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    Intraoperative corneal thickness changeand clinical outcomes after corneal

    collagen crosslinking: Standard crosslinkingversus hypotonic riboflavin

    Elan Rosenblat, MD, Peter S. Hersh, MD

    2016 A


    PURPOSE: To determine intraoperative changes in corneal thickness and outcomes of cornealcollagen crosslinking (CXL) using 2 intraoperative regimens: riboflavindextran or hypotonicriboflavin.

    SETTING: Cornea and refractive surgery practice, Teaneck, New Jersey, USA.

    DESIGN: Prospective randomized case series.

    METHODS: Eyes with keratoconus or corneal ectasia were treated. All eyes received preloading withriboflavin 0.1% in 20% dextran. During ultraviolet-A (UVA) exposure, patients were randomlyassigned to 1 of 2 study arms; that is, riboflavindextran or hypotonic riboflavin. Intraoperativepachymetry was measured before and after the corneal epithelium was removed, after initialriboflavin loading, and after UVA light exposure. Patients were evaluated for maximumkeratometry (K), uncorrected distance visual acuity (UDVA), corrected distance visual acuity,corneal thickness, and endothelial cell count (ECC).

    RESULTS: Forty-eight eyes were treated. After removal of the epithelium and riboflavin loading, themean pachymetry was 430 mm and 432 mm in the standard group and hypotonic group, respec-tively. Immediately after 30-minute UVA administration, the mean pachymetry was 302 mm and342 mm, respectively. There was no statistically significant difference in the postoperativemaximum K change, UDVA, corneal thickness, or ECC between the 2 groups.

    CONCLUSIONS: The cornea thinned substantially during the CXL procedure. The use of hypotonicriboflavin rather than riboflavindextran during UVA administration decreased the amount ofcorneal thinning during the procedure by 30%, from 128 mm to 90 mm. However, there were nosignificant differences in clinical efficacy or changes in ECC or function between groups postoper-atively. In general, corneal thinning during CXL did not seem to compromise the safety of theendothelium.

    Financial Disclosures: Dr. Hersh is a consultant to Avedro, Inc. Dr. Rosenblat has no financial orproprietary interest in any material or method mentioned.

    J Cataract Refract Surg 2016; 42:596605 Q 2016 ASCRS and ESCRS

    Corneal collagen crosslinking (CXL)1 is a treatment todecrease the progression of keratoconus2 in particularand other corneal thinning processes such as ectasiaafter laser in situ keratomileusis (LASIK) and photore-fractive keratectomy (PRK).3 Studies have suggestedthat CXL also can have beneficial visual and opticaleffects.46 We have reported a number of studiesshowing an improvement in corrected (CDVA) and

    SCRS and ESCRS

    by Elsevier Inc.

    uncorrected (UDVA) distance visual acuities, maxi-mum and average keratometry (K) values,4 keratoco-nus topographic indices,7 higher-order aberrations(HOAs),8 and subjective visual function9 after CXL.

    As first described,1 the CXL protocol uses riboflavin0.1% in 20% dextran solution, both for initial cornealsaturation and during ultraviolet-A (UVA) adminis-tration. Hypotonic riboflavin solution (riboflavin in a



    distilled water carrier without dextran) has been usedto swell corneas before UVA exposure in patients withcorneas thinner than 400 mm, with the goal of protect-ing the corneal endothelium from damage by theUVAriboflavin interaction.10

    In previous work,A we reported significant thinningof the cornea during the CXL procedure using the ribo-flavindextran formulation. Conversely, it has beensuggested that the thicker riboflavindextran solutionforms a biofilm important for procedure reproduc-ibility and safety by blocking some of the incomingUVA light.11 This attribute, however, might reducethe crosslinking effect compared with a thinner viscos-ity solution by attenuating UVA light delivery to thedeeper stroma. Given these observations, we attemp-ted to answer 4 questions: (1) Howmuch corneal thin-ning occurs during the CXL procedure in general? (2)Is this thinning related to the efficacy and safety of theprocedure? (3) Is there a difference in the intraopera-tive thinning of the cornea between treatments usingriboflavin in a dextran carrier and hypotonic ribo-flavin? (4) Is there a difference in efficacy (change inmaximum K and visual acuity) or safety (change inendothelial cell count [ECC]) outcomes between the2 riboflavin solutions regimens?

    This randomized controlled clinical trial, therefore,was designed with 2 study arms. The first receivedstandard treatment with riboflavindextran solutionduring both the saturation and UVA phase. Thesecond received hypotonic riboflavin during the30-minute UVA exposure.

    Submitted: November 2, 2015.Final revision submitted: January 11, 2016.Accepted: January 16, 2016.

    From the Cornea and Laser Eye InstituteHersh Vision Group, CLEICenter for Keratoconus, Teaneck, and the Department of Ophthal-mology, Rutgers-New Jersey Medical School, Newark, New Jersey,USA.

