Visual and Keratometric Outcomes of Keratoconus Patients After Sequential Corneal Crosslinking and Topography-Guided Surface Ablation: Early United States Experience

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ARTICLE Visual and keratometric outcomes of keratoconus patients after sequential corneal crosslinking and topography-guided surface ablation: Early United States experience

Alanna Nattis, DO, Eric D. Donnenfeld, MD, Eric Rosenberg, DO, MSE, Henry D. Perry, MD

Purpose: To evaluate a sequential treatment algorithm for visual were analyzed for significance and a correlation with visual and and keratometric improvement in keratoconus patients after astigmatic outcomes. corneal crosslinking (CXL) followed by topography-guided photorefractive keratectomy (PRK). Results: The study comprised 56 patients (62 eyes), 34 who had both topographic and refractive treatment and 28 patients who had Setting: Ophthalmic Consultants of Long Island, Garden City, treatment of topographic irregularities only. The mean age was New York, USA. 38.08 years G 13.07 (SD) at CXL and 40.33 G 13.44 years at topography-guided PRK. Six months after PRK, there was a Design: Retrospective case series. significant improvement in UDVA and CDVA in the refractive group (20/60 and 20/30, respectively) versus the nonrefractive Methods: This study reviewed patients with keratoconus who group (20/100 and 20/40, respectively). Ninety-three percent of had CXL followed by custom topography-guided PRK between eyes that had refractive treatment had 20/40 or better CDVA. April 2016 and December 2016. The following data were There were no significant adverse events in any case. collected at baseline, the time of CXL, and 3 months and 6 months after PRK: uncorrected (UDVA) and corrected (CDVA) Conclusions: The data support the use of refractive treatment in distance visual acuities, keratometric astigmatism, spherical addition to topographic treatment for visual improvement in pa- equivalent, maximum and mean keratometry readings, and tients with keratoconus having CXL and PRK. corneal thickness at the cone apex. Demographic data, age at time of CXL and PRK, and time elapsed between CXL and PRK J Cataract Refract Surg 2018; 44:1003–1011 Q 2018 ASCRS and ESCRS

eratoconus is a noninﬂammatory progressive treatment modalities might correct vision for a period of ectasia of the cornea characterized commonly by time; however, in at least 20% of patients keratoconus K bilateral, asymmetric degeneration, leading to pro- can still progress to the point of requiring a penetrating trusion and paracentral thinning.1,A Nonsurgical treat- keratoplasty or deep anterior lamellar keratoplasty.1,A ment of the reduced vision often seen in keratoconus Cornea crosslinking (CXL) for keratoconus has been includes spectacle correction, rigid gas-permeable contact shown to improve the biomechanics of the cornea.1,A It lenses, and scleral lenses. Surgical treatment modalities shows that the collagen is disorganized in keratoconus, that do not require corneal transplantation include epiker- leading to alteration of the refractive function, high myopia, – atoplasty, photorefractive keratectomy (PRK), and intra- and irregular astigmatism.1 3,A,B Keratoconic corneas also stromal corneal ring segment (ICRS) implantation.1 have increased levels of collagenolysis, loss of keratocytes, These surgical techniques might help correct refractive reduced collagen crosslinks, and significantly weakened – error but not halt disease progression.1 Ultimately, these stress-versus-strain responses.1 3,A,B Wollensak et al.1

Submitted: January 4, 2018 | Final revision submitted: May 1, 2018 | Accepted: May 25, 2018 From Lindenhurst Eye Physicians and Surgeons (Nattis), Babylon, Ophthalmic Consultants of Long Island (Donnenfeld), Garden City, the Department of Ophthalmology (Rosenberg), New York Medical College, Valhalla, Nassau University Medical Center (Perry), and Ophthalmic Consultants of Long Island (Perry), Rockville Centre, New York, USA. Presented in part at the ASCRS Symposium on Cataract, IOL and Refractive Surgery, Los Angeles, California, USA, May 2017. Corresponding author: Alanna Nattis, DO, Lindenhurst Eye Physicians and Surgeons PC, 500 West Main Street, Babylon, New York 11702, USA. Email: asn516lu@gmail. com.

