Keratoconusandallergicoculardiseases 窑ClinicalResearch窑 Effectsofvernalandallergicconjunctivitisonseverity ofkeratoconus

DepartmentofOphthalmology,FacultyofMedicine,Dicle INTRODUCTION University,Diyarbakir,Turkey llergicconjunctivitis(AC)whichcomprisesa Correspondenceto: YasinCinar.Dicle niversitesiTip A heterogeneousgroupofclinicopathologicconditions 譈 Fakultesi,GozHastaliklariA.D.21280Kampus,Diyarbakir, withawidevarietyofsignsandsymptoms,rangingfrom [email protected] simpleintermittenttearing,itching,orhyperemiatosevere Received:2012-06-26Accepted:2013-04-20 sight-threateningcornealcomplicationsaffectsapproximately 25%oftheworldpopulation [1-3].Vernalkeratoconjunctivitis Abstract (VKC)whichisseasonallyexacerbated,allergicinflammation ·AIM:Todemonstratetheeffectsoftwodifferenttypes oftheocularsurfaceinvolvingtarsaland/or bulbar conjunctivaespeciallyseeninchildrenandyoungadults ofallergicconjunctivitisonseverityofkeratoconus(KC). livingintheregionswithhotanddryclimatesuchasMiddle · METHODS:Weretrospectivelyreviewedthemedical East,NorthAfricaandsomepartsofSouthAmericaanditis recordsof171KCpatientsreferredbetweenJune2010 rareinNorthAmericaandEurope [4]. andJune2011.TheKCpatientsweredividedinto3 Keratoconus(KC)isabilateral,non-inflammatory, groups as KC (group A), KC with vernal keratoconjunctivitis(VKC)(groupB)andKCwithallergic progressiveconditionassociatedwithcornealectasia,that conjunctivitis (AC) (groupC).Mainoutcomemeasures thinningandprotrusionofthecorneacausingprogressive weredemographicandocularclinicalfeaturesincluding myopiaandirregularastigmatismespeciallyafterpuberty. ageatpresentation,gender,sphericalequivalent(SE), PreviouslyitsassociationswithVKC,atopyandeyerubbing bestspectaclecorrectedvisualacuity (BCVA),mean werereported [5,6].Chronicoculartraumacouldbeoneofthe keratometric measurement (Km), central corneal importantenvironmentalfactorsthatleadtodevelopmentof thickness(CCT),andintraocularpressure(IOP).Groups KCingeneticallypredisposedindividuals.Inatopic werecomparedintermofstudyvariables. individuals,fasterprogressionofKC,earlyneedforsurgery · RESULTS: Themedianageat presentation was andmoreoftensurgicalandimmunologiccomplications significantlyloweringroupB ( <0.001).Accordingto werepreviouslyreported [7].Thetissuedamagecouldbe themedianSE( =0.003),BCVA( =0.022),Km( <0.001), causedbychroniccornealepithelialtraumaresultingin CCT( =0.015)andAmsler-Krumeichclassification( < prolonged,slowreleaseofsmallamountsofdegradative 0.001),KCwasmoresevereingroupB.Therewasno enzymescalledmatrixmetalloproteinases(MMP) [8-10]. significantdifferenceintermsofIOPandcorrectedIOP ThesoutheastpartofTurkey,withhot-dryclimate,poor amongthegroups ( =0.44),howevertherewere4 socioeconomicconditionsandwidespreadmarriagebetween patientswhohadincreasedcorrectedIOPdeveloped after topical corticosteroid use in group B. The relatives,isdifferentinmanywaysfromdevelopedregions differences among the groups persisted even after ofTurkey.Weevaluatedkeratoconicpatientslivingin controllingforageandgender. southeastpartofTurkeywithorwithoutocularallergic · CONCLUSION:Ourfindingsdemonstratedamore disease(ACandVKC),whereboththeallergicocular severeKCinVKCpatientsdespitetheiryoungerage diseaseandKCwereseenfrequently,todemonstratethe whichsuggestsevaluationofVKCpatientsasaseparate effectsoftwodifferenttypesofallergicconjunctivitisonthe groupinkeratoconusdisease. severityofKC. · KEYWORDS: keratoconus;vernalkeratoconjunctivitis; SUBJECTSANDMETHODS Three-hundred-fifteeneyesof171consecutivepatientswith allergicconjunctivitis;intraocularpressure KCwereincludedinthisretrospectivestudy.TheKC DOI:10.3980/j.issn.2222-3959.2013.03.21 patientsweredividedinto3groups;92patientsonlywithKC

