Presence of Fleischer ring and prominent corneal nerves in keratoconus relatives and normal controls

PresenceofFleischerringandprominentcornealnerves inkeratoconusrelativesandnormalcontrols 窑ClinicalResearch窑 DepartmentofOphthalmology,UniversityofDebrecen ClinicalCenter,Debrecen4032,Hungary Correspondence to: LiliTak觃cs. Departmentof Ophthalmology,UniversityofDebrecenMedicalSchool, H4032Debrecen,Nagyerdeikrt,98,Hungary.ltakacs@med. unideb.hu Received:2014-09-24 Accepted:2015-02-03 Abstract ·AIM:Toexaminetheoccurrenceofcommonlyknown clinicalsignsofkeratoconus (KC), Fleischerring, prominent corneal nerves and thinning, among unaffectedfamilymembersofKCpatientsandhealthy controlindividuals. ·METHODS:Dataofbotheyesof117relativesofKC patients having no manifest disease based on videokeratography indices (KC relatives), and 142 controlswereusedforPearsoncorrelationand -test statistics.CorrelationofFleischerring,prominentcorneal nervesandcentralpachymetrydataweretestedwith eachotherandwithvideokeratographyindices(KSI, KISA,3and6mmFourierasymmetry,andI-S) ·RESULTS:Amoderatecorrelationwasfoundbetween Fleischerringandallexaminedtopographicalindices. Mostimportantcorrelationwaspresentwith6mm Fourierasymmetry,andcornealpachymetry(=0.272, < 0.001; =-0.234, =0.027,respectively).Similarcorrelations werefoundwithprominentcornealnerves(=0.234, < 0.001for6mmFourierasymmetryand =-0.235, = 0.0265 for pachymetry). KC family members who exhibitedFleischerringorprominentnerveshadthinner and more asymmetric corneas than those without Fleischerringorprominentcornealnerves ( <0.05for pachymetryandtopographicindiceswith -testand Mann-Whitneyranksumtest).Thoughrarely,Fleischer ringandprominentcornealnervesoccurredamong normalcontrols,indicatingtheexistenceofformefruste casesinthenormalpopulation.Controlsubjects,who hadcornealFleischerringorprominentnerveshad corneasmoresimilartoKCthanothercontrols(-test: increased KSI and KISA, =0.048 and 0.012, respectively). ·CONCLUSION:InKCfamilymembersandhealthy individuals,Fleischerringandprominentcornealnerves areassociatedwithfeaturesofKCandmaysuggesta possibilityofformefrusteKC.Searchingforthepossible presenceofFleischerringorprominentnervesonthe corneamayhelpinthedecisionwhetherornotto diagnosesubclinicalKCinaborderlinecase. ·KEYWORDS: formefruste/subclinicalkeratoconus; Fleischerring; cornealnerves; cornealthinning; videokeratographicindices;iatrogenickeratectasia DOI:10.3980/j.issn.2222-3959.2015.05.12 Kriszt 魣,LosonczyG,BertaA,Tak觃csL.PresenceofFleischerring andprominentcornealnervesinkeratoconusrelativesandnormal controls. 2015;8(5):922-927 INTRODUCTION Keratoconus(KC,OMIM#148300)isaprogressive, bilateral,primaryectaticdiseaseofthecornea, characterizedbynon-inflammatorythinningandconical protrusion [1].Inthegeneralpopulation,itsestimated prevalenceliesbetween50and230per100000 [2],but dependingondiagnosticcriteriaandethnicity,itcanreach 2.34%[3].KCisfrequentlyanisolatedcondition,butitmay associatewithothersystemicoroculardisorders [1,4].Thereis awell-recognisedgeneticcomponenttoKC,asevidencedby twin [5] andfamilystudies [1,6-8];however,theetiologyofthe diseaseiscomplex,multifactorialwithbothgeneticand environmentalfactorsplayingarole[9,10]. Amsler [11] demonstratedsimilarbutlesspronouncedcorneal topographicalchangesbyPlacidodiscinrelativesofKC patients,andcalledthisquitefrequentphenomenonforme frusteKC.HeprovedthatclassicandformefrusteKC