Q 2018 ASCRS and ESCRS 0886-3350/$ - see frontmatter Published by Elsevier Inc. https://doi.org/10.1016/j.jcrs.2018.05.020 1004 VISUAL AND KERATOMETRIC OUTCOMES OF CXL FOR KERATOCONUS found that the application of riboflavin eyedrops in eyes outcomes based on time elapsed between CXL and ablation with keratoconus followed by exposure to ultraviolet-A and examination of the influence of variables such as sex, (UVA) light at a specific wavelength (370 nm, 3 mW/ corneal thickness, age at time of ablation, and keratometric cm2) halted the progression of keratoconus in all patients indices on these outcomes have yet to be elucidated. studied. In addition, 70% of patients had regression, with The goal of this study was to evaluate the visual and astig- reduction in the maximum keratometry (K) reading by matic outcomes of patients with keratoconus who had CXL 2.01 diopters (D) and the refractive error by 1.14 D.1,3 followed by topography-guided ablation at least 3 months The corneal and lens clarity, endothelial cell counts, and later. Based on our observations and results, we suggest a intraocular pressure remained unchanged after CXL, with treatment algorithm for improving vision in keratoconus – improved vision in 65% of patients.1 3,A,B patients. After the introduction of CXL internationally in 2003 and United States Food and Drug Administration approval in PATIENTS AND METHODS 2016, the procedure has gained acceptance worldwide as a This was a retrospective case review of patients with a diagnosis of method of halting the progression of ectasia in keratoconus keratoconus who had CXL followed by custom topography- and yielding potential visual improvement and rehabilita- guided PRK using the Wavelight EX500 excimer laser (Alcon Sur- 2,3,A,B gical, Inc.). All surgery was performed by the same surgeon tion. At this time, there is no clear treatment algo- (E.D.D.) between April 2016 and December 2016 at a single- rithm for visual enhancement after CXL in keratoconus. practice setting. Given the irregular contour of the cornea and the focal thin- Inclusion criteria were a history of keratoconus as obtained ning that can persist after CXL, conventional or optimized from the medical record and documented by Scheimpflug tomog- excimer laser ablations are usually not indicated. However, raphy (Pentacam, Oculus Surgical, Inc.) as well as satisfactory image capture by topography (Topolyzer, Alcon Surgical, Inc.). to date multiple studies have shown the efficacy of Exclusion criteria included additional ocular procedures (extraoc- topography-guided surface ablation/PRK in patients with ular or intraocular) performed in the period between CXL and – keratoconus who had previous CXL.4 8 topographic ablation that could influence visual and/or astigmatic Topography-guided custom PRK is a technique using an outcomes and discovered or preexisting ocular pathology, excimer laser to treat corneas with variable topographic including retinal pathologies that could potentially limit visual – – outcomes. indices, as in keratoconus.7 9,C G Conventional and wavefront-guided laser therapies used for uncomplicated Surgical Technique laser in situ keratomileusis and PRK work by reducing Corneal Crosslinking Before the CXL procedure was initiated, the corneal tissue to a lower level, thus removing a great informed consent was obtained and all questions were answered. deal of tissue to create a more spherical cornea based on The ocular surface was anesthetized with topical proparacaine hy- – – the flattest part of the cornea.7 9,C I This can be challenging drochloride solution 0.5%. A modified epithelium-on (epi-on) (or impossible) in eyes with high refractive errors or signif- technique was performed with a cotton-tipped applicator gently 7,F,G rolled over the cornea to create superficial punctate epithelial ero- icant corneal irregularities. Thus, in cases in which it is sions to improve penetration of the riboflavin. Next, isotonic ribo- essential to correct irregularity without large tissue reserves flavin 0.5% solution without dextran was applied to the operative available (ie, keratoconus), wavefront laser treatment is not eye every 2 minutes for 1 hour, and the eye was checked at the slit- – – an optimal option or is not an option at all.6 9,C G lamp for stromal riboflavin absorption and flare in the anterior Topography-guided laser ablation aims to remove tissue chamber. If the riboflavin saturation of the cornea was inadequate, additional riboflavin was applied and the cornea was reevaluated from the peaks of corneal curvature with a focal myopic before proceeding to UVA light application. After adequate ribo- ablation and steepen flatter areas by performing a hyper- – flavin saturation was achieved, the CCL-Vario 365 system opic ablation.4 8,C,H (Peschke Trade GmbH) was applied for 5 minutes (365 nm wave- 2 Topography-guided ablation removes significantly less length, 15 mW/cm fluence). After completion of treatment, a tissue than wavefront-guided ablation, frequently saving bandage contact lens was placed and the patient was given oflox- 7–9,C–G acin 0.3% 4 times a day until epithelial closure, prednisolone ace- one third more tissue. Using this technique broadens tate 1.0% drops 4 times a day for 1 week, and every day for 1 week, the spectrum of treatable patients, even those with signifi- – – as well as bromfenac 0.07% 2 times a day for 3 days. All patients cant surface irregularities.7 10,C H Before treatment, an ac- were followed closely to ensure proper healing. curate preoperative image of the cornea is required. In addition, at the time of treatment, topography-guided abla- Photorefractive Keratectomy tions collect and analyze over 20 000 datapoints (as opposed For the eyes treated for both topographic abnormality and refrac- to wavefront ablation, which may collect approximately tive error, the goal was to treat the total refractive error; however, if – – 1000 datapoints).7 10,C H treating this put the patient at risk for significant corneal thinning (!300 mm), treatment was prioritized for correction of as much Several studies have shown the efficacy of CXL per- corneal cylinder, followed by sphere, as possible. formed simultaneously, before, or after topographic abla- Photorefractive keratectomy was not performed until the eye tion in improving vision in keratoconus patients, appeared stable (no change in refraction or topography for at least although no clear treatment algorithm has been estab- 3 months) after CXL. Before each treatment, at least 8 high-quality – lished.4 8 To our knowledge, studies evaluating a large se- topographic images were acquired using the topography system. The technique for image acquisition and software calculation for ries of patients with keratoconus who have had CXL preoperative refractive planning has been described.8,9,E,F followed by topography-guided PRK have yet to be pub- After analysis by the topography system, the surgeon devised a lished. In addition, evaluation of visual and astigmatic PRK surgical plan. The goal for each patient was to not only treat

