Essentials in Ophthalmology

Cornea and External Eye Disease

Corneal Allotransplantation, Allergic Disease and Trachoma

Bearbeitet vonThomas Reinhard, Frank Larkin

1. Auflage 2007. Buch. xx, 234 S. HardcoverISBN 978 3 540 33680 8

Format (B x L): 17 x 24,2 cmGewicht: 681 g

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Core Messages

■ Fuchsendothelialdystrophy (FED) is aprogressive disorder of the corneal en-dothelium with accumulation of focalexcrescences called guttae and thicken-ingofDescemet’smembrane,leadingtostromaledemaandlossofvision

■ The inheritance of FED is autosomaldominant, with modifiers such as in-creasedprevalenceintheelderlyandinfemales

■ Corneal endothelial cells are the major“pump”cellsofthecorneathatallowforstromalclarity

■ Descemet’s membrane is grossly thick-ened inFED,withaccumulationofab-normal wide-spaced collagen and nu-merousguttae

■ Corneal endothelial cells in end-stageFEDarereducedinnumberandappearattenuated, causing progressive stromaledema

■ Symptoms include visual blurring pre-dominantlyinthemorningwithstromalandepithelialedemafromrelativelylowtearfilmosmolality

■ FED can be classified into four stages,from early signs of guttae formation toend-stagesubepithelialscarring

■ Diagnosisismadebybiomicroscopicex-amination;othermodalities,suchascor-neal pachymetry, confocal microscopy,andspecularmicroscopycanbeusedinconjunction

■ Exact pathogenesis is unknown, butpossible factors include endothelial cellapoptosis,sexhormones,inflammation,andaqueoushumorflowandcomposi-tion

■ Mutations in collagen VIII, a majorcomponent of Descemet’s membranesecreted by endothelial cells, have beenlinkedtoFED

■ Medical management includes topicalhypertonicsaline,theuseofahairdryerto dehydrate the precorneal tear film,andtherapeuticsoftcontactlenses

■ Definitive treatment is surgical in theformofpenetratingkeratoplasty(PK)

■ New surgical modalities such as vari-ousformsofendothelialkeratoplastyaregaining popularity in the treatment ofFED

■ DLEK and DSEK avoid the surgicalcomplicationsofPK,suchaswoundde-hiscence, suture breakage/infection andhighpostoperativeastigmatism

■ Future directions in the treatment ofFED include gene or cell therapy andcontinuedadvancesinendothelialkera-toplasty

Chapter 1

1Fuchs Endothelial Dystrophy: Pathogenesis and ManagementLeejee H. Suh, M. Vaughn Emerson, Albert S. Jun

1

� Fuchs Endothelial Dystrophy: Pathogenesis and Management

1.1 IntroductionFuchsendothelialdystrophy(FED)isaprimary,progressivedisorderofthecornealendotheliumthatresultsincornealedemaandlossofvision.The initial stages of FED typically begin in thefifth through seventh decades of life and arecharacterizedbyprogressiveaccumulationoffo-calexcrescences,termed“guttae,”andthickeningof Descemet’s membrane, a collagen-rich layersecretedbyendothelialcells.Eventually,thereisloss of endothelial cell density and functional-ityasthe“pump”ofthecornea,causingvision-threatening corneal edema. Although cornealguttaearenotpathognomonic forFED, thede-velopmentof stromal edemadefines thisdisor-der.

1.� Historical PerspectiveIn1902ErnstFuchsinitiallydescribedthedisor-derthatwouldlaterbearhisname,andhepos-tulatedthatthisdiseaseoftheelderlywasrelatedtochanges in theposteriorcornea thatallowedforincreasedfluidmovementfromtheaqueousintothecornealstroma[11].Helaterpublishedacaseseriesof13patientswithFEDinwhichhesuggestedpathologicinvolvementofboththeen-dothelialandepithelialcorneallayers[12].Aftertheintroductionoftheslit-lampbiomicroscopein1911,Vogtwasthefirsttoreportdetailedbio-microscopic observations of FED and coinedthe term “cornea guttata,” in reference to focalexcrescences on the endothelial surface, whichwhen confluent, resembled beaten bronze [58].The natural progression of FED from isolated,asymptomatic guttae to the formation of cor-neal edemawithpainful lossofvisionwasfirstnoted in 1953 [53]. These and other importantobservations led to the understanding of FEDasaprimarydiseaseofthecornealendotheliumwith secondary involvement of the other layersofthecornea.

