Simultaneous Topography-Guided PRK with CXL Versus CXL Alone in Kconus: Prospective Comparative Study

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1 This paper was conferred with the AIOS CORNEA AWARD for the BEST PAPER of CORNEA Sessions. This paper was also judged the BEST PAPER of CORNEA - II Session. Simultaneous Topography-Guided PRK with CXL Versus CXL Alone in Kconus: Prospective Comparative Study Dr. Vardhaman Kankaria, Dr. George Kontadakis, Dr. George D Kymionis, Dr. Michael Grentzelos Successful treatment of ectatic disorders keratoconus, pellucid marginal degeneration and iatrogenic corneal ectasia- confronts two distinct parameters; the corneal biomechanical stability and the optical inefficiency of the irregular cornea. Throughout the past decades penetrating Keratoplasty was the standard technique for the treatment of the disease, especially in advanced cases. Lamellar keratoplsty and epikeratophakia have also been utilized. Other treatments both non surgical, such as rigid contact lenses, and surgical such as intracorneal rings insertion, has been proposed mainly for vision rehabilitation of the patients. After the introduction of corneal collagen crosslinking (CXL) the issue of stabilization has been successfully confronted, according to the current experience. 7,8 Most of the studies of CXL show that the technique has excellent results in halting the progression of ectatic disorders. Despite that, the topography and the visual performance of patients treated with CXL show minimal improvement. The application of excimer laser surface ablation has been introduced formerly for the correction of keratoconus with the main drawback being that it is a tissue removal technique. Several studies have reported the application of surface ablation techniques to correct astigmatism in cases of stable or forme fruste keratoconus 4-6 with variable results. 4-6 The combination with excimer laser for the integrated treatment of keratoconus has come up as a new emerging technique. The goal of this combination is to treat keratoconic patients and offer them both stability and functional vision. Reaching functional vision consists of improvement of uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA) and normalization of corneal topography which indicates that these patients are less dependent on contact lenses to achieve higher postoperative vision quality. Despite the fact that the technique has been described in the literature, no study has compared the results of the combined technique with the standard protocol of CXL so far. The purpose of this study is to compare the refractive

2 AIOC 2014, Agra results and the confocal microscopic findings in patients treated with simultaneous tprk-cxl and patients treated with CXL in the same center. MATERIALS AND METHODS This is a prospective comparative interventional case series of patients with progressive keratoconus treated either with t-cxl or with CXL alone. 42 patients (60 eyes) were included. 30 eyes received topography guided PRK with a solid state laser (maximum ablation depth 50μm) followed by CXL with the standard protocol, and 30 eyes received only CXL. Inclusion criteria were: progressive keratoconus, hard contact lens and full spectacle correction intolerance, expected central corneal thickness (CCT) after PRK more than 400μm and no other corneal pathological signs. Keratoconus was described as progressive when there was an increase in the cone apex keratometry of -0.75D or alteration of -0.75D in the spherical equivalent, in a period of at least six months. Patients were thoroughly informed about the experimental nature of the intervention, the possible outcomes and the current clinical experience and have given their written consent according to the declaration of Helsinki and the institutional guidelines. Clinical evaluation Preoperative evaluation consisted of general and ocular health history assessment, autorefractometry and autokeratometry (Canon autorefractor), corneal topography (itrace, Tracey Tech. Houston Texas), assessment of uncorrected visual acuity (UCVA), best spectacle corrected visual acuity (BSCVA), manifest and cycloplegic refraction, scotopic pupillometry, central ultrasound pachymetry (Sonogage Corneo Gage Plus), and slitlamp examination of the anterior and posterior segments of the eyes. In this prospective interventional case series, we included subjects from a continuous cohort of patients with keratoconus who visited the Institute of Vision and Optics of the University of Crete seeking for consultation. Patients with progressive keratoconus, without any other systemic or ocular disease were included in the study. Diagnosis of keratoconus was based on the axial topography map (itrace, Tracey tech. Houston TX). 31 Keratoconus was described as progressive when there was an increase in the cone apex keratometry of 0.75 diopters (D) or alteration of 0.75D in the spherical equivalent refraction in a period of at least 6 months. Upon confirmation of progression, we proposed CXL as a treatment for keratoconus in order to halt its progression. Patients were thoroughly counselled about the possible outcomes and complications, as well as the current clinical experience. We obtained informed written consent from all subjects according to the institutional guidelines and the declaration of Helsinki. Institutional Review Board (IRB)/Ethics Committee approval was obtained.