CinguAK,CinarY,TurkcuFM,SahinA,AriS,YukselH,SahinM, asgroupAincluding166eyes,35patientswithKCplus CacaI.Effectsofvernalandallergicconjunctivitisonseverityof VKCasgroupBincluding68eyesand44patientswithKC keratoconus. 2013;6(3):370-374 plusACasgroupCincluding81eyes.Afterhistorytaking,

370 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 6熏晕燥援 3熏 Jun.18, 圆园13 www.IJO.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-82210956 耘皂葬蚤造押ijopress岳员远猿援糟燥皂 demographiccharacteristicsofpatientswerenoted,and investigatedistributionpatternofdata.Sincethedatadidnot detailedophthalmologicalexaminationwasperformed followGaussians'distributiontheKruskal-Wallistestwas containingbestcorrectedvisualacuityonaSnellenscale,slit usedtotestdifferencesinthecontinuousvariablesamongthe lampbiomicroscopy,refraction,retinoscopy,intraocular groups.Mann-WhitneyUtestwasusedtomakeapairwise pressuremeasurementwithapplanationtonometry,indirect comparison,whenasignificantdifferencefoundamongthree ophthalmoscope,centralcornealthickness(CCT)with groups.Categoricaldatawereanalyzedwiththechi-squareor ultrasonicpachymetry(US-4000,Echostar,Nidek,Japan), theFisherexacttests.Totesttheinfluenceofageandsexon andplacidodiscbasedvideokeratography(Magellanmapper; independentvariablesmultivariateanalysisofcovariance Nidektechnologies,Vigonza,Italy).Thepatients'refractive (MANCOVA)wasperformed.SE,cylindricalvalue,VA, errorswererecordedandsphericalequivalentswere BCVA,Km,CCT,KCgradingaccordingtoAmsler- calculated.Thepatientswithhistoryofpreviousocular Krumeichclassification,IOP,andcorrectedIOPwereused surgery,oculartrauma,andrecentuseofcontactlenseswere asindependentvariablesandageandsexwereselectedas excluded. covariatesinMANCOVA. valuelessthan0.05acceptedas Allpatientswereexaminedbythesametwodoctors significant. (KC&YC).DiagnosisofACandVKCwerebasedonhistory RESULTS andbiomicroscopicsigns.ACwasdiagnosedaccordingto Ofthe315affectedeyes,166wereingroupA,68werein presenceofitchingatpresentationorhistoryofitching groupB,and81wereingroupC.Vernalkeratoconjonctivitis especiallyduringspringandsummer,andpresenceofserous patientscomplainedaboutintractableitchinganddifferent conjunctivaldischarge,conjunctivalhyperemiaandmild degreesofeyerubbingallaroundtheyear.However,itching papillaeontheuppertarsalconjunctivainbiomicroscopic wasdescribedtobepresentespeciallyduringthespringand examination.DiagnosisofVKCwasmadeaccordingto summerbythepatientswithAC. presenceofsevereandintractableitching,giantpapillaeon Comparisonsofthepresentingdemographicand theuppereyelid,Horner-Tranta'sdots,ropydischargeand ophthalmologicfeaturesofpatientsareshowninTables1 and2.Whiletherewasnosignificantdifferenceamongthe infiltrationinthelimbus.Presenceofpunctuateepithelial groupsingenderandlaterality;themedianageat