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Simultaneous topography-guided partial photorefractive keratectomy and corneal collagen crosslinking for keratoconus
ARTICLE
Simultaneous topography-guided partial photorefractive keratectomy and corneal collagen crosslinking for keratoconus Hani Sakla, MD, PhD, Wassim Altroudi, MD, Gonzalo Mu~ noz, MD, PhD, FEBO, Cesar Albarran-Diego, MSc
PURPOSE: To report the visual, refractive, and clinical outcomes of simultaneous topographyguided partial photorefractive keratectomy (PRK) and corneal collagen crosslinking (CXL) in eyes with keratoconus. SETTING: Private practice surgery center, Dubai, United Arab Emirates. DESIGN: Retrospective cohort study. METHODS: Refraction, uncorrected (UDVA) and corrected (CDVA) distance visual acuities, flat and steep keratometry (K) readings, and complications were evaluated 1, 3, 6, and 12 months postoperatively. RESULTS: The study enrolled 31 eyes of 31 patients aged 21 to 42 years. All study parameters showed a statistically significant improvement at 3, 6, and 12 months over baseline values. At 12 months, the mean UDVA improved to 0.23 logMAR G 0.33 (SD) from 0.79 G 0.36 logMAR (P<.001) and the CDVA improved to 0.06 G 0.07 logMAR from 0.28 G 0.20 logMAR (P<.001). The mean defocus decreased from 3.45 G 1.60 diopters (D) to 1.88 G 1.58 D (P<.001). The flat K and steep K readings showed significant flattening. The mean refractive astigmatism decreased from 2.77 G 1.47 D to 0.98 G 0.76 D (P<.001). The improvement in study parameters plateaued after 3 months. CONCLUSION: Simultaneous topography-guided partial PRK and CXL was effective, safe, and stable in keratoconus patients. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2014; 40:1430–1438 Q 2014 ASCRS and ESCRS
Keratoconus is a bilateral nonsymmetrical progressive corneal dystrophy that results in biomechanical weakening and progressive steepening.1,2 As keratoconus progresses to a stage where contact lenses are not tolerated, surgical intervention is warranted to gain useful vision. Two major aspects that must be considered in the treatment of keratoconus are irregular astigmatism and corneal biomechanical instability.3 Therefore, keratoconus surgical procedures can be classified as corneal regularization and corneal stabilization.4,5 Corneal regularization can be further categorized as subtractive, such as excimer laser ablation, or additive, such as lamellar keratoplasty and intrastromal corneal ring segment (ICRS) implantation, depending on whether tissue is removed or added to the cornea, respectively.6–8 1430
Q 2014 ASCRS and ESCRS Published by Elsevier Inc.
Although subtractive corneal regularization techniques, such as excimer laser surface ablation, were attempted more than a decade ago,9–11 they did not gain acceptance because tissue removal was associated with an increased risk for progression of keratoconus. Unlike standard photorefractive keratectomy (PRK), the recently developed surface ablation topography-guided PRK technique attempts to regularize the cornea based on topography measurements. Although the conventional refractive components of sphere and cylinder can be simultaneously incorporated into the treatment profile, in the management of keratoconus, tissue sparing is a prime consideration. Therefore, topography-guided partial PRK typically limits the maximum depth of the tissue ablation to less than 50 mm.12–14 0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2013.12.017
SIMULTANEOUS COMBINED PRK AND CXL FOR KERATOCONUS
Separately, corneal stabilization using corneal collagen crosslinking (CXL) has been shown to successfully retard or eliminate the progression of keratoconus.15,16 There is a potential to combine a corneal regularization technique, such as topography-guided partial PRK, with CXL to achieve regularization of the aberrated corneal shape and to strengthen the cornea, thereby addressing the lacunae of a subtractive technique. Preliminary studies of the combined procedure3,12,17 found that topography-guided partial PRK with or without partial refractive correction can reduce irregular astigmatism and refractive errors on the one hand and increase biomechanical strength with CXL on the other hand, with the goal of allowing longterm visual rehabilitation. In the current study, we systematically examined the evolution of the visual and refractive changes through the first year after simultaneous topography-guided partial PRK with partial correction of refraction followed by CXL in patients with keratoconus. PATIENTS AND METHODS This retrospective nonrandomized interventional clinical study comprised patients having simultaneous topographyguided partial PRK and CXL for keratoconus. All patients provided written informed consent before surgery in accordance with the Declaration of Helsinki, and institutional review board approval was obtained from the hospital ethics committee. Inclusion criteria were age older than 18 years, the presence of keratoconus as manifested by topography, a clear central cornea, a history of contact lens intolerance, and an expected residual corneal stromal bed thickness greater than 350 mm after a maximum ablation of 50 mm at the corneal center. Exclusion criteria included a history of corneal refractive surgery or delayed epithelial healing and pregnancy or nursing during the course of the study. Preoperatively, all patients had a full ophthalmologic examination including uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), refraction, slitlamp evaluation, tonometry, gonioscopy, fundoscopy, corneal pachymetry, keratometry, and topography (Allegro Oculyzer, Wavelight Laser Technology AG).
