ARTICLE
Changes in straylight and densitometry values after corneal collagen crosslinking Niklas Pircher, MD, Mojtaba Pachala, MD, Franz Prager, MD, Stefan Pieh, MD, Gerald Schmidinger, MD
PURPOSE: To evaluate the change in backward-directed and forward-directed corneal straylight in eyes after corneal collagen crosslinking (CXL) and its correlation with corrected distance visual acuity (CDVA) and changes in corneal topography. SETTING: Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. DESIGN: Retrospective cohort study. METHODS: Following the Dresden protocol, corneal CXL was performed in eyes with progressive keratoconus. Corneal light scattering was evaluated using densitometry measurements from different corneal layers and zones obtained using Scheimpflug tomography (Pentacam HR). Retinal straylight values were measured using the C-Quant device. The CDVA was recorded during each follow-up examination. Changes in corneal topography were measured using Scheimpflug tomography. RESULTS: The study evaluated 31 eyes of 31 patients. The mean densitometry of different corneal layers and in 3 different zones increased 3 months postoperatively and decreased thereafter. The mean densitometry in the 0.0 to 2.0 mm zone remained statistically significantly elevated after 12 months (P < .05). The mean preoperative retinal straylight was 1.14 log(s) G 0.28 (SD). The mean straylight peaked after 1 month and then decreased continuously but remained elevated after 1 year at 1.26 G 0.21 log(s). There was an increase in CDVA and flattening of the steepest keratometry (K) value (maximum K). Eyes with the greatest maximum K reduction also had the highest densitometry values. CONCLUSIONS: Crosslinking-induced stromal changes resulted in an increase in densitometry, especially in the anterior stroma of the central (0.0 to 2.0 mm) zone. These changes correlated with an increase in retinal straylight but not with the postoperative CDVA values. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2015; -:-–- Q 2015 ASCRS and ESCRS
Despite promising clinical results, corneal collagen crosslinking (CXL) frequently causes a reduction in visual acuity during the initial postoperative phase.1–4 This loss of visual acuity might be from epithelial changes, changes in corneal topography, or a loss in transparency of the corneal stroma. Typically, at the early follow-up visits a slitlamp examination will show a demarcation line at varying depths of the stroma. Koller et al.2 concluded that the demarcation line could be used to determine the effectiveness of the treatment. Furthermore, an increase in corneal optical density (haze) of the stroma above the demarcation line is frequently observable during the first Q 2015 ASCRS and ESCRS Published by Elsevier Inc.
months after CXL. Several studies have used confocal microscopy to try to identify the cause of this haze.3–6 Another study showed that this type of opacification takes at least 12 months to resolve.7 Light entering an opacified corneal stroma is scattered in all directions. Backward-scattered light can be observed as haze at the slitlamp or on Scheimpflug imaging.7 Forward-scattered light that reaches the retina reduces optical quality by increasing halo and glare and has small effects on high-contrast visual acuity and contrast sensitivity.8 Because straylight is an aspect of vision quality, forward-scattered and backward-scattered light might be a significant http://dx.doi.org/10.1016/j.jcrs.2014.07.043 0886-3350
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parameter to measure the outcomes of corneal CXL.8 Because the effect of CXL is confined to the area of ultraviolet (UV) light exposure,9 one might assume that haze is restricted to the UV-exposed area and that there could be differences in the stromal opacity at different depths and concentric zones in the stroma. Because corneal scarring is correlated with flattening of the corneal surface,10 a correlation between postoperative haze intensity and the flattening effect of the CXL treatment might be assumed. This study used densitometry and retinal straylight measurements to evaluate the change in backward and forward corneal light scattering. In addition, it assessed the changes in corneal haze after corneal CXL and their correlation with visual acuity and the changes in corneal topography. PATIENTS AND METHODS This retrospective evaluation of prospectively collected data study was performed in accordance with the Declaration of Helsinki. The local ethics committee approved the protocol of the prospective trial. Informed written consent was obtained from all patients before surgical intervention in accordance with institutional and legal requirements. The trial included eyes of consecutive patients from the institution’s outpatient department that had progressive keratoconus and were scheduled for corneal CXL.
Surgical Technique The same surgeon (G.S.) performed all procedures using the standard Dresden protocol for corneal CXL. The treatment protocol has been described in detail.11,12 Irradiation of ultraviolet-A (UVA) light was applied in a 9.0 mm radius. The UVA irradiation device (UVX-1000, IROC Innocross AG) has a Gaussian beam profile with a higher irradiation intensity in the center of the cornea. Postoperatively, a therapeutic contact lens was placed in the eye and left in place until epithelial closure.
Follow-up Patients received antibiotic treatment for 1 week and antiinflammatory and lubricating drops for 4 weeks. Postoperative follow-up examinations were performed until reepithelialization was complete and then again at 1, 3, 6, and 12 months. During each examination, the corrected distance visual acuity (CDVA), corneal topography,
Submitted: July 18, 2014. Final revision submitted: July 18, 2014. Accepted: July 20, 2014. From the Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. Corresponding author: Gerald Schmidinger, MD, Department of Ophthalmology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. E-mail: gerald.schmidinger@ meduniwien.ac.at.
densitometry, and retinal straylight values were recorded. The changes in the maximum keratometry (K) values induced by corneal CXL were compared as vectors by calculating the mean preoperative centroids and postoperative centroids as described by Holladay et al.13 The centroid (the mean of a set of x values and y values [xm/ym]) was calculated using the mean of each variable obtained using a rotating Scheimpflug camera (Pentacam HR, Oculus Optikger€ ate GmbH). The centroid (mean maximum K) was then converted back to standard polar notation.