erosion,shieldulcerandpseudogerontoxonwerealsonoted. presentationwassignificantlyloweringroupBcompared AccordingtoCameronclassificationVKCwastypedas withothertwogroups( <0.001).Therewasalsoasignificant limbal,palpebralormixed [11].KCdiagnosiswasmadeby differencebetweenthegroupAandCinage ( =0.014) evaluationofscissorreflexonretinoscopy,centralor (Table1). paracentralsteepeningoncornealtopography,andpresence Althoughthemediansphericalequivalentwassignificantly ofcentralorparacenralthinning,protrusionofcornea, higheringroupBthanthatoftheothertwogroups( =0.003, Fleischer'sring,Vogt'sstria,Descementsbreaks,apicalscars =0.002),nosignificantdifferencewasfoundincylindrical inbiomicroscopicexamination. valueamongthegroups.MedianBSCVAvalue was Thekeratoconusclinicalstagewasdefinedusingthe significantlyworse( =0.013, =0.013),meanKvaluewas Amsler-Krumeichclassificationsystem [12].Incaseofcorneal significantlygreater( <0.001, =0.001),andmedianCCT scarringduetocornealhydropswithconiccorneainwhich readingwassignificantlythinner(=0.008, =0.013)in cornealtopographycouldnotbeapplied;KCdiagnosiswas groupBcomparedwithgroupAandC.Therewasno madebyclinicalexaminationandthesecorneaswere significantdifferenceincorrectedIOPamongthegroups( = assumedtohavesevereKC.Whentherewasdifficultyin 0.44,Table2)buttherewere4patients(11.4%)having performingvideokeratographytotheeyeswithcornealscars correctedIOPlevelmorethan21mmHginVKCgroup. duetohydropssequelaecentral3mmcornealreadingswere Thepercentageofeyesclassifiedasgrade4KCaccordingto achievedbyuseofmanualkeratographifpossible. theAmsler-KrumeichclassificationingroupA,BandCwas Wenotedbestspectaclecorrectedvisualacuities(BSCVA) 22%,58.5%,and28.4%,respectively( <0.001)(Table3). ofallpatientsforcomparisoninthegroups.Visualacuities Twenty-oneof35patientswerepalpebraltype,4patients wereconvertedtoalogarithmoftheminimalangle werelimbaltype,and10patientsweremixedtypeinVKC resolution(logMAR)equivalentsforstatisticalevaluation. group.AlloftheVKCandmostoftheACpatientshadthe Measuredintraocularpressures(IOP)adjustedaccordingto historyoftopicalcorticosteroideyedropsuseindifferent thereferenceCCTof545 mandcalculatedwithfollowing 滋 typesanddosesbeforereferral. formula: Thestatisticaldifferencesobservedbetweengroupsinterms [13] CorrectedIOP=MeasuredIOP-(CCT-545)/50 2.5mmHg . ofSE,cylindricalvalue,VA,BCVA,meanKvalue,CCT, 伊 StatisticalAnalysis SPSSstatisticalsoftware,version11.5 IOP,correctedIOPandgradeofKChavepersistedeven (SPSSInc.,Chicago,Illinois,USA),wasusedforthe aftercontrollingforageandgenderbymultivariateanalysis statisticalanalysis.Kolmogorov-Smirnovtestwasusedto ofthedata. 371 Keratoconusandallergicoculardiseases

Table 1 Comparison of the presenting demographic features of the patients with KC in group A, B, and C n (%) Group A Group B Group C P (n=92) (n=35) (n=44) Features Mean (SD) Kruskal-Wallis Mann Whitney U Median (SEM) (3 groups) (2 groups) range Chi-squire Gender Male 48 (52.2) 19 (54.3) 15 (34.1) 0.10 Female 44 (47.8) 16 (45.7) 29 (65.9) Laterality Unilateral 18 (19.6) 2 (5.7) 8 (18.2) 0.15 Bilateral 74 (80.4) 33 (94.3) 36 (81.8) Age at presentation (a) 22.2 (7.6) 13.8 (3.8) 19.0 (5.4) 1<0.001 20 (0.8) 13 (0.6) 18 (0.8) <0.001 2<0.001 11-56 9-23 8-36 30.014 Group A: Patients with