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400 laser system (Wavelight Laser Technologie AG). Next, CXL was performed with the CCL-365 Corneal CrossLinking System (Peschke Meditrade GmbH) using the standard procedure. Under topical anesthesia, the central 9.0 mm epithelium was removed using a surgical brush (Hyperopic Amoils Epithelial Scrubber, Innovative Excimer Solutions, Inc.). Topography-guided partial PRK was performed on a 5.5 mm optical zone. Partial PRK refers to the correction of up to 70% of astigmatism and some of the spherical component without exceeding a 50 mm ablation (corneal center) for planned stromal removal. The topography-guided partial PRK procedure finished with mitomycin-C 0.02% application for 30 seconds, after which the MMC was copiously washed out of the eye. To compensate for possible torsional movements with the patient supine on the surgical bed, eyes were marked preoperatively along the horizontal meridian at the limbus at 3 o'clock and 9 o'clock with the patient seated at the slitlamp. The CXL procedure was performed according to the methodology described by Wollensak et al.18 Riboflavin 0.1% in 20.0% dextran T500 solution in corneas with residual beds of 400 mm or more or riboflavin 0.1% in hypotonic solution in corneas with residual stromal beds between 350 mm and 400 mm was administered topically every 2 minutes for 30 minutes. Riboflavin absorption throughout the corneal stroma and anterior chamber was confirmed by slitlamp examination. The cornea was aligned and exposed to ultraviolet-A (UVA) 365 nm light for 30 minutes at an irradiance of 3.0 mW/cm2. During UVA exposure, riboflavin administration was continued every 2 minutes. Antibiotic and corticosteroid drops were administered, and a bandage soft contact lens was placed. Postoperative topical therapy included moxifloxacin eyedrops (Vigamox), prednisolone acetate 1.0% (Pred Forte), and lubricant eyedrops for 4 weeks. The contact lens was removed after the epithelial defect had closed (3 to 5 days postoperatively).
Postoperative Assessment Patients had complete examinations 1, 3, 6, and 12 months after surgery. Study parameters included the UDVA, CDVA, manifest refraction, and flat and steep keratometry (K) readings recorded from the topography data. Corneal haze was documented at each postoperative visit and graded on a scale of 0 to 4 (0 Z clear cornea; 1 Z mild haze; 2 Z moderate haze; 3 Z severe haze; 4 Z reticular haze obstructing iris anatomy).
Surgical Technique
Data Management and Statistical Analysis
Two experienced surgeons (H.S, W.A.) performed all surgeries. The topography-guided partial PRK procedures were performed using the T-Cat software of the Allegretto Eye Q
Visual acuity values were converted to logMAR notation for averaging and comparison. Vector analysis of refractive results was performed as previously reported.19,20 Spherocylindrical refractions were converted into vectors defined by a set of 3 coordinates (M, J0, and J45) in a 3-dimensional space. This power vector space results in an intuitive representation, with the spherical equivalent (SE) (M) along 1 axis, whereas the other 2 axes, J0 and J45, define the astigmatic plane. The length of this vector (B Z [M2 C J02 C J452]1/2) shows the amount of refractive error and the blur related to it.21 Statistical analysis was performed using SPSS software (version 17, International Business Machines Corp.). The normality of all data samples was evaluated with the Shapiro-Wilk test. The paired t test or Wilcoxon signed-
Submitted: June 5, 2013. Final revision submitted: November 11, 2013. Accepted: December 4, 2013. From Ebsaar Eye Surgery Center, Dubai, United Arab Emirates. Corresponding author: Cesar Albarran-Diego, MSc, Ebsaar Eye Surgery Center, Dubai, United Arab Emirates. E-mail: cesar.albarran@ gmail.com.
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Table 1. Descriptive statistics of patients. Parameter
Mean G SD
Range
Age (y) Refractive sphere (D) Refractive cylinder (D) Flat keratometry (D) Steep keratometry (D)
28.6 G 5.4 1.77 G 1.88 2.77 G 1.47 43.69 G 2.32 46.52 G 2.88
21, 42 7.25, C2.00 0.25, 5.75 38.00, 49.25 41.00, 52.50
rank test was used to compare presurgical and postsurgical parameters depending on whether normality was found or was not found, respectively. Friedman repeated-measures analysis of variance (ANOVA) on ranks with Tukey post hoc testing and descriptive statistics were used to analyze the change from baseline to 1-, 3-, 6-, and 12-month values as well as other successive time intervals (ie, 1 to 3 months; 3 to 6 months; 6 to 12 months). Results are presented as the mean G SD; a P value of 0.05 was considered statistically significant. Sigmaplot software (version 11.0, Systat Software Inc.) was used to calculate the sample size needed to reach an appropriate statistical power. Considering a minimum detectable difference in mean visual acuities of 0.2 log units (given that those patients had large aberrated corneas with low visual acuity values) and considering an expected SD of residuals as 0.3 log units (based on preliminary data of differences in UDVA), the sample size needed to reach a power of 0.80 was 36. For a power of 0.75, the sample size needed was 29.
Figure 1. Haze evolution (mean score G SD) over time.
RESULTS Data were collected from 31 eyes (sample power between 0.75 and 0.80) of 31 patients (22 men, 9 women).
Table 2. Comparison between preoperative and 12-month postoperative data. Mean G SD Parameter Refraction (D) M J0 J45 B Sphere Cylinder Defocus K1 K2 Acuity LogMAR UDVA Decimal UDVAz LogMAR CDVA Decimal CDVAz
Preoperative
Postoperative
P Value
3.16 G 1.83 0.13 G 1.04 0.10 G 1.18 3.58 G 1.70 1.77 G 1.88 2.77 G 1.47 3.45 G 1.60 43.69 G 2.32 46.52 G 2.88
1.10 G 1.94 0.10 G 0.47 0.01 G 0.40 1.65 G 1.61 0.61 G 2.04 0.98 G 0.76 1.88 G 1.58 42.52 G 2.78 43.97 G 2.99
!.001* .872* .519* !.001* !.001* !.001* !.001* !.001† !.001†
0.79 G 0.36 0.16 G 3.61 0.28 G 0.20 0.52 G 2.02
0.23 G 0.33 0.59 G 3.28 0.06 G 0.07 0.88 G 0.73
!.001* !.001* !.001† !.001*
B Z overall blurring strength B of spherocylindrical refractive error; CDVA Z corrected distance visual acuity; J0 Z Jackson cross-cylinder, axes at 180 and 90 ; J45 Z Jackson cross-cylinder, axes at 45 and 135 ; K1 Z keratometry in flat meridian; K1 Z keratometry in steep meridian; M Z spherical lens equal to the spherical equivalent of the given refractive error; UDVA Z uncorrected distance visual acuity *Paired t test (normality test passed) † Wilcoxon signed-rank rest (normality test failed) z Standard deviation in decimal notation given in lines of vision
Figure 2. Efficacy (top) and improvement in the UDVA (bottom) 12 months after combined topography-guided partial PRK and CXL (CDVA Z corrected distance visual acuity; UDVA Z uncorrected distance visual acuity).