Volume 44 Issue 8 August 2018 VISUAL AND KERATOMETRIC OUTCOMES OF CXL FOR KERATOCONUS 1005 corneal topographic irregularities but also as much refractive error 70 years). The mean time between CXL and PRK was as could be safely permitted. Restrictions in treatment were 30.5 G 27.99 months (range 4 to 10 months). Patients defined by a limit of astigmatic treatment by the laser (3.00 D) m H who had refractive treatment tended to be significantly and a residual stromal bed (RSB) thickness of 300 m. If it was G determined that treatment of the refractive error would leave the younger at the time of CXL (34.62 4.52 versus patient with an RSB of less than 300 mm, only topographic irreg- 42.29 G 4.81 years, respectively; P Z .021, t test) and ularities were treated and the ablation optical zone was reduced PRK (36.56 G 4.56 versus 44.89 G 5.00 years, respec- from 6.5 mm to 6.0 mm to conserve corneal tissue. tively; P Z .015,ttest). There was no statistically signifi- Photorefractive keratectomy was performed in the standard cant difference between whether or not refractive fashion using the excimer laser. The eye was anesthetized using topical proparacaine hydrochloride solution 0.5%. Patients were treatment was performed and the time between CXL treated with a 6.5 mm optical zone unless the residual bed was and PRK (35.61 G 10.80 versus 26.29 G 9.48 months; calculated to be 300 mm or less. In these cases, a 6.0 mm optical P Z .198, t test). The majority of patients (35 [57.7%]) zone was used. After review and confirmation of the treatment were treated with an optical zone of 6.5 mm, while 27 pa- plan, the epithelium was debrided using a blunt spatula. The eye tients (42.3%) were treated with an optical zone of was centered and focused beneath the laser, the image was regis- tered, and the treatment was performed. Ofloxacin 0.3%, prednis- 6.0 mm. There was no statistical correlation between olone acetate 1.0%, and bromfenac 0.07% ophthalmic drops were size of optical zone treated and whether refractive treat- placed onto the eye followed by a bandage contact lens. All pa- ment was performed (P Z .344, t test). In addition, there tients were given ofloxacin 0.3% 4 times a day until epithelial was no significance between UDVA at baseline (P Z .111, closure, prednisolone acetate 1.0% 4 times a day tapered over t test) or immediately after CXL (P Z .596, t test) in either 1 month, and bromfenac 0.07% twice a day for 3 days. Patients were followed closely to ensure proper healing. group, whether or not refractive treatment was performed. There was no significance between CDVA at baseline Z Z Data Collection (P .266, t test) or after CXL (P .651, t test) for those The following data were collected at baseline, the time of CXL, and treated for refractive error versus topographic treatment 3 months and 6 months after PRK: uncorrected distance visual alone. Table 1 shows the overall data across all groups. acuity (UDVA); corrected distance visual acuity (CDVA); keratometric, manifest, and topographic astigmatism; manifest refrac- Overall Cohort tion; spherical equivalent (SE); maximum K reading; mean K reading; and corneal thickness (CCT) at apex of cone. Topo- After Corneal Crosslinking After CXL, there was no change in graphic parameters were evaluated using the reports from UDVA and a 1-line gain in CDVA. Corneal astigmatism Scheimpflug tomography scans. In addition, the data on age, decreased by a mean of À0.41 D. The SE became more hy- sex, ocular history (eg, surgeries, contact lens wear), age at the peropic by C1.37 D. There mean decrease in CCT was time of CXL and PRK, and the time between CXL and PRK 20.2 mm. The mean K decreased by À0.05 D, and the were analyzed for significance and a correlation with visual and À astigmatic outcomes. mean maximum K decreased by 0.20 D. No patient required retreatment after CXL. Statistical Analysis Three Months After Photorefractive Keratectomy Compared Study variables were analyzed by appropriate statistical methods to assess for the differences between patients and eyes treated as with baseline values, there was no change in UDVA and a an entire group and broken down between the refractive treatment 1-line gain in CDVA 3 months after PRK. There was a group and nonrefractive treatment group. Correlations between mean change in corneal astigmatism of C0.26 D, in steep- demographics (ie, age, sex) as well as baseline UDVA, CDVA, est K of C0.50 D, in mean K of C1.50 D, and in CCT steepest K, mean K, and mean corneal astigmatism were assessed of À51.91 mm. There was a C0.33 D hyperopic shift in using analysis of variance (ANOVA), the chi-square test, the t test, and the Fisher Z-transformation test to evaluate the sample corre- SE at 3 months. lation (r) for significance. For calculations, Snellen visual acuity was converted to decimal notation. Two-way ANOVA was used Six Months After Photorefractive Keratectomy Data were to compare UDVA and CDVA at baseline, after CXL, 3 months available for 41 eyes (26 refractive, 15 topographic treat- after PRK, and 6 months after PRK. The same analysis was per- ment alone) at the 6-month follow-up. At this point, there formed for the mean K readings, CCT, mean corneal astigmatism, was a 1-line gain in UDVA and a 2-line gain in CDVA. and steepest K across all timepoints. A P value of 0.05 less or was considered statistically significant. There was a mean change in corneal astigmatism of C0.29 D, in maximum K of À0.77 D, and in mean K of C À m RESULTS 0.43 D. The CCT decreased by a mean of 58.07 m, C Charts of 62 eyes of 56 patients (36 men, 20 women) were the SE became more hyperopic by a mean of 0.02 D. reviewed and analyzed. Of all patients treated, 28 (50%) had the right eye treated, 22 (39%) had the left eye treated, Nonrefractive Group and 6 (11%) had bilateral treatment. Thirty-four eyes of The mean age of the patients who had topographic treat- 28 patients had both topographic and refractive treatment; ment only was 42.49 G 12.19 years (range 19 to 69 years) 28 eyes of 28 patients had only topographic irregularities at the time of CXL and 44.89 G 12.67 years (range 20 to treated (ie, did not have refractive error treated). The 70 years) at time of PRK. The mean time between CXL mean age at CXL was 38.08 years G 13.07 (SD) (range and PRK was 35.64 G 27.31 months (range 3 to 98 months). 17 to 69 years); the mean age at time of topography- Table 2 shows the data across all timepoints for these guided PRK was 40.33 G 13.44 years (range 19 to patients.

