Corneal Cross-Linking as a Treatment for Keratoconus

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  • Corneal Cross-Linking as a Treatment forK

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    Purpose: To report the 4-year outcomes of corneal cross-linking (CXL) for progressive keratoconus in apo

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    90pulation of different age groups.Design: Retrospective, single-center, nonrandomized clinical study.Participants: Four hundred consecutive eyes treated with corneal CXL for progressive keratoconus fromril 2006 through April 2010.Intervention: After removal of the epithelium, the cornea was irrigated for 30 minutes with a solution of 0.1%oflavin and 20% dextran, followed by irradiation with an ultraviolet A light of 3 mW/cm2 for 30 minutes.Main Outcome Measures: Best-corrected visual acuity (BCVA), sphere and cylinder refraction, cornealpography, Scheimpflug tomography, and aberrometry were assessed at baseline and at 1, 6, 12, 24, 36, andmonths after corneal CXL treatment. The compiled data were stratified according to age (group A, younger

    an 18 years; group B, 1829 years; group C, 3039 years; and group D, older than 40 years).Results: Comparative analysis included 400 eyes of 301 patients. Functional results showed a significantrease in BCVA in group A by a mean reduction of 0.11 logarithm of the minimum angle of resolution (logMAR)er 12 months, in group B by a mean reduction of 0.31 logMAR after 36 months, in group C by a meanduction of 0.33 logMAR after 36 months, and in group D by a mean reduction of 0.26 logMAR after 36onths. Morphologic results showed an analogous regularization of corneal shape with a significant reductionopposite sector index by a mean value of 0.53 at 12 months in group A, 1.14 at 36 months in group B, 1.1036 months in group C, and 0.55 at 12 months for group D. Optical quality improvement was demonstrateda mean significant reduction of coma 1.52 m after 12 months in group A, 1.58 m after 24 months in group2.57 m after 36 months for group C, and 0.25 m after 36 months in group D.Conclusions: Outcomes stratified by age indicate the efficacy of corneal CXL in stabilizing the progressionectatic disease in all age groups and improving the functional and morphologic parameters in select groups.sults indicated better functional and morphologic results in the population between 18 and 39 years of age.Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.hthalmology 2013;120:908916 2013 by the American Academy of Ophthalmology.

    ratoconus is a slowly progressive, asymmetric, bilateralgenerative corneal disease that presently is the majoruse of corneal transplantation in Europe and is the secondst common cause in the United States.1,2 The incidencekeratoconus varies with the diagnostic parameters used

    d is estimated to be between 1 in 2000 and 1 in 320rsons.3,4 Usually, keratoconus is diagnosed in adoles-nce or childhood.57 The time of diagnosis is a negativegnostic factor for increased risk of corneal transplantation,8

    th younger patients tending to have a more aggressive pro-ssion.9 Treatment strategies for pediatric and young patientsan important concern for the physician because penetrating

    ratoplasty in children is a highly challenging and demanding

    procedure associated with a high risk of graft failure or failureof amblyopia treatment in clear grafts.10 Corneal collagencross-linking (CXL) is the only treatment that potentially canslow down or block the progression of ectatic disease.1114 It isbased on a photo-oxidative reaction, catalyzed by riboflavin(B2 vitamin), that induces an increase in corneal stiffness15 anda biomechanical response16 that blocks the progression of thedisease. Cross-linking induces many changes in collagen, froman increased number of intrafibrillar and interfibrillar covalentbonds to an increased resistance to enzymatic degradation.17,18

    These changes in corneal biomechanics are known to be as-sociated with an improvement in visual acuity as well as morpho-logic and functional indices at the 12-month follow-up.13 Many

    8 2013 by the American Academy of Ophthalmology ISSN 0161-6420/13/$see front matterPublished by Elsevier Inc. http://dx.doi.org/10.1016/j.ophtha.2012.10.023eratoconus

    our-Year Morphologic and Cespect to Patient Age

    ccardo Vinciguerra, MD,1,2 Mario R. Romano, MD, Phaudio Azzolini, MD,2 Silvia Trazza, Orth,3 Emanuela Mical Outcomes with

    Fabrizio I. Camesasca, MD,1

    nghi, PhD,1 Paolo Vinciguerra, MD1

  • reports in the literature have demonstrated the long-termresults with regard to the efficacy and safety of corneal CXLin 11,1924ofoudif

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    Vinciguerra et al CXL as a Treatment for Keratoconusthe treatment of progressive keratoconus. The aimthis retrospective study was to evaluate the long-term

    tcome of corneal CXL in a population of patients fromferent age groups.

    tients and Methods

    udy Design

    is was a retrospective, single-center, nonrandomized clinicaldy.