Corneal Densitometry To evaluate the changes in corneal transparency, backward light scattering was measured using Scheimpflug tomography. All measurements were performed by the same experienced operator in a dark room. The patients were instructed to blink 2 times immediately before the examination and then to open their eye as wide as possible to ensure the cornea was not covered by the eyelid. Only examinations with automatic Scheimpflug scans (25 images in 2 seconds) that passed the device’s software quality check were used. This was done to avoid the estimation of unmeasured areas and to ensure the analysis of the full area of 10.0 mm diameter and the patient’s fixation (ie, quality specification parameter “OK”). The outcome of the software for the standardized Scheimpflug densitometry analysis was expressed in gray-scale units (GSUs). The GSU scale was calibrated using proprietary software in which light scatter is defined on a scale of 0 (minimum scatter; maximum transparency) to 100 (maximum scatter; minimum transparency) to enable the investigator to evaluate the optical density at various stromal depths and concentric zones of the cornea. Densitometry values were obtained preoperatively and 1, 3, 6, and 12 months postoperatively. The relative values of backward light scatter were measured in different layers of the cornea and separately in different concentric zones. Corneal backward-scattered light measurements were recorded for the anterior 150 mm and the posterior 80 mm of the corneal stroma and for the stroma between these 2 layers. In addition, backward light scatter intensities were evaluated in the 0.0 to 2.0 mm, 2.0 to 6.0 mm, and 6.0 to 10.0 mm zones through the entire depth of the cornea.
Retinal Straylight Measurement The retinal (forward-directed) light-scattering was measured using the C-Quant straylight meter (Oculus Optikger€ ate GmbH).14 A dark test field divided in half was superimposed on a bright, flickering light source to induce straylight. In one half of the test field, a compensation light was presented to allow patients to perceive the flickering. During the test, a series of limited-duration stimuli was presented that varied in the compensation light intensity. The straylight log(s) parameter was deduced based on the patient’s responses about which test-field flickering was stronger.8,15 The measurements were performed 3 times in all patients. Measurements deemed unreliable by the straylight meter were excluded. Only measurements with a standard deviation (SD) less than 0.08 and a quality factor greater than 1 as displayed by the straylight meter’s software were analyzed.
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Statistical Analysis Continuous variables are given as the mean G SD. ShapiroWilks analysis was performed to determine whether the distribution was normal. The Wilcoxon signed-rank test was used with the G*power freeware (version 3.1.3) to perform the post hoc power analysis. To explore statistically significant differences, SPSS software (version 22.0.0.0, International Business Machines Corp.) was used to perform repeatedmeasures analysis of variance on comparable data. A 2-sided probability value less than 0.05 was considered statistically significant. Pearson correlation coefficients (r) were calculated to assess the correlation of CDVA with retinal straylight and with corneal densitometry values.
RESULTS The study included 31 eyes of 31 patients. The mean age of the 22 men and 9 women was 30 G 11 years (range 18 to 58 years). All patients attended all postoperative examinations during the 12-month follow-up. No surgery-related complication was observed. Epithelial closure was observed after 4 days in all patients. The results of a Shapiro-Wilks test showed that the collected data were normally distributed (P O .05). The post hoc power analysis showed the power (1ß probability of error) for this study to be 0.98 for densitometry data, 0.84 for retinal straylight data, and 0.90 for visual acuity data. Corrected Distance Visual Acuity Table 1 shows CDVA data. The change in the mean CDVA from preoperatively to 1 year postoperatively was statistically significant (P ! .05). Corneal Straylight Table 2 shows the corneal densitometry results for backward light scattering. By 1 month after CXL, the corneal densitometry in the anterior, middle, and posterior stromal layers had increased over the preoperative level (Figure 1). The densitometry values peaked at 3 months in all 3 layers. At 6 and 12 months, the densitometry readings decreased. At 1 year, the density measurements in the middle and posterior stromal layers approximated preoperative values. Densitometry readings in the anterior stromal layer remained higher than preoperatively (Figure 1), although not statistically significantly so (Table 2). The mean densitometry increased in all 3 zones of the entire depth of the cornea. The increase in the 0.0 to 2.0 mm zone and the 2.0 to 6.0 mm zone 3 months postoperatively was statistically significant (Table 2 and Figure 2). One year after CXL, the densitometry values in the 2.0 to 6.0 mm zone and the 6.0 to 10.0 mm zone returned to the preoperative or lower levels, whereas the densitometry values in the 0.0 to 2.0 mm zone remained statistically significantly elevated (Table 2 and
Table 1. Changes in CDVA, retinal straylight, and maximum K data after corneal CXL. Mean G SD Timepoint Preop Postop 1 mo 3 mo 6 mo 12 mo
CDVA (LogMAR)
Straylight (Log[s])
Maximum K (D)
0.27 G 0.18
1.14 G 0.28
57.22 G 6.90
0.28 G 0.18 0.22 G 0.13 0.19 G 0.13 0.16 G 0.12
1.41 G 0.20 1.38 G 0.24 1.30 G 0.22 1.26 G 0.21
57.77 G 6.41 57.49 G 6.67 56.01 G 6.41 55.49 G 6.34
CDVA Z corrected distance visual acuity; CXL Z collagen crosslinking; K Z keratometry