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Table 1. Overall data across all groups and eyes (topographic alone D topographic and refractive treatment). Parameter Baseline Post-CXL 3 Mo Post- PRK 6 Mo Post-PRK UDVA (Snellen) Mean 20/100 20/100 20/100 20/80 Range HM, 20/25 CF, 20/30 CF, 20/30 CF, 20/25 CDVA (Snellen) Mean 20/50 20/40 20/40 20/30 Range 20/400, 20/20 20/100, 20/20 20/400, 20/20 20/150, 20/20 Corneal astigmatism (D) Mean G SD 4.10 G 2.57 3.69 G 1.89 4.36 G 2.38 4.39 G 2.67 Range 0.8, 12.9 0.5, 7.9 0.9, 9.0 0.7, 12.7 Maximum K (D) Mean G SD 54.05 G 5.58 54.25 G 4.57 54.55 G 6.07 53.28 G 4.98 Range 37.7, 70.7 43.4, 65.9 48.6, 72.4 45.5, 65.5 Mean K (D) Mean G SD 47.37 G 4.77 47.42 G 4.60 48.87 G 5.04 47.8 G 4.09 Range 37.0, 60.2 35.2, 56.1 41.1, 62.7 40.6, 54.4 CCT (mm) Mean G SD 483.11 G 57.43 462.91 G 61.52 431.2 G 65.16 425.04 G 50.61 Range 371, 643 360, 651 279, 525 312, 537 SE (D) Mean G SD À5.88 G 6.21 À4.51 G 3.99 À5.55 G 3.91 À5.86 G 3.76 Range À23.87, C2.38 À15.50, C3.36 À15.00, C1.00 À13.50, À0.25 20/40 or better UDVA (%) 11 7 14 6 20/40 or better CDVA (%) 51 55 57 69

CCT Z central corneal thickness (apical corneal thickness); CDVA Z corrected distance visual acuity; CF Z counting fingers; HM Z hand motions; K Z keratometry; SE Z spherical equivalent; UDVA Z uncorrected distance visual acuity

After Corneal Crosslinking After CXL, 1 line of UDVA was maximum K of C0.87 D, and in mean K of À0.11 D. There lost and there was no change in CDVA. There was a was a mean hyperopic change in SE of C2.03 D and a mean mean change in corneal astigmatism of À0.25 D, in change in CCT of À19.7 mm.