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Figure 3. Predictability of the combined treatment 12 months postoperatively (J0 Z Jackson cross-cylinder, axes at 180 degrees and 90 degrees; J45 Z Jackson cross-cylinder, axes at 45 degrees and 135 degrees; M Z spherical lens equal to the spherical equivalent of the given refractive error).
Table 1 shows the preoperative data. All patients completed the 12-month follow-up. Adverse Events No serious complications occurred during the surgical procedure or follow-up. Figure 1 shows the mean haze scores during the follow-up. The Friedman test showed statistically significant differences in haze postoperatively (P!.001), with post hoc testing showing stability was achieved at 3 months. Efficacy and Improvement in Uncorrected Distance Visual Acuity There was a statistically significant increase in the mean logMAR UDVA postoperatively (P!.001) (Table 2). Twenty-six eyes (83.9%) gained 3 or more lines of UDVA and 1 eye (3.2%) lost 1 line of UDVA,
with no eye losing more than 1 line of UDVA (Figure 2). The decimal UDVA was 0.5 (20/40) or better in 26 eyes (83.9%) and 0.8 (20/25) or better in 17 eyes (54.8%) (Figure 2). The efficacy index (postoperative mean decimal UDVA divided by preoperative mean decimal CDVA) was 1.14 at 12 months. Predictability The 12-month postoperative SE was significantly reduced (Table 2), with 12 eyes (38.7%) within G0.50 D of the target and 18 eyes (58.1%) within G1.00 D. The mean defocus also decreased significantly, with 11 eyes (35.5%) within G1.00 D (Figure 3). There was a statistically significant decrease in the mean refractive cylinder power from 2.77 G 1.47 D preoperatively to 0.98 G 0.76 D 12 months postoperatively (P!.001) (Table 2). Eleven eyes (35.5%) and 22
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Figure 6 shows stability of the spherical and cylindrical components of refraction, corneal power, the UDVA and CDVA. Regarding corneal power, the Friedman test showed differences in values along the follow-up (P!.001) in K1 (flat K reading) and K2 (steep K reading). Post hoc testing showed stability in K1 values at 1 month and in K2 values at 3 months. The UDVA and CDVA achieved stability at 3 months.
Figure 4. Safety of the combined treatment 12 months postoperatively (CDVA Z corrected distance visual acuity).
eyes (71.0%) had less than 0.50 D and 1.00 D of astigmatism, respectively. Safety There was a statistically significant improvement in logMAR CDVA after surgery (P!.001). All eyes gained 1 line or more of CDVA, with 19 eyes (61.3%) gaining 3 or more lines. No eye lost 1 or more lines of CDVA (Figure 4). The safety index (ratio of postoperative over preoperative mean decimal CDVA) was 1.69 at 12 months. Stability Table 3 shows the distribution of the preoperative and postoperative refractive errors after vector conversion. Friedman repeated-measures ANOVA on ranks showed differences over time in M (P!.001) but not in J0 (PZ.06) or J45 (PZ.60). The post hoc Tukey test showed that M became stable after 3 months (Figure 5).
DISCUSSION The present study evaluated a new approach to the treatment of keratoconus using simultaneous topography-guided partial PRK and CXL. The visual outcomes in relation to the safety index (1.69) were very satisfactory, with all eyes having improved CDVA and most (61.3%) gaining 3 or more lines. At 12 months, the efficacy index was high (1.14); 48.4% of eyes had 20/20 or better CDVA compared with 0% at baseline; and the proportion of eyes with 20/40 or better UDVA was 83.9% compared with 12.9% preoperatively. Considering that the procedure did not intend to correct the full refractive preoperative error, the predictability of SE correction was also good, with 58.1% of eyes within the G1.00 D range and manifest refractive cylinder decreasing from 2.77 D at baseline to 0.98 D postoperatively. The stability of the UDVA, CDVA, and postoperative refraction was achieved soon after surgery, with minor changes after the 3-month follow-up visit that were likely related to improvement in corneal clarity. It is known that CXL alone can induce a refractive improvement in certain cases, so it could be thought that PRK after a procedure that can change refraction could lead to a bad outcome (given that data for PRK correction refer to the refractive status prior to CXL), but this is not expected to occur when both techniques are performed at the same time with the partial PRK performed using T-Cat software, because the
Table 3. Stability of refraction after t-PRK plus CXL in keratoconus. Mean (D) G SD Postoperative Parameter
Preoperative
1 Month
3 Months
6 Months
12 Months
M J0 J45
3.16 G 1.83 0.13 G 1.04 0.10 G 1.18
1.89 G 2.10 0.04 G 0.65 0.12 G 0.53
1.39 G 2.05 0.01 G 0.54 0.03 G 0.48
1.12 G 1.94 0.15 G 0.53 0.04 G 0.40
1.10 G 1.94 0.10 G 0.47 0.01 G 0.40
J0 Z Jackson cross-cylinder, axes at 180 and 90 ; J45 Z Jackson cross-cylinder, axes at 45 and 135 ; M Z spherical lens equal to the spherical equivalent of the given refractive error
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Figure 5. Stability plots (mean G SD) for refractive vector components (J0 Z Jackson cross-cylinder, axes at 180 degrees and 90 degrees; J45 Z Jackson cross-cylinder, axes at 45 degrees and 135 degrees; M Z spherical lens equal to the spherical equivalent of the given refractive error).
