Accelerated corneal crosslinking concurrent with laser in situ keratomileusis

ARTICLE

Accelerated corneal crosslinking concurrent with laser in situ keratomileusis H. Ugur Celik, MD, Nese Alag€ oz, MD, Yusuf Yildirim, MD, Alper Agca, MD, John Marshall, MD, PhD, FRCOphth, FRCPath, Ahmet Demirok, MD, Omer Faruk Yilmaz, MD

PURPOSE: To assess accelerated corneal collagen crosslinking (CXL) applied concurrently with laser in situ keratomileusis (LASIK) in a small group of patients. SETTING: Beyoglu Eye Research and Training Hospital, Istanbul, Turkey. DESIGN: Prospective pilot interventional case series. METHODS: In May 2010, patients had LASIK with concurrent accelerated CXL in 1 eye and LASIK only in the fellow eye to treat myopia or myopic astigmatism. The follow-up was 12 months. The attempted correction (spherical equivalent) ranged from 5.00 to 8.50 diopters (D) in the LASIK–CXL group and from 3.00 to 7.25 D in the LASIK-only group. Main outcome measures were manifest refraction, uncorrected (UDVA) and corrected (CDVA) distance visual acuities, and the endothelial cell count. RESULTS: Eight eyes of 3 women and 1 man (age 22 to 39 years old) were enrolled. At the 12-month follow-up, the LASIK–CXL group had a UDVA and manifest refraction equal to or better than those in the LASIK-only group. No eye lost 1 or more lines of CDVA at the final visit. The endothelial cell loss in the LASIK–CXL eye was not greater than in the fellow eye. No side effects were associated with either procedure. CONCLUSIONS: Laser in situ keratomileusis with accelerated CXL appears to be a promising modality for future applications to prevent corneal ectasia after LASIK treatment. The results in this pilot series suggest that evaluation of a larger study cohort is warranted. Financial Disclosure: Drs. Yilmaz and Marshall are paid consultants to Avedro, Inc. No other author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2012; 38:1424–1431 Q 2012 ASCRS and ESCRS

Laser in situ keratomileusis (LASIK) is the most commonly performed refractive surgical procedure for the correction of ametropia. It causes little discomfort

Submitted: January 22, 2012. Final revision submitted: March 20, 2012. Accepted: March 24, 2012. €z, From Beyoglu Eye Training and Research Hospital (Celik, Alago Yildirim, Agca, Yilmaz) and the Department of Ophthalmology (Demirok), Medeniyet University, Istanbul, Turkey; the Institute of Ophthalmology (Marshall), London, United Kingdom. Supported by grants from Avedro, Inc., Boston, Massachusetts, USA. Corresponding author: H. Ugur Celik, MD, Beyoglu Eye Training and Research Hospital, Bereketzade camii Sok., 34421, Kuledibi, Beyoglu, Istanbul, Turkey. E-mail: [email protected].

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Q 2012 ASCRS and ESCRS Published by Elsevier Inc.

and results in faster visual recovery than surface ablations.1 Keratectasia is a severe complication that can arise after LASIK. Patients with this complication present with increasing myopia and astigmatism, loss of uncorrected distance visual acuity (UDVA), and often loss of corrected distance visual acuity (CDVA) due to progressive corneal steepening that occurs centrally or inferiorly.2,3 Ectatic changes can occur as early as 1 week after LASIK or can be delayed up to several years after the initial procedure.4,5 In many cases, penetrating keratoplasty is eventually performed to manage this complication. The incidence of keratectasia after LASIK has been estimated to range from 0.04% to 0.60%6,7; however, accurate clinical studies of the incidence are not available.8,9 Although several clinical risk factors have been reported, the mechanisms of post-LASIK keratectasia remain unclear.10 0886-3350/$ - see front matter doi:10.1016/j.jcrs.2012.03.034