1.3 Epidemiology and InheritanceThe prevalence of FED is difficult to estimategiven its lateronset, slowprogression,and lack

of symptoms in the early stages. Furthermore,mildguttae canoccur innormal individuals insuchconditionsasaging,oculartrauma,ocularinflammation,andglaucoma.Inalargestudyof2002normalindividuals,Lorenzettietal.foundscatteredcentralguttaein0.18%ofeyesinthosebetween the ages of 20 and 39, and in 3.9% ofeyesinthoseabove40yearsofage[33].DespitethelackofanaccurateestimateoftheprevalenceofFED,itremainsoneofthemostcommonin-dicationsforcornealtransplantation,accountingforupto29%ofcases[1].

Fuchs endothelial dystrophy can be eithersporadic or hereditary. In hereditary cases, theinheritanceofFEDhasbeendemonstratedtobeautosomaldominant,withpenetranceashighas100% [10, 35]. In a large study of 228 relativesfrom 64 pedigrees with FED, Krachmer et al.observed that 38% of first-degree relatives over40yearsofagewereaffected,suggestingautoso-maldominantinheritancewithpossiblegeneticor environmental modifiers [30]. Some studies,includingFuchs’originalcaseseries,alsoreportan increased prevalence and severity in femalepatients[12,30,49].Thismayreflectapossiblerecruitment bias or a physiologic effect of sexhormones on corneal endothelial cell functionand survival [1, 62]. The incidence of FED hasbeen reported to be similar among white andblack patients, and much lower in Japanese in-dividuals[17].CentralcornealguttaehavebeenreportedinJapanese individualsandsignificantvisionlossisrareinthesepatients[29].

Summary for the Clinician

■ Corneal guttae can be present in non-affected individuals and are associatedwith conditions such as aging, inflam-mation,trauma,andglaucoma

■ Fuchs endothelial dystrophy is definedas the accumulation of corneal guttaewithstromaledema

■ InheritanceofFED isautosomaldomi-nant,butsporadicformscanoccur

1.4 PathologyThe corneal endothelium is a neural crest-de-rived cellular monolayer that utilizes an ATP-dependent pump to maintain physiologic stro-malhydrationnecessary forcornealclarity [13,61].Cornealendothelialcellsinhumansdonotnormallyproliferateinvivo[25,26].Cornealen-dothelial cells are normally lost throughout lifeat an estimated rate of 0.6% per year, althoughhigher rates of cell loss occur in the settings oftrauma(bothsurgicalandnonsurgical)andpri-maryendotheliopathies[3,7].Cornealendothe-lialcell lossiscompensatedforthroughflatten-ingandenlargementofremainingcellswithoutcell division in order to maintain a continuousmonolayer[61].

The corneal endothelial cells in end-stageFEDarereducedinnumberandappearthinnedwithattenuatednuclei, as seenby lightmicros-copy(Fig.1.1)[17].Withscanningelectronmi-croscopy,cornealendothelialcellsshowevidenceofdegenerationwithlargevacuolesandswollenorganelleswithdisruptedmembranes[17].Cor-neal endothelial cells also demonstrate dilatedsacsofendoplasmicreticulumfilledwithafinelygranularmaterialalongwithamarked increaseincytoplasmicfilamentsandribosomes,suggest-ingtransformationtoafibroblasticcelltype[17,20,62].

Normal corneal endothelial cells produceDescemet’s membrane, beginning in utero andcontinuing throughout postnatal life [34]. His-tologically and ultrastructurally, Descemet’smembraneconsistsofananterior“banded”zonesubjacent to thecorneal stromaandcontaining110nmofbandedcollagenandaposterior“non-banded” zone that lies anterior to the cornealendothelium[62].Atbirth,thethicknessoftheanteriorbandedzoneisapproximately3μm,andthisvarieslittlethroughoutlife[62].Incontrast,the thickness of the posterior nonbanded zoneincreases fromapproximately3μmatage20to10μmatage80[9],reflectingtheongoingsyn-thesis and deposition of Descemet’s membranebythecornealendothelium[22].