    pulation

    is retrospective study included all eyes that underwent cornealL from April 2006 through April 2010 at the Department ofhthalmology, Istituto Clinico Humanitas, Rozzano, Milan, It-. The inclusion criteria for the treatment of corneal CXL werecumentation of the progression of keratoconus, patients oldern 9 years, signed informed consent, and corneal pachymetryults of more than 400 m.The preoperative progression of keratoconus was demonstratedat least 2 optical pachymetry results and corneal differentialography results obtained after approximately 6 months or ap-ximately 3 months for patients younger than 18 years and 1nth for patients younger than 12 years. This difference inoperative evaluation time is supported by the evidence in therature that keratoconus in children is more aggressive than inlts.9 For this reason, pediatric patients were evaluated more

    quently to detect early progression. The parameters consideredestablish keratoconus progression always were proved withferential maps as change in curvature in the cone area of at leastdiopters obtained with an istantaneous map or as thinning of

    re than 20 m in minimal pachymetry (depending on the timingthe different age groups). When progression was not demon-ated, follow-up in the pediatric group took place after 3, 6, andmonths to prove the stability.Exclusion criteria were pachymetry results of less than 400 m,istory of herpetic keratitis, dry eye, severe corneal infection, andcomitant ocular or systemic autoimmune disease. Other exclu-

    n criteria were a previous pregnancy or breastfeeding, thesence of central or paracentral opacities, low compliance, anduse of rigid contact lenses for more than 4 weeks before the

    eline evaluation.The institutional review board ruled that approval was notuired for this record review study. It was conducted accordinglythe ethical standards set in the 1964 Declaration of Helsinki, asised in 2000. All patients provided informed consent.During the preoperative and postoperative course (1, 6, 12, 24,

    , and 48 months), the following parameters were assessed:t-corrected visual acuity (BCVA), slit-lamp biomicroscopy,ldmann tonometry, dilated fundoscopy, corneal topography andrrometry for the evaluation of low- and high-order aberrations

    PD II; Nidek, Gamagori, Japan), and optical tomography andhymetry with a Pentacam (Oculus Optikgerate GmbH, Wetzlar,rmany).Specifically, the Nidek OPD II was used to study topographicices that provide data on the corneal shape, altered in kerato-us. The surface asymmetry index (SAI) detects alterations inneal regularity and is defined by the central weighted summa-n of corneal power differences between corresponding points0 apart on the mires. The opposite sector index (OSI) andI provides the greatest difference in average power between anyectors. Simulated keratometry 1 (SimK1) calculates the average

    er on steepest meridian, and simulated keratometry 2 (SimK2)es the average power of the meridian orthogonal to the steepest.e Nidek OPD II was also used to perform total (corneal andernal) wavefront analysis, but special attention was given in thisdy to corneal-generated aberrations. The Pentacam softwares used to analyze anterior chamber and whole cornealhymetry, including central, superior, inferior, nasal, temporal,

    nimal, and apex pachymetry.All preoperative and postoperative functional and morphologicts were performed in a manner identical to those in a previouslylished clinical study.13 All data obtained were combined, andrelation coefficients to age were assessed. No significant linearrelation was found. For this reason, data were stratified accord-to decades of age: younger than 18 years, 18 to 29 years, 30 to

    years, and older than 40 years. Because of the small number ofients between 18 and 19 years of age, this subgroup was mergedh the group 20 to 29 years of age.

    rneal Cross-Linking Procedure

    oflavin ultraviolet Ainduced corneal CXL was performed as a-surgery procedure. It was conducted under topical anesthesiah 2 applications of 4% lidocaine drops and 0.2% oxybuprocainerochloride. Thirty minutes before the procedure, pain medica-

    n was administered and 2% pilocarpine drops were instilled ineye to be treated to reduce the amount of ultraviolet light

    ching the retina.13 The procedure was conducted under sterilerating conditions. After the lid speculum was applied, theneal epithelium was removed in a central 9-mmdiameter areah an Amoils brush (Amoils Brush Epithelial Scrubber; Visionhnology Co, Seoul, Korea). A solution of 0.1% riboflavin and

    dextran (Ricrolin; Sooft, Montegiorgio, Italy) was instilledry minute for 30 minutes to irrigate the cornea fully. Duringgation, corneal thickness was tested using an ultrasoundhymeter (SP-2000; Tomey, Erlangen, Germany) to avoid ex-ure to ultraviolet light when pachymetry results were less thanm. When required, a hypo-osmolar 0.1% riboflavin solution,

    duced by diluting 0.5% vitamin B2-riboflavin-5-phosphate (G.euli & Co. AG, Uznach, Switzerland) with physiological saltution (B. Braun Medical AG, Sempach, Switzerland), wastilled to promote corneal swelling. A 7.5-mm diameter of thetral cornea then was irradiated with an irradiance of 3 mW/cm2-X System; Peschke Meditrade GmbH, Huenenberg, Switzer-

