km, p G 0.05) and the thinnest point (j31.4 Km, p G 0.05) within the first 3 months and a statistically significant increase during the next 3 months (apex: +18 Km, p G 0.05; thinnest point: +20.2 Km, p G 0.05). At
1 year after CXL, the pachymetry was still below baseline (apex: j8.2 Km, p G 0.05; thinnest point: j12.1 Km, p G 0.05). Koller et al.34 also demonstrated a reduced pachymetry at 1 year after CXL (j12 Km, p G 0.05). Grewal et al.,29 who also measured the corneal thickness using Scheimpflug tomography at the apex and the pupil center within 1 year after CXL, did not find any statistically significant pachymetric changes. Thus, a trend for an initially decreasing and subsequently increasing pachymetry after CXL could also be established. The same trend (without statistical significance) within 1 year after CXL was demonstrated by Goldich et al.32 using an Orbscan II for corneal thickness measurement. Transient mild haze is a common side effect after CXL. This haze formation could affect and bias the accuracy of optical pachymetry by leading to a misinterpretation of the anterior and posterior edges of the cornea.34,35 Gutierrez et al.,36 using Pentacam densitometry, demonstrated a significant increase of corneal density within the first 3 months after CXL, which decreased to baseline at 1 year after CXL. Holopainen and Krootila,37 measuring corneal pachymetry with ultrasound, demonstrated an initial decrease in corneal thinning of 50 Km within the first 3 months after CXL, which exceeds the results for reduced pachymetry acquired using the Pentacam. Ucakhan et al.38 found a significantly thinner central corneal thickness using the Pentacam compared with ultrasound pachymetry and a relatively poor correlation between the two techniques. There have been various theories for this poor correlation, including postinterventional haze and stromal edema being responsible for possibly incorrect thickness measurements, but up to now, no accepted explanation for the lower thickness measurements within the first month or then a gradual increase thereafter has been found.34,38Y40 The temporal inferior decentration of both TPCT and Kmax is pathognomonic for keratoconus eyes. The more heterogeneous distribution of Kmax is attributed to the fact that the position of maximum keratometry is not as stationary as the TPCT during keratoconus progression. In summary, our data confirm that CXL is a potent treatment modality for temporarily halting corneal ectasia progression in keratoconus eyes. Furthermore, the increased radius of K1 and K2 and a decrease in topographic asymmetry parameters support the verifiable improvement of corneal topography after CXL, which is of major importance for the visual acuity rehabilitation of the patient and the corresponding increase in vision-related quality of life.22,41 The coexistent increase in the elevation data derived from the posterior corneal surface and decrease in central corneal thickness might indicate an ongoing ectatic process within the posterior part of the cornea, despite the stabilized anterior surface. The position of Kmax and TPCT remained stable and no trend toward recentration (i.e. reversed displacement) was identified. Regarding the follow-up after CXL, corneal topography proved to be superior to corneal tomography because of the significant changes that were detectable using topographic analysis and because of the potential methodological errors when using optical corneal tomography after CXL.
ACKNOWLEDGMENTS The authors thank Vasyl Druchkiv for supporting and supervising the database and expert statistical analysis. M. Ahmadiyar and J. Steinberg contributed equally and should be considered co-first authors.
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Corneal Changes after Crosslinking for KeratoconusVSteinberg et al. The authors had no conflict of interest and no financial support regarding this study. Received April 26, 2013; accepted October 17, 2013.
