ARTICLE

Accelerated corneal c

rosslinking concurrentwith 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

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PURPOSE: To assess accelerated corneal collagen crosslinking (CXL) applied concurrently withlaser 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 LASIKonly in the fellow eye to treat myopia or myopic astigmatism. The follow-up was 12 months. Theattempted correction (spherical equivalent) ranged from �5.00 to �8.50 diopters (D) in theLASIK–CXL group and from �3.00 to �7.25 D in the LASIK-only group. Main outcomemeasures were manifest refraction, uncorrected (UDVA) and corrected (CDVA) distance visualacuities, and the endothelial cell count.

RESULTS: Eight eyes of 3 women and 1man (age 22 to 39 years old) were enrolled. At the 12-monthfollow-up, the LASIK–CXL group had a UDVA andmanifest refraction equal to or better than those inthe LASIK-only group. No eye lost 1 or more lines of CDVA at the final visit. The endothelial cell lossin the LASIK–CXL eye was not greater than in the fellow eye. No side effects were associated witheither procedure.

CONCLUSIONS: Laser in situ keratomileusis with accelerated CXL appears to be a promisingmodality for future applications to prevent corneal ectasia after LASIK treatment. The results inthis 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 authorhas 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 com-monly performed refractive surgical procedure forthe correction of ametropia. It causes little discomfort

uary 22, 2012.ubmitted: March 20, 2012.ch 24, 2012.

Eye Training and Research Hospital (Celik, Alag€oz,, Yilmaz) and the Department of Ophthalmologydeniyet University, Istanbul, Turkey; the Institute of(Marshall), London, United Kingdom.

grants from Avedro, Inc., Boston, Massachusetts,

author: H. Ugur Celik, MD, Beyoglu Eye TrainingHospital, Bereketzade camii Sok., 34421, Kuledibi,ul, Turkey. E-mail: h.ugurcelik@gmail.com.

SCRS and ESCRS

by Elsevier Inc.

and results in faster visual recovery than surfaceablations.1

Keratectasia is a severe complication that can ariseafter LASIK. Patients with this complication presentwith increasing myopia and astigmatism, loss ofuncorrected distance visual acuity (UDVA), and oftenloss of corrected distance visual acuity (CDVA) due toprogressive corneal steepening that occurs centrally orinferiorly.2,3 Ectatic changes can occur as early as1 week after LASIK or can be delayed up to severalyears after the initial procedure.4,5 In many cases,penetrating keratoplasty is eventually performed tomanage this complication. The incidence of keratec-tasia after LASIK has been estimated to range from0.04% to 0.60%6,7; however, accurate clinical studiesof the incidence are not available.8,9 Although severalclinical risk factors have been reported, the mecha-nisms of post-LASIK keratectasia remain unclear.10

0886-3350/$ - see front matter

doi:10.1016/j.jcrs.2012.03.034

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

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

1425CXL WITH LASIK

Studies of the histologic changes in post-LASIKkeratectasia report variable degrees of corneal thin-ning in the stromal bed and the flap.11 Althoughdisruption of Bowman layer, which is typically ob-served in keratoconus, has not been seen in most casesof post-LASIK keratectasia, other pathologic findings,such as macrostriae in the stromal bed, thinning of thestromal collagen lamellae, minimal scarring at theflap–stromal bed interface, lack of inflammation, andthe presence of an iron ring around the steepening,have been reported.12,13 Keratectasia after LASIKhas topographic and clinical characteristics similar tothose of keratoconus, a noninflammatory disease char-acterized by thinning of the corneal stroma, defects inBowman layer, and eventual protrusion of the centralcornea.14,15

At present, there are few prognostic tools todetermine who is at risk for post-LASIK keratectasia.Randleman et al.16,17 describe several parameters,such as high myopic corrections, thin corneas, andresidual corneal bed thickness, that are major risk fac-tors for this condition.