    d) for 30 minutes. During exposure time, the riboflavin solutions again applied every 5 minutes. A calibrated ultraviolet Ater (LaserMate-Q; Laser 2000, Wessling, Germany) was usedore treatment to check the irradiance at a 1.0-cm distance. Bothical anesthetics were added as needed during irradiation.A soft therapeutic contact lens was applied until re-epithelializations complete. After surgery, topical levofloxacin (Oftaquix; Tubi-, Pahrama, Pomezia, Italy) and cyclopentolate (Ciclolux; Aller-, Rome, Italy) was prescribed 4 times daily for 7 days and, afteroval of contact lens, 0.15% dexamethasone 21-phosphateps (Etacortilen; Sifi, Lavinaio, Italy) twice daily for 10 days and5% sodium hyaluronate drops (BluYal; Sooft) 6 times daily fordays were prescribed. In addition, all patients received oralino acid supplements (Aminoftal; Sooft) for 7 days.25

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    Ophthalmology Volume 120, Number 5, May 2013

    91atistical Analysista are expressed as number and percentage or meanndard deviation, as appropriate. The comparison of variabless performed on paired data to evaluate the improvement orapse of individual patients over time. Differences betweenta were evaluated with the Wilcoxon signed rank test, thei-square test with Fisher correction when necessary, andalysis of variance.Variations of data over time are presented with box-and-whiskersts (Figures 17). The graphs present the distribution of vari-es: the box represents from the 25th to the 75th percentile, andinternal line represents the median. The whiskers are limited by

    per and lower adjacent values. Outside the whiskers, outliers canseen. A P value of less than 0.05 was considered significant.tistical analysis was performed using Stata software version 11ata Corp., College Station, TX).

    esults

    ur hundred eyes of 301 patients were evaluated. The compara-e functional analysis comprised the following: 49 eyes of

    ure 1. Box-and-whisker plot for simulated keratometry 1 (SimK1) showiglobal population and (B) for the age-related subgroups. *P0.05; **P

    ure 2. Box-and-whisker plot for opposite sector index (OSI): showing diffulation and (B) for the age-related subgroups. *P0.05; **P0.01. mos

    0ients between 9 and 17 years of age (12.25%), 185 eyes ofients between 18 and 29 years of age (46.25%), 115 eyespatients between 30 and 39 years of age (28.75%), and 51 eyespatients older than 40 years of age (12.75%). The mean age ofients was 2910 years, and the sex distribution was 27.25%ale (109 eyes). The postoperative follow-up period was dis-uted as follows: 53.5% of patients had a 1-year minimum

    low-up, 12.75% of patients had a 2-year follow-up, and 5% and5% of patients had a 3- and 4-year follow-up periods, respec-ely.

    obal Population

    uctural Analysis. Topographic Results. Comparative SimK1ults showed a mean increase at month 1, followed by a signif-nt decrease at 6, 12, 24, 36, and 48 months of follow-up (seeo Fig 1A). The SimK2 results for the global population showeda similar to the SimK1 results, except for a nonsignificantprovement at the 48-month follow-up visit. Comparative resultsthe topographic SAI, DSI, and OSI showed a mean increasepared with baseline at month 1, followed by a significant

    uction at all follow-up times (see Fig 2A).

    fferences between follow-up and preoperative values of SimK1 (A) of. mos months.

    es between follow-up and preoperative values of OSI (A) for the globalonths.erenc mpat

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    Vinciguerra et al CXL as a Treatment for KeratoconusPachymetry Results. Pachymetry results for the global pop-tion are summarized in Table 3 (available online at http://journal.org). All pachymetry values were decreased signifi-tly at month 1 compared with preoperative values. Allaining follow-up values were compared with those from month

    o evaluate the previously reported increase in collagen thicknesser corneal CXL.18,26 Minimal and apex pachymetry showednificant improvement at months 12 and 24 (Fig 3A); a trendard improvement also was reported at month 36 (P 0.059 for

    th minimal and apex pachymetry).Functional Analysis. Visual acuity, refractive, and topo-phic results are summarized in Table 1 (available online atp://aaojournal.org).Visual Acuity. After an initial increase at month 1 resultingm epithelial thickness change, the BCVA improved signifi-tly at 6, 12, 24, 36, and 48 months of follow-up (Fig 4A).Refractive Results. Except for an increase at month 1, com-ative spherical equivalents showed a significant reduction after