Figure 2). Furthermore, all measurements showed the highest mean densitometry values in the 0.0 to 2.0 mm zone for the entire corneal depth (Table 2). No correlation between corneal densitometry values and CDVA (r ! 0.3) or forward-directed straylight log(s) (r ! 0.2) was observed at any postoperative examination. Retinal Straylight Figure 3 and Table 1 show the results for retinal straylight before and after CXL. The increase in mean retinal straylight was statistically significant from preoperatively to 1, 3, and 6 months postoperatively (all P ! .05), with the increase peaking at 1 month, then dropping at 3 months and again at 6 months. At 1 year, the mean retinal straylight remained above the preoperative level (Figure 3), but not statistically significantly so (P Z1.00). No correlation was observed between retinal straylight and CDVA at any postoperative timepoint (r ! 0.3). Keratometry Values Table 1 shows the maximum K data. The mean K reading decreased from 48.40 G 3.97 diopters (D) (range 42.70 to 57.95 D) preoperatively to 47.56 G 3.96 D (range 42.30 to 56.25 D) 1 year postoperatively (P ! .05). The decrease in the mean maximum K from preoperatively to 1 year was also statistically significantly (P ! .05). The mean maximum K vector was 57.22 G 6.90 134 before CXL and 55.49 G 6.34 134 after 12 months. Eyes with the greatest decrease in maximum K readings at 1 year also showed the highest densitometry values in the anterior 150 mm and the 0.0 to 2.0 mm zone at 1 year. DISCUSSION Although CXL has become an essential tool to manage corneal ectatic diseases, during the initial postoperative phase a reduction in visual acuity frequently is
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Table 2. Scheimpflug densitometry measurements in stromal layers and concentric zones over time. Timepoint Parameter Stromal layer Anterior Middle Posterior Zone (mm) 0.0 to 2.0 2.0 to 6.0 6.0 to 10.0z
Timepoint
Preop
1 Mo Postop
3 Mo Postop
P Value*
6 Mo Postop
12 Mo Postop
P Value†
20.44 G 2.45 14.96 G 2.12 14.85 G 2.12
25.21 G 2.94 17.13 G 2.38 16.32 G 2.53
26.20 G 5.01 17.57 G 3.12 16.88 G 3.32
!.05 !.05 .08
23.79 G 2.66 16.92 G 1.96 16.69 G 2.32
21.45 G 3.41 14.81 G 2.16 14.44 G 2.12
1.00 1.00 1.00
18.26 G 1.97 16.64 G 2.01 15.35 G 3.07
23.06 G 3.17 19.94 G 2.46 15.67 G 2.44
24.83 G 4.69 20.27 G 3.57 15.54 G 3.26
!.05 !.05 1.00
23.00 G 3.04 18.91 G 1.96 15.48 G 2.32
20.28 G 3.36 16.57 G 2.20 13.85 G 2.36
!.05 1.00 1.00
*From preoperatively to 3 months postoperatively † From 3 months to 6 months postoperatively z Entire depth of the cornea
observed.7,16 This loss of visual acuity might be induced by an increase in straylight caused by a loss of transparency of the corneal stroma. Various reasons for this transparency reduction have been proposed. These include an increase in collagen fiber diameter,17 a cellular reaction by activation of keratocytes,18,19 and a change in the refractive index of the stroma after corneal CXL. The most likely cause for the delayed onset of corneal haze is the transformation of keratocytes into myofibroblasts as a result of a complex woundhealing process induced by CXL.18,19 Myofibroblasts have been associated with stromal remodeling through the regeneration of collagen, glycosaminoglycans, and other extracellular matrix components.20 To our knowledge, this is the first study to evaluate forward and backward light scattering and their effect on clinical parameters such as CDVA in 1 cohort. This study used a new software for the Scheimpflug imaging device that enabled assessment of stromal changes in different areas and corneal depths. Although global changes in corneal transparency have been described7 and CXL’s effect on retinal straylight has been investigated,21 to our knowledge no study has analyzed the
exact relationship between the different occurrences of transparency change in the different layers of the cornea and its potential relevance to changes in visual acuity and corneal topography. The eyes in this study showed representative CXL outcomes for the clinical parameters usually used to describe the effectiveness of the procedure.22,23 A transient reduction in CDVA was observed 1 month postoperatively, after which the CDVA continuously improved to a total increase of approximately 1 line at 1 year. Studies22,23 have described significant flattening of the cornea (change in maximum K O1.00 D) or at least a stabilization (within G0.50 D) after 1 year. The mean K readings and maximum K readings in our study also decreased statistically significantly 1 year postoperatively. The maximum K value decreased statistically significantly in 55% of eyes and remained stable in 33%. One eye showed a 1.1 D increase in the maximum K value. The maximum
Figure 1. Changes in densitometry readings over time in the anterior 150 mm of the cornea (anterior), the central cornea (middle), and the posterior 80 mm of the cornea (posterior) in a diameter of 10.0 mm. The whiskers indicate the 95% confidence interval.
Figure 2. Statistical significance of changes in corneal densitometry in different concentric zones 3 months after CXL (left half) and 12 months after CXL (right half).
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Figure 3. Change in retinal straylight at each timepoint compared with preoperative measurements.
K readings increased at 1 month and continuously decreased thereafter. At 1 year, the mean K readings decreased by 0.8 D and the maximum K readings decreased by 1.2 D. No eye showed an increase in the mean K reading at 1 year. Like in other studies,21,24 we observed an increase in retinal straylight after CXL. However, unlike those studies,21,24 in our study the greatest increase in retinal straylight occurred 1 month postoperatively. The retinal straylight decreased during the follow-up but did not return to preoperative levels. Retinal straylight measurements at 12 months remained statistically significantly elevated over the preoperative measurements. One explanation for this result might be that the eyes in the present study had substantially higher preoperative K readings. In correlation with the increase of retinal straylight, the backward-directed straylight increased in all corneal layers during the first months after CXL. Densitometry increased 1 month postoperatively, peaked at 3 months, and then decreased over the following months. Evaluation of the densitometry readings in different corneal depths showed the highest increase of straylight to be in the anterior stromal layer. Although a remarkable increase in straylight was also observed in the middle and posterior stromal layers, the anterior 150 mm showed a remarkably higher increase. In addition, straylight in the anterior stromal layers did not decrease to preoperative values by 1 year, possibly because the CXL effect is mediated by the riboflavin concentration in the tissue, the UVA intensity available at the respective corneal depth, and the accessible oxygen. Because riboflavin concentration, UVA intensity,9,25 and oxygen concentration26 decline in deeper stromal layers, the effect of CXL is more pronounced in the anterior layers. Although a previous study7 showed that densitometry values did not decrease to preoperative values 12 months after CXL, our results show that this increase in densitometry is restricted to the anterior layers of the cornea.