Table 2. Data across all timepoints for patients treated for topographic irregularities alone. Parameter Baseline Post-CXL 3 Mo Post-PRK 6 Mo Post-PRK UDVA (Snellen) Mean 20/80 20/100 20/100 20/100 Range HM, 20/25 20/400, 20/30 CF, 20/50 CF, 20/50 CDVA (Snellen) Mean 20/40 20/40 20/50 20/40 Range 20/400, 20/20 20/100, 20/20 20/400, 20/25 20/150, 20/20 Corneal astigmatism (D) Mean G SD 4.19 G 2.07 3.94 G 1.97 4.78 G 2.61 4.77 G 2.72 Range 0.9, 8.5 0.5, 7.3 0.9, 9.0 0.7, 12.7 Maximum K (D) Mean G SD 54.46 G 6.44 55.33 G 4.64 54.00 G 3.66 54.44 G 5.16 Range 37.7, 70.7 44, 64.9 49.1, 61.1 45.5, 64.4 Mean K (D) Mean G SD 47.42 G 5.48 47.31 G 5.36 48.29 G 4.71 48.09 G 4.63 Range 37.0, 60.2 35.2, 58.2 41.1, 55.25 40.6, 57.5 CCT (mm) Mean G SD 475.06 G 62.09 455.36 G 63.82 425.5 G 65.71 423.33 G 51.88 Range 372, 643 352, 652 364, 525 312, 537 SE (D) Mean G SD À6.16 G 6.14 À4.13 G 4.27 À7.37 G 4.38 À7.16 G 3.99 Range À18.63, 2.38 À14.38, 3.37 À15.38, 0.50 À12.88, 0.25 20/40 or better UDVA (%) 18 12.5 0 0 20/40 or better CDVA (%) 66 64 38 54

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Three Months After Photorefractive Keratectomy Compared Three Months After Photorefractive Keratectomy At 3 months, with baseline, there was 1 line of UDVA and CDVA lost. UDVA and CDVA had both improved by 2 lines. Corneal There was a mean change in corneal astigmatism of astigmatism decreased by 0.62 D, which was accompanied C0.59 D, in maximum K of À0.46 D, and in mean K of by a mean change of C2.47 D in maximum K and of C0.87 D. There was a mean myopic change in SE of C3.17 D in mean K. There was a mean hyperopic shift in À1.21 D and a mean change in CCT of À49.56 mm. SE of C1.95 D and a mean change in CCT of À34.19 mm. Compared with the nonrefractive group at this time- Six Months After Photorefractive Keratectomy Six months af- point, there was a significant improvement in UDVA and ter PRK, there was no change in UDVA or CDVA CDVA (P Z .007 and P Z .004, respectively; t test). There compared with baseline. There was a mean change in was a significant improvement in SE (toward emmetropia) corneal astigmatism of C0.58 D, in maximum K of C C 3 months after PRK in the refractive group versus the non- 0.02 D, and in mean K of 0.67 D. There was a mean ! myopic change in SE of À1.00 D and a mean change in refractive group (P .001, t test). À m CCT of 51.73 m. Six Months After Photorefractive Keratectomy At 6 months, there was a mean 3-line improvement in UDVA and a Refractive Group 2-line improvement in CDVA. There was a mean change The mean age at CXL of patients treated for both topo- in astigmatism of À0.63 D, in steepest K of À3.40 D, and graphic abnormality and refractive error was in mean K of À0.36 D. The CCT decreased by a mean of 34.62 G 12.75 years (range 17 to 65 years) at the time of À m G 58.76 m, and the SE became more hyperopic by a CXL and 36.56 12.87 years (range 19 to 67 years) at mean of C1.59 D. time of PRK. The mean time between CXL and PRK was There was a significant improvement in UDVA (P ! .001, 26.29 G 27.81 months (range 4 to 105 months). Table 3 t test) and CDVA (P Z .049) in the refractive group versus the shows the data across all timepoints for eyes treated for nonrefractive group 6 months after PRK. In addition, there refractive error and topographic irregularities. was a significant improvement in SE (toward emmetropia) After Corneal Crosslinking There was no change in UDVA at 6 months after PRK in the refractive group versus the non- from baseline to post-CXL, while there was a 1-line gain refractive group (P Z .014, t test). Figures 1 and 2 show sam- in CDVA. Corneal astigmatism decreased by a mean of ple topographies of 1 refractive patient who had visual 0.60 D, which was accompanied by a mean change of improvement as well as clear improvements in keratometry À0.38 D in maximum K and of C0.21 D in mean K. There and topography. This patient had a preoperative Snellen was a mean hyperopic shift in SE of C0.80 D and a mean UDVA of 20/100 and CDVA of 20/50. At the 6-month change in CCT of À17.45 mm. follow-up, the UDVA was 20/70 and the CDVA was 20/30.