CXL WITH LASIK

Studies of the histologic changes in post-LASIK keratectasia report variable degrees of corneal thinning in the stromal bed and the flap.11 Although disruption of Bowman layer, which is typically observed in keratoconus, has not been seen in most cases of post-LASIK keratectasia, other pathologic findings, such as macrostriae in the stromal bed, thinning of the stromal collagen lamellae, minimal scarring at the flap–stromal bed interface, lack of inflammation, and the presence of an iron ring around the steepening, have been reported.12,13 Keratectasia after LASIK has topographic and clinical characteristics similar to those of keratoconus, a noninflammatory disease characterized by thinning of the corneal stroma, defects in Bowman layer, and eventual protrusion of the central cornea.14,15 At present, there are few prognostic tools to determine who is at risk for post-LASIK keratectasia. Randleman et al.16,17 describe several parameters, such as high myopic corrections, thin corneas, and residual corneal bed thickness, that are major risk factors for this condition. Collagen corneal crosslinking (CXL) has emerged as a promising technique to slow or stop the progression of post-LASIK ectasia.18,19 The CXL technique involves photopolymerization of stromal fibers by the combined action of a photosensitizing substance (riboflavin) and ultraviolet-A (UVA) light. Photopolymerization increases the rigidity of the corneal collagen and its resistance to deformation. Wollensak et al.20 described the most commonly used procedure for CXL. The UVA illumination associated with this method uses a 3 mW/cm2 irradiance, 370 nm source illuminating the riboflavin-treated eye for 30 minutes (cumulative dose 5.4 J/cm2). Recent advances in UV light sources and CXL techniques have led to the development of uniform, high-powered UVA light sources. The combination of LASIK and accelerated CXL may provide a method to reduce the risk for postoperative keratectasia in a population in which at-risk patients are difficult to discern. In this small sample pilot group, we assessed the applicability of the technique of accelerated CXL procedures when performed in conjunction with LASIK at the time of surgery.

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Figure 1. System for accelerated CXL (UVA Z ultraviolet-A light).

a CDVA of 20/32 or better in each eye, and stable refraction (0.5 diopter [D] or less change in spherical equivalence for at least 1 year). A normal corneal topography with a minimum corneal thickness of 475 mm was also required. The primary exclusion criteria were a history of intraocular or corneal surgery, a history of systemic disease or use of systemic medication likely to affect corneal wound healing, anterior segment pathology, residual or active ocular disease, and a history of herpes keratitis.

Crosslinking Device The KXL system for accelerated CXL (Avedro, Inc.) has a uniform output with a root mean square deviation of less

PATIENTS AND METHODS This prospective single-center pilot study was performed as an interventional case series at Beyoglu Eye Research and Training Hospital, Turkey. Institutional review board approval was obtained. In May 2010, patients had LASIK with concurrent accelerated CXL in 1 eye and LASIK only in the fellow eye for the treatment of myopia or myopic astigmatism. The follow-up was 12 months. The primary inclusion criteria were bilateral myopia or myopia with astigmatism, age older than 18 years,

Figure 2. Energy profile (365 nm nominal) of the accelerated CXL system.

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than 3% across the beam and has an output of up to 45 mw/cm2 (Figure 1). This device significantly reduces exposure time while maintaining the same treatment dose; hence, the description “accelerated.” After riboflavin 0.1% solution (Vibex) is applied to the corneal bed, the system delivers UVA light (365 nm wavelength) in a uniform circular pattern onto the cornea (Figure 2). Irradiating the riboflavin results in photochemical activation and extends the effects of the irradiation to the surrounding tissue. After exposure, the riboflavin is excited into a triplet state and generates singlet oxygen via a combination of type I and type II pathways.21 Excited riboflavin and associated singlet oxygen appear to facilitate corneal CXL through mechanisms that are still being elucidated. These induce the formation of new covalent bonds between the amino acids of neighboring collagen fibers and result in stiffening of the cornea.22 The wavelength of 370 nm is used to achieve maximum absorption by the riboflavin while remaining below harmful DNA and retinal radiation levels.23 The UVA flux and irradiation time at the cornea are controlled by an internal computer system. The optics head houses the UVA irradiation mechanism, which emits UVA radiation at a wavelength of 365 nm at a userselectable intensity of 3 to 30 mw/cm2 over a 9.0 mm diameter spot. Alignment lasers aid the user in focusing the beam on the patient's cornea. Fine alignment of the UVA beam through observation of the alignment lasers is controlled through a wireless remote. The device is battery powered and portable. It has an articulating arm to allow movement of the system for alignment of the UVA beam to the patient's cornea. The treatment parameters (induction period, UVA

exposure time, UVA intensity, and beam diameter) are selected through a touch-screen user interface.