5
The UVA-irradiation device used in this study has a Gaussian beam profile. The highest UVA intensities are in the center of its beam, and the irradiation intensity declines gradually toward the periphery.27 The higher intensities in the center produce a deeper CXL effect in the central cornea. This explains why the demarcation line in the peripheral corneal regions typically is more shallow in eyes treated using this device.2 Accordingly, we found a statistically significant increase in the densitometry readings at 3 months in the 0.0 to 2.0 mm and 2.0 to 6.0 mm corneal zones but not in the 6.0 to 10.0 mm zone, despite the UVA irradiation being performed in a 9.0 mm diameter. At 12 months, the densitometry readings remained significantly elevated in the 0.0 to 2.0 mm zone only. Using newer UVA devices that have flat beam profiles or donut-shaped beam profiles might result in different densitometry readings and in a decrease in straylight because of reduced irradiation intensity in the center of the cornea. Different irradiation procedures should be studied to evaluate the effect on vision. The CDVA decreased slightly at the 1-month visit and then increased continuously. A recent study7 did not show a correlation between changes in global densitometry values and visual acuity outcomes. In the present study, the changes in CDVA also did not correlate with forward or backward light scattering at any timepoint. Although the total retinal straylight and densitometry increased after 12 months, the CDVA actually improved. Because an increase in straylight has only a minimal effect on high-contrast visual acuity,8 the current results were foreseeable. Other factors, such as changes in topography or in optical aberrations, might have more impact on visual acuity changes after CXL. Eyes with a greater decrease in K readings after 1 year (ie, with more than 2.0 D of flattening) had significantly higher densitometry values than eyes with less flattening. Because of newly introduced treatment protocols,26 the finding that a more pronounced decrease in maximum K correlates with a greater increase in densitometry values could be important. Nevertheless, when changing treatment parameters of the CXL protocol, straylight should be included as an outcome parameter because it represents an independent aspect of vision quality. In conclusion, corneal changes induced by corneal collagen CXL performed using the UVX-1000 irradiation device seemed to be greatest in the anterior 150 mm of the cornea and in the 0.0 to 2.0 mm zone. Although post-CXL corneal transparency remained altered for at least 12 months, this transparency change did not seem to affect high-contrast visual acuity; no correlation was found between corneal straylight and retinal straylight and CDVA. This study also provides evidence that a more pronounced transparency loss in
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the central anterior layer seems to be associated with a more pronounced reduction in maximum K readings.
9.
WHAT WAS KNOWN Corneal transparency loss (haze) after CXL endures for at least 1 year. WHAT THIS PAPER ADDS Corneal CXL had a significant effect on the visual-function parameter straylight in the first postoperative months. The post-CXL increase in densitometry readings and retinal straylight did not seem to affect high-contrast visual acuity. The highest densitometry changes from corneal CXL were in the anterior stroma at the central (0.0 to 2.0 mm) zone of the cornea. More pronounced flattening of the cornea was associated with a more pronounced transparency loss in the anterior 150 mm of the cornea and in the 0.0 to 2.0 mm zone of the cornea. Changes in treatment parameters might reduce the amount of straylight induced by CXL. REFERENCES P, Malet F, Garra C, Gallois A, 1. Asri D, Touboul D, Fournie Malecaze F, Colin J. Corneal collagen crosslinking in progressive keratoconus: multicenter results from the French National Reference Center for Keratoconus. J Cataract Refract Surg 2011; 37:2137–2143 2. Koller T, Schumacher S, Fankhauser F II, Seiler T. Riboflavin/ultraviolet A crosslinking of the paracentral cornea. Cornea 2013; 32:165–168 3. Herrmann CIA, Hammer T, Duncker GIW. Haze-Bildung nach Vernetzungstherapie bei Keratokonus [Hazeformation (corneal scarring) after cross-linking therapy in keratoconus]. Ophthalmologe 2008; 105:485–487 4. Mazzotta C, Balestrazzi A, Baiocchi S, Traversi C, Caporossi A. Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation [letter]. Clin Exp Ophthalmol 2007; 35:580–582 5. Raiskup F, Hoyer A, Spoerl E. Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. J Refract Surg 2009; 25:S824–S828 €r6. Wollensak G, Hammer T, Herrmann CIA. “Haze” oder bandfo mige Keratopathie nach Crosslinking-Behandlung? [Haze or calcific band keratopathy after crosslinking treatment?] [letter] Ophthalmologe 2008; 105:864–865 7. Greenstein SA, Fry KL, Bhatt J, Hersh PS. Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: Scheimpflug and biomicroscopic analysis. J Cataract Refract Surg 2010; 36:2105–2114. Available at: http://www.vision-institute.com/UserFiles/File/CXL%20Haze% 20Published.pdf. Accessed January 9, 2015 8. van den Berg TJTP, Fransen L, Coppens JE. Ocular media clarity and straylight. In: Dartt DA, Besharse JC, Dana R, eds, Encyclopedia of the Eye. Oxford, UK, Academic Press, 2010; vol 3, 173–183. Available at: http://www.nin.knaw.nl/portals/0/
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department/berg/documents/vdberga2010encycleye00230.pdf. Accessed January 9, 2015 €ttmann G, Stachs O. ImSteven P, Hovakimyan M, Guthoff RF, Hu aging corneal crosslinking by autofluorescence 2-photon microscopy, second harmonic generation, and fluorescence lifetime measurements. J Cataract Refract Surg 2010; 36:2150–2159 Hafezi F. Significant visual increase following infectious keratitis after collagen cross-linking. J Refract Surg 2012; 28:587–588 Spoerl E, Hoyer A, Pillunat LE, Raiskup F. Corneal cross-linking and safety issues. Open Ophthalmol J 2011; 5:14–16. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3052642/pdf/ TOOPHTJ-5-14.pdf. Accessed January 9, 2015 Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A–induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003; 135:620–627. Available at: http://grmc.ca/assets/ files/collagen_crosslinking_2003_wollensak.pdf. Accessed January 9, 2015 Holladay JT, Moran JR, Kezirian GM. Analysis of aggregate surgically induced refractive change, prediction error, and intraocular astigmatism. J Cataract Refract Surg 2001; 27:61–79 van den Berg TJTP, Franssen L, Kruijt B, Coppens JE. History of ocular straylight measurements: a review. Z Med Phys 2013; 23:6–20 Franssen L, Coppens JE, van den Berg TJTP. Compensation comparison method for assessment of retinal straylight. Invest Ophthalmol Vis Sci 2006; 47:768–776. Available at: http:// www.iovs.org/cgi/reprint/47/2/768. Accessed January 9, 2015 Seiler T, Hafezi F. Corneal cross-linking-induced stromal demarcation line. Cornea 2006; 25:1057–1059 Wollensak G, Wilsch M, Spoerl E, Seiler T. Collagen fiber diameter in the rabbit cornea after collagen crosslinking by riboflavin/ UVA. Cornea 2004; 23:503–507 Wollensak G, Spoerl E, Wilsch M, Seiler T. Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment. Cornea 2004; 23:43–49 Wilson SE, Kim W-J. Keratocyte apoptosis: implications on corneal wound healing, tissue organization, and disease. Invest Ophthalmol Vis Sci 1998; 39:220–226. Available at: http://www. iovs.org/cgi/reprint/39/2/220. Accessed January 9, 2015 sio R Jr, Hutcheon AEK, Netto MV, Mohan RR, Ambro Zieske JD, Wilson SE. Wound healing in the cornea. a review of refractive surgery complications and new prospects for therapy Cornea 2005; 24:509–522 Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety of UVA– riboflavin cross-linking of the cornea. Cornea 2007; 26:385–389 Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg 2008; 24:S720–S725 Koller T, Pajic B, Vinciguerra P, Seiler T. Flattening of the cornea after collagen crosslinking for keratoconus. J Cataract Refract Surg 2011; 37:1488–1492 Guber I, Guber J, Kaufmann C, Bachmann LM, Thiel MA. Visual recovery after corneal crosslinking for keratoconus: a 1-year follow-up study. Graefes Arch Clin Exp Ophthalmol 2013; 251:803–807 Kamaev P, Friedman MD, Sherr E, Muller D. Photochemical kinetics of corneal cross-linking with riboflavin. Invest Ophthalmol Vis Sci 2012; 53:2360–2367. Available at: http://www.iovs.org/ content/53/4/2360.full.pdf. Accessed January 9, 2015 Marshall J, Hersh P, Muller D. Corneal Collagen Cross-linking; Past, Present, Future [ebook]. Waltham, MA, Avedro, Inc., 2013 Rozema JJ, Koppen C, Bral N, Tassignon M-J. Changes in forward and backward light scatter in keratoconus resulting from corneal cross-linking. Asia-Pac J Ophthalmol 2013; 2:15–19
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Changes in straylight and densitometry values after corneal collagen crosslinking Niklas Pircher, MD, Mojtaba Pachala, MD, Franz Prager, MD, Stefan Pieh, MD, Gerald Schmidinger, MD
PURPOSE: To evaluate the change in backward-directed and forward-directed corneal straylight in eyes after corneal collagen crosslinking (CXL) and its correlation with corrected distance visual acuity (CDVA) and changes in corneal topography. SETTING: Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. DESIGN: Retrospective cohort study. METHODS: Following the Dresden protocol, corneal CXL was performed in eyes with progressive keratoconus. Corneal light scattering was evaluated using densitometry measurements from different corneal layers and zones obtained using Scheimpflug tomography (Pentacam HR). Retinal straylight values were measured using the C-Quant device. The CDVA was recorded during each follow-up examination. Changes in corneal topography were measured using Scheimpflug tomography. RESULTS: The study evaluated 31 eyes of 31 patients. The mean densitometry of different corneal layers and in 3 different zones increased 3 months postoperatively and decreased thereafter. The mean densitometry in the 0.0 to 2.0 mm zone remained statistically significantly elevated after 12 months (P < .05). The mean preoperative retinal straylight was 1.14 log(s) G 0.28 (SD). The mean straylight peaked after 1 month and then decreased continuously but remained elevated after 1 year at 1.26 G 0.21 log(s). There was an increase in CDVA and flattening of the steepest keratometry (K) value (maximum K). Eyes with the greatest maximum K reduction also had the highest densitometry values. CONCLUSIONS: Crosslinking-induced stromal changes resulted in an increase in densitometry, especially in the anterior stroma of the central (0.0 to 2.0 mm) zone. These changes correlated with an increase in retinal straylight but not with the postoperative CDVA values. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2015; -:-–- Q 2015 ASCRS and ESCRS
Despite promising clinical results, corneal collagen crosslinking (CXL) frequently causes a reduction in visual acuity during the initial postoperative phase.1–4 This loss of visual acuity might be from epithelial changes, changes in corneal topography, or a loss in transparency of the corneal stroma. Typically, at the early follow-up visits a slitlamp examination will show a demarcation line at varying depths of the stroma. Koller et al.2 concluded that the demarcation line could be used to determine the effectiveness of the treatment. Furthermore, an increase in corneal optical density (haze) of the stroma above the demarcation line is frequently observable during the first Q 2015 ASCRS and ESCRS Published by Elsevier Inc.
months after CXL. Several studies have used confocal microscopy to try to identify the cause of this haze.3–6 Another study showed that this type of opacification takes at least 12 months to resolve.7 Light entering an opacified corneal stroma is scattered in all directions. Backward-scattered light can be observed as haze at the slitlamp or on Scheimpflug imaging.7 Forward-scattered light that reaches the retina reduces optical quality by increasing halo and glare and has small effects on high-contrast visual acuity and contrast sensitivity.8 Because straylight is an aspect of vision quality, forward-scattered and backward-scattered light might be a significant http://dx.doi.org/10.1016/j.jcrs.2014.07.043 0886-3350
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parameter to measure the outcomes of corneal CXL.8 Because the effect of CXL is confined to the area of ultraviolet (UV) light exposure,9 one might assume that haze is restricted to the UV-exposed area and that there could be differences in the stromal opacity at different depths and concentric zones in the stroma. Because corneal scarring is correlated with flattening of the corneal surface,10 a correlation between postoperative haze intensity and the flattening effect of the CXL treatment might be assumed. This study used densitometry and retinal straylight measurements to evaluate the change in backward and forward corneal light scattering. In addition, it assessed the changes in corneal haze after corneal CXL and their correlation with visual acuity and the changes in corneal topography. PATIENTS AND METHODS This retrospective evaluation of prospectively collected data study was performed in accordance with the Declaration of Helsinki. The local ethics committee approved the protocol of the prospective trial. Informed written consent was obtained from all patients before surgical intervention in accordance with institutional and legal requirements. The trial included eyes of consecutive patients from the institution’s outpatient department that had progressive keratoconus and were scheduled for corneal CXL.