Table 3. Data for eyes treated for refractive error and topographic irregularity. Parameter Baseline Post-CXL 3 Mo Post-PRK 6 Mo Post-PRK UDVA (Snellen) Mean 20/100 20/100 20/70 20/60 Range CF, 20/40 HM, 20/50 20/400, 20/30 20/100, 20/25 CDVA (Snellen) Mean 20/50 20/40 20/30 20/30 Range 20/400, 20/25 20/100, 20/25 20/100, 20/20 20/150, 20/20 Corneal astigmatism (D) Mean G SD 4.04 G 2.92 3.44 G 1.78 3.42 G 1.35 3.41 G 2.26 Range 0.8, 12.9 0.5, 7.9 0.9, 5.25 0.75, 7.8 Maximum K (D) Mean G SD 53.71 G 4.71 53.33 G 4.29 56.18 G 10.18 50.31 G 2.79 Range 41.7, 59.1 43.4, 65.9 47.25, 72.4 47.2, 55.3 Mean K (D) Mean G SD 47.33 G 4.13 53.33 G 4.29 50.50 G 5.58 46.97 G 1.55 Range 37.9, 56.6 36.4, 51.2 44.7, 62.7 44.8, 49 CCT (mm) Mean G SD 488.19 G 53.68 470.74 G 58.35 454 G 57.56 429.43 G 46.91 Range 384, 642 360, 648 374, 507 335, 493 SE (D) Mean G SD À5.64 G 6.25 À4.84 G 3.69 À3.69 G 2.70 À4.05 G 2.53 Range À23.87, C2.25 À13.88, C0.50 À6.63, C1.00 À12.00, À1.25 20/40 or better UDVA (%) 5 0 19 14 20/40 or better CDVA (%) 39 62.5 73 93

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Figure 1. Preoperative (after corneal crosslinking) topography shows keratoconus and irregular astigmatism.

In addition, the tomography shows the smoothing effect of There was no statistically significant difference in corneal topography-guided PRK. astigmatism, CCT, maximum K, or mean K between the refractive group and nonrefractive group at baseline Other Statistical Considerations (P Z .837, P Z .472, P Z .640, and P Z .942, respectively), There was no significant correlation between maximum K, after CXL (P Z .343, P Z .372, P Z .110, and P Z .854, UDVA, CDVA, or corneal astigmatism and age at baseline, af- respectively), 3 months after PRK (P Z .165, P Z .533, ter CXL, 3 months after PRK, or 6 months after PRK. In addi- P Z .467, and P Z .303, respectively), or 6 months after tion, there was no statistical correlation between eye treated PRK (P Z .27, P Z .486, P Z .067, and P Z .549, and whether or not refractive treatment was performed. respectively).

Figure 2. Tomography 6 months after topography- guided photorefractive keratectomy shows improvement in corneal astigmatism and increased corneal surface regularity.

