clinical study rate of corneal collagen crosslinking redo in … · 2019. 7. 31. · clinical study...

Clinical StudyRate of Corneal Collagen Crosslinking Redo in Private PracticeRisk Factors and Safety

Joelle Antoun12 Elise Slim1 Rami el Hachem1 Elias Chelala1 Elyse Jabbour1

Georges Cherfan2 and Elias F Jarade23

1 Saint Joseph University Hospital Faculty of Medicine PO Box 166830 Beirut Lebanon2 Beirut Eye Specialist Hospital Al-Mathaf Square PO Box 116-5311 Beirut Lebanon3Mediclinic Dubai Mall Dubai UAE

Correspondence should be addressed to Elias F Jarade ejaradeyahoocom

Received 13 May 2014 Revised 20 September 2014 Accepted 21 October 2014

Academic Editor John A Kanellopoulos

Copyright copy 2015 Joelle Antoun et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Objective To report the rate of progression of keratectasia after primary crosslinking (CXL) and evaluate the safety and efficiencyof CXL redo Materials and Methods We conducted a retrospective analysis of the patients who underwent CXL between 2010and 2013 at the Beirut Eye Specialist Hospital Lebanon Progression of keratectasia was based on the presence of an increase inmaximum keratometry of 100D a change in the map difference between two consecutive topographies of 100D a deteriorationof visual acuity or any change in the refraction Primary and redo CXL were done using the same protocol Results Among the221 eyes of 130 patients who underwent CXL 7 eyes (317) of five patients met the criteria of progression All patients reporteda history of allergic conjunctivitis and eye rubbing and progressed within 9 to 48 months No complications were noted and allpatients were stable 1 year after CXL redo Conclusion Allergic conjunctivitis and eye rubbing were the only risk factors associatedwith keratoconus progression after CXL A close followup is thus mandatory even years after the procedure CXL redo seems to bea safe and efficient technique to halt the progression after a primary CXL

1 Introduction

Keratoconus (KC) is a noninflammatory corneal diseasecharacterized by corneal deformation and thinning caused bystructural changes in the corneal collagen inducing irregularastigmatism myopia and protrusion which leads to mild tomarked impairment in vision quality [1] Corneal ectasia isone of the most devastating complications after laser-assistedin situ keratomileusis (LASIK) The disease is characterizedby a progressive thinning and steepening of the central andinferior portions of the cornea inducing a loss of uncorrectedvisual acuity best-corrected visual acuity and topographicevidence of asymmetric inferior corneal steepening [2ndash5]

Corneal collagen crosslinking (CXL) was introduced in2003 byWollensak et al to halt the progression of keratectasia[6ndash8] During CXL riboflavin interacts with ultraviolet-A(UV-A) light to cause crosslinking of protein fibrils followedby formation of interchain disulfide bonds thus arresting

the progression of keratoconus by increasing the biome-chanical stability of the cornea [7 8] In the meantimeCXL has become an increasingly well-accepted low invasiveintervention with high success and low complication rates[9ndash11] Long-term stabilization and improvement after CXLhave been reported inmany prospective studies [11ndash13] How-ever failure and progression of keratectasia after CXL havebeen reported Recently Kymionis et al [14] reported thattopographic keratoconus progression might occur severalyears after CXL despite stability for a long-term periodWhile Greenstein and Hersh showed that no preoperativecharacteristics were predictive of CXL failure for keratectasia[15] other studies attributed progression after primary CXLto specific risk factors and patient characteristics Koller etal reported an 8 CXL failure rate one year after CXL forkeratoconus with preoperative maximum 119870 value of morethan 580D as a risk factor for progression [16] In additiondue to the few cases of progression after CXL there is no

Hindawi Publishing CorporationJournal of OphthalmologyVolume 2015 Article ID 690961 8 pageshttpdxdoiorg1011552015690961

2 Journal of Ophthalmology

consensus about the definition of progression of keratectasiaafter CXL The number of cases of keratoconus progressionafter original CXLprocedure is expected to increasewith timewith no clear consensus about the best treatment modality ofthose cases

To our knowledge no previous study evaluated the safetyand efficiency of CXL redo We hence report the rate ofprogression and the risk factors after CXL in our privatepractice and evaluate the technique safety and efficiency ofCXL redo after primary CXL

2 Materials and Methods

21 Setting We conducted a retrospective analysis of thepatients with progressive keratectasia who underwent CXLbetween March 2010 and March 2013 at the Beirut EyeSpecialist Hospital Beirut Lebanon Diagnosis of kerato-conus was based on a combination of computed slit-scanningvideokeratography of the anterior and posterior cornealsurfaces keratometric readings and corneal pachymetryKeratoconus was classified into four stages based on cornealpower astigmatism corneal transparency and corneal thick-ness according to the classification of Amsler-Krumeich [17]

22 Participants All patients included in this study had ahistory of progressive keratectasia either from keratoconusor from corneal ectasia after LASIK in one or both eyes andunderwent a primary CXL in order to stabilize the disease

All patients included in this study had a central cornealthickness gt400 120583m Central corneal thickness (CCT) andthinnest corneal location were measured using Pentacamtopography with epithelium on prior to the procedureBecause of the potential deswelling effect in the cornealstroma of the dextran in riboflavin solution [18] the CCT andthinnest corneal location were measured using ultrasoundpachymeter all through the period of riboflavin applicationduring the entire period of CXL procedure Therefore afterremoving the epithelium CCT and thinnest corneal locationwere measured although the period of riboflavin applicationand hypoosmolar riboflavin was additionally instilled every20 seconds for 5 minutes and repeated up to 2 times untiladequate minimal corneal thickness of more than 400 120583mwas reached

Exclusion criteria for primary and redo CXL were pre-operative corneal opacities ocular pathology other thankeratectasia especially the cornea guttata or other endothelialirregularities age younger than 18 years actual or intendedpregnancy not available for follow-up examinations for 1 yearand connective tissue disease