Surgical Technique The same surgeon (G.S.) performed all procedures using the standard Dresden protocol for corneal CXL. The treatment protocol has been described in detail.11,12 Irradiation of ultraviolet-A (UVA) light was applied in a 9.0 mm radius. The UVA irradiation device (UVX-1000, IROC Innocross AG) has a Gaussian beam profile with a higher irradiation intensity in the center of the cornea. Postoperatively, a therapeutic contact lens was placed in the eye and left in place until epithelial closure.
Follow-up Patients received antibiotic treatment for 1 week and antiinflammatory and lubricating drops for 4 weeks. Postoperative follow-up examinations were performed until reepithelialization was complete and then again at 1, 3, 6, and 12 months. During each examination, the corrected distance visual acuity (CDVA), corneal topography,
Submitted: July 18, 2014. Final revision submitted: July 18, 2014. Accepted: July 20, 2014. From the Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. Corresponding author: Gerald Schmidinger, MD, Department of Ophthalmology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. E-mail: gerald.schmidinger@ meduniwien.ac.at.
densitometry, and retinal straylight values were recorded. The changes in the maximum keratometry (K) values induced by corneal CXL were compared as vectors by calculating the mean preoperative centroids and postoperative centroids as described by Holladay et al.13 The centroid (the mean of a set of x values and y values [xm/ym]) was calculated using the mean of each variable obtained using a rotating Scheimpflug camera (Pentacam HR, Oculus Optikger€ ate GmbH). The centroid (mean maximum K) was then converted back to standard polar notation.
Corneal Densitometry To evaluate the changes in corneal transparency, backward light scattering was measured using Scheimpflug tomography. All measurements were performed by the same experienced operator in a dark room. The patients were instructed to blink 2 times immediately before the examination and then to open their eye as wide as possible to ensure the cornea was not covered by the eyelid. Only examinations with automatic Scheimpflug scans (25 images in 2 seconds) that passed the device’s software quality check were used. This was done to avoid the estimation of unmeasured areas and to ensure the analysis of the full area of 10.0 mm diameter and the patient’s fixation (ie, quality specification parameter “OK”). The outcome of the software for the standardized Scheimpflug densitometry analysis was expressed in gray-scale units (GSUs). The GSU scale was calibrated using proprietary software in which light scatter is defined on a scale of 0 (minimum scatter; maximum transparency) to 100 (maximum scatter; minimum transparency) to enable the investigator to evaluate the optical density at various stromal depths and concentric zones of the cornea. Densitometry values were obtained preoperatively and 1, 3, 6, and 12 months postoperatively. The relative values of backward light scatter were measured in different layers of the cornea and separately in different concentric zones. Corneal backward-scattered light measurements were recorded for the anterior 150 mm and the posterior 80 mm of the corneal stroma and for the stroma between these 2 layers. In addition, backward light scatter intensities were evaluated in the 0.0 to 2.0 mm, 2.0 to 6.0 mm, and 6.0 to 10.0 mm zones through the entire depth of the cornea.
Retinal Straylight Measurement The retinal (forward-directed) light-scattering was measured using the C-Quant straylight meter (Oculus Optikger€ ate GmbH).14 A dark test field divided in half was superimposed on a bright, flickering light source to induce straylight. In one half of the test field, a compensation light was presented to allow patients to perceive the flickering. During the test, a series of limited-duration stimuli was presented that varied in the compensation light intensity. The straylight log(s) parameter was deduced based on the patient’s responses about which test-field flickering was stronger.8,15 The measurements were performed 3 times in all patients. Measurements deemed unreliable by the straylight meter were excluded. Only measurements with a standard deviation (SD) less than 0.08 and a quality factor greater than 1 as displayed by the straylight meter’s software were analyzed.
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Statistical Analysis Continuous variables are given as the mean G SD. ShapiroWilks analysis was performed to determine whether the distribution was normal. The Wilcoxon signed-rank test was used with the G*power freeware (version 3.1.3) to perform the post hoc power analysis. To explore statistically significant differences, SPSS software (version 22.0.0.0, International Business Machines Corp.) was used to perform repeatedmeasures analysis of variance on comparable data. A 2-sided probability value less than 0.05 was considered statistically significant. Pearson correlation coefficients (r) were calculated to assess the correlation of CDVA with retinal straylight and with corneal densitometry values.
RESULTS The study included 31 eyes of 31 patients. The mean age of the 22 men and 9 women was 30 G 11 years (range 18 to 58 years). All patients attended all postoperative examinations during the 12-month follow-up. No surgery-related complication was observed. Epithelial closure was observed after 4 days in all patients. The results of a Shapiro-Wilks test showed that the collected data were normally distributed (P O .05). The post hoc power analysis showed the power (1ß probability of error) for this study to be 0.98 for densitometry data, 0.84 for retinal straylight data, and 0.90 for visual acuity data. Corrected Distance Visual Acuity Table 1 shows CDVA data. The change in the mean CDVA from preoperatively to 1 year postoperatively was statistically significant (P ! .05). Corneal Straylight Table 2 shows the corneal densitometry results for backward light scattering. By 1 month after CXL, the corneal densitometry in the anterior, middle, and posterior stromal layers had increased over the preoperative level (Figure 1). The densitometry values peaked at 3 months in all 3 layers. At 6 and 12 months, the densitometry readings decreased. At 1 year, the density measurements in the middle and posterior stromal layers approximated preoperative values. Densitometry readings in the anterior stromal layer remained higher than preoperatively (Figure 1), although not statistically significantly so (Table 2). The mean densitometry increased in all 3 zones of the entire depth of the cornea. The increase in the 0.0 to 2.0 mm zone and the 2.0 to 6.0 mm zone 3 months postoperatively was statistically significant (Table 2 and Figure 2). One year after CXL, the densitometry values in the 2.0 to 6.0 mm zone and the 6.0 to 10.0 mm zone returned to the preoperative or lower levels, whereas the densitometry values in the 0.0 to 2.0 mm zone remained statistically significantly elevated (Table 2 and