ablation is limited to 50 mm. In fact, there were no severe adverse events in our study. Corneal CXL seeks to increase the degree of interfibrillar linkages, potentially increasing the biomechanical stability of the cornea.22–24 Several studies16,25,26 have documented the successful
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cessation of progression of keratoconus after CXL. However, CXL does not improve the refractive status of the eye.27 In fact, CXL in itself is believed to freeze the non-ideal shape of the keratoconus cornea. It is therefore logical to improve the refractive status of the eye before freezing the corneal shape. Because the newer techniques of topography-guided partial PRK attempt to decrease surface irregularity, thereby effectively minimizing the irregular astigmatism of keratoconus,28–30 it is logical to combine this technique with CXL to address the irregular corneal shape and structural collagen weakening of progressive keratoconus.14 Previous studies3,12,17,31 found simultaneous use of topography-guided partial PRK and CXL to be safe and effective and to provide good functional vision in eyes with keratoconus. Initial studies by Kymionis et al.3 and Kanellopoulos and Binder14 to ascertain the best time to combine the 2 procedures found that topography-guided partial PRK followed immediately by CXL produced better outcomes than sequential treatment. In a comparative study of sequential versus simultaneous topography-guided partial PRK and CXL in 325 keratoconus eyes with a mean follow-up of 36 months, Kanellopoulos12 found improvement in the UDVA and CDVA, a greater mean reduction in SE and keratometry, and less corneal haze in the simultaneous group than in the sequential group. Similarly, Kymionis et al.31 report encouraging results in 31 keratoconus eyes with simultaneous topography-guided partial PRK and CXL. The combined treatment reduced the refractive error and K readings, yielding improvements in the UDVA and CDVA that remained stable at a mean follow-up of nearly 20 months. The procedure has also been evaluated in eyes that developed corneal ectasia after laser in situ keratomileusis, with significant clinical improvement and apparent stability of the ectasia in 5 cases with follow-up ranging from 11 to 37 months.32,33 Kanellopoulos12 and Kymionis et al.31 used a different surgical approach than we used in our study; however, the results are similar. This means that the epithelium-removal technique has no determining influence on the final result. This is probably because the objective of the topography-guided partial PRK is not total correction of the refractive error but rather regularization of the corneal surface. The aim of the present study was to systematically examine the evolution of the visual and refractive changes through the first year after simultaneous topography-guided partial PRK and CXL. Significant improvements in the UDVA, CDVA, and flat and steep K readings from preoperative levels were apparent as early as 1 month after the procedure. At 3 months,
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Figure 6. Stability plots for spherocylindrical refraction, corneal curvature, UDVA, and CDVA (CDVA Z corrected distance visual acuity; CYL Z cylinder; K1 Z flat keratometry; K2 Z steep keratometry; SPH Z sphere; UDVA Z uncorrected distance visual acuity).
significant improvement over baseline values was found in all the parameters. The UDVA and CDVA achieved stability after 3 months of follow-up. The presence of haze in our study corresponds to previous studies of the occurrence and natural course of haze after CXL. Postoperative haze after CXL increases initially up to 1 month and gradually diminishes between 3 months and 12 months.34 In the present study the incidence of haze was minimal, which concurs with findings reported by Kymionis et al.3 and Kanellopoulos.12 Both studies found less corneal haze development after simultaneous topographyguided partial PRK and CXL than after sequential procedures. Although all the parameters in our study improved further between 6 months and 12 months, the improvement was not statistically significant, indicating stabilization of visual and refractive outcomes. The sample size in our study resulted in a statistical power between 0.75 and 0.80; thus, the stability after 3 months must be carefully interpreted. On the other hand, it must be determined whether the stability continues after 12 months, which was the follow-up in our study.
In the past decade, there has been a gradual shift in the timing of administration of surgical intervention for keratoconus35,36 from late-stage corneal transplantation37 to ICRS implantation when patients become intolerant to contact lens4,38,39 to early-stage CXL at the diagnosis of keratoconus progression.5,40,41 Because keratoconus deteriorates most measures of quality of life, even in its initial stages,42 the ultimate aim of keratoconus treatment should be to treat the disease as early as possible. If the outcomes remain good over the long term, simultaneous topographyguided partial PRK and CXL may emerge as a reasonable option to treat the keratoconus eyes soon after its diagnosis. In summary, simultaneous topography-guided PRK and CXL was a safe and effective surgical alternative for keratoconus, yielding improvement in the UDVA, CDVA, and refractive status. Stabilization was achieved as early as 3 months after surgery. Future studies with larger cohorts of patients and longer follow-up periods are needed to determine whether the safety and efficacy are maintained as the patient with keratoconus ages.
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WHAT WAS KNOWN Keratoconus can be surgically treated with a combination of PRK and CXL with good results and little complications. WHAT THIS PAPER ADDS Stability of corneal haze, corneal curvature, refraction, and visual acuity after combined and simultaneous topography-guided partial PRK and CXL for keratoconus was achieved 3 months postoperatively.