constitutedthesameentityandthatmustbeconsideredin geneticstudies.TopographicexaminationofrelativesofKC patientsrevealedaggregationofasymmetriccornealpatterns andincreasedvideokeratoscopyindices [7,12].Topographic featuressimilartoformefrusteKCwereobservedamong somerefractivesurgerycandidates,especiallyamongthe ones sufferingfromprogressivekeratectasia afterthe intervention [13].RelativesofpatientswithKChaveahigh prevalenceofundiagnosedKCandKCtraits,therefore, keratorefractivesurgeryshouldbeconsideredcautiouslyin theseindividuals[14,15]. KCseveritywasfoundtobeassociatedwithanincreasing rateofslit-lampbiomicroscopicsigns, Vogtstriae, Fleischerringinkeratoconusrelatives 922 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 8熏晕燥援 5熏Oct.18, 圆园15 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 Fleischerring,prominentnerves,hazeandthinningofthe cornea.FleischerringispresentinmostKCcorneaswhereas prominentnervesarelessfrequentandspecificforKC[1,16]. DiagnosingformefrusteorsubclinicalKCisstillchallenging inmanycases.However,identifyingsuchcasesisnecessary bothforgeneticstudiesandscreeningpotentialhighrisk refractivesurgerycandidates.Inourpreviouswork,we observedtheoccurrenceofFleischerringandprominent cornealnervesinunaffectedKCfamilymembers [9].Forme frusteKCisknowntooccurfrequentlyamongKCfamily members,thereforemanystudiesexamineKCfamily memberstodefinesubtlecharacteristicsassociatedwith formefrusteorsubclinicalKC [15,17].Inthepresentstudy,we investigatedthecorrelationofcornealFleischerringand prominentnerveswithvideokeratographicsignsofKCboth amongunaffectedfamilymembersandhealthycontrol individualstofindoutifthesesignscanbeusedtobetter identifyformefrusteKC. SUBJECTSANDMETHODS Subjects Ourstudy'sdesignfollowedthetenetsofthe HelsinkiDeclarationwithinstitutionalresearchethicsboard approval,informedconsentofpatientsandcontrolswas obtainedbeforeexamination.KCfamilieswererecruitedby mailingletterstopatientstreatedinourdepartmentforKC, informingthemabouttheaimsofthestudyandaskingfor participationoftherelatives,too.Healthycontrolswere recruitedfromstudents,personnelandpatientsofthe departmentwithhealthycorneas.Alloftheenrolledsubjects wereHungarianpatientswithCaucasianancestry.Table1 showsthegroupsofindividualsenrolledinthestudy. Non-affectedKCfamilymembersweredefinedashaving 臆 3Dastigmatismor 臆6Dsphericalrefractiveerrorandnot havingKCbasedonkeratoconussevertyindex(KSI)or KISA(valuesbelow30%and100%,respectively).Noneof the familymembershadanyoftheknowngenetic associationsofKC( Downsyndrome,Marfansyndrome ).Of142controlindividualswithoutfamilyhistoryofKC andwithouthistoryofcornealdiseaseoreyesurgerywere selected,with 臆3Dastigmatismor 臆6Dspherical refractiveerror.Onlyeyesthathadnopreviouscornealinjury andsurgery,including perforating keratoplasty,were involvedinthestudy. Methods ForeachKCproband,diagnosiswasbasedon clinicalexamination,includingmeasurementofvisualacuity, slit-lampbiomicroscopy,directophthalmoscopy,retinoscopy andvideokeratography. AllKCfamilymembersandcontrolindividualsconsented cornealtopography,slit-lampclinicalexamination,and86 consentedultrasonicpachymetry(27eyesof15KCpatients, 89eyesof45familymembersand52eyesof26controls; Table1). Byslit-lampbiomicroscopy,thepresenceofFleischerringin theepithelium,prominentcornealnervesweresearchedfor infamilymembersofKCpatientsandcontrols.Fleischer ringwasconsideredaspresentwhenatleast2mmcurved paracentralsubepithelialirondeposit(incomplete)ora