3 Surgical procedure T-PRK with CXL All procedures were performed in our institute by the same surgeon (G.D.K.). After topical anaesthesia with tetracaine 1% and oxybuprocaine 0.4% eyedrops, the epithelium was mechanically removed within an 8.5 mm diameter. A solidstate laser with a wavelength of 213nm (Pulzar Z1, CustomVis, Perth, WA) was used for the PRK procedure. The wavelength is generated using a major Nd:YAG laser system of 1064nm and through special cultivated crystals the 213 nm is finally used. The customization was performed based on the corneal higher order aberrations. System software allows the use of a percentage of customization from 0 to 100%. Using 0 percent would be equivalent to a conventional laser treatment and 100 percent would be equivalent to a full customized treatment. Adjusting this percentage, attempted correction and ablation zone could lower the maximum depth of tissue removed. Maximum ablation depth was 50μm. Patients attempted correction and maximum ablation depth. Next, riboflavin (0.1% solution 10 mg riboflavin-5-phosphate in 10 ml dextran-t % solution) was applied every 3 minutes for approximately 20 minutes until the stroma was completely penetrated and aqueous was stained yellow (riboflavin shielding). A commercially available UVA system ((UV- X illumination system version 1000) was used for Ultraviolet-A irradiation. Before treatment, the intended 3 mw/cm 2 surface irradiance (5.4 J/cm 2 surface dose after 30 minutes) was calibrated using the UVA meter YK-34UV (Lutron Electronic) which is supplied with the UV-X device. During treatment, riboflavin solution was applied every 5 minutes to ensure saturation. After the treatment, a bandage contact lens was applied until the epithelium completely healed, followed by application of fluorometholone 0.1% eyedrops (FML Liquifilm) twice daily for 2 weeks. CXL surgical technique After topical anaesthesia with proparacaine hydrochloride 0.5% eyedrops was administered, the corneal epithelium was removed within a 8.0 mm diameter exclusively. Next, commercially available riboflavin (Riboflavin 0.1% isotonic eye drops with 20% dextran 500, Medicross, Medio Haus, Behrensbrook, Neudorf, Germany) was applied every 3 minutes for approximately 30 minutes. Ultraviolet-A irradiation was accomplished using a commercially available UVA system (UV-X, Peschke Meditrade, Germany) with Koehler optics. Before treatment, the intended 3 mw/cm 2 surface irradiance (5.4 J/cm 2 surface dose after 30 minutes) was calibrated using the UVA meter YK-34UV (Lutron Electronic). During treatment, riboflavin solution was applied every 5 minutes to ensure saturation.