    , 24, and 36 postoperative months (see also Fig 5A). The globalpulation results for cylinder variation presented a significant

    ure 3. Box-and-whisker plot for minimal pachymetry showing differenceglobal population and (B) for the age-related subgroups (B). *P0.05; *

    ure 4. Box-and-whisker plot for best-corrected visual acuity (BCVA) shothe global population and (B) for the age-related subgroups. *P0.05; *rease at month 1 compared with baseline, followed by a returna nonsignificant improvement at the other follow-up timesinimum P 0.224).Aberrometric Results. Aberrometric results are summa-ed in Table 2 (available online at http://aaojournal.org). Therrometric results included fewer observations because theD software is not always able to acquire the specific cornealrrations in advanced keratoconus, limiting the calculation to

    al aberrations. All comparisons between aberrometric datare made with absolute values to evaluate possible aberromet-shifts from negative to positive. The diameter of the wave-nt area evaluated was 6 mm and the order was up to thehth order of Zernike polynomials. Comparative results foral aberrometry showed a significant improvement at allnths of follow-up to 48 months, excluding month 1. Thebal populations results for comatic aberration showed in-ad a significant reduction at all follow-up periods (Fig 6A).herical aberration, after an initial increase at month 1, im-ved significantly at the 24- and 36-month follow-up visitsg 7A).

    een follow-up and preoperative values of minimal pachimetry (A) of0.01. mos months.

    differences between follow-up and preoperative values of BCVA (A).01. mos months.

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    Ophthalmology Volume 120, Number 5, May 2013

    91diatric Population

    ucture Analysis. Topographic Results. The analysis of theographic results for the pediatric population showed a signifi-t increase of SimK1, SimK2, OSI, and DSI at month 1 com-ed with baseline. After month 1, the pediatric populationwed significant SAI improvement at month 12. All other pa-eters showed improvement that was not significant.Pachymetry Results. After a significant reduction at month 1,

    nimal and apex pachymetry showed no significant differencespared with 1 through 24 months of follow-up (Fig 3B).Functional Analysis. Visual Acuity. A maximum of 2 yearsfollow-up was available for visual acuity results in the pediatricpulation. Comparative results showed a significant improvementBCVA at 6 and 12 postoperative months; after this time, theprovement was not significant because of the small number ofa (Fig 4B).Refractive Results. In the pediatric subgroup, no significant

    provement in spherical equivalent was reported, except fornth 1 (Fig 5B). Comparative results for cylinder showed anificant increase for this group at months 6 and 12.

    ure 5. Box-and-whisker plot for spherical equivalent showing differencesglobal population and (B) for the age-related subgroups. *P0.05; **P

    ure 6. Box-and-whisker plot for coma aberration showing differences betwulation and (B) for the age-related subgroups. *P0.05; **P0.01. mos

    2Aberrometric Results. Comparative results for total aber-etry did not show any significant differences, whereas co-

    tic aberration showed a significant decrease at months 1, 6,12 (Fig 6B). Excluding a significant increase at month 1,

    erical aberration exhibited no significant change from base-e through 12 months of follow-up (Fig 7B).

    pulation 18 to 29 Years of Age

    uctural Analysis. Topographic Results. A significant in-ase in SimK1, SimK2, OSI, and DSI was observed at month 1

    pared with baseline. After month 1, this group showed anificant decrease in SimK1 at 12, 24, and 36 months oflow-up (Fig 1B). Similarly, SimK2 decreased significantly atnths 6, 12, and 24. A significant decrease of SAI was observedll follow-up periods; OSI also decreased significantly at months24, and 36 (Fig 2B), and DSI improved at 6, 12, 24, and 36

    nths of follow-up.Pachymetry Results. After a significant reduction at month 1,imal pachymetry showed a significant increase, compared with

    een follow-up and preoperative values of spherical equivalent (A) for. mos months.

    ollow-up and preoperative values of coma aberration (A) for the globalonths.een f mbetw0.01

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    Vinciguerra et al CXL as a Treatment for Keratoconusnth 1, after 6 and 12 months of follow-up (Fig 3B). Apexhymetry showed a similar response in these follow-up periodsan additional improvement at 24 months and 1 month, yet no

    nificant improvement at month 36 (P 0.07).Functional Analysis. Visual Acuity. Again excludingnth 1, comparative results for BCVA in the 18- to 29-year agecket showed significant improvement for up to 36 months oflow-up (Fig 4B).Refractive Results. Except in month 1, no significant in-ase in spherical equivalent or cylinder was reported for up to 48nths of follow-up (Fig 5B).Aberrometric Results. Comparative results for total aber-etry showed a significant improvement after 6, 12, 24, and

    months. Comatic aberration showed a significant mean de-ase, compared with baseline, until the 24-month follow-upit (Fig 6B). Spherical aberration showed a significant meanrease at month 1, followed by a nonsignificant decrease (atand 36 months of follow-up, P 0.062 and P 0.068,

    pectively; Fig 7B).