completeFleischerringwasdetected(Figure1). Videokeratography Topographicexaminationwas performedonbotheyesofeachstudyparticipant,usinga TMS-4videokeratoscope(TomeyCorporation,Nagoya, Japan).Atleastfourimagespereyeweretaken,discarding thosethatweremisaligned,outoffocusorofpoorquality. Carewastakentoavoidartifactsduringtheexamination whichcouldberesponsibleforpseudokeratoconusimages[18]. Dataobtainedfromthebestimageofeacheye,selectedupon thequalityofthekeratoscopymiresbyvisualinspection, wereused.Topographicalimagesandparametersofoperated eyeswereignored. Videokeratographyindicesofkeratoconus VideokeratographyindicesyieldedbytheTMS-4softwareandthose calculatedfromthemwereselectedforfurtheranalysis. KISA ValuesofKISAabove100weretakentoindicate manifestKC,below60healthyeyes,andtheinterval betweenthetwobeingconsideredformefrustecases[19]. Keratoconusseverityindex KSIexpressestheseverityof thediseaseinpercentage, KCsuspect>15%,manifest KC>30%[20]. ThreeandsixmilimeterFourierasymmetryindices Decentration(firstharmonic)component,onmirerings1-9, Table 1 Characteristics of the examined 47 KC families and control individuals KC families (n=47) KC patients KC family members Healthy controlsc No. of subjects 49 (87 eyes) a 117 (233 eyes) a 142 (279 eyes) b Age (a): (range) 33.3 ± 11.7 (15-64) 41.3 ± 18.6 (9-81) 35.9 ± 13.7 (14-74) No. of subjects having additional central corneal pachymetry measurements 15 (27 eyes) 45 (89 eyes) 26 (52 eyes) No. of subjects having Fleischer ring 33 (71.7%) 36 (30.8%) 3 (2.1%) No. of subjects having prominent corneal nerves 7 (15.2%) 17 (14.5%) 4 (2.8%) All subjects underwent slit-lamp and topographic examination, and a subpopulation had additional central corneal pachymetry measurements. a In two families, two members were affected. Data of operated eyes were excluded (3 and 5 probands underwent bilateral and unilateral keratoplasty, respectively, and one relative had previous eye injury); bFive eyes having previous injuries were excluded; cControls were not significantly different from the members of KC families, concerning age (P=0.11) and gender distribution (P=0.153). s x ± 923 andrings1-20whichapproximatelyrepresentthecentral3or 6mmofthecornea[21,22]. I-S AbsolutevaluesoftheI-S (inferior-superiordioptric asymmetry)[23].[I-S]逸1.4wasconsideredabnormal. Cornealpachymetry Cornealultrasonicpachymetrywas usedtomeasurethecentralcornealthicknessonbotheyesof 86individuals:15KCprobands,45non-affectedrelatives and26controls(Table1). StatisticalAnalysis Forcalculatingstatistics,dataofboth therightandlefteyesofeachindividualwereincluded.In KCfamilymembers,3seriesofcorrelationstatisticswere tested:thepresenceofFleischerring,centralcorneal pachymetrydataandthepresenceofprominentcorneal nerves,withoneanotherandwithvideokeratographyindices. Correlationstatisticswere not performedincontrol individualsbecausethelownumberofcaseswithFleischer ringorprominentcornealnerves.ThepresenceofFleischer ringandprominentnervesinthecorneawerebinary variables. Centralcornealpachymetrydataandall videokeratographyindiceswerecontinuousvariables. CorrelationbetweenvariableswascalculatedusingPearson correlation statistic, valueandthecorrelation coefficient ( )weredetermined.Parametervaluesbetween groupswerecomparedwith -testorMann-Whitneyrank sumtest.TheprogramSigmaStat3.5versionwasusedfor statisticsand 琢=0.05wasthelevelofsignificance. RESULTS