23 Data Collection Progressive keratectasia was suspectedby an increase inmaximum119870 readings in several consecutiverecordings in the last 6 months with or without progressivecorneal thinning as well as deterioration in visual acuity andmanifest refractionWe evaluated the progression of KC afterCXL based on the presence of 2 or more of the followingcriteria increase (ge1 D) in 119870 value (1198961 1198702 or 119870 max)a change in the map difference between two consecutive

topographies of ge1 D a deterioration of VA defined as a dropof one or more lines or any change in the refraction as achange of 05D

Based on our observation the cornea may endure majortopographic changes in the first 6 months after CXL withsignificant changes in manifest refraction and visual acuityWe set a baseline corneal topography 6 month after CXLtreatment and we noticed no further clinically significantchanges are happening then after apart from a nonsignificantminor flattening of 119896-reading over time with no furthersteepening happening 6months after CXL treatment in stablekeratoconus Any steepening in 119896-reading that happens 6months after primary CXL is considered as sign of kerato-conus progression mainly when it was associated with oneof the aforementioned criteria of keratoconus progressionTherefore the effect of CXL is considered only 6months afterprimary CXL and corneal stability is judged after that

All patients undergoing CXL were followed up closely inthe postoperative period at day one one week one month3 months sixth months and one year and then half yearlyafter Corneal topography was repeated at each visit starting3 months after CXL and then 6 months after CXL cornealtopography is considered as the baseline topography afterCXL based on which the progression of KC is consideredThus all patients are evaluated at 6 months after CXLby a complete ophthalmic workup including assessment ofuncorrected distance visual acuity (UDVA) corrected dis-tance visual acuity (CDVA) manifest and cycloplegic refrac-tions and anterior and posterior segment evaluation withdilated fundus examination as well as an anteriorposteriortopography Corneal topography (Pentacam 70700 OculusGermany) was conducted with undilated pupils under sco-topic conditions by a single experienced technician Baselinestrategy for the treatment of recurrent allergic episodes wasbased on topical mild steroids (Fluorometholone 01) tobe used four times a day for 10 to 14 days as needed Incase of severe exacerbations topical antihistamine and topicalcyclosporine 01 were added to the regimen

24 Surgical Procedure Primary and redo corneal collagencrosslinking (CXL) were done using the same protocol Allsurgeries were performed by the same surgeon (EJ) Theeye to be treated was anesthetized by applying proparacainehydrochloride 05 drops on three occasions spaced by fiveminutes After positioning the patient under the operatingmicroscope a lid speculum was inserted and the central 9mm corneal epithelium was removed with a blunt spatulaA mixed riboflavin 01 dextran solution (Collagex isotonic01 Lightmed USA Inc) was instilled every 2 minutes untilthe riboflavin penetrated the cornea that is after approxi-mately 30 minutes The ultraviolet (UV) lamp (UV-X illumi-nation system version 1000 IROC AG Zurich Switzerland)was then focused on the apex of the cornea at a distance of5 cm for a total of 30 minutes providing a radiant energy of30 plusmn 03mWcm2 The required irradiance of 30mWcm2was calibrated prior to each treatment using a UVA meter(LaserMate-Q LASER 2000 Wessling Germany) Dur-ing UVA administration riboflavin drops were applied to

Journal of Ophthalmology 3

the cornea every 2minutesThinnest and central pachymetrywere continuously monitored to ensure that none of thetwo parameters dropped below 400120583m After treatment theeye surface was washed with balanced salt solution and twodrops of gatifloxacin 03 were instilled followed by theplacement of a bandage soft contact lens Postoperativelypatients received acetaminophen 500mg twice daily for 3days one drop of gatifloxacin 03 six times daily for 7 daysalong with one drop of tobramycin-dexamethasone 01 fourtimes daily for 10 days followed by one drop of Loteprednol05 5 times daily slowly tapered over 5 weeks The bandagesoft contact lens was removed on postoperative day 4 and theeye examined by slit-lamp microscopy to confirm completecorneal epithelialization

Complications after CXL redo such as significant stromalhaze sterile corneal infiltrates recurrent erosion syndromecorneal edema Descemets membrane folds corneal meltingand perforationwere noted if present Stability afterCXL redowas also assessed

3 Results

31 Primary CXL Two hundred twenty-one eyes of 130patients underwent a corneal collagen CXL for progres-sive keratoconus or post-LASIK ectasia in our departmentbetween March 2010 and March 2013 The demographic andtopographic data of the initial 221 eyes are mentioned inTable 1

32 CXL Redo Although the majority of the eyes remainedstable after primary CXL (according to the aforementionedcriteria) seven eyes (317) of five patients met the cri-teria of progression and necessitated a CXL redo Patientscharacteristics are summarized in Table 2 Mean age was26 (one patient was 19 years old and 4 patients were agedbetween 26 and 30 years) with malefemale ratio of 32All patients who progressed reported a history of allergicconjunctivitis and eye rubbingTheir preoperative maximum119870 value was gt 580D in 3 eyes and lt58D in 4 eyes (meanof 586D) Two eyes (of one patient) had CXL alone 4 eyeshad CXL subsequent to ICRS implantation and one eyehad simultaneous CXL with PRK Four eyes had a stage 2keratoconus 2 eyes had a stage 4 keratoconus and one eyehad a post-LASIK ectasia

Progression of KC was noticed more than one year (14to 48 months) after the original CXL in 6 eyes of fourpatients (2 males and 2 females one patient was 19 yearsold and 3 were 26ndash28 years old) and one eye (30-year-oldmale) was diagnosed with KC progression 9 months afterthe original CXL The mean time of KC progression afteroriginal CXL was 2914 months Progression was noted byall the patients after a decrease in CDVA and was evidencedby progression in corneal topography (Figure 1) Progressionwas simultaneously noted in both eyes in all patients who hadbilateral disease evolution

No major complications after CXL do and redo such assignificant stromal haze sterile corneal infiltrates recurrenterosion syndrome corneal edema Descemets membrane

Table 1 Baseline patient characteristics of 221 eyes of 130 patientswho underwent CXL between March 2010 and March 2013 at ourprivate clinic PRK photorefractive keratectomy ICRS intrastromalcorneal ring segments 119899 number (percentage)

Characteristics ValueGenderMale (119899) 68 (52)Female (119899) 62 (48)

Age years16ndash30 95 (731)30ndash50 35 (269)