NormalDescemet’smembranecontainscolla-genIV,collagenVIII,fibronectin,entactin,lam-inin,andperlecan[31,32].Thesupramolecularstructure of Descemet’s membrane resembles

stacks of hexagonal lattices arranged parallel tothe surface of the membrane [52]. Monoclonalantibodyanalysishasshownthe latticearrayofDescemet’smembranetobecomposedofcollagenVIII,anonfibrillarshortchaincollagen[50,52].

The abnormalities of Descemet’s membraneareastriking featureofFED.Descemet’smem-braneisinvariablythickenedinFEDupto20μmorgreater[62].ThickenedDescemet’smembranealsocontainsnumerousfocalexcrescences(gut-tae)alongitsposteriorsurface(Fig.1.2a).

Descemet’s membrane also differs strikinglyfrom normal on electron microscopy. In addi-tiontoarelativelynormalanteriorbandedzoneproduced in fetal life, the posterior nonbandedzone of Descemet’s membrane is attenuated orabsent in FED and is replaced by a markedlythickenedposteriorcollagenouslayerwithanav-eragethicknessof16.6μm(Fig.1.3a)[7,20].Theposteriorcollagenouslayerischaracterizedbyadiffuse,granularbandingpattern,focalposteriorguttae,and theaccumulationof spindle-shapedbundleswith110-nmcollagenbanding,knownaswide-spacedcollagen(Fig.1.3b)[7].Thecom-positionofwide-spacedcollagenintheposteriorcollagenouslayerofFEDcorneaswasshownbyimmunoelectronmicroscopytobecollagenVIII[31].

Summary for the Clinician

■ Cornealendotheliumisamonolayerofcellsthatactsasthemajorpumptode-turgescethecorneaandensureclarity

■ Thereisanormalattritionrateofendo-thelialcellsof0.6%peryear;therateisacceleratedinFED

■ Normal endothelial cells produce Des-cemet’s membrane, made up of an an-terior banded zone and posterior non-bandedzone,thelatterofwhichexpandswithage

■ InFED,Descemet’smembraneisabnor-mallythickened,withattenuationorab-sence of the posterior nonbanded zoneand replacement with abnormal colla-gen,knownaswide-spacedcollagen

1.4 Pathology 3

1

4 Fuchs Endothelial Dystrophy: Pathogenesis and Management

Fig. 1.2  aSlit-lampbiomicroscopyofstageIFuchsendothelialdystrophy(FED;seeTable1.1). Note scattered, punctate, refractile endothelial guttae to the left of thearrow.b Stage III FED. Note thickening of the cornea, with the irregular surfaceandepithelialbullaeindicatedbyscatteredsurfacereflection(dashed arrow).(PhotoscourtesyofWalterJ.Stark,M.D.)

Fig. 1.1  aLightmicroscopysectionofanormalhumancornea.Notenumerousendothelialcellnucleiliningtheposteriorsurface(arrow).bLightmicroscopysectionofFEDcornea.NotethemarkedlythickenedDescemet’smembraneandtheabsenceofendothelialcellnucleiontheposteriorsurface(dashed arrow).(PhotoscourtesyofW.RichardGreen,M.D.)

Fig. 1.3  aLowpowerelectronmicrographofDescemet’smembrane fromaFEDpatient. Note the normal anterior banded zone (arrow), the markedly thickenedanddiffuselybandedposteriorcollagenouszone(PCL; dashed arrow),andthefo-calposteriorexcrescences(guttae,asterisks).bHigh-powerelectronmicrographofPCLshowingaspindle-shapedbundlewith110-nmcollagenbanding(wide-spacedcollagen,white arrow).(PhotoscourtesyofW.RichardGreen,M.D.)

1.5 Clinical FindingsThe earliest clinical signs of FED includefew (<10), central, focal excrescences (gut-tae) of Descemet’s membrane (Fig.1.2a). Overdecades, accumulation of guttae coincides withthe normal, gradual attrition of corneal endo-thelialcellsoccurringthroughoutpostnatal life.Normal adult central corneal endothelial celldensity isapproximately2,500cells/mm2,andadensityofapproximately500–1,000cells/mm2istheminimumthresholdforphysiologiccornealdeturgescence. Once this threshold is crossed,cornealedemaoccurs,resultinginlossofvisionand pain due to formation of epithelial bullae(Fig.1.2b).