Collagen corneal crosslinking (CXL) has emerged asa promising technique to slow or stop the progres-sion of post-LASIK ectasia.18,19 The CXL techniqueinvolves photopolymerization of stromal fibers bythe combined action of a photosensitizing substance(riboflavin) and ultraviolet-A (UVA) light. Photopoly-merization increases the rigidity of the corneal colla-gen and its resistance to deformation.

Wollensak et al.20 described the most commonlyused procedure for CXL. The UVA illumination asso-ciated with this method uses a 3 mW/cm2 irradiance,370 nm source illuminating the riboflavin-treated eyefor 30 minutes (cumulative dose 5.4 J/cm2).

Recent advances in UV light sources and CXLtechniques have led to the development of uniform,high-powered UVA light sources. The combinationof LASIK and accelerated CXL may provide a methodto reduce the risk for postoperative keratectasia ina population in which at-risk patients are difficult todiscern. In this small sample pilot group, we assessedthe applicability of the technique of accelerated CXLprocedures when performed in conjunction withLASIK at the time of surgery.

PATIENTS AND METHODS

This prospective single-center pilot study was performed asan interventional case series at Beyoglu Eye Research andTraining Hospital, Turkey. Institutional review board ap-proval was obtained. In May 2010, patients had LASIKwith concurrent accelerated CXL in 1 eye and LASIK onlyin the fellow eye for the treatment ofmyopia ormyopic astig-matism. The follow-up was 12 months.

The primary inclusion criteria were bilateral myopiaor myopia with astigmatism, age older than 18 years,

J CATARACT REFRACT SURG -

a CDVA of 20/32 or better in each eye, and stable refraction(0.5 diopter [D] or less change in spherical equivalence for atleast 1 year). A normal corneal topography with a minimumcorneal thickness of 475 mm was also required.

The primary exclusion criteria were a history of intraocu-lar or corneal surgery, a history of systemic disease or use ofsystemic medication likely to affect corneal wound healing,anterior segment pathology, residual or active ocular dis-ease, and a history of herpes keratitis.

Crosslinking Device

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

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1426 CXL WITH LASIK

than3%across thebeamandhasanoutputofupto45mw/cm2

(Figure 1). This device significantly reduces exposure timewhile maintaining the same treatment dose; hence, the de-scription “accelerated.” After riboflavin 0.1% solution(Vibex) is applied to the corneal bed, the system deliversUVA light (365 nmwavelength) in a uniform circular patternonto the cornea (Figure 2). Irradiating the riboflavin results inphotochemical activation and extends the effects of the irradi-ation to the surrounding tissue.After exposure, the riboflavinis excited into a triplet state and generates singlet oxygen viaa combination of type I and type II pathways.21 Excitedriboflavin and associated singlet oxygen appear to facilitatecorneal CXL through mechanisms that are still being eluci-dated. These induce the formation of new covalent bonds be-tween the amino acids of neighboring collagen fibers andresult in stiffening of the cornea.22 The wavelength of370 nm is used to achieve maximum absorption by theriboflavin while remaining below harmful DNA and retinalradiation levels.23 The UVA flux and irradiation time at thecornea are controlled by an internal computer system. Theoptics head houses the UVA irradiation mechanism, whichemits UVA radiation at a wavelength of 365 nm at a user-selectable intensity of 3 to 30 mw/cm2 over a 9.0 mm diame-ter spot. Alignment lasers aid the user in focusing the beamon the patient's cornea. Fine alignment of the UVA beamthrough observation of the alignment lasers is controlledthrough a wireless remote. The device is battery poweredand portable. It has an articulating arm to allow movementof the system for alignment of the UVA beam to the patient'scornea. The treatment parameters (induction period, UVA

Table 1. Results in LASIK-CXL eyes.