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17. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-AYinduced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620Y7. 18. Read SA, Collins MJ, Iskander DR. Diurnal variation of axial length, intraocular pressure, and anterior eye biometrics. Invest Ophthalmol Vis Sci 2008;49:2911Y8. 19. Bonett DG, Price RM. Statistical inference for a linear function of medians: confidence intervals, hypothesis testing, and sample size requirements. Psychol Methods 2002;7:370Y83. 20. Legare ME, Iovieno A, Yeung SN, Kim P, Lichtinger A, Hollands S, Slomovic AR, Rootman DS. Corneal collagen cross-linking using riboflavin and ultraviolet A for the treatment of mild to moderate keratoconus: 2-year follow-up. Can J Ophthalmol 2013;48:63Y8. 21. Vinciguerra P, Albe E, Trazza S, Rosetta P, Vinciguerra R, Seiler T, Epstein D. Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology 2009;116:369Y78. 22. Wagner H, Barr JT, Zadnik K. Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study: methods and findings to date. Cont Lens Anterior Eye 2007;30:223Y32. 23. Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR. A randomized controlled trial of corneal collagen crosslinking in progressive keratoconus: preliminary results. J Refract Surg 2008;24:S720Y5. 24. Coskunseven E, Jankov MR, 2nd, Hafezi F. Contralateral eye study of corneal collagen cross-linking with riboflavin and UVA irradiation in patients with keratoconus. J Refract Surg 2009;25:371Y6. 25. Fournie P, Galiacy S, Arne JL, Malecaze F. Corneal collagen crosslinking with ultraviolet-A light and riboflavin for the treatment of progressive keratoconus. J Fr Ophtalmol 2009;32:1Y7. 26. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008;34:796Y801. 27. Koller T, Pajic B, Vinciguerra P, Seiler T. Flattening of the cornea after collagen crosslinking for keratoconus. J Cataract Refract Surg 2011;37:1488Y92. 28. Hassan Z, Szalai E, Modis L, Jr., Berta A, Nemeth G. Assessment of corneal topography indices after collagen crosslinking for keratoconus. Eur J Ophthalmol 2013;23:635Y40. 29. Grewal DS, Brar GS, Jain R, Sood V, Singla M, Grewal SP. Corneal collagen crosslinking using riboflavin and ultraviolet-A light for keratoconus: one-year analysis using Scheimpflug imaging. J Cataract Refract Surg 2009;35:425Y32. 30. Knappe S, Stachs O, Zhivov A, Hovakimyan M, Guthoff R. Results of confocal microscopy examinations after collagen cross-linking with riboflavin and UVA light in patients with progressive keratoconus. Ophthalmologica 2011;225:95Y104. 31. Wollensak G, Sporl E, Mazzotta C, Kalinski T, Sel S. Interlamellar cohesion after corneal crosslinking using riboflavin and ultraviolet A light. Br J Ophthalmol 2011;95:876Y80. 32. Goldich Y, Marcovich AL, Barkana Y, Mandel Y, Hirsh A, Morad Y, Avni I, Zadok D. Clinical and corneal biomechanical changes after collagen cross-linking with riboflavin and UV irradiation in patients with progressive keratoconus: results after 2 years of follow-up. Cornea 2012;31:609Y14. 33. Greenstein SA, Shah VP, Fry KL, Hersh PS. Corneal thickness changes after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg 2011;37:691Y700. 34. Koller T, Iseli HP, Hafezi F, Vinciguerra P, Seiler T. Scheimpflug imaging of corneas after collagen cross-linking. Cornea 2009;28:510Y5.
Optometry and Vision Science, Vol. 91, No. 2, February 2014
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186 Corneal Changes after Crosslinking for KeratoconusVSteinberg et al. 35. Kim SW, Byun YJ, Kim EK, Kim TI. Central corneal thickness measurements in unoperated eyes and eyes after PRK for myopia using Pentacam, Orbscan II, and ultrasonic pachymetry. J Refract Surg 2007; 23:888Y94. 36. Gutierrez R, Lopez I, Villa-Collar C, Gonzalez-Meijome JM. Corneal transparency after cross-linking for keratoconus: 1-year followup. J Refract Surg 2012;28:781Y6. 37. Holopainen JM, Krootila K. Transient corneal thinning in eyes undergoing corneal cross-linking. Am J Ophthalmol 2011;152: 533Y6. 38. Ucakhan OO, Ozkan M, Kanpolat A. Corneal thickness measurements in normal and keratoconic eyes: Pentacam comprehensive eye scanner versus noncontact specular microscopy and ultrasound pachymetry. J Cataract Refract Surg 2006;32:970Y7. 39. Caporossi A, Mazzotta C, Baiocchi S, Caporossi T. 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: 585Y93. 40. Poli M, Cornut PL, Balmitgere T, Aptel F, Janin H, Burillon C. Prospective study of corneal collagen cross-linking efficacy and tolerance in the treatment of keratoconus and corneal ectasia: 3-year results. Cornea 2013;32:583Y90. 41. Kymes SM, Walline JJ, Zadnik K, Gordon MO. Quality of life in keratoconus. Am J Ophthalmol 2004;138:527Y35.