    Supported in part by an unrestricted grant to the Department ofOphthalmology, Rutgers-New Jersey Medical School, Newark,New Jersey, from Research to Prevent Blindness, New York, NewYork, USA.

    The investigational product was provided by Peschke Trade GmbH;they played no role in study design, data collection, data analysis,manuscript preparation, or the decision to submit the report forpublication.

    Corresponding author: Peter S. Hersh, MD, Cornea and Laser EyeInstituteHersh Vision Group, CLEI Center for Keratoconus, 300Frank W. Burr Boulevard, Teaneck, New Jersey 07666, USA.E-mail:



    Patients with keratoconus and ectasia after LASIK wereenrolled as part of a single-center prospective randomizedcontrolled clinical trial.B This study was performed undera physician-sponsored Investigational New Drug, wasapproved and monitored by an investigational reviewboard, and was compliant with the U.S. Health InsurancePortability and Accountability Act. Informed consent wasobtained from all patients.

    The inclusion criteria included patients 18 years or olderwith a diagnosis of keratoconus or corneal ectasia after laserrefractive surgery and axial corneal topography consistentwith keratoconus or ectasia. Exclusion criteria included a his-tory of corneal surgery other than laser refractive surgery,chemical injury, delayed epithelial healing, and a cornealpachymetry (including the epithelium) less than 300 mm.All patients included in the ectasia group were post-LASIKpatients; no patient was post-PRK.

    Surgical Technique

    Crosslinking was performed according to the methoddescribed byWollensak et al.1 Topical anesthesiawas admin-istered, and the corneal epitheliumwas removed bymechan-ical debridement over the central 9.0mm. Riboflavin (0.1% in20.0% dextran T500 solution, Medio Cross, Peschke TradeGmbH) was then administered topically every 2 minutesfor a total of 30 minutes. After riboflavin administration,riboflavin absorption throughout the corneal stroma andanterior chamber was confirmed by slitlamp examination.

    Ultrasonic pachymetry was performed. If the cornea wasthinner than 400 mm, hypotonic riboflavin (0.1% in sterilewater, Medio Cross hypotonic) was administered, 1 dropevery 10 seconds for 2-minute sessions, after which ultra-sonic pachymetry was performed to confirm that the stromahad swollen to more than 400 mm. This was repeated until acorneal thickness of 400 mm or more was obtained.

    The cornea was exposed to UVA 365 nm light (UV-X sys-tem, IROC Innocross AG) for 30 minutes at an irradiance of3.0 mW/cm2. During UVA exposure, riboflavin drops of 1 of2 formulations were continued every 2 minutes, as deter-mined by preoperative randomization. The first groupcontinued to receive riboflavin in dextran solution (0.1% in20.0% dextran T500); the second group received hypotonicriboflavin (0.1% in sterile water) every 2 minutes duringUVA exposure.

    Postoperatively, antibiotic and corticosteroid drops wereadministered and a therapeutic soft contact lens (AcuvueOasys, Vistakon Pharmaceuticals, LLC)was placed. The con-tact lens was removed after epithelial healing, typically 3 to5 days postoperatively. Antibiotic drops were continued for1 week, and corticosteroid drops were continued for2 weeks.


    Intraoperative corneal thickness measurements weretaken by ultrasound (US) pachymetry (Corneo-Gage Plus,Sonogage, Inc.) before the corneal epithelium was removedand after the following steps: epithelium removal, initial30-minute riboflavin loading just before UVA light expo-sure, swelling with hypotonic riboflavin if necessary, and30 minutes of UVA light exposure. At least 5 pachymetrymeasurements were taken at each timepoint, and thelowest was used for analysis. Pachymetry measurements

    - VOL 42, APRIL 2016

  • Table 1. Baseline patient characteristics.

    Standard Hypotonic


    preoperatively and 1, 3, 6, and 12 months postoperativelyalso were taken at the thinnest point using a rotatingScheimpflug camera (Pentacam, Oculus OptikgerateGmbH).

    CharacteristicRiboflavin(n Z 26)

    Riboflavin(n Z 20)

    Visual Acuity

    Pathology, n (%)Keratoconus 18 (69) 15 (75)Ectasia 8 (31) 5 (25)

    Mean age (y) 29 28Sex, n (%)Male 20 (77) 16 (80)Female 6 (23) 4 (20)

    Mean maximum K (D) G SD 58.9 G 10.9 61.7 G 11.5Mean UDVA (logMAR) G SD 0.77 G 0.37 0.87 G 0.26

    The UDVA and CDVA were measured preoperativelyand postoperatively at 1, 3, 6, and 12 months. Visual acuitymeasurements were obtained under controlled lightingconditions using a modified Early Treatment DiabeticRetinopathy Study visual acuity test (2nd edition, Light-house International) with Sloan letters. Patients were tested4 m from the visual acuity chart. If patients could not readany letters at 4 m, they were tested at 2 m. Visual acuitywas recorded and analyzed as the logMAR value.