The clinical course of FED can be di-vided into four stages (Table1.1) [1]. Stage I ischaracterized by biomicroscopic evidence ofcentral corneal guttae, with a possibly thick-ened, grayish Descemet’s membrane (Fig.1.2a).At this stage, the patient is asymptomatic. InstageIIdisease,thevisionmaybepredominantlyblurred in the morning because of decreasedtear evaporation, which lowers tear film osmo-lality when the eyes are closed [36]. Stromaland epithelial edema is notable on biomicros-copy.StageIIIandIVdiseasearecharacterizedbythepresenceofepithelialbullae,whichcausepainuponrupture(Fig.1.2b).StageIVisdistin-guishedbythepresenceofsubepithelialscartis-sue,resultinginfurtherworseningofvisualacu-ity,butrelieffrompain.

The diagnosis of FED is made principallyon the basis of the biomicroscopic examina-tion. Other modalities that have been used inconjunction with slit-lamp biomicroscopy in-cludecornealpachymetry,confocalmicroscopy,and noncontact specular microscopy. Cornealpachymetrymeasuresareoflimitedutilitygiventhewidevariationincornealthicknessofnormalindividuals.Thegreatestutilityofpachymetryisin theconsiderationofpenetratingkeratoplasty(PK)inknownorsuspectedFEDpatientsbeingevaluatedforcataractsurgery(seeSect.1.8).

Confocalmicroscopyandnoncontactspecu-larmicroscopyrelyonslightlydifferentmethodsof light emission and different patterns of lightreflection at the interface between Descemet’smembrane and corneal endothelial cells. Theabsence of corneal endothelial cells adjacent toand overlying guttae leads to transmission oflight without reflection in these areas. Cornealendothelial cells (Fig.1.4a) and corneal guttae(Fig.1.4b)canbeeasilydemonstratedwithcon-focal microscopy. Both confocal and specularmicroscopycanaidindemonstratingcornealen-dothelialcellpolymorphismandpleomorphism,as well as measuring endothelial cell density.Thesecharacteristicshavepotentialclinicalandresearchapplicationsasmarkersofdiseasepro-gression.

Confocal microscopy is superior to specularmicroscopy forevaluating thecornealendothe-liallayerinthesettingofcornealstromaledema[8, 16]. However, the benefits of specular mi-

Table 1.1 ClinicalstagesofFuchsendothelialdystrophya

Stage Symptoms Clinical findings Visual acuity

StageI Nosymptoms Fewtomoderatecornealguttae Normal(20/20)

StageII Mildtomoderatelossofvision,nopain

Moderatetonumerouscornealguttae,mildcornealedema

Mildtomoder-atereduction(20/20to20/80)

StageIII Moderatetoseverelossofvisionandpain

Confluentcornealguttae,moderatetoseverecornealedema,epithelialbullae

Moderatetoseverereduction(20/100to20/400)

StageIV Severelossofvision,reducedpain Subepithelialscar,fewerepithelialbullae

Severereduction(20/400orworse)

aAdaptedfrom[1].

1.5 Clinical Findings 5

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� Fuchs Endothelial Dystrophy: Pathogenesis and Management

croscopy over confocal microscopy include itsrelativecost-effectivenessanditseaseofuse[8].Neithermodalityiseffectiveincasesofextremecornealedemaorstromalopacity[16].Inaddi-tion,theutilityoftheseauxiliarytestsinthedi-agnosisofFEDisprimarilyinunusualcases,asthediagnosiscanusuallybemadeonthebasisofslit-lampbiomicroscopy.

Summary for the Clinician

■ DiagnosisofFEDisprimarilymadebytheappearanceofguttaewithorwithoutcornealedemaonbiomicroscopy

■ Fuchsendothelialdystrophycanbeclas-sified into four stages: (I) presence ofsubclinical central guttae; (II) presenceof stromal and epithelial edema; (III)presence of epithelial bullae; (IV) pres-enceofsubepithelialscarring

1.� Pathophysiology and GeneticsStudies of FED have been predominantly lim-ited to end-stage corneas because milder casesareasymptomaticandthereforelessreadilyavail-able for clinicopathologic correlation. Many oftheobservationslikelyreflectcomplexsecondarychangesoccurringasaresultofcornealendothe-lialcelldecompensation.Furthermore,initiatingevents are largely unexplored, and virtually no

informationexistsaboutearlycellularandextra-cellularmatrixchangesleadingtocornealendo-thelialcellloss.