Stage of KC (Amsler-Krumeich)Stage 1 (119899) 96 (43)Stage 2 (119899) 100 (45)Stage 3 (119899) 25 (12)

Keratometry dioptersFlattest meridian40ndash44 132 (60)44ndash46 89 (40)

Steepest meridian45ndash58 122 (55)58ndash68 99 (45)

Maximal keratometry48ndash58 103 (47)58ndash68 118 (53)

Pachymetry microns400ndash450 156 (70)450ndash580 65 (30)Associated surgeries 119899 70 (32)ICRS 119899 50 (23)PRK 119899 20 (9)

folds corneal melting and perforation were noted in anypatient At one year after CXL redo all patients remainedstable by either UDVA CDVA or topographic readings Thecharacteristics of the 5 patients are summarized in Tables 23 and 4

4 Discussion

Despite the proven effect of CXL in halting the progressionof KC and corneal ectasia with stabilization in the majorityof cases [7 19 20] KC progression still can happen afterprimary CXL treatment [14 16] In most of the studies thereported failure rate varied from 0 [6 21] to 165 [22]The time of progression after CXL was reported to be asearly as few months [16] to 5 years after CXL [14] The mostadopted definition of KC progression after CXL in most ofthe reports in the literature was an increase in the maximumkeratometry readings of gt100D over the 6 months after CXLvalue [14 16] In our study 2 eyes (eye 1 and eye 4) presentedwith evidence of progression based on worsening of theirvisual acuity despite a progression of their 119896 readings of less


Table 2 Patient characteristics all eyes had allergic conjunctivitis lowast missing data CCT central corneal thickness PRK photorefractivekeratectomy ICRS intrastromal corneal ring segments LASIK laser-assisted in situ keratomileusis

Eye Age Gender Diagnosis Stage ofKc

BaselineCCT

Allergicconjunctivitis

Associatedsurgeries

Time(months)since firstCXL

Slit lampevaluation (first

visit)

Eye 1 27 F Keratoconus Stage 2 489 Yes PRK 14 No haze papillaeEye 2 19 F Keratoconus Stage 2 523 Yes ICRS 38 No haze papillae

Eye 3 30 M Post-LASIKectasia 420 Yes ICRS 9 No haze papillae

Eye 4 26 M Keratoconus Stage 4 414 Yes None 23 Striae papillae

Eye 5 26 M Keratoconus Stage 4 418 Yes None 24 Striae + hazepapillae

Eye 6 28 M Keratoconus Stage 2 lowast Yes ICRS 48 No haze papillaeEye 7 28 M Keratoconus Stage 2 lowast Yes ICRS 48 No haze papillae

Figure 1 A map difference showing progression after primary corneal collagen crosslinking B represents corneal topography 6 months afterprimary CXL and A shows corneal topography 12 months after primary CXL The map difference (difference A-B) shows the progressionafter initial CXL with +25 and +34D of difference between successive topographies (white circle)

than 100D (09 in eye 1 and 068 in eye 2) Thus a changein the map difference between two consecutive topographiesof 100D (or maybe less) a deterioration of visual acuity(excluding other possible non-cornea-related reasons fordeterioration) or any change in the refraction must be takeninto account when evaluating the stability after CXL Any ofthese indicators are considered as progression and necessitatea redo of CXLThe failure of CXL as a continued progression

of keratoconus during the first year postoperatively has beenreported in several studies [16 23 24] The failure rate hasbeen reported to be around 7 to 9 Koller et al reporteda failure rate of 76 during the first postoperative year [16]Hersh et al and Sloot et al [23 24] reported a failure rate of98 and 9 respectively while Baenninger et al reporteda failure rate of 165 in patients aged lt35 years [22] Inour study we found that the failure rate is 317 which


Table 3 Progression of keratometric readings119870 readings remained stable one year after CXL redo lowast missing data difference

Eye Preoperatively 6 months after CXL At diagnosis of progression Sign of progression One year after CXL redo1198701 1198702 119896max 119870

10158401 119870

10158402 119870

1015840max 119870101584010158401 119870101584010158402 11987010158401015840max 119870and1 119870and2 119870and3

Eye 1 406 502 539 412 455 507 421 462 513k1 09DKmax 06DdarrCDVA

4200 458 5100

Eye 2 452 489 513 4293 4545 lowast 4315 4667 lowast k2 122D 4300 4687 lowast

Eye 3 5353 6025 675 4084 4116 4522 405 4338 4997 k2 184Dkmax 475D 4000 4325 4980

Eye 4 516 551 571 527 5438 lowast 532 5506 lowast

k1 05Dkmax 068DdarrCDVA

5298 549 lowast

Eye 5 545 568 632 483 514 lowast 5705 5933 lowastk1 875Dk2 792D 568 592 lowast

Eye 6 lowast lowast lowast 4407 4745 594 4449 475 6211 kmax 271D 443 469 6189Eye 7 lowast lowast lowast 4769 5005 5951 4774 4971 617 kmax 219D 478 4959 612

is significantly less than the rates in the previous reportsAlthough ourCXL technique is the same technique describedin the aforementioned reports the lower failure rate at ourpractice can be attributed to any of the following factors Firstthis chart review was performed in our private clinic andthe lower failure rate might be due mostly to the fact thatunhappy progressive keratoconus patients might be lost tofollowup Second many of the patients at our private clinichad CXL associated refractive surgeries (32) such as PRK(9) or ICRS (23) Few reports imply not only the safety ofthe latter procedures but also their possibility to add up toCXLrsquos collagen stabilization [25ndash28] Such procedures mighthave reduced our failure rate Third we considered 6 monthsafter CXL as baseline data and KC progression was judgedbased on the corneal topography performed at 6months afterinitial CXL Therefore we might have reduced the selectionerror due to the keratometric fluctuation during the first 6months after CXL which may have contributed to the lowerrate of KC progression in our study In fact some studiesreported that the initial fluctuation and maybe worseningof keratometric readings are observed in the first monthsfollowing CXL [16] This change may be due to transienthaze corneal edema and remodeling [29 30] Accordinglywe evaluated significant changes in keratometric values forassessment of CXL efficacy only 6 months after CXL