    pulation 30 to 39 Years of Age

    uctural Analysis. Topographic Results. Compared witheline, SimK1, SimK2, SAI, OSI, and DSI all were increasednificantly at month 1. After this, topographic indices showednificant improvement in the following: SimK1 at months 6, 12,, and 36 (Fig 1B); SimK2 at months 6 and 12; SAI at alllow-up times; OSI at months 6, 12, 24, and 36 (Fig 2B); andI at months 6, 12, 24, and 36.Pachymetry Results. After a significant reduction at month 1,

    nimal pachymetry increased, compared with month 1, at monthsand 24 (Fig 3B). Again, after a significant reduction at month

    apex pachymetry increased significantly, compared with monthat months 12 and 24.Functional Analysis. Visual Acuity. Comparative resultswed a significant improvement of BCVA at 12, 24, and 36

    stoperative months (Fig 4B); at 48 months, the improvements not significant because of the small number of data (P 68).Refractive Results. Results of spherical equivalent, after an

    tial worsening, showed a significant improvement at 12 and 24stoperative months (Fig 5B). Cylinder also showed, after antial worsening, a significant decrease for this group at month 24.

    ure 7. Box-and-whisker plot for spherical aberration showing differences bbal population and for the age-related subgroups. *P0.05; **P0.01. mAberrometric Results. Total aberrometry showed a signif-nt improvement at 6, 12, and 48 postoperative months. Comas decreased significantly at months 1, 6, 12, 24, and 36 (Fig). Spherical aberration did not show a significant difference

    pared with baseline in any follow-up time (Fig 7B).

    pulation Older Than 40 Years of Age

    uctural Analysis. Topographic Results. At month 1, a sig-cant increase of SimK1 and SimK2 was observed comparedh baseline. After the first postoperative month, a significantrease of SimK1 was seen at 6, 12, and 24 months of follow-upg 1B). Only at month 24 did SimK2 decrease significatly. Theographic index revealed a significant decrease in SAI and OSI12 months (Fig 2B); DSI showed a nonsignificant decrease atnth 12 (P 0.057).Pachymetry Results. After a significant reduction at month 1,

    nimal and apex pachymetry showed no significant difference,pared with month 1, for up to 48 months of follow-up (Fig

    ).Functional Analysis. Visual Acuity. The BCVA for thisup showed a significant difference, compared with baseline, atmonths of follow-up (P 0.034).Refractive Results. Results for spherical equivalent revealedignificant improvement after 24 months of follow-up (Fig 5B).

    significant difference in cylinder was reported until the 48-nth follow-up visit.Aberrometric Results. Total aberrometry showed a signifi-t improvement after the first postoperative month. Comaticrration decreased significantly at months 1, 6, and 12 (Fig 6B).

    herical aberration did not show any significant difference, com-ed with baseline, for up to 48 months of follow-up (Fig 7B).ne of the patients required a second corneal CXL treatment.

    mparison of 1-Year Resultsmparison after 1 year of follow-up was performed in the globalulation and in the subgroups on an explorative basis. Thisparison indicated that the group aged 30 to 39 years was the

    t responder compared with the other age groups. The compar-e analysis for the parameters visual acuity (P 0.059 withiatric group, P 0.014 with the group 18 to 29 years of age,P 0.071 with group older than 40 years), cylinder, and

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    Ophthalmology Volume 120, Number 5, May 2013

    91iscussion

    rneal collagen CXL modifies the natural history of pro-ssive keratoconus by stabilizing the corneal tissue, pre-

    nting and slowing the progression of the ectatic dis-se.1114 The outcome of this procedure was stratified ins retrospective study according to age. Because kera-onus in children is more aggressive,9 pediatric patientsre evaluated more frequently than adults. The avail-ility of an extended 48-month follow-up allowed fortensive data collection aimed at defining how well thebility induced by corneal CXL in these patients isintained.

    lobal Population

    ter an initial worsening, there was a significant improvementvisual acuity for up to 48 months of follow-up. Parallel tos improvement of visual acuity, significant morphologicanges were demonstrated. In particular, a significant de-ase in spherical equivalent and a decrease in topographic

    rameters such as SimK1, SimK2, SAI, OSI, and DSI con-ed data from previous reports demonstrating that cornealL can regularize corneal shape.1113,27 The aberrometricults included fewer observations because the OPD soft-re cannot always detect specific corneal aberrations invanced keratoconus, thus limiting the study to the calcu-ion of total aberrometry. These data for total aberrometryowed a significant decrease throughout the follow-upriod, excluding month 1; conversely, the comatic aberra-n decreased significantly through the follow-up periodm the first postoperative month. These findings suggestt remodeling induced by corneal CXL and the conse-ent improvement in visual acuity not only is the result of

    improvement of refraction and topographic parameters,t also of improvement of aberrations that can not beessed with simple refractive indices. Finally, results for

    ex and minimum pachymetry showed a significant de-ase of corneal thickness in the first month of follow-up,lowed by a significant increase. This initial drop wasown to be the result of a decrease in interlamellar space,d the subsequent rise was shown to be the result of anrease over time in the diameter of corneal collageners.18,28 From the analysis, either the minimal or the apexchymetry is not statistically different from the preopera-e measurements after 36 months of follow-up.These results suggest that corneal CXL induces a higher

    gree of corneal stability, even beyond the estimated 2 toyears it takes for corneal collagen turnover.29,30 Thisuld be explained by 3 hypotheses: a change in the char-teristics of the keratocyte population, a slower turnover ofss-linked fibrils, or that the corneal collagen turnover iswer than what was estimated. The first hypothesis couldsupported by the evidence that stromal keratocytes in

    ratoconus are associated with a patchy loss of CD34munoreaction, a marker of keratocytes. Six months after