Using scanningfluorophotometry,Wilsonetal. demonstrated a decreased endothelial pumprateincorneaswithadvancedFED[63].McCart-neyetal.demonstratedadeclineinthedensityofATPasepumpsitesinthebasolateralcornealen-dothelialcellmembranes[39].Nucleuslabeling,transmission electron microscopy, and TUNELassays were used to demonstrate apoptosis incornealendothelialcellsofadvancedstageFEDcorneas [6]. Serial analysis of gene expressionstudiesofFEDcornealendothelialcellsdemon-strateddecreasedtranscriptsrelatedtoapoptosisdefense and mitochondrial energy production[14].WhethercornealendothelialcellapoptosisisprimaryinthepathogenesisofFEDorsecond-arytoanabnormalityofthebasementmembraneremainstobeelucidated.Otherproposedfactorswithunclearrelevanceincludefibrinogen/fibrin,reduced sulfur content and increased calciumofDescemet’smembrane,aqueoushumorflow/composition, sex hormones, and inflammation[5].

To date, only mutations in the α2 colla-gen VIII (COL8A2) gene have been identi-fied as causing FED [4, 15]. Biswas et al. per-formed genetic linkage analysis of a pedigreewith three affected generations and identi-fiedanFEDlocusonchromosome1p34.2-p32.DNA sequencing revealed a mutation in theCOL8A2generesultinginasubstitutionofgluta-minewithlysineataminoacid455(Q455K).This

Fig. 1.4  a Invivoconfocalmicroscopy imageofnormalcorneal endothelial cells(CECs). Note ordered, hexagonal array of cells.b Confocal microscopy image ofCECsinFED.Notethenumerousexcrescences(guttae)ofDescemet’smembraneaswellastheirregularsizeandshapeofthecells

mutation cosegregated with FED in this pedi-gree and was absent in 244 ethnically matchedcontrol individuals [4]. The COL8A2 gene wassequenced in115additionalunrelatedFEDpa-tients,withatotalof8individualsdemonstratingmutations in the COL8A2 gene [4]. Gottsch etal.performedgeneticlinkageanalysisinalargeearly-onset FED pedigree originally describedbyMagovern[35]andidentifiedasecondpointmutationinCOL8A2ataminoacid450,result-inginasubstitutionofleucinewithtryptophan(L450W) [15]. In contrast to common FED,membersofthispedigreehadanearlieronsetofdiseasewithchildrenasyoungas3yearsofageaffectedandwithdistinctfeaturessuchasafine,patchydistributionofguttae.

Collagen VIII is a major component of nor-mal Descemet’s membrane and forms the ab-normally thick posterior collagenous layer inFEDcorneas.Furthermore,thecharacteristicag-gregates of wide-spaced collagen in Descemet’smembraneofFEDconsistofcollagenVIII[31].Basedontheimpliedfunctionaleffectsofthesemutations, one pathophysiologic hypothesis isthat amino acid substitutions reduce the turn-overofCOL8A2, resulting in theabnormalac-cumulation of collagen VIII and abnormalitiesof Descemet’s membrane. These abnormalitieseventually become incompatible with endo-thelial cell function and survival, resulting inapoptosis. If this model proves accurate, ad-ditional candidategenes forFEDcould includeother protein constituents of Descemet’s mem-brane. To date, however, no published reportshave associated mutations in these genes withFED.

Alternatively, the accumulation of colla-gen VIII in FED may occur as a secondary re-sponse to another primary insult to the endo-thelium. This possibility is consistent with theobservationthataposteriorcollagenouslayerofDescemet’s membrane, presumably composedof collagen VIII, is present in other hereditaryand acquired diseases of the corneal endothe-lium [23, 31, 38, 48]. Thus, a more complexrelationship may exist between corneal endo-thelial cell dysfunction and abnormal accumu-lations of collagenous material in Descemet’smembrane[15,31].

Summary for the Clinician

■ ThepathogenesisofFEDisunclear.Pos-sible factors include sex hormones, in-flammation,andendothelialcellapopto-sis

■ CollagenVIII is amajor componentofDescemet’smembraneandissecretedbyhealthyandpathologiccornealendothe-lialcells

■ Mutations in collagen VIII have beenlinkedtoFED

1.7 Differential DiagnosisThediagnosisofFED isbasedonclinicalfind-ings, mainly slit-lamp biomicroscopy. Distin-guishing FED from other entities is importantbecausethediagnosishasimplicationsfortreat-ment and prognosis of both patients and theirfamily members. Other entities that must bedifferentiatedfromFEDincludeotherposteriordystrophies, including posterior polymorphousdystrophy. In this autosomal dominant condi-tion,groupsofsmallroundvesiclesarefoundatthe level of the endothelium, interspersed withsheetsofgraymaterialwithinDescemet’smem-brane[60].Thisconditionisnotgenerallyassoci-atedwithstromalorepithelialedemaorcornealguttae.