Johannes Steinberg Department of Ophthalmology University Medical Center Hamburg-Eppendorf Martinistrasse 52 20246 Hamburg Germany e-mail: [email protected]
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ORIGINAL ARTICLE
Anterior and Posterior Corneal Changes after Crosslinking for Keratoconus Johannes Steinberg*, Mariam Ahmadiyar, Anika Rost†, Andreas Frings*, Filip Filev*, Toam Katz*, and Stephan J. Linke‡
ABSTRACT Purpose. To evaluate anterior and posterior changes in corneal topography and tomography after corneal crosslinking (CXL) in eyes with progressive keratoconus. Methods. Scheimpflug analyses (Pentacam, Oculus) of 20 eyes with keratoconus performed before and after corneal CXL were included into retrospective analysis. Mean follow-up was 2 years. Changes in topographic, tomographic, and pachymetric values were statistically analyzed applying analysis of variance. Further, the distance and direction between the anterior maximum keratometry (Kmax) and the apex as well as the distance and direction between the thinnest point in corneal thickness (TPCT) and the corneal apex before and after CXL were studied. Results. Two years after CXL, a statistically significant reduction of the keratometry at the flat meridian (j0.8 D, p G 0.05), the steep meridian (j0.5 D, p G 0.05), the ‘‘index of surface variance’’ (j5.3, p G 0.05), and the ‘‘index of highest decentration’’ (j0.05, p G 0.05) could be demonstrated. While the elevation of the front surface at the apex decreased (j1.5 Km, p G 0.05), the back elevation at the apex (+2 Km, p G 0.05) increased. Although not reaching statistical significance, the maximum front and back elevation demonstrated the same trend; while maximum front elevation data remained stable (j0.3 Km, p = 0.961), maximum back elevation data increased (+6.7 Km, p = 0.122). The corneal thickness at the apex (j22.0 Km, p G 0.001) and the TPCT (j20.0 Km, p G 0.001) decreased, leading to an increase of the corneal thickness progression from the corneal apex to the periphery. The position of Kmax and TPCT remained stable. Conclusions. Corneal topography proved to be useful in the follow-up for CXL because of significant changes in the keratometry. Increasing posterior elevation values, despite a stabilized anterior corneal surface, might be a sign of ongoing ectatic changes in the posterior corneal surface. (Optom Vis Sci 2014;91:178Y186) Key Words: keratoconus, corneal crosslinking, topography, tomography, Pentacam
K
eratoconus is a corneal degeneration characterized by stromal thinning and conical ectasia.1,2 Because of the progressive course of the disease, the increasing keratometry and the irregular astigmatism often result in a decreased visual acuity. In advanced stages, because of corneal scarring and contact lens intolerability, corneal grafting may be necessary for visual rehabilitation. For the last few years, corneal collagen crosslinking (CXL) has been established by study groups all over the world as an effective and safe treatment for keratoconus and other ectatic corneal
*MD † BSc(Optom) ‡ MD, PhD Department of Ophthalmology, UKE - University Medical Center HamburgEppendorf, Hamburg (JS, MA, AF, FF, TK, SJL); Fielmann Academy ‘Schloss Plo¨n’, Plo¨n (AR); and Care-Vision Germany, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (TK, SJL).
disorders.3Y7 Crosslinking is based on a photo-oxidative reaction, catalyzed by riboflavin, which induces an increase in corneal stiffness, and a biomechanical response that decreases the progression of the disease.8 Because CXL may stop, but not necessarily reverse the corneal ectasia, early treatment is important. In particular, corneal tomography based on the Scheimpflug technique has proved to be highly sensitive for the early detection of keratoconus9,10 because this technique analyzes both the anterior and the posterior corneal surfaces with high precision and repeatability.11 Despite slightly reduced repeatability after CXL, the Pentacam still provides accurate and reliable in vivo analysis during follow-up.12,13 Most of the existing clinical studies on follow-up after CXL focus on corneal topography and visual acuity changes.3,6,7,14 We, therefore, decided to analyze the effect of CXL on the anterior and posterior corneal surfaces by using Scheimpflug topography and tomographic parameters. While a potential stabilization of the anterior corneal
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Corneal Changes after Crosslinking for KeratoconusVSteinberg et al.
surface after CXL is essential for the visual acuity, potential changes in the posterior surface could indicate an ongoing ectatic process or CXL-related changes. To the best of our knowledge, the effect of CXL on posterior elevation data is not well established. To verify the stabilizing effect of the CXL, we also studied the potential changes in the position of the thinnest point in corneal thickness (TPCT) and the position of maximum keratometry of the anterior corneal surface (Kmax) after CXL.