4 AIOC 2014, Agra At the end of the procedure, a combination of steroid and antibiotic drop (Tobradex; Alcon Lab), was administered in all patients and a siliconhydrogel bandage contact lens (Lotrafilcon B, Air Optix, Ciba Vision 14.0mm diameter, 8.6 base curvature, Dk=140 barrers) was kept in place until full corneal re-epithelialization occurred. After reepithelialisation, a course of fluorometholone 0.1% eyedrops (FML Liquifilm) with weekly tapering was applied for a month, and patients were advised to use preservative-free artificial tears for the first 6 postoperative months. All procedures were carried out in our centre by the same surgeon (G.D.K.). Statistical analysis We examined the distribution of continuous variables with the Shapiro-Wilk test for normality. Comparisons between preoperative and postoperative values at each time point were performed for corneal sensitivity, Schirmer s I test result, TFBUT, and nerve length. The differences between preoperative and postoperative values were assessed with the paired samples t-test if variables had a normal distribution, and with the Wilcoxon signed rank test if the variables did not have a normal distribution. The statistical package SPSS 15.0 was used (SPSS Inc., Chicago, IL, USA). A p value less than 0.05 was considered to be statistically significant. RESULTS Mean follow up was 30±11 months. Mean age,keratoconus stage and pre-op BCVA were matched in both groups. At last follow up CDVA was 0.09±0.11 in the t-cxl group and 0.18±0.13 in the CXL group (p<0.05). In both groups no patient lost more than 1 line of Snellen VA, whereas in the t-cxl group 18 eyes and in the CXL group 6 eyes gained 2 or more lines of VA. DISCUSSION Simultaneous PRK followed by CXL Despite the encouraging results of the case report on CXL followed by PRK, there are three limitations with this approach. First, the stiffened cross linked corneal tissue is removed in a second step by the PRK (potentially decreasing the benefits of CXL). Second, the efficacy of this approach is limited since the corneal ablation rate could be different in cross linked corneas than in the virgin cornea (this could lead to unpredictable refractive results). Third, there is an increased possibility of post-prk haze formation (after CXL the anterior stroma is repopulated by new keratocytes after six months according to in vivo confocal microscopy). 10 Due to these aspects it was considered that a better option for treating ectatic disorders is topography guided PRK immediately followed by CXL in a single surgical procedure. The first report of this technique was in a case of

5 pellucid marginal degeneration where both eyes of the patient were treated by Kymionis et. al. 11 A limited topography guided PRK was performed followed by CXL according to the standard procedure. The patient achieved functional vision and independency from contact lenses. The main advantage of this technique is that ablation does not interfere with the already cross linked part of the cornea. In addition, cross liking of the ablated stroma offers the advantage of depopulating keratocytes in the anterior stroma thus avoiding the possibility of anterior haze formation by the activated keratocytes. The application of this technique on eyes with keratoconus was described the same year from the same institute in a series of patients 12. Fourteen eyes were treated with simultaneous topography-guided PRK followed by CXL. The patients treated in this study showed a marked improvement in topography and stability during the follow up period. The major consideration in the planning of this procedure was the postoperative corneal thickness. PRK treatment was planned based on the patients corneal thickness. Restricted treatments of up to 50μm were performed, while the ablation depth was mapped out by modifying the target correction (expected central corneal thickness after PRK and prior CXL more than 400μm). Undercorrection of sphere and cylinder was planned and the amount of customization was also adjusted. The results of this study indicate that the combination of treatments (PRK and CXL) leads to a slight overcorrection of the planned treatment. A comparison of sequential versus same-day simultaneous collagen crosslinking and topography-guided PRK for treatment of keratoconus was published in 2009 by Kanellopoulos. 13 In this study, a series of patients treated with the same day procedure, was compared retrospectively with a series of patients treated with the CXL followed by PRK after a time interval of at least 6 months. Comparisons were made between of groups in terms of visual acuity; manifest refraction spherical equivalent, keratometry, topography, central corneal thickness, endothelial cell count, corneal haze, and ectatic progression. Mean follow- up was 36 months. According to the results, the group of patients treated with the same day procedure performed better in all parameters. The surface ablation in these cases was also limited to 50 μm. The author concludes that the same day procedure is superior to the sequential due to three parameters: the patients comfort (single-day procedure for each eye instead of two-step), the minimum stromal scarring of the simultaneous procedure, and the fact that the same-day procedure does not remove cross linked stroma. The combined procedure has been also reported in a series of patients with keratoconus and pellucid marginal degeneration treated by Stojanovitz et