Another formofendothelialdystrophy,con-genital hereditary endothelial dystrophy, ispresent at birth or early in postnatal life and ischaracterizedbyedemaoftheentirecorneaandsevere visual impairment [60]. Hassall-Henlebodieshave thesameappearanceasguttae,butare located only in the peripheral cornea andarenotassociatedwithprogressivevisuallossorcornealedema[23].Aphakicandpseudophakicbullous keratopathies are caused by endothelialcelldysfunctionrelatedtotraumaduringoraf-tercataractextractionandpresupposeanormalcornealendotheliumpriortocataractextraction[23]. Inflammatory diseases, such as anterioruveitis or interstitial keratitis, may be mistakenforFEDandcanbedifferentiatedbyresolutionof keratic precipitates with proper treatment inthecaseofanterioruveitis,oronthebasisofse-

1.7 Differential Diagnosis 7

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� Fuchs Endothelial Dystrophy: Pathogenesis and Management

rologictestingforsyphilisinthecaseofintersti-tialkeratitis[59].

1.� Management

1.�.1 MedicalEarly treatment modalities are not specific forFED,butarecommonlyappliedtoalletiologiesof corneal epithelial and stromal edema. Theseapproachesinvolveartificiallyraisingtheosmo-lalityofthetearfilmandincludehypertonicsa-line solutionsandointments, aswell as theuseof a hairdryer in the morning to dehydrate theprecornealtearfilm[62].Theuseoftherapeuticsoftcontactlensesmayhelpinrelievingthepainfromrecurrentepithelialerosions,whiledecreas-ingirregularastigmatismincasesthathavepro-gressed to bullous keratopathy [62]. The use ofcycloplegicsandnonsteroidalanti-inflammatoryagentsmayalsoaidindiminishingcornealpainfrombullouskeratopathy.Theuseofintraocularpressure-loweringmedicationsmayreducecor-nealedemainpatientswithelevatedorevennor-malintraocularpressure[1].

1.�.� SurgicalIfconservativemanagementoptionsdonotpro-videadequateclarityofthevisualaxisorallevia-tionofdiscomfortorpain,surgicaloptionsmaybeconsidered[37].PKhasbeenregardedasthedefinitiveprocedureinpatientswithcornealde-compensation due to FED. In one study of PKinpatientswithFED,theproportionofpatientswithvisualacuityof20/40orbetterwas50%at3monthspostoperatively,andincreasedto80%by24months[47].Theauthorsattributethisim-provement over time to corneal healing, sutureremoval, and fitting of rigid contact lenses. A10-yearfollow-upstudyof908patientswhoun-derwentPKforFEDfoundagraftsurvivalrateof97%at5yearsand90%at10years[56].Themostcommoncauseofgraftfailureinthesepa-tientswasendothelialrejection,followedbynon-immunologic endothelial failure. Uncorrectableirregularastigmatismwasanotherleadingcauseofpoorpostoperativevisualacuity.Othershave

reportedgraftsurvivalratesof89%atameanfol-low-upof8.4years[44],and81%after10years’follow-up[18]inpatientswithFED.

However,visualfunctionafterPKmaynotbedramaticallyimproved,asonestudyfound42%of patients who had undergone corneal trans-plant forFEDhadvisualacuitiesofworse than20/200atanaverageof50monthsaftersurgery[42].Thedisparitybetweentheseresultssuggeststhatoutcomesmaybeoperator-dependent,andsurgeonswithmoreexperiencetendtohavebet-terresults[57].

BecausemanypatientswithFEDandcornealdecompensation also have cataracts, attentionhasturnedtowardcombinedversusstagedsurgi-calmanagementofthecataractandcornea.IthasbeensuggestedthatcombinedproceduresinthehandsofanexperiencedsurgeonhavethesameoutcomeasstagedprocedureswithPKprecedingcataractextraction[2].TheAmericanAcademyof Ophthalmology suggests that corneal thick-nessmeasurementsgreaterthan600μmportendapoorprognosisfollowingcataractsurgeryandrecommendsconsiderationofcombinedcataractextraction and PK in these patients [21]. How-ever,inthehandsofaskilledsurgeon,onestudysuggests that cataract extraction may be safelyperformed in patients with corneal thicknessmeasurementsupto640μm[51].