METHODS This retrospective study was performed at the Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Germany. Pentacam analyses of 20 patients with keratoconus (mean age = 30 T 11 yr; range = 13Y50 yr) were included into this study. Measurements were performed with a rotating Scheimpflug imaging system (Pentacam HR; Oculus, Inc., Dudenhofen, Germany). The patients were instructed to keep both eyes open and fixated on the black target in the center of the blue fixation beam. After attaining perfect alignment, the instrument automatically took a single scan containing 25 Scheimpflug images within 2 seconds. If, on examination, the scan obtained an ‘OK’ quality specification grade, it was saved if not, it was repeated. A diagnosis of keratoconus was made if the Pentacam analyses (setting, best-fit sphere; float, 8 mm) demonstrated a posterior elevation of 20 Km or greater and a locally corresponding elevation of the anterior surface of 15 Km or greater and/or a locally corresponding TPCT of less than 500 Km in at least one eye of the patient. These criteria are recommended by the Pentacam interpretation guideline and coincide with our clinical experience. In addition, a topographic keratoconus classification (TKC) of 1 or higher and a Belin/Ambrosio Enhanced Ectasia Display greater than 2.5 verified the keratoconus diagnosis in the affected eye. The TKC is calculated by the Pentacam software, including a variety of topographic parameters of the anterior corneal surface.15 The Belin/Ambrosio Enhanced Ectasia Display combines an elevation-based and a pachymetric corneal evaluation in one comprehensive display to give the clinician a global view of the tomographic structure of the cornea. Normal deviation values were implemented for the front- and back-enhanced elevations, pachymetric distribution, and vertical displacement of the thinnest point in relation to the apex. The final display showed less than 5% false-positives or false-negatives.16 Only patients with a documented preoperative progression of keratoconus (second Pentacam analysis obtained after approximately 3Y6 mo) were included in the study. Ectatic progression was diagnosed on the basis of corneal tomography and topographic changes, including progressive elevation of the posterior and/or anterior surface, progressive corneal thinning at the thinnest point, and an increase in corneal anterior keratometry steepening combined with an irregular astigmatism in the cone area. All eyes investigated in this study received standard 0.1% riboflavinYultraviolet A (UVA) CXL treatment according to the methodology described by Wollensak et al.17 Postoperatively, antibiotic, nonsteroidal anti-inflammatory eyedrops, and hyaluronic acid drops were administered, and a bandage soft contact lens was fitted. The contact lens was removed after the epithelial defect had healed. After epithelial closure, only corticosteroid
179
eyedrops (one drop four times daily during the first 4 weeks, reducing by one drop every 2 wk) and hyaluronic acid drops (every 2 hr for at least 4 wk) were administered. Pentacam imaging before CXL (T0; median = 2 mo, range = 1Y3 mo), within 6 months after CXL (T1; median = 3 mo, range = 2Y6 mo), and from the last available examination (T2; median = 24 mo, range = 12Y40 mo) were included into the statistical analysis. Data were exported to a Microsoft Excel spreadsheet and included the parameters displayed in Table 1. The Pentacam centers its scan (topography map center) on the most forward-protruding corneal spot (corneal apex). We identified the position of the maximum keratometry value of the front surface (Kmax) applying x and y coordinates derived from the Pentacam analysis (the x and y values mark the distance of Kmax from the apex on the x and y axis). We then analyzed the distance and direction (vector length) between the Kmax and the apex, as well as the vector length between TPCT and the apex before and after CXL. Results were displayed on bar charts as relative change in the initial vector length before CXL. Informed consent for retrospective data analysis was obtained from patients with keratoconus, and the local ethics committee Hamburg, Germany, approved the study. For patients using contact lenses, a minimum of 14 days (hard lenses) or 4 days (soft lenses) of contact lens abstinence was maintained. To avoid a potential bias attributed to diurnal variations of the corneal thickness and the anterior and posterior corneal surface, Pentacam analyses were performed within a total timeframe of 3 hours (between 12:00 and 15:00 h).18
Statistical Analysis We used the Shapiro-Wilk test for normality to test for normal distribution of the analyzed parameters. To test the equality of matched pairs of observations between specific time intervals, a parametric repeated-measures analysis of variance (ANOVA) was applied when the data were normally distributed (and the assumption of sphericity was satisfied), and a nonparametric alternative Friedman ANOVA if this was not the case. To follow up the omnibus tests of both methods, we compared the mean (or median) differences by applying a planned contrast after the repeated measures ANOVA and a Wilcoxon signed rank test after the Friedman ANOVA. Both were adjusted with the Bonferroni method for multiple comparisons. To analyze the relative change in Kmax and the TPCT between before and after CXL, we applied the Bonett-Price method and the Bonett-Price standard error.19 To examine the effect of age, we calculated the mean differences between T0 and T2 and compared them between the age groups defined as 30 years and younger and older than 30 years.
RESULTS Topography-, Pachymetry-, and Tomography-Related Changes After CXL Table 2 displays the considered topographic and tomographic parameters at T0, T1, and T2. A significant reduction in the flat meridian ([K1]; j0.8 D, p G 0.05) was demonstrated between T0 and T2 (long-term effect after