Table1showsthecharacteristicsoftheexaminedpopulation. Controlswerenotsignificantlydifferentfromthemembersof KCfamilies,concerningage(=0.11)andgender distribution(=0.153).InKCpatients,Fleischerringwas detectedin71.7%,andprominentnervesofthecorneain 15.2%.InKCfamilymembers,cornealFleischerringwas observedin30.8%andprominentnervesweredetectedin 14.5%. Amongcontrolindividuals,Fleischerringandprominent nerveswerenotcompletelyabsentbutoccurredin2.1%and 2.8%,respectively(Table1;Figure1). CorrelationstatisticsinKCrelativesamongKCfamily members,therewasasignificantnegativecorrelation betweencentralcornealpachymetryandFleischerring(= -0.234;Table2).Foreachtopographicindex,therewasa significantpositivecorrelationwithFleischerring(Table2). ThesecorrelationresultsimplythatFleischerringoccurredin thinnerandmoreasymmetriccorneasofKCrelatives.There wasasignificantpositivecorrelationwithprominentcorneal nervesforalltopographicindices,exceptforI-S.Significant negativecorrelationbetweenprominentnervesandcentral Figure1Slit-lampandvideokeratographicimagesoftwo healthycontrolindividuals A:Slit-lampphotographyofa39 year-oldmanwhohascornealFleischerring(arrows)andprominent nerves(arrowheads);B:Videokeratographicimageofthesameman showsasymmetriccornealpattern;C:Slit-lampphotographyofa32 year-oldwomanwhohascornealirondeposition,whichdidnot reach2mmlength,thereforeitwasnotconsideredasFleischerring (arrow),butshehasprominentcornealnerves(arrowheads);D: Videokeratographicimageofthesamewomanshowsasymmetric cornealpatternwithskewedradialaxis. Table 2 Correlation statistics in KC relatives Pearson correlation Parameters r P Fleischer ring Pachymetry -0.234 0.027 KSI 0.169 0.00958 KISA 0.155 0.0178 3 mm Fourier asymmetry 0.214 0.001 6 mm Fourier asymmetry 0.272 0.0000261 I-S 0.229 0.000419 Pachymetry Prominent nerves -0.235 0.0265 KSI -0.377 0.000271 KISA -0.342 0.00104 3 mm Fourier asymmetry -0.425 0.0000328 6 mm Fourier asymmetry -0.427 0.0000303 I-S -0.338 0.00119 Prominent nerves Fleischer ring 0.00437 0.947 KSI 0.237 0.000261 KISA 0.246 0.000148 3 mm Fourier asymmetry 0.228 0.000463 6 mm Fourier asymmetry 0.234 0.000308 I-S -0.0287 0.663 The presence of Fleischer ring in KC relatives showed significant correlation with central corneal pachymetry data and all topographic indices. Central corneal pachymetry data displayed significant correlation with the presence of prominent nerves and all topographic indices. The presence of prominent corneal nerves showed significant correlation with all topographic indices except for I-S. r: Correlation coefficient. Fleischerringinkeratoconusrelatives 924 陨灶贼允韵责澡贼澡葬造皂燥造熏灾燥造援 8熏晕燥援 5熏Oct.18, 圆园15 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 cornealpachymetrydataindicatedthatprominentnerves weremorelikelytoappearinthinnercorneas(=-0.235; Table2). Centralcornealpachymetryvaluesnegativelycorrelatedwith allexaminedtopographicindices(<-0.3forallindices, correlationwasthehighestforFourierasymmetryindices3 and6mm =-0.425,-0.427,respectively). TherewasnosignificantcorrelationbetweenFleischerring andprominentnervesinthesecorneas,indicatingthat prominentnervesandFleischerringdidnotfrequentlyoccur inthesameindividuals(Table2). Inaccordancewithcorrelationstatistics,siginificant differenceswerefoundbetweenrelativeshavingornot havingclinicalsignsofKC,by -tests.Table3.showsthat relativeswithFleischerringhadsignificantlythinnercorneas andhighervaluesofeachvideokeratographyindexcompared