New posterior lamellar techniques to selec-tively replace diseased endothelium, as in FED,havebeendevelopedandaregainingpopularityover traditional PK. In 1998, Melles described“posterior lamellarkeratoplasty,”orPLK,whichconsisted of manually dissecting both recipientanddonortissuesat80–90%stromaldepthandtransplanting the donor posterior lamellar discthrough a scleral incision [40]. This techniquewas later modified and popularized as deep la-mellarendothelialkeratoplasty(DLEK)byTerryandOusley[54].

DeeplamellarendothelialkeratoplastyhastheadvantageoverPKofbeinga “sutureless” tech-nique, therebyavoiding thepotential infectiousandrefractivecomplicationsassociatedwithsu-tures. This technique also has the advantage ofmaintaining the tensile strength of the cornea,whichisnotpossiblewithPK.Thelargestdisad-vantageofDLEKis its technicaldifficulty,evenfor highly-experienced anterior segment sur-

geons,andthepotentialmediaopacitycreatedbyirregularities in the lamellar dissection stage oftheprocedure.EarlyresultsofDLEKareencour-aging,withmeanbestcorrectedvisualacuitiesof20/46and20/50andmeanaverageastigmatismof1.34and2.3Dat6and12monthsrespectively[43,55].

Morerecently,Descemet’sstrippingwithen-dothelialkeratoplasty,orDSEK,hasbeendevel-oped,whicheliminatestheneedtoperformtherecipientlamellardissectionandposteriorbuttonexcisioninDLEK.DSEKreplacesthesometimeslaboriouslamellardissectionoftherecipientcor-nea by simply stripping Descemet’s membraneand endothelium, a maneuver first introducedin 2004 by Melles et al. [41]. The folded donorposteriorlamellarbuttonistheninsertedintotherecipient anterior chamber and allowed to un-fold adjacent to the bare stromal surface, whilemaintaining the proper endothelial orientation.Anintracameralairbubbleisplacedtopromote

attachment of the disc to the recipient stromalbed,andthepatientismaintainedinthesupinepositionpostoperatively.Withattachmentofthedonor posterior lamellar disc, the donor endo-thelialcellsdeturgescetherecipientstromaandepithelium,allowingforaclearcornea(Fig.1.5).Anterior chamber optical coherence tomogra-phy (AC-OCT) can be utilized to demonstrateattachmentofthedonorposteriordisc(Fig.1.6).

Initially,thedonorlamellarbuttonforDSEKwascreatedwithmanuallamellardissection.Re-cently,however,preparationofthedonorendo-thelialbuttonhasbeensimplifiedbyuseofanau-tomatedmicrokeratometocutthecornealbuttonmountedonanartificialchamber.ThisvariationhasbeentermedDescemet’sstrippingwithauto-matedendothelialkeratoplasty(DSAEK).How-ever,thetermsDSEKandDSAEKhavegenerallybecomeinterchangeable,asuseoftheautomatedmicrokeratomefordonorbuttonpreparationhasgainedpopularity.

Fig. 1.5  aSlit-lampexaminationofacorneaafterDescemet’sstrippingwithendo-thelialkeratoplasty(DSEK)showsaclearstromawitharemainingairbubblethatre-solvespostoperatively.bSlit-lampbeamshowsthinningoftherecipientstromawithanattacheddonorposteriordisc.(PhotoscourtesyofWilliamW.Culbertson,M.D.)

Fig. 1.6  Anteriorchamberopticalcoherencetomography(AC-OCT)imageshowsacross-sectionofarecipientcorneawithanattacheddonorposteriordisc.(ImagecourtesyofWilliamW.Culbertson,M.D.)