Pt/Age (Y)/Eye Manifest Refraction (D) UDVA CDV

1/22/REPreop �4.50, �1.00 � 180 20/120 20/0Postop (mo)

1 G0.00, G0.00 � 180 20/020 20/06 G0.00, G0.00 � 180 20/020 20/012 �0.25, �0.25 � 130 20/020 20/0

2/30/LEPreop �4.25, �1.50 � 175 20/400 20/0Postop (mo)

1 C0.25, �0.25 � 180 20/020 20/06 C0.25, G0.00 � 180 20/020 20/012 C0.25, G0.00 � 180 20/020 20/0

3/37/LEPreop �6.00, �1.50 � 145 20/250 20/0Postop (mo)

1 G0.00, �0.50 � 180 20/025 20/26 G0.00, �0.25 � 005 20/025 20/212 �0.25, �0.25 � 015 20/025 20/2

4/25/LEPreop �7.50, �2.00 � 160 20/400 20/0Postop (mo)

1 �0.25, G0.00 � 180 20/020 20/06 �0.25, G0.00 � 180 20/020 20/012 �0.50, G0.00 � 180 20/020 20/0

CCT Z central corneal thickness; CDVA Z corrected distance visual acuity; ECDPt Z patient; UDVA Z uncorrected distance visual acuity

J CATARACT REFRACT SURG -

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

Surgical Technique

The same surgeon (O.F.Y.) performed all surgicalprocedures. After a drop of proparacaine hydrochloride(Alcaine) was applied, a wire lid speculum was placed inthe eye. For the LASIK procedure, flaps (superior hinge)were made in all cases using a pendular microkeratomewith a 110 mm head (Schwind eye-tech-solutions) in botheyes. All patients had stromal ablation with an Amaris705S laser (Schwind eye-tech-solutions), attempting toachieve emmetropia in treatment zones based on the pa-tient'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 CXL-treated eye; the solutionwas applied to the corneal bedwithin1.5 minutes of ablation. Once the riboflavin solution was ap-plied, the corneal flapwas repositionedandallowed to adhere.TheCXLdevicewasused to applyUVA lightwithin 3minutesof flap closure. The UVA exposure was performed for 3 min-utes at a power of 30 mw/cm2 (total dose 5.4 j/cm2). At theend of the procedure, a bandage contact lens was placed andthe lid speculumwas removed from the eye.

Postoperative Treatment and Clinical Assessment

Patients received the same postoperative treatment inboth eyes. Postoperative medication included diclofenac

A CCT (mm) Mean K (D) ECD (Cells/mm2)

20 593 44.3 3002

20 497 40.1 287720 498 40.2 290220 492 40.2 2908

20 578 41.8 2433

20 479 37.4 239020 470 37.4 242020 474 37.3 2417

25 572 42.8 2906

0C 464 37.0 28500C 472 37.0 28380C 466 37.0 2895

20 522 40.8 2849

20 417 33.7 279020 415 34.8 282020 412 34.6 2811

Z endothelial cell density; Mean K Z mean keratometry (K1 C K2)/2;

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1427CXL WITH LASIK

sodium 0.1% (Voltaren) 4 times daily as well as combinedmoxifloxacin 0.5% (Vigamox) and dexamethasone (PredForte) eyedrops 4 times daily until the removal of the thera-peutic lens. After the therapeutic lens was removed, all eyesreceived dexamethasone eyedrops 4 times daily in a tapereddose for 4 weeks and moxifloxacin 0.5% drops 4 times dailyfor 1 week. Artificial tears were prescribed to be used at thepatient's discretion.

Patients were examined 1 day postoperatively for removalof the therapeutic lens. All patients were examined pre-operatively and 1 week and 1, 3, 6, and 12 months post-operatively. Evaluations included manifest refraction,UDVA and CDVA (Optec Vision Tester 6500, Stereo OpticalCo. Inc.), slitlamp biomicroscopy, corneal topography byScheimpflug imaging (Pentacam, Oculus, Inc.), keratometry,central ultrasound pachymetry, specular microscopy, andfundus examination.

Postoperative anterior stromal hazewas graded accordingto the scale described by Nakamura et al.24 as follows: 0 Zclear, 0.5 Z faint corneal haze, 1 Z mild corneal haze seenonlywithoblique indirect illumination, 2Zmoderate cornealhaze seen with direct illumination, 3Z easily visible opacitynot affecting refraction, and 4Z dense opacity impairing theview of intraocular structures, possibly affecting refraction.