tothosewithoutFleischerring.Relativeswithprominent cornealnervesdisplayedhigherKSI,3and6mmFourier asymmetryindicesthanthosehavingnoprominentnerves (Table3).SinceFleischerringandprominentcornealnerves werenotfrequentlyconcomitant,comparisonofcorneaswith prominentnervestoallotherfamilymembercorneas includingcorneaswithFleischerring-whichwerethinner andmoreasymmetrical-yieldedsignificantdifferencesonly forKSIand6mmFourierasymmetry.Accordingly,when corneasofrelativeswithprominentnerveswerecomparedto thosewhohadneitherprominentcornealnervesnorFleischer ringsignificantdifferenceswerefoundforallparameters exceptforKISA(Table3). Outof142controlindividuals,1hadonlyFleischerring,2 hadbothFleischerringandprominentnerves,2hadonly prominentnerves.Correationstatisticsinthisdatasetwasnot reliablebecauseoflownumberofcases. ControlindividualswithFleischerringandprominentcorneal nervesshowedsignificantlyhighervaluesofKSI(=0.048) andKISA ( =0.012)indices,butwerenotsignificanly thinnerthancontrolswithoutFleischerringandwithout prominentnerves( >0.1). DISCUSSION Inourdatasetof47sporadicKCfamilies,occurrenceof Fleischerringandprominentcornealnerveswasobservedon corneasofunaffectedrelatives.Ofthesepathognomicclinical signs,themostremarkableonewasthecornealFleischerring whichwaspresentinalmosteverythirdfamilymember (30.8%).ThisresultissimilartotheoccurrenceofFleischer ringdetectedinmildKC(27.27%in<45Dkeratometry readings) [24].InmanifestKC,wefoundFleischerringin 71.7%ofthepatients,whichisconsistentwiththeresultsof previousstudiesof57%-87% [25,26].Inthehealthycontrol population,Fleischerring(2.1%),prominentnerves(2.8%) andcornealasymmetrystilloccurredrarely(Figure1).Inthe examinedpopulation,Fleischerringwasmostlyfaintinthe corneasofKCfamilymembersandcontrols.Tothebestof theauthors'knowledge,thisisthefirststudyofan examinationofFleischerringandprominentcornealnerves amongunaffectedrelativesofKCpatients. Basedonourcorrelationand -testresults,thepresenceof Fleischerringandprominentnerveswasassociatedwith featuresofKC.FamilymemberswhoexhibitedFleischer ringandprominentnerveshadthinnerandmoreasymmetric corneasthanthosewithoutFleischerringandprominent nerves.Incontrolsubjects,corneasdisplayingaFleischer ringandprominentnervesweremoresimilartoKCcorneas (shownbysignificantlyhigherKSIandKISAvalues),but werenotthinnerthanothernormalcorneas. Table 3 Comparison of groups of individuals in the studied population Parameters of KC family members (n) Pachymetry KSI KISA 3 mm Fourier asymmetry 6 mm Fourier asymmetry I-S With Fleischer ring (36) 510.87 (±40.23) 6.20 (±15.94) 261.37 (±1497.80) 0.43 (±0.35) 0.67 (±0.54) 2.48 (±4.91) Without Fleischer ring (81) 530.17 (±32.90) 2.49 (±9.50) 19.02 (±91.67) 0.30 (±0.23) 0.43 (±0.30) 1.06 (±2.50) P 0.017 0.010 <0.001 <0.001 <0.001 <0.001 With prominent nerves (17) 506.72 (±48.44) 10.45 (±23.31) 566.07 (±2163.86) 0.50 (±0.43) 0.74 (±0.74) 1.41 (±2.07) Without prominent nerves (100) 527.96 (±31.79) 2.48 (±8.22) 13.24 (±28.19) 0.31 (±0.24) 0.47 (±0.31) 1.51 (±3.67) P 0.083 0.006 0.467 0.002 0.008 0.349 With prominent nerves (17) 506.72 (±48.44) 10.45 (±23.31) 15.60 (±2163.86) 0.50 (±0.43) 0.74 (±0.74) 1.41 (±2.07) Without prominent nerves and without Fleischer ring (70) 530.55 (±31.86) 2.02 (±8.17) 12.90 (±31.79) 0.28 (±0.21) 0.41 (±0.26) 1.03 (±1.50) P 0.024 0.001 0.907 <0.001 <0.001 0.029 KC family members having corneal Fleischer ring compared to those without Fleischer