keratoconus, Group B: Patients with keratoconus plus vernal keratoconjunctivitis, Group C: Patients with keratoconus plus allergic conjunctivitis, SD: standard deviation, SEM: standard error of mean. 1Group A vs group B; 2Group B and group C; 3Group A vs group C. Mann-Whitney U test. Table 2 Comparison of the presenting features of the keratoconic eyes in group A, B, and C Group A Group B Group C P n= 166 eyes n= 68 eyes n=81 eyes Features Mean (SD) Kruskal-Wallis Mann Whitney U Median (SEM) (3 groups) (2 groups) range Spherical equivalent (D) -6.62 (4.61) -10.5 (7.61) -5.84 (3.95) 0.003 10.003 -5.62 (0.37) -9.68 (0.99) -5.00 (0.47) 20.002 -25.5/-0.88 -27.0/-0.25 -16.7/-0.38 30.32 Cylindrical value (D) -4.48 (2.23) -4.63 (2.43) -4.91 (2.59) -4.25 (0.18) -4.62 (0.31) -5.00 (0.30) 0.34 -9.75-0.25 -10.5-0.80 -9.75-0.25 Visual acuity (logMAR) 0.89 (0.39) 0.96 (0.43) 0.80 (0.45) 10.1 1.0 (0.03) 1.0 (0.05) 1.0 (0.05) 0.031 20.012 0-1.9 0-1.9 0-2.0 30.12 Best spectacle corrected visual 0.40 (0.33) 0.58 (0.44) 0.40 (0.41) 10.013 acuity (logMAR) 0.30 (0.02) 0.50 (0.06) 0.30 (0.04) 0.022 20.013 0-1.9 0-1.6 0-2.0 30.57 Mean keratometry (D) 51.9 (6.57) 57.2 (8.40) 52.9 (7.34) 1<0.001 50.5 (0.51) 57.9 (1.04) 51.1 (0.81) <0.001 20.001 42.1-80.7 41.5-75.3 41.2-78.7 30.33 Central corneal thickness (µm) 482.9 477.9 (49.4) 454.2 (64.4) 10.008 (60.6) 486.0 480.0 (3.86) 451.0 (7.93) 0.015 20.013 (6.82) 367-592 274-567 365-642 30.56 Corrected IOP (mmHg) 15.1 (2.67) 15.4 (3.10) 14.6 (3.22) 14.7 (0.20) 15.3 (0.38) 14.8 (0.36) 0.44 9.5-23.3 9.3-24.3 6.15-25.0 Group A: Eyes with keratoconus, Group B: Eyes with keratoconus plus vernal keratoconjunctivitis, Group C: Eyes with keratoconus plus allergic conjunctivitis, SD: standard deviation, SEM: standard error of mean, IOP: intraocular pressure. 1 Group A versus group B; 2 Group B and group C; 3 Group A versus group C. Mann-Whitney U test.

Table 3 Grading of the keratoconic eyes according to Table 4 Biomicroscopic findings of the keratoconic eyes n (%) Amsler-Krumeich classification in the group A, B and C n (%) Group A Group B Group C Biomicroscopic findings 1P Group A Group B Group C 1P n=166 n=68 n=81 Grading (n=166) (n=68) (n=81) Vogt’s striae 99 (59.6) 56 (82.4) 49 (62) 0.003 Grade 1 46 (27.7) 10 (14.7) 25 (30.9) 0.0001 Punctuate epithelial erosion 8 (4.8) 21 (30.9) 12 (14.8) <0.001 Grade 2 66 (39.7) 15 (22) 25 (30.9) Corneal hydrops/sequela 7 (4.2) 8 (11.8) 4 (4.9) 0.07 Grade 3 18 (10.8) 4 (5.8) 8 (9.9) Group A: Eyes with keratoconus, Group B: Eyes with keratoconus plus vernal Grade 4 36 (21.6) 39 (57.3) 23 (28.4) keratoconjunctivitis, Group C: Eyes with keratoconus plus allergic conjunctivitis. 1 Group A: Eyes with keratoconus, Group B: Eyes with keratoconus P value of chi-square test between group A, B, and C. plus vernal keratoconjunctivitis, Group C: Eyes with keratoconus plus allergic conjunctivitis. 