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29. Lin DT, Holland SR, Rocha KM, Krueger RR. Method for optimizing topography-guided ablation of highly aberrated eyes with the ALLEGRETTO WAVE excimer laser. J Refract Surg 2008; 24:S439–S445 30. Pasquali T, Krueger R. Topography-guided laser refractive surgery. Curr Opin Ophthalmol 2012; 23:264–268 31. Kymionis GD, Portaliou DM, Kounis GA, Limnopoulou AN, Kontadakis GA, Grentzelos MA. Simultaneous topographyguided photorefractive keratectomy followed by corneal collagen cross-linking for keratoconus. Am J Ophthalmol 2011; 152:748–755 32. Kanellopoulos AJ, Binder PS. Management of corneal ectasia after LASIK with combined, same-day, topography-guided partial transepithelial PRK and collagen cross-linking: the Athens Protocol. J Refract Surg 2011; 27:323–331 33. Kymionis GD, Portaliou DM, Diakonis VF, Karavitaki AE, Panagopoulou SI, Jankov MR II, Coskunseven E. Management of post laser in situ keratomileusis ectasia with simultaneous topography guided photorefractive keratectomy and collagen cross-linking. Open Ophthalmol J 2011; 5:11–13. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3052643/pdf/TOO PHTJ-5-11.pdf. Accessed April 20, 2014 34. 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 nez M, Santodomingo-Rubido J, Wolffsohn JS. 35. Romero-Jime Keratoconus: a review. Cont Lens Anterior Eye 2010; 3:157–166; quiz 205 36. Tan DT, Por Y-M. Current treatment options for corneal ectasia. Curr Opin Ophthalmol 2007; 18:284–289
37. Buzard KA, Fundingsland BR. Corneal transplant for keratoconus: results in early and late disease. J Cataract Refract Surg 1997; 23:398–406 ~ero DP, Alio JL, El Kady B, Coskunseven E, Morbelli H, Uce38. Pin da-Montanes A, Maldonado MJ, Cuevas D, Pascual I. Refractive and aberrometric outcomes of intracorneal ring segments for keratoconus: mechanical versus femtosecond-assisted procedures. Ophthalmology 2009; 116:1675–1687 39. Tomalla M, Cagnolati W. Modern treatment options for the therapy of keratoconus. Cont Lens Anterior Eye 2007; 30:61–66 40. 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 41. Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol 2006; 17:356–360 42. Labiris G, Giarmoukakis A, Sideroudi H, Gkika M, Fanariotis M, Kozobolis V. Impact of keratoconus, cross-linking and cross-linking combined with photorefractive keratectomy on self-reported quality of life. Cornea 2012; 31:734–739
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First author: Hani Sakla, MD, PhD Ebsaar Eye Surgery Center, Dubai, United Arab Emirates
Simultaneous topography-guided partial photorefractive keratectomy and corneal collagen crosslinking for keratoconus Hani Sakla, MD, PhD, Wassim Altroudi, MD, Gonzalo Mu~ noz, MD, PhD, FEBO, Cesar Albarran-Diego, MSc
PURPOSE: To report the visual, refractive, and clinical outcomes of simultaneous topographyguided partial photorefractive keratectomy (PRK) and corneal collagen crosslinking (CXL) in eyes with keratoconus. SETTING: Private practice surgery center, Dubai, United Arab Emirates. DESIGN: Retrospective cohort study. METHODS: Refraction, uncorrected (UDVA) and corrected (CDVA) distance visual acuities, flat and steep keratometry (K) readings, and complications were evaluated 1, 3, 6, and 12 months postoperatively. RESULTS: The study enrolled 31 eyes of 31 patients aged 21 to 42 years. All study parameters showed a statistically significant improvement at 3, 6, and 12 months over baseline values. At 12 months, the mean UDVA improved to 0.23 logMAR G 0.33 (SD) from 0.79 G 0.36 logMAR (P<.001) and the CDVA improved to 0.06 G 0.07 logMAR from 0.28 G 0.20 logMAR (P<.001). The mean defocus decreased from 3.45 G 1.60 diopters (D) to 1.88 G 1.58 D (P<.001). The flat K and steep K readings showed significant flattening. The mean refractive astigmatism decreased from 2.77 G 1.47 D to 0.98 G 0.76 D (P<.001). The improvement in study parameters plateaued after 3 months. CONCLUSION: Simultaneous topography-guided partial PRK and CXL was effective, safe, and stable in keratoconus patients. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2014; 40:1430–1438 Q 2014 ASCRS and ESCRS
Keratoconus is a bilateral nonsymmetrical progressive corneal dystrophy that results in biomechanical weakening and progressive steepening.1,2 As keratoconus progresses to a stage where contact lenses are not tolerated, surgical intervention is warranted to gain useful vision. Two major aspects that must be considered in the treatment of keratoconus are irregular astigmatism and corneal biomechanical instability.3 Therefore, keratoconus surgical procedures can be classified as corneal regularization and corneal stabilization.4,5 Corneal regularization can be further categorized as subtractive, such as excimer laser ablation, or additive, such as lamellar keratoplasty and intrastromal corneal ring segment (ICRS) implantation, depending on whether tissue is removed or added to the cornea, respectively.6–8 1430
Q 2014 ASCRS and ESCRS Published by Elsevier Inc.
Although subtractive corneal regularization techniques, such as excimer laser surface ablation, were attempted more than a decade ago,9–11 they did not gain acceptance because tissue removal was associated with an increased risk for progression of keratoconus. Unlike standard photorefractive keratectomy (PRK), the recently developed surface ablation topography-guided PRK technique attempts to regularize the cornea based on topography measurements. Although the conventional refractive components of sphere and cylinder can be simultaneously incorporated into the treatment profile, in the management of keratoconus, tissue sparing is a prime consideration. Therefore, topography-guided partial PRK typically limits the maximum depth of the tissue ablation to less than 50 mm.12–14 0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2013.12.017
SIMULTANEOUS COMBINED PRK AND CXL FOR KERATOCONUS
Separately, corneal stabilization using corneal collagen crosslinking (CXL) has been shown to successfully retard or eliminate the progression of keratoconus.15,16 There is a potential to combine a corneal regularization technique, such as topography-guided partial PRK, with CXL to achieve regularization of the aberrated corneal shape and to strengthen the cornea, thereby addressing the lacunae of a subtractive technique. Preliminary studies of the combined procedure3,12,17 found that topography-guided partial PRK with or without partial refractive correction can reduce irregular astigmatism and refractive errors on the one hand and increase biomechanical strength with CXL on the other hand, with the goal of allowing longterm visual rehabilitation. In the current study, we systematically examined the evolution of the visual and refractive changes through the first year after simultaneous topography-guided partial PRK with partial correction of refraction followed by CXL in patients with keratoconus. PATIENTS AND METHODS This retrospective nonrandomized interventional clinical study comprised patients having simultaneous topographyguided partial PRK and CXL for keratoconus. All patients provided written informed consent before surgery in accordance with the Declaration of Helsinki, and institutional review board approval was obtained from the hospital ethics committee. Inclusion criteria were age older than 18 years, the presence of keratoconus as manifested by topography, a clear central cornea, a history of contact lens intolerance, and an expected residual corneal stromal bed thickness greater than 350 mm after a maximum ablation of 50 mm at the corneal center. Exclusion criteria included a history of corneal refractive surgery or delayed epithelial healing and pregnancy or nursing during the course of the study. Preoperatively, all patients had a full ophthalmologic examination including uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), refraction, slitlamp evaluation, tonometry, gonioscopy, fundoscopy, corneal pachymetry, keratometry, and topography (Allegro Oculyzer, Wavelight Laser Technology AG).