Risk factors associated with progression after primaryCXL remain unclear In our practice a history of allergicconjunctivitis with eye rubbing was found to be a commonrisk factor to all patients in the progression group Howeverbecause of the small number of patients with keratoconusprogression we could not conduct a multifactorial analysisto determine other risk factors Further prospective studieswith multifactorial analysis are thus necessary to determineother risk factors associated with progression of keratoconusafter a primary CXL Similarly Raiskup-Wolf et al reportedprogression in 2 patients with neurodermatitis a condition inwhich constant skin andocular rubbing is present [13] In factthe relationship between eye rubbing and keratoconus hasbeen studied in previous reports [30 31] Eye rubbing leads to

biomechanical and biochemical alterations [32] It injures theepithelium and leads to cytokine and metalloproteins release[32] Stromal thinning occurs and this contributes to thekeratoconus disease progression [32] In our case we thinkthat the eye rubbing and the mechanical trauma it causedplayed an important role in the recurrence of the disease [31ndash33] Other postulated factors for progression such as femalesex and elevatedmaximal keratometry were not predominantfactors in our study In the study of Koller et al there weredifferences between the failure subgroup with the total groupin sex where females had significantlymore failure rates thanmales (females 625 versus 388 in males 119875 = 0048)and preoperative maximum 119870 reading of less than 5800Dwas found to reduce the failure rate to 3 [34] In our casesthe gender was not a risk factor for progression (3 males 2females) nor the 119870 max (119870 max gt58D in 2 eyes and lt58Din 3 eyes) Finally one out of the five patients in our studywith CXL failure in our study had a post-LASIK ectasia Post-LASIK ectasia might have a higher rate of failure Hersh etal reported a reduced effect of CXL in cases of post-LASIKectasia compared with keratoconus [23] It was postulatedthat the reduced effect could be due to the influence of theflap which may impede the diffusion of riboflavin or changethe behavior of the anterior stroma to the crosslinking process[23] Finally the small group of failure makes multivariateanalysis nonconclusive In our study 5 out of 7 eyes hadassociated surgeries 4 eyes had CXL subsequent to ICRSimplantation and one eye had simultaneous CXL with PRKThese two types of associated surgeries were not found toincrease failure rate in literature reviews and are consideredsafe in combination with CXL in keratectasia [11 35 36]

The majority of the studies report the failure of CXL dur-ing the first year postoperatively [16 22 24] In a recent paperpublished by Kymionis et al a topographic examinationrevealed an increase in the keratometric values indicatingkeratoconus progression 4 and 5 years after CXL despitestability for a long-term period In our series four patientspresented with a progression time after crosslinking rangingfrom 14 months to 48 months To our knowledge this is


Table4Ch

ange

inerroro

frefraction(EOR)u

ncorrected

distance

visualacuity

(UDVA

)correcteddistance

visualacuity

(CDVA

)from

baselin

eto

oneyear

after

CXLredo

UDVA

and

CDVA

remainedstableon

eyeara

fterC

XLredo

lowastm

issingdataSsph

ereC

cylin

derAaxis

Eye

EOR

UDVA

CDVA

Baselin

e6m

oCX

L+associated

surgeries

Refractio

natprogression

SC

AS1015840

C1015840A1015840

S10158401015840

C10158401015840

A10158401015840

Baselin

e6mon

thsa

fter

Timeo

fprogressio

n1y

eara

fter

CXLredo

Eye1

minus15

+425

170minus05

+100

20minus275

+275

175

2010

020

30

2025

2020

2010

020

40

2010

020

40

Eye2minus70

0+3

50

150minus300

+175

170minus275

+275

1020200

2030

2070

2040

2080

2040

2010

020

40

Eye3minus900

+350

20minus05

+075

170minus050

+300

135

20400

20200

2025

2020

2050

2030

2050

2025

Eye4minus1300

+200

75minus1300

+175

70minus1600

+15

70CF

2050

CF20

30

CF20

30

CF20

30

Eye5minus1450

+075

90minus1350

+175

70minus1800

+25

55CF

2050

CF20

30

CF20

30

CF20

40

Eye6

lowastlowast

lowastminus400

+275

105minus500

+325

105

lowastlowast

2050

2025

2070

2025

2060

2030

Eye7

lowastlowast

lowastminus17

5+2

25

170minus350

+400

170

lowastlowast

2040

2030

2010

020

30

2010

020

25


the second case series reported in the literature in whichpatients with stability after CXL for a long-term periodshowed topographic recrudescence The exact pathophys-iology of keratoconus progression after years of stabilityfollowing CXL is not known but could be related to thenew collagen laydown Richoz et al evoked the role ofcorneal stromal regeneration and rejuvenation as a possibleexplanation in the recurrence of the disease [8] Also in ourstudy we found that the patientrsquos age is not predictive offailure the younger patient in our series (19 years old) hadCXL failure at 38 months postop while patients around 30years old had failure at different times 9 to 48 months

In the literature the safety efficiency and the technique ofCXL redo were not previously evaluated To our knowledgethis is the first report to assess long-term safety and efficacyof CXL redo We performed the primary and redo cornealcollagen CXL using the same classical protocol and the7 eyes we treated with CXL redo were stable 1 year afterthe second CXL No complications after CXL redo such assignificant stromal haze sterile corneal infiltrates recurrenterosion syndrome corneal edema Descemets membranefolds corneal melting and perforation were noted in any ofthe patients we treated with CXL redo However we did notperform an endothelial cell count preoperatively and afterCXL and the effect of CXL redo on the endothelial health wasnot evaluated which constitutes a limitation to our study

Recently Kanellopoulos and Asimellis introduced anovel noninvasive quantitative technique utilizing anteriorsegment OCT images to quantitatively assess the depth andcross-sectional area of CXL in the corneal stroma Despitethe usefulness of the aforementioned method OCT wasnot performed systematically in all patients who underwentCXL treatment in our study therefore the value of OCT indetermining the depth and effectiveness of CXL treatmentwas not studied in our group and this is considered as alimitation factor of our study [37]