    4ls may replace the apoptotic keratocytes. The secondpothesis is supported by Spoerl et al,31 who demonstratedt cross-linked corneas are more resistant to collagen-rading enzymes, leading to a slower turnover of colla-. It is not clear, however, what could be the maximum

    bilization time induced by corneal CXL.

    diatric Population

    nctional results for the pediatric population showed anificant improvement of BCVA at 6 and 12 months oflow-up; after this time, the improvement was not signif-nt because of the small number of data. Morphologicults for this group showed stability over time for allameters (refractive, topographic, aberrometry, andhymetry), except for a significant increase in cylinder atnd 12 months of follow-up. Comatic aberration showedthe same period a significant improvement compared

    th baseline. This evidence could explain the significantprovement of BCVA in the same follow-up period thats not supported by other improvements except for co-tic aberration. These results differ from those of a pre-usly published study that showed slightly better results inpediatric population.20

    pulation 18 to 29 Years of Age

    nctional results for this population showed a significantprovement of BCVA at all follow-up periods, excludingnth 1. Morphologic results similarly showed significantprovement in topographic indices such as SimK1,

    K2, SAI, OSI, and DSI up to a maximum of 36 monthsfollow-up. Aberrometric results indicated significant re-ctions in total aberration at up to 36 months of follow-up,allel to a reduction in specific comatic and sphericalrration for up to 24 months of follow-up. Pachymetryults showed a significant decrease at month 1 and sub-uently a significant increase compared with month 1;se results are in line with other reports in the literaturet demonstrated increased corneal thickness after an initialrease resulting from collagen packing.18,28

    pulation 30 to 39 Years of Age

    nctional results for this group showed a significant im-vement of BCVA at all follow-up visits, excludingnths 1 and 48. Morphologic results showed a parallelprovement of refractive, topographic, and aberrometricues for up to 36 months of follow-up. Similar to the 18-29-year age group, pachymetry results showed a signif-nt increase compared with those from month 1. Again,se results diverge from the age-related study by Capor-i et al20 that showed a poorer functional response inients older than 27 years. The reason for this dissimilarityld be that the authors did not consider the subgroup 30

    39 years of age, but analyzed all patients older than 27rs. The improvement in the 30- to 39-year age group wasbably not manifest in the statistical analysis of the studyause of the presence of patients older than 40 years.

  • Population Older Than 40 Years

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    Vinciguerra et al CXL as a Treatment for Keratoconusseline, no patient had progression of disease for up to 48nths of follow-up. Selected refractive, topographic, and

    errometric results (spherical equivalent, SAI, OSI, andmatic aberration) did show improvement over time afterrgery.

    Our statistical analysis divided by age does not show anynificant progression, according to the measured parame-s, in any of the age groups at any time. Moreover,tcomes divided by age demonstrate the efficacy of cor-al CXL in improving functional and morphologic param-rs in selected groups. The main finding suggests thattients between 18 and 39 years of age respond best torneal CXL therapy. This result is in contrast to a recentdy that reports worse results in patients older than 27ars.20Although a lesser degree of success was observed in the

    diatric patients and those older than 40 years comparedth the other age groups, corneal CXL nevertheless wasle to stabilize the ectatic disease and to improve visualuity in the pediatric group, as well as improve othernificant morphologic changes in patients older than 40ars. A more aggressive disease in the pediatric popula-n9,20 probably resulted in the observed reduced therapeu-efficacy of corneal CXL.In patients older than 40 years, the limited improvementcorneal CXL is probably the result of so-called age-

    ated cross-links. These bonds, which are catalyzed spon-eously or enzymatically from a reducible state, are moreble32 and, for this reason, less prone to the formation ofw corneal CXL.Altered collagen metabolism is at the basis of the patho-ic process in keratoconus. Cannon and Davison32 andnnon and Foster33 reported that in keratoconic corneas,specific activity of reduced keratoconus corneal collagen

    higher than in normal corneas but substantially lower thana fetus or child. As reported by the authors, collagen CXLnds are reducible when first formed, but then, eitherontaneously or by enzyme catalysis, this reducible char-ter is lost in normal tissue. In keratoconus, the persistencereducible cross-links in old tissue may be the result ofodeling changes, continued slow turnover, or replace-

    nt synthesis, indicating that an abnormally high catabo-m may be present in this disease. In a fetus and inildren, the increase in reducible bonds is believed to be

    result of an increase in collagen synthesis.32,33 Thisreased turnover of collagen fibers, even present in normal