RESULTS

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

Table 2. Results in combined LASIK-only eyes.

Pt/Age (Y)/Eye Manifest Refraction (D) UDVA CD

1/22/LEPreop �2.75, �0.50 � 155 20/120 20/Postop (mo)

1 �0.50, G0.00 � 180 20/025 20/6 �0.50, G0.00 � 180 20/020 20/12 �0.75, �0.25 � 050 20/025 20/

2/30/REPreop �4.00, G0.00 � 180 20/400 20/Postop (mo)

1 G0.00, �0.50 � 175 20/020 20/6 �0.25, �0.50 � 165 20/20C 20/12 �0.25, �0.25 � 140 20/020 20/

3/37/REPreop �6.00, �2.50 � 025 20/200 20/Postop (mo)

1 C0.25, �0.25 � 027 20/20C 20/6 C0.25, �0.25 x 030 20/20C 20/12 �0.75, �0.50 � 040 20/025 20/

4/25/REPreop �5.75, �0.50 � 020 20/400 20/Postop (mo)

1 �0.50, G0.00 � 180 20/20C 20/6 �0.50, �0.00 � 010 20/20C 20/12 �0.75, �0.25 � 130 20/025 20/

CCT Z central corneal thickness; CDVA Z corrected distance visual acuity; ECDPt Z patient; UDVA Z uncorrected distance visual acuity

J CATARACT REFRACT SURG -

improved UDVA with an early postoperative refrac-tion of G0.50 D. Table 1 and Table 2 show the preop-erative and follow-up features in the LASIK–CXL eyesand in the LASIK-only eyes, respectively. As a pilotstudy, no effort was made to calculate the samplesize for statistical evaluation.

Although the patients initially reported slightlyblurred vision in the CXL eye compared with thefellow 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 theLASIK–CXL group, faint stromal haze (grade 0.5)was observed in the first postoperative week buttended to resolve thereafter. By 1 month after surgery,there was no stromal haze (grade 0). However, at thefinal examination, some degree of myopic changewas observed in 2 of the LASIK-only eyes (eyes 3and 4); the change eventually resulted in 2 or morelines of UDVA loss. All eyes in the LASIK–CXL grouppreserved the UDVA throughout the study period(Tables 1 and 2).

Postoperatively, the CDVA improved in both eyesof 1 patient (#3), while all other eyes maintained thesame level as at the initial examination. No eye lost1 or more lines loss in CDVA at the final visit.

VA CCT (mm) Mean K (D) ECD (Cells/mm2)

020 602 44.3 3175

020 552 41.8 3094020 545 41.8 3102020 547 41.9 3075

020 579 41.3 2364

020 502 37.8 2290020 510 37.9 2314020 504 37.9 2320

032 584 43.4 2816

20C 472 37.7 268020C 478 37.6 274020C 470 37.6 2720

020 527 40.7 2770

020 442 36.0 2620020 448 36.4 2680020 440 36.4 2672

Z endothelial cell density; Mean K Z mean keratometry (K1 C K2)/2;

VOL 38, AUGUST 2012

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

1428 CXL WITH LASIK

The corneal thickness measured by ultrasoundpachymetry was stable in both groups (Tables 1and 2). No eye had a progressive loss of corneal thick-ness throughout the 12-month follow-up. The changein central corneal thickness between early visits andlate visits was less than 10 mm.

Because LASIK treatment for myopia results incorneal flattening in all eyes, the change in cornealcurvature change was evaluated. Tables 1 and 2 andFigures 3 to 6 show the keratometric measurementsover time. Both eyes of patient 4 had a minimalchange in keratometry (C0.90 D in the LASIK–CXLeye and C0.40 D in the LASIK-only eye) at 12months compared with the 1-month postoperative

Figure 4. Preoperative (left) and 12-month postoperative (right) Scheimpfl

J CATARACT REFRACT SURG -

examination; no significant steepening was observedin any eye.