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There was a statistically significant improvement in SE PRK in the nonrefractive group increased. Although coun- toward emmetropia 3 months and 6 months after PRK in terintuitive, this might be the result of treating topographic the refractive group versus the nonrefractive group irregularities in this population rather than creating a com- (P ! .001 and P Z .014, respectively). However, there plete flattening effect, as seen in wavefront-guided thera- was no detectable difference between the 2 groups at base- pies. In inferior cones, the myopic ablation is also inferior line or after CXL (P Z .770 and P Z .501, respectively). to the visual axis, which can create a hyperopic profile The mean K at baseline did not appear to have a statisti- that increases central steepening. Therefore, the treatment cally significant influence on UDVA or CDVA 6 months af- might have created a mild amount of increased corneal ter PRK (P Z .970 and P Z .439, respectively). There was no steepening as measured by Scheimpflug tomography. It is statistical correlation between maximum K at baseline and also possible that while aiming to steepen the flat areas of UDVA (P Z .771) or CDVA 6 months after PRK (P Z .303). the cornea, overall steepness was increased, leading to our There was no statistical correlation between corneal findings. In addition, those treated for refractive error had astigmatism or CCT at baseline and UDVA (P Z .725 decreased amounts of astigmatism (cornea, mean K, and P Z .191, respectively) or CDVA after PRK at 6 months maximum K), which is consistent with the refractive error (P Z .983 and P Z .614, respectively). being treated. As seen in Table 3, at the 3-month mark in the refractive group, the SE trended more toward emmetro- DISCUSSION pia while the maximum K values increased. This was fol- Our data are in concordance with results in previous studies lowed by an overall decrease in maximum K values and a showing the efficacy and potential visual improvement in slight myopic shift in SE at 6 months after PRK. This could – – keratoconus patients having CXL and PRK.4 8,10 17,J It is have been secondary to corneal remodeling after PRK as well established that alterations in corneal shape have a sig- well to as variability in data secondary to the smaller sample nificant refractive effect requiring multifaceted patient- of patients at 6 months. More research into the corneal – specific treatment planning.10,12 19,G,J biomechanics and remodeling after topography-guided Support of this treatment algorithm is found in several pub- PRK is necessary to elucidate the exact cause of the relative lished case reports by Krueger and Kanellopoulos7 and Kanel- increase in corneal astigmatism. lopoulos and Binder8 that report the efficacy of coupled The findings that baseline mean K, maximum K, corneal topography-guided PRK and CXL in eyes with corneal irreg- astigmatism, and CCT did not appear to influence final visual ularities (eg, after transplantation, in keratoconus). In these outcome (UDVA or CDVA) are unique to our study and was – – cases, topography-guided ablation provided a custom not addressed in previous studies.4 10,12 15,18,19,D,F,G,J This is approach that effectively treated the measured extreme an interesting finding because we would expect patients corneal irregularities.8 In a 2016 American Society of Cataract with lower baseline astigmatism to have proportionately bet- and Refractive Surgery presentation, Holland and LinJ estab- ter outcomes. In concert with this, we would expect patients lished that transepithelial PRK with simultaneous CXL in pa- with thicker corneas to have potentially better outcomes tients with keratoconus was efficacious, with 50% of eyes because they have “more room to treat” based on necessary achieving a UDVA of at least 20/40. In addition, 62% had tissue availability for refractive treatment. Each keratoconus improved CDVA by 2 or more lines and a mean reduction patient in our study had varying amounts of corneal astigma- in SE by À2.74 D. The best outcomes were in patients with tism and corneal thickness at baseline; thus, these findings central irregular astigmatism, and a combination of CXL also support the usefulness of topography-guided PRK across and topography-guided PRK offered improved UDVA and a wide range of patients. Based on these findings, the treat- CDVA to patients with keratoconus, ectasia, or “regular cor- ment appeared to be equally efficacious across the variance neas” with a low CCT.J Studies by Sakla et al.12,14 also found in corneal astigmatism and CCT values. However, further significant improvement in the manifest refraction, UDVA, studies would be useful in elucidating the validity and repro- CDVA, and K values over baseline with simultaneous CXL ducibility of these results using a larger sample. and topography-guided PRK, while Knezovicetal.13 found Comparison of the 2 groups (refractive versus non- that partial topography-guided PRK combined with CXL refractive) showed that treatment of refractive error led to an improvement in CDVA of 4 lines. significantly improved visual results. Although visual In the present study, we found there was a modest gain in improvement was not as greatinthenonrefractive UDVA and CDVA overall. However, when separating group, many of the patients were able to more comfort- those treated for solely topographic irregularities and those ably resume contact lens wear and even noted increased treated for refractive error, the latter set of patients had sig- quality of vision after treatment. It is possible that in nificant visual and astigmatic improvement, with a 3-line treating topographic irregularities, some higher-order average gain in UDVA and a 2-line average gain in aberrations (HOAs) were decreased or eliminated, allow- CDVA. In addition, at the end of the 6-month period, of ing for better visual quality, although this was not eyes whose treatment included some degree of refractive formally addressed in our study.9,G,H Analysis of HOAs correction, 93% had a CDVA of at least 20/40 or better before and after topography-guided treatment would and a statistically significant improvement in SE. be needed to show this hypothesized effect and could Despite visual improvement, the amounts of corneal be performed in future studies. No patient had an astigmatism, mean K values, and maximum K values after adverse event, such as infection, scarring, or excessive