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400 laser system (Wavelight Laser Technologie AG). Next, CXL was performed with the CCL-365 Corneal CrossLinking System (Peschke Meditrade GmbH) using the standard procedure. Under topical anesthesia, the central 9.0 mm epithelium was removed using a surgical brush (Hyperopic Amoils Epithelial Scrubber, Innovative Excimer Solutions, Inc.). Topography-guided partial PRK was performed on a 5.5 mm optical zone. Partial PRK refers to the correction of up to 70% of astigmatism and some of the spherical component without exceeding a 50 mm ablation (corneal center) for planned stromal removal. The topography-guided partial PRK procedure finished with mitomycin-C 0.02% application for 30 seconds, after which the MMC was copiously washed out of the eye. To compensate for possible torsional movements with the patient supine on the surgical bed, eyes were marked preoperatively along the horizontal meridian at the limbus at 3 o'clock and 9 o'clock with the patient seated at the slitlamp. The CXL procedure was performed according to the methodology described by Wollensak et al.18 Riboflavin 0.1% in 20.0% dextran T500 solution in corneas with residual beds of 400 mm or more or riboflavin 0.1% in hypotonic solution in corneas with residual stromal beds between 350 mm and 400 mm was administered topically every 2 minutes for 30 minutes. Riboflavin absorption throughout the corneal stroma and anterior chamber was confirmed by slitlamp examination. The cornea was aligned and exposed to ultraviolet-A (UVA) 365 nm light for 30 minutes at an irradiance of 3.0 mW/cm2. During UVA exposure, riboflavin administration was continued every 2 minutes. Antibiotic and corticosteroid drops were administered, and a bandage soft contact lens was placed. Postoperative topical therapy included moxifloxacin eyedrops (Vigamox), prednisolone acetate 1.0% (Pred Forte), and lubricant eyedrops for 4 weeks. The contact lens was removed after the epithelial defect had closed (3 to 5 days postoperatively).
Postoperative Assessment Patients had complete examinations 1, 3, 6, and 12 months after surgery. Study parameters included the UDVA, CDVA, manifest refraction, and flat and steep keratometry (K) readings recorded from the topography data. Corneal haze was documented at each postoperative visit and graded on a scale of 0 to 4 (0 Z clear cornea; 1 Z mild haze; 2 Z moderate haze; 3 Z severe haze; 4 Z reticular haze obstructing iris anatomy).
Surgical Technique
Data Management and Statistical Analysis
Two experienced surgeons (H.S, W.A.) performed all surgeries. The topography-guided partial PRK procedures were performed using the T-Cat software of the Allegretto Eye Q
Visual acuity values were converted to logMAR notation for averaging and comparison. Vector analysis of refractive results was performed as previously reported.19,20 Spherocylindrical refractions were converted into vectors defined by a set of 3 coordinates (M, J0, and J45) in a 3-dimensional space. This power vector space results in an intuitive representation, with the spherical equivalent (SE) (M) along 1 axis, whereas the other 2 axes, J0 and J45, define the astigmatic plane. The length of this vector (B Z [M2 C J02 C J452]1/2) shows the amount of refractive error and the blur related to it.21 Statistical analysis was performed using SPSS software (version 17, International Business Machines Corp.). The normality of all data samples was evaluated with the Shapiro-Wilk test. The paired t test or Wilcoxon signed-
Submitted: June 5, 2013. Final revision submitted: November 11, 2013. Accepted: December 4, 2013. From Ebsaar Eye Surgery Center, Dubai, United Arab Emirates. Corresponding author: Cesar Albarran-Diego, MSc, Ebsaar Eye Surgery Center, Dubai, United Arab Emirates. E-mail: cesar.albarran@ gmail.com.
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Table 1. Descriptive statistics of patients. Parameter
Mean G SD
Range
Age (y) Refractive sphere (D) Refractive cylinder (D) Flat keratometry (D) Steep keratometry (D)
28.6 G 5.4 1.77 G 1.88 2.77 G 1.47 43.69 G 2.32 46.52 G 2.88
21, 42 7.25, C2.00 0.25, 5.75 38.00, 49.25 41.00, 52.50
rank test was used to compare presurgical and postsurgical parameters depending on whether normality was found or was not found, respectively. Friedman repeated-measures analysis of variance (ANOVA) on ranks with Tukey post hoc testing and descriptive statistics were used to analyze the change from baseline to 1-, 3-, 6-, and 12-month values as well as other successive time intervals (ie, 1 to 3 months; 3 to 6 months; 6 to 12 months). Results are presented as the mean G SD; a P value of 0.05 was considered statistically significant. Sigmaplot software (version 11.0, Systat Software Inc.) was used to calculate the sample size needed to reach an appropriate statistical power. Considering a minimum detectable difference in mean visual acuities of 0.2 log units (given that those patients had large aberrated corneas with low visual acuity values) and considering an expected SD of residuals as 0.3 log units (based on preliminary data of differences in UDVA), the sample size needed to reach a power of 0.80 was 36. For a power of 0.75, the sample size needed was 29.
Figure 1. Haze evolution (mean score G SD) over time.
RESULTS Data were collected from 31 eyes (sample power between 0.75 and 0.80) of 31 patients (22 men, 9 women).