    ildren compared with adults, could be at the root of moreere disease and reduced improvement in children.To the best of our knowledge, there are no other pub-

    hed procedures with better outcomes for the age group 1839 years. One study34 reported a better outcome in

    olescents treated with corneal transplantation, whereasother study showed worse outcomes in pediatric pa-nts.35 One report from 2008 showed good results ofracorneal ring segments (INTACS) in all the evaluatede groups.36ues used for the treatment of keratoconus aim to replaceectatic tissue (transplantation) or to remodel it (refrac-

    e surgery or INTACS). Corneal CXL uses a completelyferent approach that aims to increase the biomechanicalfness of the tissue; this could lead to the difference in

    tcome.In conclusion, this analysis suggests better results forneal CXL treatment of keratoconus patients between 1839 years of age. This information could be valuable forophthalmic surgeon when selecting appropriate patientspredicting the outcomes of this procedure for the treat-

    nt of keratoconus.

    ferences

    Dobbins KR, Price FW Jr, Whitson WE. Trends in the indi-cations for penetrating keratoplasty in the midwestern UnitedStates. Cornea 2000;19:8136.Al-Yousuf N, Mavrikakis I, Mavrikakis E, Daya SM. Pene-trating keratoplasty: indications over a 10 year period. Br JOphthalmol 2004;88:9981001.Nielsen K, Hjortdal J, Aagaard Nohr E, Ehlers N. Incidenceand prevalence of keratoconus in Denmark. Acta OphthalmolScand 2007;85:8902.Steele TM, Fabinyi DC, Couper TA, Loughnan MS. Preva-lence of Orbscan II corneal abnormalities in relatives of pa-tients with keratoconus. Clin Experiment Ophthalmol 2008;36:82430.Hall KG. A comprehensive study of keratoconus. Br J PhysiolOpt 1963;20:21556.Rabinowitz YS, Rasheed K, Yang H, Elashoff J. Accuracy ofultrasonic pachymetry and videokeratography in detectingkeratoconus. J Cataract Refract Surg 1998;24:196201.Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998;42:297319.Reeves SW, Stinnett S, Adelman RA, Afshari NA. Risk fac-tors for progression to penetrating keratoplasty in patients withkeratoconus. Am J Ophthalmol 2005;140:60711.Tuft SJ, Moodaley LC, Gregory WM, et al. Prognostic factorsfor the progression of keratoconus. Ophthalmology 1994;101:43947.Vanathi M, Panda A, Vengayil S, et al. Pediatric keratoplasty.Surv Ophthalmol 2009;54:24571.Caporossi A, Mazzotta C, Baiocchi S, Caporossi T. Long-term results of riboflavin ultraviolet A corneal collagencross-linking for keratoconus in Italy: the Siena Eye CrossStudy. Am J Ophthalmol 2010;149:58593.Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagencrosslinking with riboflavin and ultraviolet-A light inkeratoconus: long-term results. J Cataract Refract Surg 2008;34:796801.Vinciguerra P, Albe E, Trazza S, et al. Refractive, topo-graphic, tomographic, and aberrometric analysis of kerato-conic eyes undergoing corneal cross-linking. Ophthalmology2009;116:36978.Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A-induced collagen crosslinking for the treatment of keratoco-nus. Am J Ophthalmol 2003;135:6207.Wollensak G, Spoerl E, Seiler T. Stress-strain measurementsof human and porcine corneas after riboflavin-ultraviolet-A-

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  • induced cross-linking. J Cataract Refract Surg 2003;29:17805.

    16. Spoerl E, Terai N, Scholz F, et al. Detection of biomechanicalchanges after corneal cross-linking using Ocular ResponseAnalyzer software. J Refract Surg 2011;27:4527.

    17. Wollensak G, Iomdina E. Biomechanical and histologicalchanges after corneal crosslinking with and without epithelialdebridement. J Cataract Refract Surg 2009;35:5406.

    18. Wollensak G, Wilsch M, Spoerl E, Seiler T. Collagen fiberdiameter in the rabbit cornea after collagen crosslinking byriboflavin/UVA. Cornea 2004;23:5037.

    19. Ashwin PT, McDonnell PJ. Collagen cross-linkage: a com-prehensive review and directions for future research. Br JOphthalmol 2010;94:96570.

    20. Caporossi A, Mazzotta C, Baiocchi S, et al. Age-related long-term functional results after riboflavin UV A corneal cross-linking. J Ophthalmol [serial online] 2011;2011:608041. Avail-able at: http://www.hindawi.com/journals/jop/2011/608041/.Accessed September 24, 2012.

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    23. Kampik D, Koch M, Kampik K, Geerling G. Corneal riboflavin/

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    25. Torres Munoz I, Grizzi F, Russo C, et al. The role of aminoacids in corneal stromal healing: a method for evaluatingcellular density and extracellular matrix distribution. J RefractSurg 2003;19(suppl):S22730.