Volume 44 Issue 8 August 2018 1010 VISUAL AND KERATOMETRIC OUTCOMES OF CXL FOR KERATOCONUS corneal thinning, after treatment or during the follow-up the behavioral characteristics of post-CXL eyes having sur- period. face ablation. Although many studies have performed simultaneous It is important to highlight that our study use a modified epi- – topography-guided PRK and CXL,7,8,10,12 14,16,17,19,F we on accelerated CXL technique, which differs from the standard – believe it is important to allow the cornea to stabilize be- Dresden protocol.1,4,11 Although multiple studies20 24 have tween treatments. It has been shown that the cornea un- validated accelerated and transepithelial CXL, using this tech- dergoes significant remodeling after CXL, and this can niqueasperformedinourstudymight have affected some re- affect not only refractive planning but also postoperative results. Among possible changes in corneal architecture with sults. Waiting for post-CXL stabilization not only ensures transepithelial CXL is corneal epithelial remodeling, which – that the corneal topography has stabilized but might also can differ from traditional epithelium-off (epi-off) CXL.20 24 – reduce the risk for adverse events such as delayed healing Also, some studies20 23 report that CXL does not penetrate when combining CXL with excimer laser photoablation, as deeply into the stroma if it is performed epi-on, and there- – as noted in previous reports.8,10,13,15 17 fore, corneal astigmatism, curvature, and the response to abla- In concordance with results in previous studies, custom tion might differ as well. More corneal flattening is seen in – topography-guided PRK for keratoconic eyes after CXL conventional epi-off CXL than in transepithelial CXL.20 24 was safe and effective in our patients. Topography-guided Therefore, this might produce variability in K readings, as – PRK performed at least 3 months after CXL treatment pro- seen in our study.20 24 Based on our literature search, there duced an average 2-line improvement in UDVA, 2-line does not appear to be a head-to-head trial of our modified improvement in CDVA, and for those treated for refractive epi-on CXL technique versus traditional epi-off CXL followed error, a 3.00 D improvement in the steepest K values at by topography-guided PRK to evaluate possible, and likely 6 months. In addition, when both refractive and topographic subtle topographic, changes secondary to the CXL technique. errors were treated, 93% of patients achieved a CDVA of 20/ In addition, although transepithelial CXL was performed, all 40 or better. We have also noted that in cases in which the patients had a stable refractive error and corneal astigmatism refractive error will not permit a full correction (eg, insuffi- before treatment for topography-guided PRK was planned. cient stromal bed thickness), a proposed treatment of only We believe that epithelial analysis after CXL (both modified the irregular astigmatic component can significantly improve epi-on and standard epi-off) as well as measurements of the CDVA outcomes, but not necessarily the UDVA. corneal flattening in a head-to-head trial would be not only Given that topography-guided treatment is based on ob- interesting but also of benefit in determining whether the taining good quality preoperative topographic images, the method of CXL is truly significant and which CXL strategy ocular surface should be optimized and if necessary, treated serves as a better surgical foundation before PRK treatment. – before further intervention.4,5,7 9,G In addition, when using Our study adds to current literature because it is the largest topography-guided ablation in irregular eyes, there may be U.S. case series showing the safety and efficacy of topography- – some residual hyperopia or myopia.4,5,7,8,12 19,F,J In these guided PRK in keratoconuspatients after CXL.Weperformed cases, it should be thoroughly explained to patients that a our treatment in a stepwise approach to allow for regulariza- second refining laser treatment to address residual refraction of the corneal surface after CXL before taking preoperative error might be considered as long as there is a sufficient tive measurements for PRK. We strongly believe this RSB and a good topographic image can be ob- treatment algorithm allows for better preoperative planning – tained.4,5,7,8,12 19,F,J We advocate the use of a large ablation as well as more accurate postoperative results. zone and prefer a 6.5 mm optical zone. However, when there is an insufficient RSB, use of a small (6.0 mm) optical zone can be an effective in conserving corneal tissue. Pa- WHAT WAS KNOWN tients should be informed that after PRK, epithelial remod- Cornea crosslinking for keratoconus has been shown to eling (both hyperplasia and hypoplasia) occurs and improve corneal biomechanics. improvement of vision can continue for up to Given the irregular contour of the cornea as well as focal – – 6 months.9,12 14,16 19,J Although other studies have shown thinning that can persist after CXL, conventional excimer laser ablations are usually not indicated. the long-term efficacy of topography-guided PRK as a treatment post-CXL (and its use in addition to other treat- WHAT THIS PAPER ADDS 6–8,12–17 ment modalities, such as ICRS or phakic toric At least 3 months after CXL, or once cornea topography and intraocular lens implantation), a study of long-term refraction have stabilized, topography-guided PRK appears follow-up of these patients using our sequential technique to be an efficacious and safe method of visual improvement is necessary to show stability of refraction and visual acuity in keratoconus patients. in this patient population. Another consideration in post- When there is sufficient stromal bed, the refractive component should be treated in addition to the topographic CXL patients is that the laser treatment should be applied ablation. with caution because the cornea might have different abla- More than 90% of patients achieved a CDVA of at least 20/ 7,8,12–14,16–19 tion behavior from that of a normal cornea. 40 after the use of PRK to treat refractive error in kerato- For this reason, it has been recommended that the conus patients as well as topographic irregularities after surgeon undercorrect the sphere and cylinder by CXL. 25%.4,5,7,8 More studies are needed to further understand

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