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180 Corneal Changes after Crosslinking for KeratoconusVSteinberg et al. TABLE 1.
Analyzed topographic and tomographic parameters Parameter Unit Topography
K1 K2 Astig. Kmax ISV IVA
D§ D§ D§ D§
IHA IHD Elevation
Ele_f_AP Km|| Ele_f_TP Km|| Ele_f_max Km|| Ele_b_AP Km|| Ele_b_TP Km|| Ele_b_max Km||
Pachymetry
TPCT CCT RPI_avg
ART_avg
Km|| Km||
Definition/explanation Flat meridian of the anterior corneal surface Steep meridian of the anterior corneal surface Astigmatism (K1 j K2) Corneal dioptric power in the steepest meridian of the anterior corneal surface Index of surface variance; the ISV gives deviation of individual corneal radii from mean values* Index of vertical asymmetry; the IVA gives degree of asymmetry of corneal radii with respect to horizontal meridian as axis of reflection* Index of highest asymmetry; the IHA displays the degree of asymmetry of height data across horizontal meridian (analogous to IVA) Index of highest decentration; the IHD gives the degree of decentration of height data in vertical direction* Front surface elevation at the corneal apex† Front surface elevation at the thinnest point† Front surface elevation at the point with highest value within the 4-mm (diameter) zone centered at the apex† Back surface elevation at the corneal apex‡ Back surface elevation at the thinnest point‡ Back surface elevation at the point with highest value within the 4-mm (diameter) zone centered at the apex‡ Corneal thickness at the thinnest point Central corneal thickness (corneal thickness at the apex) Average pachymetric progression index. The RPI is calculated for every 1- meridian along the complete 360-, starting at the thinnest point. The RPI_avg displays the average of all meridians.14 RPI will be higher if the cornea gets thicker in a more accentuated pattern from the thinnest point out to the periphery Ambro´sio relational thickness average. ART_avg is calculated as the ratio of the TPCT and the RPI_avg. Because the ART_avg displays the thickness progression in relation to the TPCT, the thickness progression results are less biased by differences in baseline corneal thickness.14
*Pentacam-derived topographic asymmetry index. †Reference surface is the best-fit sphere of the central 8 mm (diameter) of the corneal front surface centered at the corneal apex. ‡Reference surface is the best-fit sphere of the central 8 mm (diameter) of the corneal back surface centered at the corneal apex. §Diopters. ||Micrometer. ART_avg, Ambro´sio relational thickness average; Astig., topometric astigmatism; CCT, corneal thickness at the apex; Ele_b_Ap, back surface elevation at the apex using the 8-mm best-fit sphere; Ele_b_max, back surface elevation at the point with highest value within the 4-mm (diameter) zone centered at the apex using the 8-mm best-fit sphere; Ele_b_TP, back surface elevation at the thinnest point using the 8-mm best-fit sphere; Ele_f_Ap, front surface elevation at the apex using the 8-mm best-fit sphere; Ele_f_max, front surface elevation at the point with highest value within the 4-mm (diameter) zone centered at the apex using the 8-mm best-fit sphere; Ele_f_TP, front surface elevation at the thinnest point using the 8-mm best-fit sphere; IHA, index of highest asymmetry; IHD, index of highest decentration; ISV, index of surface variance; IVA, index of vertical asymmetry; K1, flat meridian of the anterior surface; K2, steep meridian of the anterior surface; Kmax, steepest keratometry of the anterior surface; RPI_avg, average pachymetric progression index; TPCT, corneal thickness at the thinnest point.
CXL). In parallel, the steepest keratometry (Kmax) also decreased, but this tendency was statistically not significant (j2.7 D, p = 0.082). Analysis of variance revealed an overall significant decrease after CXL of the steep meridian ([K2]; j0.5 D, p G 0.05) and the asymmetry indices ISV (index of surface variance, j5.3, p G 0.05) and IHD (index of highest decentration, j0.05, p G 0.05). None of the analyzed topographic parameters indicated signs of aggravation of the ectasia as a long-term effect of CXL. Analyzing the posterior surface of the cornea after CXL, we demonstrated an overall statistically significant increase of the back elevation at the apex ([Ele_b_Ap]; +2 Km, p G 0.05). In contrast, the front elevation at the apex (Ele_f_Ap) decreased on a significant level (Y1.5 Km, p G 0.05). The maximum front
(Ele_f_max) and back elevation (Ele_b_max) demonstrated the same trend as apex elevation data, although statistical significance was not reached: while maximum front elevation data (Ele_f_max) remained stable (j0.3 Km, p = 0.961), maximum back elevation data (Ele_b_max) increased (+6.7 Km, p = 0.122) as a long-term effect of CXL. We further analyzed changes in the pachymetry and pachymetry progression from the thinnest point to the corneal periphery. Regarding pachymetry, we could demonstrate a statistically significant decrease in the TPCT and the central corneal thickness (CCT) within the first 3 month after CXL, as well as 2 years after CXL (TPCT: T0 j T1= j24.0 Km, p G 0.001; T0 j T2: j20.0 Km, p G 0.001; CCT: T0 j T1: j34.0 Km, p G 0.001; T0 j T2: j22.0 Km, p G 0.001).
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Corneal Changes after Crosslinking for KeratoconusVSteinberg et al.
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TABLE 2.