Table 2. Comparison between preoperative and 12-month postoperative data. Mean G SD Parameter Refraction (D) M J0 J45 B Sphere Cylinder Defocus K1 K2 Acuity LogMAR UDVA Decimal UDVAz LogMAR CDVA Decimal CDVAz
Preoperative
Postoperative
P Value
3.16 G 1.83 0.13 G 1.04 0.10 G 1.18 3.58 G 1.70 1.77 G 1.88 2.77 G 1.47 3.45 G 1.60 43.69 G 2.32 46.52 G 2.88
1.10 G 1.94 0.10 G 0.47 0.01 G 0.40 1.65 G 1.61 0.61 G 2.04 0.98 G 0.76 1.88 G 1.58 42.52 G 2.78 43.97 G 2.99
!.001* .872* .519* !.001* !.001* !.001* !.001* !.001† !.001†
0.79 G 0.36 0.16 G 3.61 0.28 G 0.20 0.52 G 2.02
0.23 G 0.33 0.59 G 3.28 0.06 G 0.07 0.88 G 0.73
!.001* !.001* !.001† !.001*
B Z overall blurring strength B of spherocylindrical refractive error; CDVA Z corrected distance visual acuity; J0 Z Jackson cross-cylinder, axes at 180 and 90 ; J45 Z Jackson cross-cylinder, axes at 45 and 135 ; K1 Z keratometry in flat meridian; K1 Z keratometry in steep meridian; M Z spherical lens equal to the spherical equivalent of the given refractive error; UDVA Z uncorrected distance visual acuity *Paired t test (normality test passed) † Wilcoxon signed-rank rest (normality test failed) z Standard deviation in decimal notation given in lines of vision
Figure 2. Efficacy (top) and improvement in the UDVA (bottom) 12 months after combined topography-guided partial PRK and CXL (CDVA Z corrected distance visual acuity; UDVA Z uncorrected distance visual acuity).
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Figure 3. Predictability of the combined treatment 12 months postoperatively (J0 Z Jackson cross-cylinder, axes at 180 degrees and 90 degrees; J45 Z Jackson cross-cylinder, axes at 45 degrees and 135 degrees; M Z spherical lens equal to the spherical equivalent of the given refractive error).
Table 1 shows the preoperative data. All patients completed the 12-month follow-up. Adverse Events No serious complications occurred during the surgical procedure or follow-up. Figure 1 shows the mean haze scores during the follow-up. The Friedman test showed statistically significant differences in haze postoperatively (P!.001), with post hoc testing showing stability was achieved at 3 months. Efficacy and Improvement in Uncorrected Distance Visual Acuity There was a statistically significant increase in the mean logMAR UDVA postoperatively (P!.001) (Table 2). Twenty-six eyes (83.9%) gained 3 or more lines of UDVA and 1 eye (3.2%) lost 1 line of UDVA,
with no eye losing more than 1 line of UDVA (Figure 2). The decimal UDVA was 0.5 (20/40) or better in 26 eyes (83.9%) and 0.8 (20/25) or better in 17 eyes (54.8%) (Figure 2). The efficacy index (postoperative mean decimal UDVA divided by preoperative mean decimal CDVA) was 1.14 at 12 months. Predictability The 12-month postoperative SE was significantly reduced (Table 2), with 12 eyes (38.7%) within G0.50 D of the target and 18 eyes (58.1%) within G1.00 D. The mean defocus also decreased significantly, with 11 eyes (35.5%) within G1.00 D (Figure 3). There was a statistically significant decrease in the mean refractive cylinder power from 2.77 G 1.47 D preoperatively to 0.98 G 0.76 D 12 months postoperatively (P!.001) (Table 2). Eleven eyes (35.5%) and 22
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Figure 6 shows stability of the spherical and cylindrical components of refraction, corneal power, the UDVA and CDVA. Regarding corneal power, the Friedman test showed differences in values along the follow-up (P!.001) in K1 (flat K reading) and K2 (steep K reading). Post hoc testing showed stability in K1 values at 1 month and in K2 values at 3 months. The UDVA and CDVA achieved stability at 3 months.
Figure 4. Safety of the combined treatment 12 months postoperatively (CDVA Z corrected distance visual acuity).
eyes (71.0%) had less than 0.50 D and 1.00 D of astigmatism, respectively. Safety There was a statistically significant improvement in logMAR CDVA after surgery (P!.001). All eyes gained 1 line or more of CDVA, with 19 eyes (61.3%) gaining 3 or more lines. No eye lost 1 or more lines of CDVA (Figure 4). The safety index (ratio of postoperative over preoperative mean decimal CDVA) was 1.69 at 12 months. Stability Table 3 shows the distribution of the preoperative and postoperative refractive errors after vector conversion. Friedman repeated-measures ANOVA on ranks showed differences over time in M (P!.001) but not in J0 (PZ.06) or J45 (PZ.60). The post hoc Tukey test showed that M became stable after 3 months (Figure 5).
DISCUSSION The present study evaluated a new approach to the treatment of keratoconus using simultaneous topography-guided partial PRK and CXL. The visual outcomes in relation to the safety index (1.69) were very satisfactory, with all eyes having improved CDVA and most (61.3%) gaining 3 or more lines. At 12 months, the efficacy index was high (1.14); 48.4% of eyes had 20/20 or better CDVA compared with 0% at baseline; and the proportion of eyes with 20/40 or better UDVA was 83.9% compared with 12.9% preoperatively. Considering that the procedure did not intend to correct the full refractive preoperative error, the predictability of SE correction was also good, with 58.1% of eyes within the G1.00 D range and manifest refractive cylinder decreasing from 2.77 D at baseline to 0.98 D postoperatively. The stability of the UDVA, CDVA, and postoperative refraction was achieved soon after surgery, with minor changes after the 3-month follow-up visit that were likely related to improvement in corneal clarity. It is known that CXL alone can induce a refractive improvement in certain cases, so it could be thought that PRK after a procedure that can change refraction could lead to a bad outcome (given that data for PRK correction refer to the refractive status prior to CXL), but this is not expected to occur when both techniques are performed at the same time with the partial PRK performed using T-Cat software, because the
Table 3. Stability of refraction after t-PRK plus CXL in keratoconus. Mean (D) G SD Postoperative Parameter
Preoperative
1 Month
3 Months
6 Months
12 Months
M J0 J45
3.16 G 1.83 0.13 G 1.04 0.10 G 1.18
1.89 G 2.10 0.04 G 0.65 0.12 G 0.53
1.39 G 2.05 0.01 G 0.54 0.03 G 0.48
1.12 G 1.94 0.15 G 0.53 0.04 G 0.40
1.10 G 1.94 0.10 G 0.47 0.01 G 0.40
J0 Z Jackson cross-cylinder, axes at 180 and 90 ; J45 Z Jackson cross-cylinder, axes at 45 and 135 ; M Z spherical lens equal to the spherical equivalent of the given refractive error
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Figure 5. Stability plots (mean G SD) for refractive vector components (J0 Z Jackson cross-cylinder, axes at 180 degrees and 90 degrees; J45 Z Jackson cross-cylinder, axes at 45 degrees and 135 degrees; M Z spherical lens equal to the spherical equivalent of the given refractive error).