5 Conclusion

In conclusion according to our understanding of keratocytesturnover in the cornea the effect of CXL may be transientand progression of KC after primary CXLmay happenThusa close followup is mandatory in patients after CXL evenafter a stability of years after the procedure and CXL redoprocedures for those cases who progressed seems to be a safeand efficient technique to halt the progression of keratoconusor post-LASIK corneal ectasia after a failed primary CXL

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] R H KennedyWM Bourne and J A Dyer ldquoA 48-year clinicaland epidemiologic study of keratoconusrdquo American Journal ofOphthalmology vol 101 no 3 pp 267ndash273 1986

[2] J B Randleman B Russell M AWard K PThompson and RD Stulting ldquoRisk factors and prognosis for corneal ectasia afterLASIKrdquo Ophthalmology vol 110 no 2 pp 267ndash275 2003

[3] A S RadM Jabbarvand andN Saifi ldquoProgressive keratectasiaafter laser in situ keratomileusisrdquo Journal of Refractive Surgeryvol 20 no 5 pp S718ndashS722 2004

[4] I G Pallikaris G D Kymionis and N I Astyrakakis ldquoCornealectasia induced by laser in situ keratomileusisrdquo Journal ofCataract and Refractive Surgery vol 27 no 11 pp 1796ndash18022001

[5] I F Comaish and M A Lawless ldquoProgressive post-LASIK era-tectasia biomechanical instability or chronic disease processrdquoJournal of Cataract and Refractive Surgery vol 28 no 12 pp2206ndash2213 2002

[6] GWollensak E Spoerl and T Seiler ldquoRiboflavinultraviolet-a-induced collagen crosslinking for the treatment of keratoconusrdquoTheAmerican Journal of Ophthalmology vol 135 no 5 pp 620ndash627 2003

[7] G Wollensak ldquoCrosslinking treatment of progressive kerato-conus new hoperdquo Current Opinion in Ophthalmology vol 17no 4 pp 356ndash360 2006

[8] O Richoz N Mavrakanas B Pajic and F Hafezi ldquoCorneal col-lagen cross-linking for ectasia after LASIK and photorefractivekeratectomy long-term resultsrdquo Ophthalmology vol 120 no 7pp 1354ndash1359 2013

[9] G Li Z-J Fan and X-J Peng ldquoCorneal collagen cross-linking in the treatment of progressive keratoconus-preliminaryresultsrdquo Chinese Journal of Ophthalmology vol 49 no 10 pp896ndash901 2013

[10] G D Kymionis D G Mikropoulos D M Portaliou I CVoudouragkaki V P Kozobolis and A G P Konstas ldquoAnoverview of corneal collagen cross-linking (CXL)rdquo Advances inTherapy vol 30 no 10 pp 858ndash869 2013

[11] B J Dahl E Spotts and J Q Truong ldquoCorneal collagen cross-linking an introduction and literature reviewrdquo Optometry vol83 no 1 pp 33ndash42 2012

[12] H Hashemi M A Seyedian M Miraftab A Fotouhi andS Asgari ldquoCorneal collagen cross-linking with riboflavin andultraviolet a irradiation for keratoconus long-term resultsrdquoOphthalmology vol 120 no 8 pp 1515ndash1520 2013

[13] F Raiskup-Wolf A Hoyer E Spoerl and L E PillunatldquoCollagen crosslinking with riboflavin and ultraviolet-A lightin keratoconus long-term resultsrdquo Journal of Cataract andRefractive Surgery vol 34 no 5 pp 796ndash801 2008

[14] G D Kymionis A E Karavitaki M A Grentzelos DA Liakopoulos K I Tsoulnaras and G A KontadakisldquoTopography-based keratoconus progression after corneal col-lagen crosslinkingrdquo Cornea vol 33 no 4 pp 419ndash421 2014

[15] S A Greenstein and P S Hersh ldquoCharacteristics influencingoutcomes of corneal collagen crosslinking for keratoconus andectasia implications for patient selectionrdquo Journal of Cataractand Refractive Surgery vol 39 no 8 pp 1133ndash1140 2013

[16] T Koller M Mrochen and T Seiler ldquoComplication andfailure rates after corneal crosslinkingrdquo Journal of Cataract andRefractive Surgery vol 35 no 8 pp 1358ndash1362 2009

[17] K Kamiya R Ishii K Shimizu and A Igarashi ldquoEvaluation ofcorneal elevation pachymetry and keratometry in keratoconiceyes with respect to the stage of Amsler-Krumeich classifica-tionrdquo British Journal of Ophthalmology vol 98 no 4 pp 459ndash463 2014


[18] J M Vetter S Brueckner M Tubic-Grozdanis UVoszligmerbaumer N Pfeiffer and S Kurz ldquoModulation of centralcorneal thickness by various riboflavin eyedrop compositionsin porcine corneasrdquo Journal of Cataract and Refractive Surgeryvol 38 no 3 pp 525ndash532 2012

[19] G D Kymionis V F Diakonis M Kalyvianaki et al ldquoOne-yearfollow-up of corneal confocal microscopy after corneal cross-linking in patients with post laser in situ keratosmileusis ectasiaand keratoconusrdquoThe American Journal of Ophthalmology vol147 no 5 pp 774e1ndash778e1 2009

[20] ACaporossi CMazzotta S Baiocchi andTCaporossi ldquoLong-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy the Siena eye cross studyrdquoAmerican Journal of Ophthalmology vol 149 no 4 pp 585ndash5932010

[21] A Caporossi S Baiocchi C Mazzotta C Traversi and TCaporossi ldquoParasurgical therapy for keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of corneal colla-gen Preliminary refractive results in an Italian studyrdquo Journalof Cataract and Refractive Surgery vol 32 no 5 pp 837ndash8452006

[22] P B Baenninger L M Bachmann L Wienecke C Kaufmannand M A Thiel ldquoEffects and adverse events after CXL forkeratoconus are independent of age a 1-year follow-up studyrdquoEye vol 28 no 6 pp 691ndash595 2014

[23] P S Hersh S A Greenstein and K L Fry ldquoCorneal collagencrosslinking for keratoconus and corneal ectasia one-yearresultsrdquo Journal of Cataract and Refractive Surgery vol 37 no1 pp 149ndash160 2011