Analyzed topographic and tomographic parameter and their changes after CXL T0 Pentacam parameter Topometry
Elevation
Pachy
Mean/ median
K1 K2 Astig. Kmax ISV IVA IHA IHD Ele_f_Ap Ele_f_TP Ele_f_max Ele_b_Ap Ele_b_TP Ele_b_max TPCT CCT RPI_avg ART_avg
T2
47.2 51.4 4.2 57.3 106.0 1.1 28.4 0.105 T1 12.0 26.1 35.8 28 T2 61.5 66.8 467 T1.T2 480 T1.T2 2.24 T1.T2 202.0
T1
SD/ Q25YQ75 Min
Max
4.0 39.3 5.0 43.8 2.2 1.5 53.1Y61.7 50.5 36.3 53.0 0.5 0.4 22.8Y50.1 13.6 0.1 0.0 8Y17 j2.0 16.3 j20.0 10.9 18.0 17Y38 j10.0 39Y78 22.0 25.9 30.0 50.9 386.0 448Y505 396.0 1.1 0.0 144Y284 0.0
55.6 63.9 9.7 90.0 187.0 1.8 116.0 0.2 36.0 55.0 57.0 100.0 181.0 135.0 605.0 618.0 4.6 649.0
Mean/ SD/ median Q25YQ75 47.3 51.7 4.4 57.5 107.0 1.1 28.3 0.1 14.0 29.5 35.6 31.0 65.5 69.4 443.0 446.0 2.7 172.5
T2 Min
Max
Mean/ SD/ median Q25YQ75
4.7 39.3 58.6 5.3 43.9 64.5 2.5 0.8 10.1 51.7Y61.9 48.2 81.8 35.9 52.0 183.0 0.4 0.5 1.7 14Y44.3 4.9 115.2 0.1 0.0 0.2 8.5Y21 j3.0 34.0 11.1 11.0 50.0 10.5 17.0 52.0 22.5Y48.5 j8.0 64.0 49.5Y81 22.0 106.0 18.8 38.0 108.0 50.4 368.0 570.0 427Y482 373.0 582.0 1.0 1.2 5.1 124Y220 82.0 469.0
46.4 50.7 4.2 54.6 100.7 1.1 20.1 0.1 10.5 28.1 35.5 30.0 64.5 73.5 447.0 458.0 2.6 173.0
4.7 4.9 2.3 51.5Y62.1 36.2 0.4 11.1Y39 0.1 5.5/17.5 11.9 12.8 24Y44.5 51.5Y78 19.8 49.2 433Y478 0.9 143Y210
Min 38.9 43.4 1.0 48.7 48.0 0.4 0.1 0.0 j2.0 10.0 14.0 j6.0 22.0 47.0 355.0 391.0 1.1 78.0
Max
p
58.4 0.011 60.8 0.015 10.3 0.692 77.8 0.082* 180.0 0.029 1.9 0.607 102.0 0.91* 0.2 0.032 46.0 0.025* 62.0 0.458 63.0 0.961 97.0 0.015* 124.0 0.331* 125.0 0.122 589.0 G0.001 601.0 G0.001* 4.7 0.019 547.0 0.037*
Superscripts indicate the significant simple contrast (p G 0.05) between T0 and T1 or between T0 and T2. All contrast were adjusted using the Bonferroni method. Tested with repeated-measures ANOVA or, if the assumption of normality is not satisfied, its nonparametric alternative Friedman ANOVA. *Tested with nonparametric Friedman ANOVA. ANOVA, analysis of variance; ART_avg, Ambro´sio relational thickness average; Astig, topometric astigmatism; CCT, corneal thickness at the apex; CXL, corneal cross-linking; Ele_b_Ap, back surface elevation at the apex using the 8-mm best-fit sphere; Ele_b_max, back surface elevation at the point with highest value within the 4-mm (diameter) zone centered at the apex using the 8-mm best-fit sphere; Ele_b_TP, back surface elevation at the thinnest point using the 8-mm best-fit sphere; Ele_f_Ap, front surface elevation at the apex using the 8-mm best-fit sphere; Ele_f_max, front surface elevation at the point with highest value within the 4-mm (diameter) zone centered at the apex using the 8-mm best-fit sphere; Ele_f_TP, front surface elevation at the thinnest point using the 8-mm best-fit sphere; IHA, index of highest asymmetry; IHD, index of highest decentration; ISV, index of surface variance; IVA, index of vertical asymmetry; K1, flat meridian of the anterior surface; K2, steep meridian of the anterior surface; Kmax, steepest keratometry of the anterior surface; RPI_avg, average pachymetric progression index; TPCT, corneal thickness at the thinnest point.
The pachymetric progression index is calculated for every 1- meridian along the complete 360-, starting at the thinnest point. The average pachymetric progression index (RPI_avg) displays the average of all meridians.16 The pachymetric index will be higher if the cornea gets thicker in a more accentuated pattern from the thinnest point to the periphery. Our data demonstrated an increased thickness progression at T1 and T2 compared to T0. We also analyzed the relational thickness parameter (ART_avg), which is calculated as the ratio of the TPCT and the RPI_avg. Because the ART_avg displays the thickness progression in relation to the TPCT, the thickness progression results are less biased by differences in baseline corneal thickness.9 Higher values indicate a limited increase in the thickness from the thinnest point to the periphery. The analysis including ART_avg confirmed the results of the RPI_avg analysis: The pachymetric increase from the TPCT to the corneal periphery was more pronounced after CXL. To control for the effect of age, we calculated the mean differences between T0 and T2 for every parameter and compared them between the age groups defined as 30 years or younger and older than 30 years. The mean age of these groups were 22 T 4 and 40 T 6 years, respectively. None of the parameters demonstrated a significant difference between the age groups.
Decentration of the Front Surface Kmax and TPCT Location We further analyzed the TPCT and Kmax position in the right (Fig. 1A) and left (Fig. 1B) keratoconus eyes before CXL. Figure 2 displays the relative change in the distance between TPCT and the apex (A) as well as between Kmax and the apex (B) before (T0) and a median of 2 years (T2) after CXL. The TPCT median vector length at 2 years after CXL (T2) increased by 5.8% compared to the preoperative state (T0). This change in vector length was not statistically significant. The median Kmax vector length at T2 increased by 9.5% compared to that at T0. This change in vector length was also not statistically significant.