ablation is limited to 50 mm. In fact, there were no severe adverse events in our study. Corneal CXL seeks to increase the degree of interfibrillar linkages, potentially increasing the biomechanical stability of the cornea.22–24 Several studies16,25,26 have documented the successful
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cessation of progression of keratoconus after CXL. However, CXL does not improve the refractive status of the eye.27 In fact, CXL in itself is believed to freeze the non-ideal shape of the keratoconus cornea. It is therefore logical to improve the refractive status of the eye before freezing the corneal shape. Because the newer techniques of topography-guided partial PRK attempt to decrease surface irregularity, thereby effectively minimizing the irregular astigmatism of keratoconus,28–30 it is logical to combine this technique with CXL to address the irregular corneal shape and structural collagen weakening of progressive keratoconus.14 Previous studies3,12,17,31 found simultaneous use of topography-guided partial PRK and CXL to be safe and effective and to provide good functional vision in eyes with keratoconus. Initial studies by Kymionis et al.3 and Kanellopoulos and Binder14 to ascertain the best time to combine the 2 procedures found that topography-guided partial PRK followed immediately by CXL produced better outcomes than sequential treatment. In a comparative study of sequential versus simultaneous topography-guided partial PRK and CXL in 325 keratoconus eyes with a mean follow-up of 36 months, Kanellopoulos12 found improvement in the UDVA and CDVA, a greater mean reduction in SE and keratometry, and less corneal haze in the simultaneous group than in the sequential group. Similarly, Kymionis et al.31 report encouraging results in 31 keratoconus eyes with simultaneous topography-guided partial PRK and CXL. The combined treatment reduced the refractive error and K readings, yielding improvements in the UDVA and CDVA that remained stable at a mean follow-up of nearly 20 months. The procedure has also been evaluated in eyes that developed corneal ectasia after laser in situ keratomileusis, with significant clinical improvement and apparent stability of the ectasia in 5 cases with follow-up ranging from 11 to 37 months.32,33 Kanellopoulos12 and Kymionis et al.31 used a different surgical approach than we used in our study; however, the results are similar. This means that the epithelium-removal technique has no determining influence on the final result. This is probably because the objective of the topography-guided partial PRK is not total correction of the refractive error but rather regularization of the corneal surface. The aim of the present study was to systematically examine the evolution of the visual and refractive changes through the first year after simultaneous topography-guided partial PRK and CXL. Significant improvements in the UDVA, CDVA, and flat and steep K readings from preoperative levels were apparent as early as 1 month after the procedure. At 3 months,
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Figure 6. Stability plots for spherocylindrical refraction, corneal curvature, UDVA, and CDVA (CDVA Z corrected distance visual acuity; CYL Z cylinder; K1 Z flat keratometry; K2 Z steep keratometry; SPH Z sphere; UDVA Z uncorrected distance visual acuity).
significant improvement over baseline values was found in all the parameters. The UDVA and CDVA achieved stability after 3 months of follow-up. The presence of haze in our study corresponds to previous studies of the occurrence and natural course of haze after CXL. Postoperative haze after CXL increases initially up to 1 month and gradually diminishes between 3 months and 12 months.34 In the present study the incidence of haze was minimal, which concurs with findings reported by Kymionis et al.3 and Kanellopoulos.12 Both studies found less corneal haze development after simultaneous topographyguided partial PRK and CXL than after sequential procedures. Although all the parameters in our study improved further between 6 months and 12 months, the improvement was not statistically significant, indicating stabilization of visual and refractive outcomes. The sample size in our study resulted in a statistical power between 0.75 and 0.80; thus, the stability after 3 months must be carefully interpreted. On the other hand, it must be determined whether the stability continues after 12 months, which was the follow-up in our study.
In the past decade, there has been a gradual shift in the timing of administration of surgical intervention for keratoconus35,36 from late-stage corneal transplantation37 to ICRS implantation when patients become intolerant to contact lens4,38,39 to early-stage CXL at the diagnosis of keratoconus progression.5,40,41 Because keratoconus deteriorates most measures of quality of life, even in its initial stages,42 the ultimate aim of keratoconus treatment should be to treat the disease as early as possible. If the outcomes remain good over the long term, simultaneous topographyguided partial PRK and CXL may emerge as a reasonable option to treat the keratoconus eyes soon after its diagnosis. In summary, simultaneous topography-guided PRK and CXL was a safe and effective surgical alternative for keratoconus, yielding improvement in the UDVA, CDVA, and refractive status. Stabilization was achieved as early as 3 months after surgery. Future studies with larger cohorts of patients and longer follow-up periods are needed to determine whether the safety and efficacy are maintained as the patient with keratoconus ages.
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WHAT WAS KNOWN Keratoconus can be surgically treated with a combination of PRK and CXL with good results and little complications. WHAT THIS PAPER ADDS Stability of corneal haze, corneal curvature, refraction, and visual acuity after combined and simultaneous topography-guided partial PRK and CXL for keratoconus was achieved 3 months postoperatively.
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First author: Hani Sakla, MD, PhD Ebsaar Eye Surgery Center, Dubai, United Arab Emirates