1P value of Fisher exact test between group A, B, and C. indirectophthalmoscopywasshowninTable4.Theratesof Vogt'sstriae( =0.003)andpunctuateepithelialerosion( < Theimportantsignsnotedinslit-lampbiomicroscopyand 0.001)weresignificantlyhigheringroupBthanthoseof 372 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 6熏晕燥援 3熏 Jun.18, 圆园13 www.IJO.cn 栽藻造押8629原愿圆圆源缘员苑圆 8629-82210956 耘皂葬蚤造押ijopress岳员远猿援糟燥皂 groupAandC.Cornealhydropsorcentralcornealscarring factorsagainstthecorneainvulnerableindividualsmayresult thatindicatehydropssequelawerenotdifferentamongthree inacutehydrops [14].Theenvironmentalfactorsmaybedry, groups( =0.07). hotanddustyclimate.Thesecomplexfactorsmaycause DISCUSSION rapidprogressionofKCdiseaseinVKCpatients. Keratoconusisknownasnoninflammatory,progressiveand MMP-2andMMP-9areknownasgelatinasesandtheyare usuallybilateralcornealectasiawiththeincidenceof normallypresentintearfluid [22].Sincetheyfunctionin approximately1/2000inthegeneralpopulation.Allergic normal epithelialturnoverinphysiologicamounts, oculardiseaseandabnormalvideokeratographicpatternsand overexpressionofthemresultsinexcessiveextracellular KCassociationwithVKChaspreviouslybeenreported [14-16]. matrixdegradationandtissuedestruction.MMP-2ismainly InourstudyallsubjectswereKCpatientsand35had originatedfromactivatedfibroblastsinthecourseofwound accompanyingVKCand44hadaccompanyingAC.We healingandMMP-9isexpressedmainlybyregenerating comparedthreegroupsofKCpatientswitheachotherto epithelialcellsandrecruitsinflammatorycellstothewound demonstratewhetherseverityofKCaffectedbypresenceof area[23].Kumagai [24] showedactiveformsofMMP-2and thesetwodifferentallergicconditionsornot. MMP-9intearfluidsofnearlyalloftheirpatientswithVKC Inthecurrentstudytherewasaslightfemalepredominance butminorityofthepatientswithACintheirstudy.Onthe (F/M=1.07/1)inthewholecohortinagreementwithsome otherhandtheydidnotfoundactivatedformofthese previousstudies [17,18].HoweverinVKCpatientstherewas enzymesinthetearfluidsofhealthyvoluntaries.These malepredominanceofKCparalleltotheresultsofsome proteinasesmayplayroleintheseverityofKCinVKC otherpreviousreports [11,14,19].Totan [14] reportedthatthe patients.TcellsalsoexpressorregulatesMMPs[25,26].Inactive meanagewas15.78yearsinVKCsubjectswithKC.Inthe diseaseinfiltrationofTlymphocyteswasshowninthe presentstudythemedianpresentingageofKCinourVKC conjunctivaoftheVKCpatients [27].Besides,theefficacyof patientswas2yearsearlierthanthatofTotans'group. topicalcyclosporinewhichisaselectiveTcellinhibitor,has FurthermoreourVKCassociatedKCpatientshave7years beenshowninVKC [28].Inthecurrentstudy,percentageof and5yearsyoungermedianpresentationagesthanthatofthe severeKCwasveryhighingroupBwhereaspercentageof patients only withKCandtheKCpatients with moderateKCwashigheringroupAandgroupC.Mostof accompanyingACrespectively. theKCpatientsparticularlywithVKChavedryeye Barreto [20] reportedthatVKCpatientshadhigher symptoms,significantpunctuateepithelialerosion,aswellas elevationvalues,thinnercorneas,andincreasedfrequencyof chroniceyerubbingwhichwaspreviouslydescribedin KCpatternsdetectedbykeratometricmapscomparedto pathogenesisofKC [5,6,29,30].Thesemaycauseincreaseinthe normalsubjects.InthepresentstudythepatientswithVKC rateofepithelialturnoverandexpressionofMMP-9which hadmoresevereKCthanthatofthepatientsinothergroups maybearapartintheprogressionofthedisease. accordingtotheirmedianSE,keratometricvalues,BCVA Inthecurrentstudy,themedianIOPofallgroupsfoundtobe andCCT.Grade4KCwerefoundtobesignificantlyhigher withinnormalranges.HoweverpatientswithoutVKC inpatientswithVKCthanthatoftheothertwogroups. showedgreatermeasuredIOPwithGoldmanapplanation