ring have significantly thinner corneas (t-test) and higher values of all topography indices (Mann-Whitney rank sum tests). KC family members with prominent corneal nerves compared to those having no prominent nerves show significantly higher values of KSI, 3 and 6 mm Fourier asymmetry indices (Mann-Whitney rank sum tests). KC family members having prominent corneal nerves compared to those without prominent nerves and without Fleischer ring have significantly thinner corneas (t-test) and higher values of all topography indices except for KISA (Mann-Whitney rank sum tests). 925 Interestingly,prominentnervesandFleischerringdidnot alwaysoccurtogetherinthesamecornea.Itiswellknown thatthesesignsoccurwithunequalfrequenciesinKC [1].Itis believedthatKCisacomplexdisease,bothgeneticand environmentalfactorsplayingaroleinitspathogenesis [9]. Fleischerringissupposedtodevelopasaconsequenceof alteredresponseofKCepithelialcellstooxidativestress[27]. Recentcorneal confocalmicroscopystudies consistentlyhaveshownthateveninmildKC,thesubbasal nervemorphologyisgrosslyabnormal [28].Thismightbe explainedbyalteredregulationofnervegrowthfactor receptorexpressionintheKCcornea [29].Thesedifferent etiologicalfactorsmightexplainwhyFleischerringand cornealnervesdonotalwaysoccurtogetherinKCorforme frustecorneas. ItwasunexpectedtofindFleischerringinnormalcontrols. Nevertheless,supposingthatformefrusteKCisan incompletely developedKC,itsoccurrenceinnormal controlsispossible.Arecentstudyreportedthepresenceof bilateralFleischerringinasubjectwhohadonlymild topographicasymmetry,averagecentralcornealthickness, lowmyopiawithstablerefraction,normalbestcorrected visualacuityandnormalretinoscopicreflexes.Theexample ofthispatient,whowasconsideredasformefrusteKC, indicatedthatthiscondition, cornealironringcanoccur withoutapositivefamilyhistoryand characteristic topographicsignsofKC[30]. Inourfamilymembers,minimaltopographicalterationswere observedandassociatedwiththepresenceofFleischerring and prominentcornealnerves. Oneoftheexamined parametersinthisstudywascentralcornealthickness measuredbyultrasound pachymetry.Centralcorneal pachymetryaloneisunreliableinthediagnosisofKC, nevertheless,decreasedthicknesscanbeagoodindicatorof similaritytoKCandtogetherwiththevideokeratographic indicesthisparametersupportedthatFleischerringand prominentnervestendtooccurincorneasmoresimilarto KC.However,theexaminationoftheposteriorcorneal surfaceandpachymetrywithmoderndiagnosticmethods( ScheimpflugimagingorOrbscan)wouldbehelpfulinfuture studies,sincetheearliestsignsofKCcanbemoreaccurately detectedwiththesetechniquesandcorrelationswillbegiven furtherimpactwiththeadditionofposteriortopographical information[31,32]. Inspiteofsophisticatedimagingtechniques,detecting subclinicalKCisstillchallenginginmanycases.Identifying subclinical/formefrustecases,however,isimportantbothfor geneticstudiesandselectinghighriskrefractivesurgery candidates [13,33,34].Basedonourresults,itcanbesuggested thatathoroughsearchforFleischerringandprominent nervesinthecorneacanhelptodecidewhetherornotto diagnosesubclinicalKCinborderlinecases. ACKNOWLEDGEMENTS Foundations: SupportedbyHungarianNationalResearch FundGrantsOTKAF046321andTAMOP-4. 2.1/B-09/1/KONV-2010-0007.Tak觃csLisrecipientofthe SzodorayFellowshipoftheUniversityofDebrecen. ConflictsofInterest:Kriszt 譧,None; LosonczyG,None; BertaA,None; Tak仳csL,None. 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