6 AIOC 2014, Agra al. 14 The authors treated 12 eyes and followed them for 12 months, showing the improvement in mean visual acuity and in topography. Also they report minimal changes in posterior surface of the patients, thus confirming stability after the procedure. Krueger and Kanellopulos in 2010 presented two cases that were followed for about 3 years. 15 In one case the progressive reduction of refractive myopia and keratometric power was demonstrated, similarly to that often observed in conventional CXL. The surgical technique in these cases consisted of limited topography guided PRK, mytomycin-c (MMC) application and then CXL according to the standard protocol. The technique was named by the authors the Athens protocol. The long term results of simultaneous topography-guided PRK followed by CXL in a series of patients were reported by Kymionis et al in In this study, transepithelial phototherapeutic keratectomy (PTK) was performed for the removal of the epithelium prior to PRK in order to facilitate further smoothening of the corneal surface due to the masking properties of the epithelium in corneas with keratoconus. MMC was not applied and CXL was subsequently performed according to the Dresden protocol. In this report patients were offered a successful visual outcome with functional vision and the long term stability of the visual outcome was confirmed in 20 month follow up. In about half of these patients the development of mild linear haze in the posterior stroma was observed in the slit lamp examination. This rather trivial complication of the simultaneous procedure has been described in a previous paper. 17 According to this report, posterior haze developed after simultaneous PRK followed by CXL in the deep stroma in about half of the studied patients. In confocal microscopy authors detected an area with high reflectance at the level of the posterior stroma characterized by spindle-shaped and linear structures. The high-reflective, spindle-shaped structures were linked with migration and activation of keratocytes. Furthermore, the linear hyperreflective structures could be associated with increased collagen deposition, collagen disorganization, and excessive production of extracellular material from the activated keratocytes. Posterior haze gradually moves anteriorly and became less dense in most of the patients. The impact of CXL and CXL combined with topography guided PRK in patients self reported quality of life has been reported by Labiri et al in recent study of patients with early stage keratoconus. 18 The authors used the National Eye Institute Visual Function -25 item questionnaire, (NEI VFQ-25) which is a well validated tool for the quantitave evaluation of health related quality of life. According to the authors both techniques offered the patients

7 an improvement in self reported quality of life. Additionally, the scores of the keratoconus patients were significantly lower than those of the matched healthy control group. The authors conclude that both techniques should be implemented as soon as possible for the treatment of keratoconus. The use of this technique for the treatment of corneal ectasia has also been studied. 19,20 The simultaneous procedure of PRK with CXL has been combined with other surgical techniques to improve the visual acuity of the patients. A case of a patient who was initially treated with intracorneal ring segment implantation and 12 months later underwent simultaneous topography guided PRK followed by CXL was reported by Kymionis et al. 21 The patient had significant improvement and stability in 9 months follow up. Iovieno et al reported Intacs implantation and 6 month later simultaneous conventional limited PRK and CXL in 5 eyes that showed significant improvement and stability. 22 Kanellopoulos reported a case of ectasia after combined topoguided PRK and CXL in an attempt to treat corneal irregularity and astigmatism, and following that a phacic intraocular lens was implanted to treat high residual myopia. 23 Conclusions Simultaneous tprk with CXL is capable of offering keratoconus patients improved vision as against CXL alone without progression risk. REFERENCES 1. Jhanji V, Sharma N, Vajpayee RB. Management of keratoconus: current scenario. Br J Ophthalmol. 2011;95: Kymionis GD, Siganos CS, Tsiklis NS, et al. Long term follow up of Intacs in keratoconus. Am J Ophthalmol 2007;143: Coskunseven E, Kymionis GD, Tsiklis NS, et al. One-year results of intrastromal corneal ring segment implantation (KeraRing) using femtosecond laser in patients with keratoconus. Am J Ophthalmol 2008;145: Alpins N, Stamatelatos G. Customized photoastigmatic refractive keratectomy using combined topographic and refractive data for myopia and astigmatism in eyes with forme fruste and mild keratoconus. J Cataract Refract Surg. 2007;33: Koller T, Iseli HP, Donitzky C, Ing D, Papadopoulos N, Seiler T. Topography- guided surface ablation for forme fruste keratoconus. Ophthalmology. 2006;113: Cennamo G, Intravaja A, Boccuzzi D, Marotta G, Cennamo G. Treatment of keratoconus by topography-guided customized photorefractive keratectomy: twoyear follow-up study. J Refract Surg. 2008;24: Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135: Raiskup-Wolf F, Hoyer A, Spoerl E et al. Collagen crosslinking with riboflavin and