Surgical Technique The same surgeon (O.F.Y.) performed all surgical procedures. After a drop of proparacaine hydrochloride (Alcaine) was applied, a wire lid speculum was placed in the eye. For the LASIK procedure, flaps (superior hinge) were made in all cases using a pendular microkeratome with a 110 mm head (Schwind eye-tech-solutions) in both eyes. All patients had stromal ablation with an Amaris 705S laser (Schwind eye-tech-solutions), attempting to achieve emmetropia in treatment zones based on the patient's mesopic pupil size (range from 6.0 mm to 7.2 mm). After the laser ablation and while the flap remained open, a drop of riboflavin 0.1% solution was instilled into the CXLtreated eye; the solution was applied to the corneal bed within 1.5 minutes of ablation. Once the riboflavin solution was applied, the corneal flap was repositioned and allowed to adhere. The CXL device was used to apply UVA light within 3 minutes of flap closure. The UVA exposure was performed for 3 minutes at a power of 30 mw/cm2 (total dose 5.4 j/cm2). At the end of the procedure, a bandage contact lens was placed and the lid speculum was removed from the eye.

Postoperative Treatment and Clinical Assessment Patients received the same postoperative treatment in both eyes. Postoperative medication included diclofenac

Table 1. Results in LASIK-CXL eyes. Pt/Age (Y)/Eye 1/22/RE Preop Postop (mo) 1 6 12 2/30/LE Preop Postop (mo) 1 6 12 3/37/LE Preop Postop (mo) 1 6 12 4/25/LE Preop Postop (mo) 1 6 12

UDVA

CDVA

CCT (mm)

Mean K (D)

ECD (Cells/mm2)

1.00  180

20/120

20/020

593

44.3

3002

G0.00, G0.00  180 G0.00, G0.00  180 0.25, 0.25  130

20/020 20/020 20/020

20/020 20/020 20/020

497 498 492

40.1 40.2 40.2

2877 2902 2908

1.50  175

20/400

20/020

578

41.8

2433

C0.25, 0.25  180 C0.25, G0.00  180 C0.25, G0.00  180

20/020 20/020 20/020

20/020 20/020 20/020

479 470 474

37.4 37.4 37.3

2390 2420 2417

6.00,

1.50  145

20/250

20/025

572

42.8

2906

G0.00, G0.00, 0.25,

0.50  180 0.25  005 0.25  015

20/025 20/025 20/025

20/20C 20/20C 20/20C

464 472 466

37.0 37.0 37.0

2850 2838 2895

7.50,

2.00  160

20/400

20/020

522

40.8

2849

0.25, G0.00  180 0.25, G0.00  180 0.50, G0.00  180

20/020 20/020 20/020

20/020 20/020 20/020

417 415 412

33.7 34.8 34.6

2790 2820 2811

Manifest Refraction (D)

4.50,

4.25,

CCT Z central corneal thickness; CDVA Z corrected distance visual acuity; ECD Z endothelial cell density; Mean K Z mean keratometry (K1 C K2)/2; Pt Z patient; UDVA Z uncorrected distance visual acuity

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sodium 0.1% (Voltaren) 4 times daily as well as combined moxifloxacin 0.5% (Vigamox) and dexamethasone (Pred Forte) eyedrops 4 times daily until the removal of the therapeutic lens. After the therapeutic lens was removed, all eyes received dexamethasone eyedrops 4 times daily in a tapered dose for 4 weeks and moxifloxacin 0.5% drops 4 times daily for 1 week. Artificial tears were prescribed to be used at the patient's discretion. Patients were examined 1 day postoperatively for removal of the therapeutic lens. All patients were examined preoperatively and 1 week and 1, 3, 6, and 12 months postoperatively. Evaluations included manifest refraction, UDVA and CDVA (Optec Vision Tester 6500, Stereo Optical Co. Inc.), slitlamp biomicroscopy, corneal topography by Scheimpflug imaging (Pentacam, Oculus, Inc.), keratometry, central ultrasound pachymetry, specular microscopy, and fundus examination. Postoperative anterior stromal haze was graded according to the scale described by Nakamura et al.24 as follows: 0 Z clear, 0.5 Z faint corneal haze, 1 Z mild corneal haze seen only with oblique indirect illumination, 2 Z moderate corneal haze seen with direct illumination, 3 Z easily visible opacity not affecting refraction, and 4 Z dense opacity impairing the view of intraocular structures, possibly affecting refraction.