[24] F Sloot N Soeters R van der Valk and N G Tahzib ldquoEffectivecorneal collagen crosslinking in advanced cases of progressivekeratoconusrdquo Journal of Cataract and Refractive Surgery vol 39no 8 pp 1141ndash1145 2013

[25] R R Krueger and A J Kanellopoulos ldquoStability of simul-taneous topography-guided photorefractive keratectomy andriboflavinUVA cross-linking for progressive keratoconus casereportsrdquo Journal of Refractive Surgery vol 26 no 10 pp S827ndashS832 2010

[26] N Li X-J Peng and Z-J Fan ldquoProgress of corneal collagencross-linking combined with refractive surgeryrdquo InternationalJournal of Ophthalmology vol 7 no 1 pp 157ndash162 2014

[27] A J Kanellopoulos ldquoComparison of sequential vs same-daysimultaneous collagen cross-linking and topography-guidedPRK for treatment of keratoconusrdquo Journal of RefractiveSurgery vol 25 no 9 pp S812ndashS818 2009

[28] G Labiris A Giarmoukakis H Sideroudi M Gkika MFanariotis and V Kozobolis ldquoImpact of keratoconus cross-linking and cross-linking combined with photorefractive ker-atectomy on self-reported quality of liferdquo Cornea vol 31 no 7pp 734ndash739 2012

[29] M Doors N G Tahzib F A Eggink T T J M Berendschot CA B Webers and R M M A Nuijts ldquoUse of anterior segmentoptical coherence tomography to study corneal changes aftercollagen cross-linkingrdquo American Journal of Ophthalmologyvol 148 no 6 pp 844e2ndash851e2 2009

[30] A Caporossi C Mazzotta S Baiocchi T Caporossi andR Denaro ldquoAge-related long-term functional results afterriboflavin UV A corneal cross-linkingrdquo Journal of Ophthalmol-ogy vol 2011 Article ID 608041 6 pages 2011

[31] J H Krachmer ldquoEye rubbing can cause keratoconusrdquo Corneavol 23 no 6 pp 539ndash540 2004

[32] C W McMonnies ldquoMechanisms of rubbing-related cornealtrauma in keratoconusrdquo Cornea vol 28 no 6 pp 607ndash6152009

[33] C W McMonnies ldquoAbnormal rubbing and keratectasiardquo Eyeand Contact Lens vol 33 no 6 pp 265ndash271 2007

[34] A Ivarsen and J Hjortdal ldquoCollagen cross-linking for advancedprogressive keratoconusrdquo Cornea vol 32 no 7 pp 903ndash9062013

[35] M K Nguyen and R S Chuck ldquoCorneal collagen cross-linkingin the stabilization of PRK LASIK thermal keratoplasty andorthokeratologyrdquo Current Opinion in Ophthalmology vol 24no 4 pp 291ndash295 2013

[36] A J Kanellopoulos and G Asimellis ldquoKeratoconus manage-ment long-term stability of topography-guided normalizationcombined with high-fluence CXL stabilization (the AthensProtocol)rdquo Journal of Refractive Surgery vol 30 no 2 pp 88ndash932014

[37] A J Kanellopoulos and G Asimellis ldquoIntroduction of quan-titative and qualitative cornea optical coherence tomographyfindings induced by collagen cross-linking for keratoconus anovel effect measurement benchmarkrdquoClinical Ophthalmologyvol 7 pp 329ndash335 2013

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


consensus about the definition of progression of keratectasiaafter CXL The number of cases of keratoconus progressionafter original CXLprocedure is expected to increasewith timewith no clear consensus about the best treatment modality ofthose cases

To our knowledge no previous study evaluated the safetyand efficiency of CXL redo We hence report the rate ofprogression and the risk factors after CXL in our privatepractice and evaluate the technique safety and efficiency ofCXL redo after primary CXL

2 Materials and Methods

21 Setting We conducted a retrospective analysis of thepatients with progressive keratectasia who underwent CXLbetween March 2010 and March 2013 at the Beirut EyeSpecialist Hospital Beirut Lebanon Diagnosis of kerato-conus was based on a combination of computed slit-scanningvideokeratography of the anterior and posterior cornealsurfaces keratometric readings and corneal pachymetryKeratoconus was classified into four stages based on cornealpower astigmatism corneal transparency and corneal thick-ness according to the classification of Amsler-Krumeich [17]

22 Participants All patients included in this study had ahistory of progressive keratectasia either from keratoconusor from corneal ectasia after LASIK in one or both eyes andunderwent a primary CXL in order to stabilize the disease

All patients included in this study had a central cornealthickness gt400 120583m Central corneal thickness (CCT) andthinnest corneal location were measured using Pentacamtopography with epithelium on prior to the procedureBecause of the potential deswelling effect in the cornealstroma of the dextran in riboflavin solution [18] the CCT andthinnest corneal location were measured using ultrasoundpachymeter all through the period of riboflavin applicationduring the entire period of CXL procedure Therefore afterremoving the epithelium CCT and thinnest corneal locationwere measured although the period of riboflavin applicationand hypoosmolar riboflavin was additionally instilled every20 seconds for 5 minutes and repeated up to 2 times untiladequate minimal corneal thickness of more than 400 120583mwas reached

Exclusion criteria for primary and redo CXL were pre-operative corneal opacities ocular pathology other thankeratectasia especially the cornea guttata or other endothelialirregularities age younger than 18 years actual or intendedpregnancy not available for follow-up examinations for 1 yearand connective tissue disease

23 Data Collection Progressive keratectasia was suspectedby an increase inmaximum119870 readings in several consecutiverecordings in the last 6 months with or without progressivecorneal thinning as well as deterioration in visual acuity andmanifest refractionWe evaluated the progression of KC afterCXL based on the presence of 2 or more of the followingcriteria increase (ge1 D) in 119870 value (1198961 1198702 or 119870 max)a change in the map difference between two consecutive

topographies of ge1 D a deterioration of VA defined as a dropof one or more lines or any change in the refraction as achange of 05D