    26. Mencucci R, Marini M, Paladini I, et al. Effects of riboflavin/UVA corneal cross-linking on keratocytes and collagen fibres inhuman cornea. Clin Experiment Ophthalmol 2010;38:4956.

    27. Vinciguerra P, Albe E, Trazza S, et al. Intraoperative andpostoperative effects of corneal collagen cross-linking on pro-gressive keratoconus. Arch Ophthalmol 2009;127:125865.

    28. Mencucci R, Marini M, Gheri G, et al. Lectin binding innormal, keratoconus and cross-linked human corneas. ActaHistochem 2011;113:30816.

    29. Nishida T. Cornea. In: Krachmer JH, Mannis MJ, Holland EJ,eds. Cornea. Vol. 1: Basic Science. St. Louis, MO: Mosby;1997:328.

    30. Smelser GK, Polack FM, Ozanics V. Persistence of donorcollagen in corneal transplants. Exp Eye Res 1965;4:34954.

    31. Spoerl E, Wollensak G, Seiler T. Increased resistance of

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    91. Wollensak G, Iomdina E. Long-term biomechanical propertiesof rabbit cornea after photodynamic collagen crosslinking.Acta Ophthalmol 2009;87:4851.

    otnotes and Financial Disclosures

    ginally received: February 1, 2012.al revision: October 7, 2012.cepted: October 17, 2012.ailable online: January 3, 2013. Manuscript no. 2012-143.umanitas Clinical and Research Center, Rozzano, Italy.epartment of Surgical and Morphological Sciences, University of In-ria, Circolo Hospital, Varese.tudio Oculistico VinciEye, Milan, Italy.

    6Ertan A, Ozkilic E. Effect of age on outcomes in patients withkeratoconus treated by Intacs using a femtosecond laser. JRefract Surg 2008;24:6905.

    sentated at: American Academy of Ophthalmology Annual Meeting,ober 2011, Orlando, Florida.ancial Disclosure(s):

    author(s) have made the following disclosure(s):lo Vinciguerra - Consultant - Nidek and Oculus.respondence:lo Vinciguerra, Istituto Clinico Humanitas, Via Manzoni 56, 20089zano (Milan), Italy. E-mail: paolo.vinciguerra@humanitas.it.UV-A collagen cross-linking (CXL) in keratoconus: two-year results [in German]. Klin Monbl Augenheilkd 2011;

    35. Limaiem R, Chebil A, Baba A, et al. Pediatric penetratingkeratoplasty: indications and outcomes. Transplant Proc 2011;. Gkika M, Labiris G, Kozobolis V. Corneal collagen cross-linking using riboflavin and ultraviolet-A irradiation: a reviewof clinical and experimental studies. Int Ophthalmol 2011;31:30919.

    . Hoyer A, Raiskup-Wolf F, Sporl E, Pillunat LE. Collagencross-linking with riboflavin and UVA light in keratoconus.Results from Dresden [in German]. Ophthalmologe 2009;106:13340.crosslinked cornea against enzymatic digestion. Curr Eye Res2004;29:3540.Cannon DJ, Davison PF. Aging, and crosslinking in mamma-lian collagen. Exp Aging Res 1977;3:87105.Cannon DJ, Foster CS. Collagen crosslinking in keratoconus.Invest Ophthalmol Vis Sci 1978;17:635.Lowe MT, Keane MC, Coster DJ, Williams KA. The outcomeof corneal transplantation in infants, children, and adolescents.

    Corneal Cross-Linking as a Treatment for Keratoconus Four-Year Morphologic and Clinical Outcomes with Respect to Patient AgePatients and MethodsStudy DesignPopulationCorneal Cross-Linking ProcedureStatistical Analysis

    ResultsGlobal PopulationStructural AnalysisTopographic ResultsPachymetry Results

    Functional AnalysisVisual AcuityRefractive ResultsAberrometric Results

    Pediatric PopulationStructure AnalysisTopographic ResultsPachymetry Results

    Functional AnalysisVisual AcuityRefractive ResultsAberrometric Results

    Population 18 to 29 Years of AgeStructural AnalysisTopographic ResultsPachymetry Results

    Functional AnalysisVisual AcuityRefractive ResultsAberrometric Results

    Population 30 to 39 Years of AgeStructural AnalysisTopographic ResultsPachymetry Results

    Functional AnalysisVisual AcuityRefractive ResultsAberrometric Results

    Population Older Than 40 Years of AgeStructural AnalysisTopographic ResultsPachymetry Results

    Functional AnalysisVisual AcuityRefractive ResultsAberrometric Results

    Comparison of 1-Year Results

    DiscussionGlobal PopulationPediatric PopulationPopulation 18 to 29 Years of AgePopulation 30 to 39 Years of AgePopulation Older Than 40 Years

    ReferencesFootnotes and Financial Disclosures

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