DISCUSSION This retrospective study analyzed the topographic and tomographic changes after CXL using riboflavin and UVA irradiation. We demonstrated a statistically significant reduction of the flat and steep meridian and of the topographic asymmetry parameters (ISV and IHD) as long-term effects after CXL. In agreement with other reports,3,5,20,21 corneal pachymetry (TPCT and CCT) decreased after CXL, leading to an increased pachymetric progression from
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182 Corneal Changes after Crosslinking for KeratoconusVSteinberg et al.
FIGURE 1. Position of the thinnest point in corneal thickness (TPCT; -) and the maximum keratometry (Kmax, +) in the right (A) and left (B) eyes before crosslinking. Optometry and Vision Science, Vol. 91, No. 2, February 2014
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Corneal Changes after Crosslinking for KeratoconusVSteinberg et al.
183
FIGURE 2. Relative changes in the vector length before and a median of 2 years after crosslinking between the corneal apex and the thinnest point in corneal thickness (A) and Kmax (B).
the thinnest point to the corneal periphery. To the best of our knowledge, the current study is the first to reveal an increased back surface elevation after CXL, whereas the typically decentered position of the TPCT and Kmax did not shift significantly after CXL. To study the natural course of the keratoconus, the collaborative longitudinal evaluation of keratoconus (CLEK) study was initiated in 1996.22 CLEK study included 1209 patients with clinical manifest keratoconus and performed an annual follow-up for 8 years. Corneal curvature was measured by manual keratometry. The flat corneal meridian increased with an annual rate of 0.20 D T 0.80 D/yr, leading to an overall 8-year increase of 1.60 D. Above, 24% of patients demonstrated an increase of 3.00 D or more. These (and other) changes led to a significant decrease in high- and lowcontrast and best-corrected visual acuity.22 We did not analyze visual acuity changes but, other than the natural course of the ectatic disease, we could demonstrate a significantly decrease of the flat (K1) and steep (K2) meridian within 2 years after CXL (K1: j0.8 D,
p G 0.05; K2: j0.7 D, p G 0.05). Further topographic or tomographic parameters like Kmax and front or back elevation values were not analyzed within the CLEK study. The first study analyzing the clinical effect of CXL in keratoconus eyes was performed by Wollensak et al.17 and included 23 eyes. The study group demonstrated a mean decrease of the anterior maximum keratometry (Kmax) of 2.01 D after a mean follow-up of 3 to 4 years. Other study groups23Y25 have described similar results. Recently, Raiskup-Wolf et al.26 studied the long-term effect of CXL (follow-up of 4Y6 yr) and demonstrated a Kmax reduction of 1.46 D after 1 year, 1.91 D after 2 years, and 2.66 D after 4 years. Our results are in line with these results by demonstrating a Kmax decrease of 2.7 D after a mean follow-up of 2 years. Despite including almost the same number of eyes in our analysis as Wollensak et al.,17 our results did not reach statistical significance. Wollensak et al.17 used the t test for their statistical analysis. We had to apply the nonparametric Friedman ANOVA because our Kmax data were
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184 Corneal Changes after Crosslinking for KeratoconusVSteinberg et al.
not normally distributed. Koller et al.27 showed that the baseline Kmax value (Kmax before CXL) is an important predictor for the amount of the Kmax decrease after CXL. They found that a Kmax 9 54.0 D was the main risk factor for a limited reduction of Kmax after CXL (odds ratio = 1.88). Vinciguerra et al.7 demonstrated an optimized morphological and clinical outcome after CXL for patients between 18 and 39 years. In our cohort with a mean age of 30 T 11 years (range = 13Y50 years) and a mean Kmax of 59.3 D before CXL, we demonstrated a marked reduction of Kmax (j2.7 D at 2 yr after the procedure), which was, however, not statistically significant. The most probable reason for the lack of statistical significance is the high variation of this value within our patient cohort (see Q25YQ75 and min/max in Table 2) and the low number of included subjects (n = 20). When controlling for the effect of age, no statistical significance was demonstrated for the analyzed parameters between the two age groups (e30 vs. 930 yr). However, because of the small sample size (n = 9 vs. n = 11), the application of the statistical tests for differences between age groups lacks power. Thus, it is difficult to estimate the real impact of age in our study, and the age effect remains an issue for further research. Besides the marked but not statistically significant reduction of Kmax, we demonstrated a statistically significant decrease in the steep and flat meridian and in the asymmetry parameters ISV and IHD. Hassan et al.,28 analyzing corneal topography changes 3 years after CXL, could not demonstrate significant changes in the analyzed asymmetry or keratometry parameters. They included 38 eyes and used the TMS-4 (Tomey) topography device. On the one hand, Hassan et al. provided a larger study population; on the other, the TMS-4 uses a different optical technique, acquiring significantly less measurement points per eye (8000 [TMS-4] vs. 138,000 [Pentacam HR]) and calculating different asymmetry indices. Nevertheless, their results and ours could demonstrate that CXL at least stops the progression of topographic asymmetry in progressive keratoconus. We demonstrated a