RESULTS Eight eyes of 3 women and 1 man (age 22 to 39 years old) were enrolled. All 8 eyes had successful LASIK and regardless of the CXL procedure, all had

improved UDVA with an early postoperative refraction of G0.50 D. Table 1 and Table 2 show the preoperative and follow-up features in the LASIK–CXL eyes and in the LASIK-only eyes, respectively. As a pilot study, no effort was made to calculate the sample size for statistical evaluation. Although the patients initially reported slightly blurred vision in the CXL eye compared with the fellow eye, it did not seem to affect the visual acuities. In eyes that had LASIK only, no stromal haze (grade 0) was observed during the entire follow-up. In the LASIK–CXL group, faint stromal haze (grade 0.5) was observed in the first postoperative week but tended to resolve thereafter. By 1 month after surgery, there was no stromal haze (grade 0). However, at the final examination, some degree of myopic change was observed in 2 of the LASIK-only eyes (eyes 3 and 4); the change eventually resulted in 2 or more lines of UDVA loss. All eyes in the LASIK–CXL group preserved the UDVA throughout the study period (Tables 1 and 2). Postoperatively, the CDVA improved in both eyes of 1 patient (#3), while all other eyes maintained the same level as at the initial examination. No eye lost 1 or more lines loss in CDVA at the final visit.

Table 2. Results in combined LASIK-only eyes. Pt/Age (Y)/Eye 1/22/LE Preop Postop (mo) 1 6 12 2/30/RE Preop Postop (mo) 1 6 12 3/37/RE Preop Postop (mo) 1 6 12 4/25/RE Preop Postop (mo) 1 6 12

UDVA

CDVA

CCT (mm)

Mean K (D)

ECD (Cells/mm2)

0.50  155

20/120

20/020

602

44.3

3175

0.50, G0.00  180 0.50, G0.00  180 0.75, 0.25  050

20/025 20/020 20/025

20/020 20/020 20/020

552 545 547

41.8 41.8 41.9

3094 3102 3075

4.00, G0.00  180

20/400

20/020

579

41.3

2364

Manifest Refraction (D)

2.75,

G0.00, 0.25, 0.25,

0.50  175 0.50  165 0.25  140

20/020 20/20C 20/020

20/020 20/020 20/020

502 510 504

37.8 37.9 37.9

2290 2314 2320

6.00,

2.50  025

20/200

20/032

584

43.4

2816

C0.25, C0.25, 0.75,

0.25  027 0.25 x 030 0.50  040

20/20C 20/20C 20/025

20/20C 20/20C 20/20C

472 478 470

37.7 37.6 37.6

2680 2740 2720

5.75,

0.50  020

20/400

20/020

527

40.7

2770

20/20C 20/20C 20/025

20/020 20/020 20/020

442 448 440

36.0 36.4 36.4

2620 2680 2672

0.50, G0.00  180 0.50, 0.00  010 0.75, 0.25  130

CCT Z central corneal thickness; CDVA Z corrected distance visual acuity; ECD Z endothelial cell density; Mean K Z mean keratometry (K1 C K2)/2; Pt Z patient; UDVA Z uncorrected distance visual acuity

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Figure 3. Preoperative (left) and 12-month postoperative (right) Scheimpflug images of patient 1 (LASIK Z laser in situ keratomileusis).

The corneal thickness measured by ultrasound pachymetry was stable in both groups (Tables 1 and 2). No eye had a progressive loss of corneal thickness throughout the 12-month follow-up. The change in central corneal thickness between early visits and late visits was less than 10 mm. Because LASIK treatment for myopia results in corneal flattening in all eyes, the change in corneal curvature change was evaluated. Tables 1 and 2 and Figures 3 to 6 show the keratometric measurements over time. Both eyes of patient 4 had a minimal change in keratometry (C0.90 D in the LASIK–CXL eye and C0.40 D in the LASIK-only eye) at 12 months compared with the 1-month postoperative

examination; no significant steepening was observed in any eye. The endothelial cell density (ECD) loss ranged from 2.0% to 4.0% in LASIK–CXL eyes and from 2.0% to 5.0% in LASIK-only eyes at 1 month; from 0.5% to 2.0% and from 2.0% to 3.0%, respectively, at 6 months; and from 0.4% to 3.0% and from 1.0% to 3.0%, respectively, at 12 months. The median ECD in the LASIK– CXL group was 2877.5 cells/mm2 preoperatively, 2820 cells/mm2 at 1 month, 2829 cells/mm2 at 6 months, and 2853 cells/mm2 at 12 months. The respective values in the LASIK-only group were 2793 cells/mm2, 2650 cells/mm2, 2710 cells/mm2, and 2696 cells/mm2.

Figure 4. Preoperative (left) and 12-month postoperative (right) Scheimpflug images of patient 2 (LASIK Z laser in situ keratomileusis). J CATARACT REFRACT SURG - VOL 38, AUGUST 2012

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Figure 5. Preoperative (left) and 12-month postoperative (right) Scheimpflug images of patient 3 (LASIK Z laser in situ keratomileusis).