AlthoughitchingwasusuallyseasonalinAC,itmayaffect tonometryandtherewere4patients(11.4%)having theseverityandprogressionofKC.Hargrave [7] reported correctedIOPlevelmorethan21mmHginVKCgroup. that,patientswithatopyshowedrapidprogressionofKCand Ultrasonicpachymetrytechniqueismostwidelyaccepted theyneedkeratoplastyearlier.Theyalsoreportedthat methodtomeasurecornealthickness.Kaya [31] reported refractiveandimmunologicalcomplicationsweremore thatkeratoconiceyeswithatopyhadlowerCCTandsteeper frequentlyseeninKCpatientswithatopy.Cornealhydrops conethanthatofeyeswithoutatopy.Consistentwiththeir maybethepresentingsignofKCasaverycommon resultsVKCpatientsinourstudyhadthinnerandsteeper complicationinVKC [21].Khan [19] reported12.5%and corneas.InKCpatientsincrementinIOPandchronic Cameron [11] reported30%ofacutehydropsinVKC glaucomawerereported[33] andalsotopicalcorticosteroiduse patientsintheirstudies.Theyalsoreportedeyerubbingasa waspreviouslyreportedtobeassociatedwithglaucoma [33,34]. riskfactorforthedevelopmentofacutehydrops.Inthe Totan [14] suggestedthatnoneoftheirpatientspresented presentstudysevereitchingandeyerubbingwerealso withincreasedIOPevenallofthemreceivedstrongsteroids commoninVKCpatients.Additionallypatientspresented forlongperiodsoftime.Inthepresentstudy,measuredIOP withacutehydropsorcentralcornealscarringthatmimic levelswerewithinnormallimitswhereasthereweresome previoushydropshistoryweresignificantlyhigheringroupB eyeswithcorrectedIOPmorethan21mmHginVKCgroup. patients(11.8%)thanthatofgroupA(4.2%)andCpatients Thismayberelatedwithuseofstrongsteroidsatdifferent (4.9%)inourstudy.Notonlyitchingandeyerubbing, timesduringtheirdiseasecoursebeforereferral.Thus,even complexinteractionsbetweenhereditaryandenvironmental incidentalmeasurementofIOPcouldbenormalinpatients

373 Keratoconusandallergicoculardiseases withVKC,theyshouldbecarefullyexaminedforglaucoma. 1997;20(2):97-102 Scheimpflugimagingsystemissuperiortoplacidodiscbased 16Lapid-GortzakR,RosenS,WeitzmanS,LifshitzT.Videokeratography cornealtopographicsystemstodetecttheposteriorelevation findingsinchildrenwithvernalkeratoconjunctivitisversusthoseofhealthy andtodetermineearlyKC.Accuratemeasurementofthe children. 2002;109(11):2018-2023 17SorsbyA.ed.ModernOphthalmology,2nd ed.London:Butterworths thinnestcornealpachymetryisnotpossiblebyuseof 1972;v.3,chap1,244 ultrasonicmethodbutultrasonicpachymetryisgoldstandard 18FranschettiA.Keratoconus.In:KingJHJr,McTigueJW,eds.The forCCT.Inthecurrentstudyweusedultrasonicpachymetry CorneaWorldCongress:Papers.Washington:Butterworths1965:157 inthemeasurementofCCT. 19KhanMD,KundiN,SaeedN,GulabA,NazeerAF.Incidenceof Thepresentstudyhassomelimitations.Aprospectivedesign keratoconusinspringcatarrh. 1988;72(1):41-43 wouldenableustoformamoreclearcauseandeffect 20BarretoJJr,NettoMV,SantoRM,José NK,BecharaSJ.Slit-scanning relationshipbetweenthevariablesnotedinthestudy. topographyinvernalkeratoconjunctivitis. 2007;143(2): However,byusingmultivariatestatisticalteststheimpactof 250-254 21RehanyU,RumeltS.Cornealhydropsassociatedwithvernal confoundingfactorshasbeencontrolledinthepresentstudy. conjunctivitisasapresentingsignofkeratoconusinchildren. 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