The endothelial cell density (ECD) loss ranged from2.0% to 4.0% in LASIK–CXL eyes and from 2.0% to5.0% in LASIK-only eyes at 1 month; from 0.5% to2.0% 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%, respec-tively, 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 at6 months, and 2853 cells/mm2 at 12 months. The re-spective values in the LASIK-only group were 2793cells/mm2, 2650 cells/mm2, 2710 cells/mm2, and2696 cells/mm2.

ug images of patient 2 (LASIK Z laser in situ keratomileusis).

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

1429CXL WITH LASIK

No complications related to LASIK or acceleratedCXL were observed during the follow-up.

DISCUSSION

In this study, the eye receiving riboflavin applied to thestromal bed immediately after LASIK and receivingUVA illumination had clinical outcomes similar tothose 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 thatwas equal to or better than those in the LASIK-only eye.

Neither procedure caused side effects. All patientsmaintained the CDVA, and the endothelial cell loss

Figure 6. Preoperative (left) and 12-month postoperative (right) Scheimpfl

J CATARACT REFRACT SURG -

in the LASIK–CXL eye was not more than in thefellow eye. These findings support the usefulness ofthe application of high-powered, short-durationUVA for CXL.

Although the development of progressive clinicalkeratectasia after LASIK can be catastrophic, it isa relatively rare phenomenon. The significant issue isthat until now, determining who is at marginal riskhas been difficult. In addition, the deterioration ofthe LASIK correction over time, in particular inpatients with moderate to high corrections and inyounger patients, is well known.25,26 Thus, a methodto stabilize the patient's refraction and the cornea afterLASIK would be useful.

ug images of patient 4 (LASIK Z laser in situ keratomileusis).

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1430 CXL WITH LASIK

Corneal CXL may provide this method. Long-termstudies27 of corneal CXL to treat keratoconus haveshown that riboflavin-mediated CXL can stabilizediseased corneas formore than 3 years. Onemay antic-ipate that the application of riboflavin–UVA CXL ina healthy eye would result in similar stabilization.

The LASIK procedure provides a natural opportu-nity for CXL. With the LASIK flap already open, theapplication of riboflavin to the stromal bed bypassesthe epithelial barrier and allows rapid diffusion ofriboflavin into the surrounding stromal tissue. Theuse of a uniform, high-powered UVA light sourceprovides rapid activation of CXL with little interrup-tion in the flow of the procedure.

The results in our study support further evaluation ofaccelerated CXL with riboflavin–UVA in combinationwith LASIK in larger groups. Our patients had noside effects, albeit ours was a small case study. The ad-dition of accelerated CXL did not appear to affect theLASIK algorithms, and LASIK–CXL patients had simi-lar or better outcomes thanpatients havingLASIKonly.

The potential to improve corneal integrity afterLASIK through corneal CXL may provide an opportu-nity to reduce keratectasia in other at-risk popula-tions. Additional clinical studies are warranted tovalidate the combination of LASIK and acceleratedcorneal CXL.

WHAT WAS KNOWN

� Laser in situ keratomileusis is the most commonly per-formed refractive surgical procedure for the correctionof ametropia. Keratectasia is a severe complication thatcan arise after LASIK.

� Corneal CXL increases the rigidity of the corneal collagenand its resistance to deformation, providing a treatmentmodality for keratectasia and keratoconus.

WHAT THIS PAPER ADDS

� Accelerated CXL with an output of up to 45 mw/cm2 pro-vides for significantly reduced exposure times while main-taining the same treatment dose.

� The combination of LASIK and accelerated CXL may pro-vide a method to reduce the risk for postoperative kera-tectasia in a population in which at-risk patients aredifficult to discern.

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VOL

38, AUGUST 2012

First author:H. Ugur Celik, MD

Beyoglu Eye Research and TrainingHospital, Istanbul, Turkey