No complications related to LASIK or accelerated CXL were observed during the follow-up. DISCUSSION In this study, the eye receiving riboflavin applied to the stromal bed immediately after LASIK and receiving UVA illumination had clinical outcomes similar to those in the fellow eye that had LASIK without CXL. In all cases at the 12-month follow-up, the LASIK– CXL eye had a UDVA and manifest refraction that was equal to or better than those in the LASIK-only eye. Neither procedure caused side effects. All patients maintained the CDVA, and the endothelial cell loss

in the LASIK–CXL eye was not more than in the fellow eye. These findings support the usefulness of the application of high-powered, short-duration UVA for CXL. Although the development of progressive clinical keratectasia after LASIK can be catastrophic, it is a relatively rare phenomenon. The significant issue is that until now, determining who is at marginal risk has been difficult. In addition, the deterioration of the LASIK correction over time, in particular in patients with moderate to high corrections and in younger patients, is well known.25,26 Thus, a method to stabilize the patient's refraction and the cornea after LASIK would be useful.

Figure 6. Preoperative (left) and 12-month postoperative (right) Scheimpflug images of patient 4 (LASIK Z laser in situ keratomileusis). J CATARACT REFRACT SURG - VOL 38, AUGUST 2012

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Corneal CXL may provide this method. Long-term studies27 of corneal CXL to treat keratoconus have shown that riboflavin-mediated CXL can stabilize diseased corneas for more than 3 years. One may anticipate that the application of riboflavin–UVA CXL in a healthy eye would result in similar stabilization. The LASIK procedure provides a natural opportunity for CXL. With the LASIK flap already open, the application of riboflavin to the stromal bed bypasses the epithelial barrier and allows rapid diffusion of riboflavin into the surrounding stromal tissue. The use of a uniform, high-powered UVA light source provides rapid activation of CXL with little interruption in the flow of the procedure. The results in our study support further evaluation of accelerated CXL with riboflavin–UVA in combination with LASIK in larger groups. Our patients had no side effects, albeit ours was a small case study. The addition of accelerated CXL did not appear to affect the LASIK algorithms, and LASIK–CXL patients had similar or better outcomes than patients having LASIK only. The potential to improve corneal integrity after LASIK through corneal CXL may provide an opportunity to reduce keratectasia in other at-risk populations. Additional clinical studies are warranted to validate the combination of LASIK and accelerated corneal CXL. WHAT WAS KNOWN  Laser in situ keratomileusis is the most commonly performed refractive surgical procedure for the correction of ametropia. Keratectasia is a severe complication that can arise after LASIK.  Corneal CXL increases the rigidity of the corneal collagen and its resistance to deformation, providing a treatment modality for keratectasia and keratoconus. WHAT THIS PAPER ADDS  Accelerated CXL with an output of up to 45 mw/cm2 provides for significantly reduced exposure times while maintaining the same treatment dose.  The combination of LASIK and accelerated CXL may provide a method to reduce the risk for postoperative keratectasia in a population in which at-risk patients are difficult to discern.

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21. Silva E, Edwards AM. Photoinduced processes in the eye lens: do flavins really play a role? In: Silva E, Edwards AM, eds, Flavins: Photochemistry and Photobiology (Comprehensive Series in Photochemical and Photobiological Sciences). Cambridge, UK, Royal Society of Chemistry, 2006; 134–136 22. Seiler T, Huhle S, Spoerl E, Kunath H. Manifest diabetes and keratoconus: a retrospective case-control study. Graefes Arch Clin Exp Ophthalmol 2000; 238:822–825 23. Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety of UVA-riboflavin cross-linking of the cornea. Cornea 2007; 26:385–389 24. Nakamura K, Kurosaka D, Bissen-Miyajima H, Tsubota K. Intact corneal epithelium is essential for the prevention of stromal haze after laser assisted in situ keratomileusis. Br J Ophthalmol 2001; 85:209–213. Available at: http://www.ncbi. nlm.nih.gov/pmc/articles/PMC1723865/pdf/v085p00209.pdf. Accessed April 23, 2012 25. Chen Y-I, Chien K-L, Wang I-J, Yen AM-F, Chen L-S, Lin P-J, Chen TH-H. An interval-censored model for predicting myopic regression after laser in situ keratomileusis. Invest

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First author: H. Ugur Celik, MD Beyoglu Eye Research and Training Hospital, Istanbul, Turkey