Based on our observation the cornea may endure majortopographic changes in the first 6 months after CXL withsignificant changes in manifest refraction and visual acuityWe set a baseline corneal topography 6 month after CXLtreatment and we noticed no further clinically significantchanges are happening then after apart from a nonsignificantminor flattening of 119896-reading over time with no furthersteepening happening 6months after CXL treatment in stablekeratoconus Any steepening in 119896-reading that happens 6months after primary CXL is considered as sign of kerato-conus progression mainly when it was associated with oneof the aforementioned criteria of keratoconus progressionTherefore the effect of CXL is considered only 6months afterprimary CXL and corneal stability is judged after that

All patients undergoing CXL were followed up closely inthe postoperative period at day one one week one month3 months sixth months and one year and then half yearlyafter Corneal topography was repeated at each visit starting3 months after CXL and then 6 months after CXL cornealtopography is considered as the baseline topography afterCXL based on which the progression of KC is consideredThus all patients are evaluated at 6 months after CXLby a complete ophthalmic workup including assessment ofuncorrected distance visual acuity (UDVA) corrected dis-tance visual acuity (CDVA) manifest and cycloplegic refrac-tions and anterior and posterior segment evaluation withdilated fundus examination as well as an anteriorposteriortopography Corneal topography (Pentacam 70700 OculusGermany) was conducted with undilated pupils under sco-topic conditions by a single experienced technician Baselinestrategy for the treatment of recurrent allergic episodes wasbased on topical mild steroids (Fluorometholone 01) tobe used four times a day for 10 to 14 days as needed Incase of severe exacerbations topical antihistamine and topicalcyclosporine 01 were added to the regimen

24 Surgical Procedure Primary and redo corneal collagencrosslinking (CXL) were done using the same protocol Allsurgeries were performed by the same surgeon (EJ) Theeye to be treated was anesthetized by applying proparacainehydrochloride 05 drops on three occasions spaced by fiveminutes After positioning the patient under the operatingmicroscope a lid speculum was inserted and the central 9mm corneal epithelium was removed with a blunt spatulaA mixed riboflavin 01 dextran solution (Collagex isotonic01 Lightmed USA Inc) was instilled every 2 minutes untilthe riboflavin penetrated the cornea that is after approxi-mately 30 minutes The ultraviolet (UV) lamp (UV-X illumi-nation system version 1000 IROC AG Zurich Switzerland)was then focused on the apex of the cornea at a distance of5 cm for a total of 30 minutes providing a radiant energy of30 plusmn 03mWcm2 The required irradiance of 30mWcm2was calibrated prior to each treatment using a UVA meter(LaserMate-Q LASER 2000 Wessling Germany) Dur-ing UVA administration riboflavin drops were applied to




3 Results














4 Discussion





BaselineCCT


Associatedsurgeries



visit)












10158401 119870

10158402 119870



4200 458 5100


Eye 3 5353 6025 675 4084 4116 4522 405 4338 4997 k2 184Dkmax 475D 4000 4325 4980



5298 549 lowast








Table4Ch

ange

inerroro

frefraction(EOR)u

ncorrected

distance

visualacuity

(UDVA

)correcteddistance

visualacuity

(CDVA

)from

baselin

eto

oneyear

after

CXLredo

UDVA

and

CDVA

remainedstableon

eyeara

fterC

XLredo

lowastm

issingdataSsph

ereC

cylin

derAaxis

Eye

EOR

UDVA

CDVA

Baselin

e6m

oCX

L+associated

surgeries

Refractio

natprogression

SC

AS1015840

C1015840A1015840

S10158401015840

C10158401015840

A10158401015840

Baselin

e6mon

thsa

fter

Timeo

fprogressio

n1y

eara

fter

CXLredo

Eye1

minus15

+425

170minus05

+100

20minus275

+275

175

2010

020

30

2025

2020

2010

020

40

2010

020

40

Eye2minus70

0+3

50

150minus300

+175

170minus275

+275

1020200

2030

2070

2040

2080

2040

2010

020

40

Eye3minus900

+350

20minus05

+075

170minus050

+300

135

20400

20200

2025

2020

2050

2030

2050

2025

Eye4minus1300

+200

75minus1300

+175

70minus1600

+15

70CF

2050

CF20

30

CF20

30

CF20

30

Eye5minus1450

+075

90minus1350

+175

70minus1800

+25

55CF

2050

CF20

30

CF20

30

CF20

40

Eye6

lowastlowast

lowastminus400

+275

105minus500

+325

105

lowastlowast

2050

2025

2070

2025

2060

2030

Eye7

lowastlowast

lowastminus17

5+2

25

170minus350

+400

170

lowastlowast

2040

2030

2010

020

30

2010

020

25





5 Conclusion




References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















3 Results














4 Discussion





BaselineCCT


Associatedsurgeries



visit)












10158401 119870

10158402 119870



4200 458 5100


Eye 3 5353 6025 675 4084 4116 4522 405 4338 4997 k2 184Dkmax 475D 4000 4325 4980



5298 549 lowast








Table4Ch

ange

inerroro

frefraction(EOR)u

ncorrected

distance

visualacuity

(UDVA

)correcteddistance

visualacuity

(CDVA

)from

baselin

eto

oneyear

after

CXLredo

UDVA

and

CDVA

remainedstableon

eyeara

fterC

XLredo

lowastm

issingdataSsph

ereC

cylin

derAaxis

Eye

EOR

UDVA

CDVA

Baselin

e6m

oCX

L+associated

surgeries

Refractio

natprogression

SC

AS1015840

C1015840A1015840

S10158401015840

C10158401015840

A10158401015840

Baselin

e6mon

thsa

fter

Timeo

fprogressio

n1y

eara

fter

CXLredo

Eye1

minus15

+425

170minus05

+100

20minus275

+275

175

2010

020

30

2025

2020

2010

020

40

2010

020

40

Eye2minus70

0+3

50

150minus300

+175

170minus275

+275

1020200

2030

2070

2040

2080

2040

2010

020

40

Eye3minus900

+350

20minus05

+075

170minus050

+300

135

20400

20200

2025

2020

2050

2030

2050

2025

Eye4minus1300

+200

75minus1300

+175

70minus1600

+15

70CF

2050

CF20

30

CF20

30

CF20

30

Eye5minus1450

+075

90minus1350

+175

70minus1800

+25

55CF

2050

CF20

30

CF20

30

CF20

40

Eye6

lowastlowast

lowastminus400

+275

105minus500

+325

105

lowastlowast

2050

2025

2070

2025

2060

2030

Eye7

lowastlowast

lowastminus17

5+2

25

170minus350

+400

170

lowastlowast

2040

2030

2010

020

30

2010

020

25





5 Conclusion




References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















BaselineCCT


Associatedsurgeries



visit)