Table 1. Changes in CDVA, retinal straylight, and maximum K data after corneal CXL. Mean G SD Timepoint Preop Postop 1 mo 3 mo 6 mo 12 mo
CDVA (LogMAR)
Straylight (Log[s])
Maximum K (D)
0.27 G 0.18
1.14 G 0.28
57.22 G 6.90
0.28 G 0.18 0.22 G 0.13 0.19 G 0.13 0.16 G 0.12
1.41 G 0.20 1.38 G 0.24 1.30 G 0.22 1.26 G 0.21
57.77 G 6.41 57.49 G 6.67 56.01 G 6.41 55.49 G 6.34
CDVA Z corrected distance visual acuity; CXL Z collagen crosslinking; K Z keratometry
Figure 2). Furthermore, all measurements showed the highest mean densitometry values in the 0.0 to 2.0 mm zone for the entire corneal depth (Table 2). No correlation between corneal densitometry values and CDVA (r ! 0.3) or forward-directed straylight log(s) (r ! 0.2) was observed at any postoperative examination. Retinal Straylight Figure 3 and Table 1 show the results for retinal straylight before and after CXL. The increase in mean retinal straylight was statistically significant from preoperatively to 1, 3, and 6 months postoperatively (all P ! .05), with the increase peaking at 1 month, then dropping at 3 months and again at 6 months. At 1 year, the mean retinal straylight remained above the preoperative level (Figure 3), but not statistically significantly so (P Z1.00). No correlation was observed between retinal straylight and CDVA at any postoperative timepoint (r ! 0.3). Keratometry Values Table 1 shows the maximum K data. The mean K reading decreased from 48.40 G 3.97 diopters (D) (range 42.70 to 57.95 D) preoperatively to 47.56 G 3.96 D (range 42.30 to 56.25 D) 1 year postoperatively (P ! .05). The decrease in the mean maximum K from preoperatively to 1 year was also statistically significantly (P ! .05). The mean maximum K vector was 57.22 G 6.90 134 before CXL and 55.49 G 6.34 134 after 12 months. Eyes with the greatest decrease in maximum K readings at 1 year also showed the highest densitometry values in the anterior 150 mm and the 0.0 to 2.0 mm zone at 1 year. DISCUSSION Although CXL has become an essential tool to manage corneal ectatic diseases, during the initial postoperative phase a reduction in visual acuity frequently is
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Table 2. Scheimpflug densitometry measurements in stromal layers and concentric zones over time. Timepoint Parameter Stromal layer Anterior Middle Posterior Zone (mm) 0.0 to 2.0 2.0 to 6.0 6.0 to 10.0z
Timepoint
Preop
1 Mo Postop
3 Mo Postop
P Value*
6 Mo Postop
12 Mo Postop
P Value†
20.44 G 2.45 14.96 G 2.12 14.85 G 2.12
25.21 G 2.94 17.13 G 2.38 16.32 G 2.53
26.20 G 5.01 17.57 G 3.12 16.88 G 3.32
!.05 !.05 .08
23.79 G 2.66 16.92 G 1.96 16.69 G 2.32
21.45 G 3.41 14.81 G 2.16 14.44 G 2.12
1.00 1.00 1.00
18.26 G 1.97 16.64 G 2.01 15.35 G 3.07
23.06 G 3.17 19.94 G 2.46 15.67 G 2.44
24.83 G 4.69 20.27 G 3.57 15.54 G 3.26
!.05 !.05 1.00
23.00 G 3.04 18.91 G 1.96 15.48 G 2.32
20.28 G 3.36 16.57 G 2.20 13.85 G 2.36
!.05 1.00 1.00
*From preoperatively to 3 months postoperatively † From 3 months to 6 months postoperatively z Entire depth of the cornea
observed.7,16 This loss of visual acuity might be induced by an increase in straylight caused by a loss of transparency of the corneal stroma. Various reasons for this transparency reduction have been proposed. These include an increase in collagen fiber diameter,17 a cellular reaction by activation of keratocytes,18,19 and a change in the refractive index of the stroma after corneal CXL. The most likely cause for the delayed onset of corneal haze is the transformation of keratocytes into myofibroblasts as a result of a complex woundhealing process induced by CXL.18,19 Myofibroblasts have been associated with stromal remodeling through the regeneration of collagen, glycosaminoglycans, and other extracellular matrix components.20 To our knowledge, this is the first study to evaluate forward and backward light scattering and their effect on clinical parameters such as CDVA in 1 cohort. This study used a new software for the Scheimpflug imaging device that enabled assessment of stromal changes in different areas and corneal depths. Although global changes in corneal transparency have been described7 and CXL’s effect on retinal straylight has been investigated,21 to our knowledge no study has analyzed the
exact relationship between the different occurrences of transparency change in the different layers of the cornea and its potential relevance to changes in visual acuity and corneal topography. The eyes in this study showed representative CXL outcomes for the clinical parameters usually used to describe the effectiveness of the procedure.22,23 A transient reduction in CDVA was observed 1 month postoperatively, after which the CDVA continuously improved to a total increase of approximately 1 line at 1 year. Studies22,23 have described significant flattening of the cornea (change in maximum K O1.00 D) or at least a stabilization (within G0.50 D) after 1 year. The mean K readings and maximum K readings in our study also decreased statistically significantly 1 year postoperatively. The maximum K value decreased statistically significantly in 55% of eyes and remained stable in 33%. One eye showed a 1.1 D increase in the maximum K value. The maximum
Figure 1. Changes in densitometry readings over time in the anterior 150 mm of the cornea (anterior), the central cornea (middle), and the posterior 80 mm of the cornea (posterior) in a diameter of 10.0 mm. The whiskers indicate the 95% confidence interval.
Figure 2. Statistical significance of changes in corneal densitometry in different concentric zones 3 months after CXL (left half) and 12 months after CXL (right half).
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STRAYLIGHT AND DENSITOMETRY VALUES AFTER CORNEAL CXL
Figure 3. Change in retinal straylight at each timepoint compared with preoperative measurements.