statistically significant increase in the posterior elevation at the apex 2 years after CXL ([Ele_b_Ap]; +2 Km) accompanied by a trend of increasing posterior elevation values at the thinnest point ([Ele_b_TP]; + 3 Km) and the point of maximum posterior elevation ([Ele_b_max]); + 6.7 Km). Grewal et al.29 and Henriquez et al.,5 also analyzing corneal changes after CXL with Scheimpflug imaging, found no significant changes in the posterior elevation. The progressive increase in the posterior elevation, despite a CXL-induced flattening effect on values for the front surface keratometry, is surprising and has not been shown before. At present, it is unclear whether this opposite trend for front surface flattening and progressive back surface elevation is due to an ongoing ectatic change within the deeper layers of the cornea (although stabilization of the anterior part of the cornea was successful)30,31 or whether it is a secondary effect induced by the observed corneal thinning after CXL. We and others29,32Y34 have found decreasing pachymetric values at the apex (1 yr after CXL: j34.0 Km, p G 0.001; 2 yr after CXL: j22.0 Km, p G 0.001) and at the TPCT (1 yr after CXL: j24.0 Km, p G 0.001; 2 yr after CXL: j20.0 Km, p G 0.001). Greenstein et al.,33 who included 53 keratoconus eyes and used Scheimpflug pachymetry, found a significant reduction of the pachymetry at the apex (j20.4 Km, p G 0.05) and the thinnest point (j31.4 Km, p G 0.05) within the first 3 months and a statistically significant increase during the next 3 months (apex: +18 Km, p G 0.05; thinnest point: +20.2 Km, p G 0.05). At
1 year after CXL, the pachymetry was still below baseline (apex: j8.2 Km, p G 0.05; thinnest point: j12.1 Km, p G 0.05). Koller et al.34 also demonstrated a reduced pachymetry at 1 year after CXL (j12 Km, p G 0.05). Grewal et al.,29 who also measured the corneal thickness using Scheimpflug tomography at the apex and the pupil center within 1 year after CXL, did not find any statistically significant pachymetric changes. Thus, a trend for an initially decreasing and subsequently increasing pachymetry after CXL could also be established. The same trend (without statistical significance) within 1 year after CXL was demonstrated by Goldich et al.32 using an Orbscan II for corneal thickness measurement. Transient mild haze is a common side effect after CXL. This haze formation could affect and bias the accuracy of optical pachymetry by leading to a misinterpretation of the anterior and posterior edges of the cornea.34,35 Gutierrez et al.,36 using Pentacam densitometry, demonstrated a significant increase of corneal density within the first 3 months after CXL, which decreased to baseline at 1 year after CXL. Holopainen and Krootila,37 measuring corneal pachymetry with ultrasound, demonstrated an initial decrease in corneal thinning of 50 Km within the first 3 months after CXL, which exceeds the results for reduced pachymetry acquired using the Pentacam. Ucakhan et al.38 found a significantly thinner central corneal thickness using the Pentacam compared with ultrasound pachymetry and a relatively poor correlation between the two techniques. There have been various theories for this poor correlation, including postinterventional haze and stromal edema being responsible for possibly incorrect thickness measurements, but up to now, no accepted explanation for the lower thickness measurements within the first month or then a gradual increase thereafter has been found.34,38Y40 The temporal inferior decentration of both TPCT and Kmax is pathognomonic for keratoconus eyes. The more heterogeneous distribution of Kmax is attributed to the fact that the position of maximum keratometry is not as stationary as the TPCT during keratoconus progression. In summary, our data confirm that CXL is a potent treatment modality for temporarily halting corneal ectasia progression in keratoconus eyes. Furthermore, the increased radius of K1 and K2 and a decrease in topographic asymmetry parameters support the verifiable improvement of corneal topography after CXL, which is of major importance for the visual acuity rehabilitation of the patient and the corresponding increase in vision-related quality of life.22,41 The coexistent increase in the elevation data derived from the posterior corneal surface and decrease in central corneal thickness might indicate an ongoing ectatic process within the posterior part of the cornea, despite the stabilized anterior surface. The position of Kmax and TPCT remained stable and no trend toward recentration (i.e. reversed displacement) was identified. Regarding the follow-up after CXL, corneal topography proved to be superior to corneal tomography because of the significant changes that were detectable using topographic analysis and because of the potential methodological errors when using optical corneal tomography after CXL.
ACKNOWLEDGMENTS The authors thank Vasyl Druchkiv for supporting and supervising the database and expert statistical analysis. M. Ahmadiyar and J. Steinberg contributed equally and should be considered co-first authors.
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Corneal Changes after Crosslinking for KeratoconusVSteinberg et al. The authors had no conflict of interest and no financial support regarding this study. Received April 26, 2013; accepted October 17, 2013.
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Johannes Steinberg Department of Ophthalmology University Medical Center Hamburg-Eppendorf Martinistrasse 52 20246 Hamburg Germany e-mail: [email protected]
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