10158401 119870

10158402 119870



4200 458 5100


Eye 3 5353 6025 675 4084 4116 4522 405 4338 4997 k2 184Dkmax 475D 4000 4325 4980



5298 549 lowast








Table4Ch

ange

inerroro

frefraction(EOR)u

ncorrected

distance

visualacuity

(UDVA

)correcteddistance

visualacuity

(CDVA

)from

baselin

eto

oneyear

after

CXLredo

UDVA

and

CDVA

remainedstableon

eyeara

fterC

XLredo

lowastm

issingdataSsph

ereC

cylin

derAaxis

Eye

EOR

UDVA

CDVA

Baselin

e6m

oCX

L+associated

surgeries

Refractio

natprogression

SC

AS1015840

C1015840A1015840

S10158401015840

C10158401015840

A10158401015840

Baselin

e6mon

thsa

fter

Timeo

fprogressio

n1y

eara

fter

CXLredo

Eye1

minus15

+425

170minus05

+100

20minus275

+275

175

2010

020

30

2025

2020

2010

020

40

2010

020

40

Eye2minus70

0+3

50

150minus300

+175

170minus275

+275

1020200

2030

2070

2040

2080

2040

2010

020

40

Eye3minus900

+350

20minus05

+075

170minus050

+300

135

20400

20200

2025

2020

2050

2030

2050

2025

Eye4minus1300

+200

75minus1300

+175

70minus1600

+15

70CF

2050

CF20

30

CF20

30

CF20

30

Eye5minus1450

+075

90minus1350

+175

70minus1800

+25

55CF

2050

CF20

30

CF20

30

CF20

40

Eye6

lowastlowast

lowastminus400

+275

105minus500

+325

105

lowastlowast

2050

2025

2070

2025

2060

2030

Eye7

lowastlowast

lowastminus17

5+2

25

170minus350

+400

170

lowastlowast

2040

2030

2010

020

30

2010

020

25





5 Conclusion




References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















10158401 119870

10158402 119870



4200 458 5100


Eye 3 5353 6025 675 4084 4116 4522 405 4338 4997 k2 184Dkmax 475D 4000 4325 4980



5298 549 lowast








Table4Ch

ange

inerroro

frefraction(EOR)u

ncorrected

distance

visualacuity

(UDVA

)correcteddistance

visualacuity

(CDVA

)from

baselin

eto

oneyear

after

CXLredo

UDVA

and

CDVA

remainedstableon

eyeara

fterC

XLredo

lowastm

issingdataSsph

ereC

cylin

derAaxis

Eye

EOR

UDVA

CDVA

Baselin

e6m

oCX

L+associated

surgeries

Refractio

natprogression

SC

AS1015840

C1015840A1015840

S10158401015840

C10158401015840

A10158401015840

Baselin

e6mon

thsa

fter

Timeo

fprogressio

n1y

eara

fter

CXLredo

Eye1

minus15

+425

170minus05

+100

20minus275

+275

175

2010

020

30

2025

2020

2010

020

40

2010

020

40

Eye2minus70

0+3

50

150minus300

+175

170minus275

+275

1020200

2030

2070

2040

2080

2040

2010

020

40

Eye3minus900

+350

20minus05

+075

170minus050

+300

135

20400

20200

2025

2020

2050

2030

2050

2025

Eye4minus1300

+200

75minus1300

+175

70minus1600

+15

70CF

2050

CF20

30

CF20

30

CF20

30

Eye5minus1450

+075

90minus1350

+175

70minus1800

+25

55CF

2050

CF20

30

CF20

30

CF20

40

Eye6

lowastlowast

lowastminus400

+275

105minus500

+325

105

lowastlowast

2050

2025

2070

2025

2060

2030

Eye7

lowastlowast

lowastminus17

5+2

25

170minus350

+400

170

lowastlowast

2040

2030

2010

020

30

2010

020

25





5 Conclusion




References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table4Ch

ange

inerroro

frefraction(EOR)u

ncorrected

distance

visualacuity

(UDVA

)correcteddistance

visualacuity

(CDVA

)from

baselin

eto

oneyear

after

CXLredo

UDVA

and

CDVA

remainedstableon

eyeara

fterC

XLredo

lowastm

issingdataSsph

ereC

cylin

derAaxis

Eye

EOR

UDVA

CDVA

Baselin

e6m

oCX

L+associated

surgeries

Refractio

natprogression

SC

AS1015840

C1015840A1015840

S10158401015840

C10158401015840

A10158401015840

Baselin

e6mon

thsa

fter

Timeo

fprogressio

n1y

eara

fter

CXLredo

Eye1

minus15

+425

170minus05

+100

20minus275

+275

175

2010

020

30

2025

2020

2010

020

40

2010

020

40

Eye2minus70

0+3

50

150minus300

+175

170minus275

+275

1020200

2030

2070

2040

2080

2040

2010

020

40

Eye3minus900

+350

20minus05

+075

170minus050

+300

135

20400

20200

2025

2020

2050

2030

2050

2025

Eye4minus1300

+200

75minus1300

+175

70minus1600

+15

70CF

2050

CF20

30

CF20

30

CF20

30

Eye5minus1450

+075

90minus1350

+175

70minus1800

+25

55CF

2050

CF20

30

CF20

30

CF20

40

Eye6

lowastlowast

lowastminus400

+275

105minus500

+325

105

lowastlowast

2050

2025

2070

2025

2060

2030

Eye7

lowastlowast

lowastminus17

5+2

25

170minus350

+400

170

lowastlowast

2040

2030

2010

020

30

2010

020

25





5 Conclusion




References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















5 Conclusion




References












































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of










































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















clinical study rate of corneal collagen crosslinking redo in … · 2019. 7. 31. · clinical study...

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