K readings increased at 1 month and continuously decreased thereafter. At 1 year, the mean K readings decreased by 0.8 D and the maximum K readings decreased by 1.2 D. No eye showed an increase in the mean K reading at 1 year. Like in other studies,21,24 we observed an increase in retinal straylight after CXL. However, unlike those studies,21,24 in our study the greatest increase in retinal straylight occurred 1 month postoperatively. The retinal straylight decreased during the follow-up but did not return to preoperative levels. Retinal straylight measurements at 12 months remained statistically significantly elevated over the preoperative measurements. One explanation for this result might be that the eyes in the present study had substantially higher preoperative K readings. In correlation with the increase of retinal straylight, the backward-directed straylight increased in all corneal layers during the first months after CXL. Densitometry increased 1 month postoperatively, peaked at 3 months, and then decreased over the following months. Evaluation of the densitometry readings in different corneal depths showed the highest increase of straylight to be in the anterior stromal layer. Although a remarkable increase in straylight was also observed in the middle and posterior stromal layers, the anterior 150 mm showed a remarkably higher increase. In addition, straylight in the anterior stromal layers did not decrease to preoperative values by 1 year, possibly because the CXL effect is mediated by the riboflavin concentration in the tissue, the UVA intensity available at the respective corneal depth, and the accessible oxygen. Because riboflavin concentration, UVA intensity,9,25 and oxygen concentration26 decline in deeper stromal layers, the effect of CXL is more pronounced in the anterior layers. Although a previous study7 showed that densitometry values did not decrease to preoperative values 12 months after CXL, our results show that this increase in densitometry is restricted to the anterior layers of the cornea.
5
The UVA-irradiation device used in this study has a Gaussian beam profile. The highest UVA intensities are in the center of its beam, and the irradiation intensity declines gradually toward the periphery.27 The higher intensities in the center produce a deeper CXL effect in the central cornea. This explains why the demarcation line in the peripheral corneal regions typically is more shallow in eyes treated using this device.2 Accordingly, we found a statistically significant increase in the densitometry readings at 3 months in the 0.0 to 2.0 mm and 2.0 to 6.0 mm corneal zones but not in the 6.0 to 10.0 mm zone, despite the UVA irradiation being performed in a 9.0 mm diameter. At 12 months, the densitometry readings remained significantly elevated in the 0.0 to 2.0 mm zone only. Using newer UVA devices that have flat beam profiles or donut-shaped beam profiles might result in different densitometry readings and in a decrease in straylight because of reduced irradiation intensity in the center of the cornea. Different irradiation procedures should be studied to evaluate the effect on vision. The CDVA decreased slightly at the 1-month visit and then increased continuously. A recent study7 did not show a correlation between changes in global densitometry values and visual acuity outcomes. In the present study, the changes in CDVA also did not correlate with forward or backward light scattering at any timepoint. Although the total retinal straylight and densitometry increased after 12 months, the CDVA actually improved. Because an increase in straylight has only a minimal effect on high-contrast visual acuity,8 the current results were foreseeable. Other factors, such as changes in topography or in optical aberrations, might have more impact on visual acuity changes after CXL. Eyes with a greater decrease in K readings after 1 year (ie, with more than 2.0 D of flattening) had significantly higher densitometry values than eyes with less flattening. Because of newly introduced treatment protocols,26 the finding that a more pronounced decrease in maximum K correlates with a greater increase in densitometry values could be important. Nevertheless, when changing treatment parameters of the CXL protocol, straylight should be included as an outcome parameter because it represents an independent aspect of vision quality. In conclusion, corneal changes induced by corneal collagen CXL performed using the UVX-1000 irradiation device seemed to be greatest in the anterior 150 mm of the cornea and in the 0.0 to 2.0 mm zone. Although post-CXL corneal transparency remained altered for at least 12 months, this transparency change did not seem to affect high-contrast visual acuity; no correlation was found between corneal straylight and retinal straylight and CDVA. This study also provides evidence that a more pronounced transparency loss in
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the central anterior layer seems to be associated with a more pronounced reduction in maximum K readings.
9.
WHAT WAS KNOWN Corneal transparency loss (haze) after CXL endures for at least 1 year. WHAT THIS PAPER ADDS Corneal CXL had a significant effect on the visual-function parameter straylight in the first postoperative months. The post-CXL increase in densitometry readings and retinal straylight did not seem to affect high-contrast visual acuity. The highest densitometry changes from corneal CXL were in the anterior stroma at the central (0.0 to 2.0 mm) zone of the cornea. More pronounced flattening of the cornea was associated with a more pronounced transparency loss in the anterior 150 mm of the cornea and in the 0.0 to 2.0 mm zone of the cornea. Changes in treatment parameters might reduce the amount of straylight induced by CXL. REFERENCES P, Malet F, Garra C, Gallois A, 1. Asri D, Touboul D, Fournie Malecaze F, Colin J. Corneal collagen crosslinking in progressive keratoconus: multicenter results from the French National Reference Center for Keratoconus. J Cataract Refract Surg 2011; 37:2137–2143 2. Koller T, Schumacher S, Fankhauser F II, Seiler T. Riboflavin/ultraviolet A crosslinking of the paracentral cornea. Cornea 2013; 32:165–168 3. Herrmann CIA, Hammer T, Duncker GIW. Haze-Bildung nach Vernetzungstherapie bei Keratokonus [Hazeformation (corneal scarring) after cross-linking therapy in keratoconus]. Ophthalmologe 2008; 105:485–487 4. Mazzotta C, Balestrazzi A, Baiocchi S, Traversi C, Caporossi A. Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation [letter]. Clin Exp Ophthalmol 2007; 35:580–582 5. Raiskup F, Hoyer A, Spoerl E. Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. J Refract Surg 2009; 25:S824–S828 €r6. Wollensak G, Hammer T, Herrmann CIA. “Haze” oder bandfo mige Keratopathie nach Crosslinking-Behandlung? [Haze or calcific band keratopathy after crosslinking treatment?] [letter] Ophthalmologe 2008; 105:864–865 7. Greenstein SA, Fry KL, Bhatt J, Hersh PS. Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: Scheimpflug and biomicroscopic analysis. J Cataract Refract Surg 2010; 36:2105–2114. Available at: http://www.vision-institute.com/UserFiles/File/CXL%20Haze% 20Published.pdf. Accessed January 9, 2015 8. van den Berg TJTP, Fransen L, Coppens JE. Ocular media clarity and straylight. In: Dartt DA, Besharse JC, Dana R, eds, Encyclopedia of the Eye. Oxford, UK, Academic Press, 2010; vol 3, 173–183. Available at: http://www.nin.knaw.nl/portals/0/
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