    Mean CDVA (logMAR) G SD 0.29 G 0.26 0.23 G 0.13Mean ECC (cells/mm2) G SD 2475 G 269 2512 G 309


    CDVAZ corrected distance visual acuity; ECCZ endothelial cell count;K Z keratometry; UDVA Z uncorrected distance visual acuity

    Topography measurements were obtained using arotating Scheimpflug camera. Topographic maximum Kwas obtained directly from the Scheimpflug data preopera-tively and 1, 3, 6, and 12 months postoperatively.

    Endothelial Cell Count

    The ECCwas obtained using specular microscopy (KonanMedical) preoperatively and 12 months postoperatively.Three measurements were taken at both timepoints, andthe mean cell count for each eye was used in the analysis.In 2 patients, it was not possible to obtain readable ECCs;these patients were excluded from this part of the analysis.

    Statistical Analysis

    Statistical analysis using a paired 2-tailed Student t testwas used to analyze the postoperative changes comparedwith baseline and to analyze the changes in postoperativeoutcomes over time. A P value less than 0.05 was consideredstatistically significant.


    Forty-eight patients with keratoconus (35) or post-LASIK ectasia (13) who had CXL were analyzed;26 patients received standard riboflavindextran solu-tion during UVA light administration, and 22 patientsreceived hypotonic riboflavin solution during UVAlight administration. Table 1 the shows baseline char-acteristics in each treatment group.

    Corneal Thickness

    Figure 1 shows themeanUS pachymetry at differentstages. There was no statistically significant differencein the mean US pachymetry measurements preopera-tively between the hypotonic group and the standardgroup (P Z 0.7). Immediately after epitheliumremoval, the mean US pachymetry was 386 mm and403 mm in the standard and hypotonic riboflavingroups, respectively (PZ .15). After 30-minute admin-istration of standard riboflavin (in both groups), if thepachymetry was less the 400 mm in either study group,


    the cornea was swelled with hypotonic riboflavin perthe study protocol until the corneal thickness was400 mm or more. Nine eyes (35%) in the standard ribo-flavin group and 6 eyes (30%) in the hypotonic studygroup required hypotonic swelling. After initialcorneal riboflavin loading and additional swelling (ifrequired), but before UVA light administration, therewas no significant difference in themeanUS pachyme-try measurements between groups (PZ .8). Postoper-atively immediately after the 30-minute UVA lightadministration, the mean pachymetry ranged from252 to 420 mm and from 271 to 448 mm in the standardgroup and hypotonic riboflavin group, respectively.During UVA exposure, the standard group thinnedby a mean of 128 mm (30%) compared with thinningof 90 mm (21%) in the hypotonic riboflavin group, afinding that was significant (P Z .0002).

    To determine whether there was any influence ofpre-UVA hypotonic swelling to ultimate intraopera-tive stromal thinning, a subset analysis was per-formed; for this analysis, all eyes requiring hypotonicriboflavin before UVA light administration wereexcluded. In this cohort, before removal of the cornealepithelium, the mean US pachymetry measurementswere 454 mm and 460 mm in the standard group andhypotonic riboflavin group, respectively (P Z .68).Immediately after epithelium removal, the meanpachymetry was 401 mm and 413 mm, respectively(P Z .31). After 30-minute administration of standardriboflavin (in both groups), the mean pachymetry was437 mm and 441 mm in the standard group and hypo-tonic riboflavin group, respectively (PZ .7). Postoper-atively, immediately after UVA light administration,the mean pachymetry was 308 mmand 346 mm, respec-tively. Thus, during UVA exposure, the standard

    - VOL 42, APRIL 2016

  • Figure 1.Mean intraoperative pachymetryobtained with US pachymetry measure-ment (UV Z ultraviolet-A light).


    group thinned by 129 mm (30%) on average comparedwith thinning of 95 mm (22%) in the hypotonic ribo-flavin group (PZ .0026), corroborating the significantfinding in the entire cohort.

    Postoperative Corneal Thickness

    The postoperative mean thinnest pachymetry byrotating Scheimpflug camera analysis in the standardriboflavin group was 414 mm, 419 mm, 420 mm, and429 mm at 1, 3, 6, and 12 months, respectively; in thehypotonic group it was 434 mm, 428 mm, 430 mm, and441 mm, respectively (P Z .189, P Z .529, P Z .470,and P Z .380, respectively) (Figure 2). The mean thin-nest pachymetry in the standard riboflavin groupchanged from 431 mm preoperatively to 429 mm at12 months; in the hypotonic riboflavin group, themean pachymetry changed from 445 mm preopera-tively to 441 mm at 12 months. The difference betweenpreoperative and 12-month postoperative pachymetrywas 2 mm and 4 mm in the standard group and hy-potonic riboflavin group, respectively (PZ .82). Thus,there was no significant change in Scheimpflug-measured c...


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