8 AIOC 2014, Agra ultraviolet-a light in keratoconus: long-term results. J Cataract Refract Surg. 2008; 34: Kanellopoulos AJ, Binder PS. Collagen cross-linking (CCL) with sequential topography-guided PRK: a temporizing alternative for keratoconus to penetrating keratoplasty. Cornea 2007;26: Kymionis GD, Diakonis VF, Kalyvianaki M, et al. One-Year Follow-up of Corneal Confocal Microscopy After Corneal Cross-Linking in Patients With Post Laser In Situ Keratosmileusis Ectasia and Keratoconus. Am J Ophthalmol. 2009;147:774-8, 778. e Kymionis GD, Karavitaki AE, Kounis GA, et al. Management of pellucid marginal corneal degeneration with simultaneous customized photorefractive keratectomy and collagen crosslinking. J Cataract Refract Surg. 2009;35: Kymionis GD, Kontadakis GA, Kounis GA, et al. Simultaneous topography-guided PRK followed by corneal collagen cross-linking for keratoconus. J Refract Surg. 2009;25:S Kanellopoulos AJ. Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus. J Refract Surg. 2009;25:S Stojanovic A, Zhang J, Chen X, Nitter TA, Chen S, Wang Q. Topography-guided transepithelial surface ablation followed by corneal collagen cross-linking performed in a single combined procedure for the treatment of keratoconus and pellucid marginal degeneration. J Refract Surg. 2010;26: Krueger RR, Kanellopoulos AJ. Stability of simultaneous topography-guided photorefractive keratectomy and riboflavin/uva cross-linking for progressive keratoconus: case reports. J Refract Surg. 2010;26:S Kymionis GD, Portaliou DM, Kounis GA, Limnopoulou AN, Kontadakis GA, Grentzelos MA. Simultaneous topography-guided photorefractive keratectomy followed by corneal collagen cross-linking for keratoconus. Am J Ophthalmol. 2011;152: Kymionis GD, Portaliou DM, Diakonis VF, et al. Posterior linear stromal haze formation after simultaneous photorefractive keratectomy followed by corneal collagen cross-linking. Invest Ophthalmol Vis Sci. 2010;51: 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 Jan 10. [Epub ahead of print] 19. 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: Kymionis GD, Portaliou DM, Diakonis VF, et al. Management of post laser in situ keratomileusis ectasia with simultaneous topography guided photorefractive keratectomy and collagen cross-linking. Open Ophthalmol J. 2011;5: Kymionis GD, Grentzelos MA, Portaliou DM, et al. Photorefractive keratectomy

9 followed by same-day corneal collagen crosslinking after intrastromal corneal ring segment implantation for pellucid marginal degeneration. J Cataract Refract Surg. 2010;36: Iovieno A, Légaré ME, Rootman DB, Yeung SN, Kim P, Rootman DS. Intracorneal ring segments implantation followed by same-day photorefractive keratectomy and corneal collagen cross-linking in keratoconus. J Refract Surg. 2011;27: Kanellopoulos AJ, Skouteris VS. Secondary ectasia due to forceps injury at childbirth: management with combined topography-guided partial PRK and collagen cross-linking (Athens Protocol) and subsequent phakic IOL implantation. J Refract Surg. 2011;27:635-6.