1.� Management �

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10 Fuchs Endothelial Dystrophy: Pathogenesis and Management

The DSEK/DSAEK procedures have largelysupplanted DLEK in the surgical treatment ofFED. Advantages over DLEK include an easiertechniqueofremovingthediseasedendothelium,lesstraumatotherecipienttissue,amorestruc-turally soundrecipient stroma,anda smoothercornealinterface[43].Inareviewof50eyesun-dergoingDSEK,Priceetal.[45]showedthatat6months, 31 eyes (62%) had best corrected vi-sualacuitiesof≥20/40and38eyes(76%)hadbestcorrectedvisualacuitiesof≥20/50.At6months,themeanmanifestcylinderwas1.5±0.94Dandthe mean manifest spherical equivalent was0.15±1.0D.Themostcommoncomplicationen-counteredinDSEKisdetachmentofthelamellardisc,whichhasbeenreportedin15–30%ofcasesintheearlypostoperativeperiod[46].Thiscom-plication,however,canbeaddressedintheimme-diate postoperative period by repositioning thebuttonand/orinjectingmoreairintotheanteriorchamber(called“rebubbling”).Figure1.7showsanAC-OCT imageofadetachedDSEKbutton(Fig.1.7a) that was repositioned and rebubbledwith subsequent reattachment and progressiveresolutionofstromaledema(Figs.1.7b–f).

Summary for the Clinician

■ Medical management of FED includestopical hypertonic saline, use of a hairdryer in the morning to dehydrate theprecorneal tear film, and therapeuticcontactlenses

■ Forseveraldecades,penetratingkerato-plasty(PK)hasbeenthestandardsurgi-caltreatmentforFED

■ Preoperative corneal pachymetry inFEDpatientscanbehelpfulinassessingtheriskofcornealdecompensationaftercataractsurgery

■ Cataract surgery alone should be con-sidered in FED patients with cornealpachymetrylessthan600–640µm

■ Variousformsofendothelialkeratoplas-tyaregainingpopularityovertraditionalPKinthetreatmentofFED

Fig. 1.7  aAnAC-OCTimageofadetacheddonorposteriordisc.bReattachmentof the disc to the recipient stromal bed with repositioning and rebubbling within1week of the DSEK procedure. c The cornea at postoperative month 3.d–f Pro-gressive deturgescence of the cornea after DSEK. (Images courtesy of William W.Culbertson,M.D.)

1.� Future DirectionsFuture therapies forFEDwould ideallyprovidedefinitivetreatmentofthediseasedendotheliumearlyinthediseasecourse,beforevisionlossordiscomfortoccurs.Improvementsinendothelialtransplantationwill likely result in less invasiveapproaches with reduced complication ratesandfastervisualrecovery.Althoughendothelialcells do not proliferate in vivo, several groupshave demonstrated the proliferative capacity ofhuman corneal endothelial cells in vitro [24].Recent work demonstrating the ability to cul-turehumancornealendothelialcellsonseveralsubstrates, such as denuded Descemet’s mem-brane and amniotic membrane [19], indicatespromising areas of future research. Additionalcell-based approaches could utilize our under-standing of the mechanisms of cell cycle arrestinhumancornealendotheliumtostimulatecelldivisioninvivo[27].

Fuchs endothelial dystrophy also representsanattractivediseaseforgenetherapy-basedap-proaches. Mutations in the COL8A2 gene havealreadybeenshowntocauseFED,andadditionalcausalmutationsindifferentgeneswillprobablybe identified. Genetic modification of cornealendothelialcellshasalreadybeenaccomplished,and FED mutations could theoretically be cor-rectedincornealendothelialcellsasapotentialtreatmentforthisdisease[28].

1.10 SummaryFuchsendothelialdystrophyisaprimarydiseaseofthecornealendotheliumthatischaracterizedbylossofendothelialcellsandabnormalitiesofDescemet’s membrane. These changes result inthe decreased capacity of the endothelium todehydrateandmaintaintheopticalclarityofthecornealstromaandepithelium,resultinginpainanddecreasedvisualacuity.Experimentalstud-iesonFEDsuggestendothelialcellapoptosisandabnormal basement membrane physiology asmediatorsinthepathogenesisofthisdisease.Todate,PKhasbeenlargelysuccessfulinmanagingadvancedFED.NewertechniquessuchasDLEK,DSEK,andDSAEKavoidthepotentialcomplica-tionsofPKandinsteadprovideincreasedglobeintegrity, minimal refractive change, and faster

recovery of vision. Future advances, includingimprovementsinendothelialkeratoplasty,endo-thelialcelltransplantation/engineering,andgenetherapy,representpromisingnewapproachestothemanagementofthiscommoncornealdisor-der.

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