algorithmic approach to diagnosis and management of post

© 2020 Indian Journal of Ophthalmology | Published by Wolters Kluwer - Medknow

Algorithmic approach to diagnosis and management of post-refractive surgery dry eye disease

Sharon D’Souza, Edwin James1, Rishi Swarup2, Sheetal Mahuvakar3, Aditya Pradhan4, Krati Gupta

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Dryeyedisease(DED)isaconditionthatisfastreachingepidemicproportionsaroundtheworld.Dryeyepost-refractivesurgeryistheleadingcauseofiatrogenicallyinducedDED.Thewidevarietyofpresentationsandthedisparitybetweensignsandsymptomsinmanypatientsmakethisaverychallengingaspectofour clinicalpractice.Therehasbeen aparadigmshift in thewayweapproachand treat this condition.TheInternationalDryeyeworkshophasaddednewknowledgeandfocustoourmanagementofdryeye.AwiderangeofnewerdiagnosticmodalitiesareavailableforthediagnosisofDED.Dryeyeisoneofthemostcommonsideeffectsofrefractivesurgeryandcanhaveabearingthepatient’sperceptionofsurgicaloutcomesaswell.Athoroughunderstandingofthepossibleunderlyingetiopathologiesofthisdiseaseandthedifferenceinetiopathogenesisofpostrefractivedryeyeisessentialforoptimaloutcomes.Itisimportanttoapproacheachcaseinauniquefashionandcustomizethetherapytothepatientpresentation.Thisreviewarticlecompilesalltheseaspectsofmanagementofdryeyeingeneral,andpostrefractivesurgerydryeyeinparticular;fromtheonescommonlypracticedintheclinictothenewermodalitiesoftherapywithinsightsintothediseasefromamorepracticalpointofview.

Key words:Algorithm,dryeye,management,postrefractive

Department of Cornea and Refractive, NarayanaNethralaya,Bangalore,Karnataka,1DepartmentofOphthalmology,GovernmentMedicalCollege,Paripally,Kerala,2DirectorandConsultantCornea,CataractandRefractive,SwarupEyeCentre,Hyderabad,Telangana,3Consultant Cataract Cornea and Refractive Surgery, RetinaFoundation,Ahmedabad,Gujarat, 4ConsultantCataract, CorneaandExternalDisease,Disha EyeHospital, Barrakpore,Kolkata,WestBengal,India

Correspondenceto:Dr.SharonD’Souza,ConsultantCornea,OcularSurface andRefractiveDepartment,NarayanaNethralaya, 121/c,ChordRoad,Rajajinagar, Bangalore - 560 010,Karnataka, India.E-mail:drsharondsouza@gmail.com

Received:14-Jun-2020 Revision:14-Sep-2020Accepted:02-Oct-2020 Published:23-Nov-2020

Dryeyedisease(DED)isoneoftheleadingcausesofocularmorbidity in theworldwith increasingnumber ofpeoplesuffering fromdry eye-related complaints.[1] It is known to have a variety of presenting symptoms and signs with underlyingocular surfacepathologies, hence it’sdiagnosisandmanagement can be challenging for the treatingophthalmologist.[2]DEDcanalsobeiatrogenic,secondarytomedical and surgical interventions like systemicor topicalmedications, contact lensusage, andpostsurgery includingrefractivesurgery.[3]Refractivesurgeryhasgainedimmensepopularityworld-wide,withmorethan16millionproceduresperformed globally,[4,5] and dry eye is one of the most commonlyreportedsideeffectoftheseprocedures.[6,7] Dry eye postrefractivesurgerycanalsoimpactthepostoperativequalityofvisionandqualityoflife[4]andthereforeneedsparticularattentionandcare.[8,9]

The2017InternationalDryEyeWorkshopII(DEWSII)reportalsodefineddryeyeasamultifactorialdiseaseandhighlightedtheimportanceofocularsurfaceinflammation,neurosensoryabnormalitiesandlossofhomeostasisinthiscondition.[10] An importantadditioninthisreportTFOSDEWSIIistheconcept

ofneuropathicpainanditsproposedmanagement.[3] Dry eye afterrefractivesurgerycanbeduetothegeneralunderlyingproblems like tear insufficiency and aqueous deficiency,meibomianglanddysfunction,orsecondarytotransectionofcornealnervesandotherspecificanatomicalandphysiologicalocularchangesduringtheprocedure.[11,12]

The identificationof theunderlying etiopathogenesis isintegral to the management of DED in general and helps us customizeprimary treatment strategies.This reviewarticleaimsathighlighting themethodological evaluationofDEDespeciallyrelatedtorefractivesurgeryandoutlinesaprotocolbasedcustomizedmanagement.

Etiopathogenesis of Post-Refractive Surgery DEDTheDEDseenpost-refractivesurgeryhasmultipleproposedmechanisms.

Denervation of the cornea leading to decreased corneal sensitivityTheflapcreationandexcimerphotoablation in laser in situ keratomileusis(LASIK)andthefemtosecondphoto-disruptionofstromawithmanualextractionoftheintrastromallenticulein small incision lenticule extraction (SMILE) results in the

Cite this article as: D’Souza S, James E, Swarup R, Mahuvakar S, Pradhan A, Gupta K. Algorithmic approach to diagnosis and management of post-refractive surgery dry eye disease. Indian J Ophthalmol 2020;68:2888-94.

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temporarypartialdenervationofthecornea.[11]Photorefractivekeratectomy (PRK) involves excimer photoablation of thecorneawithoutflap creation andhence there canbe somedamagetothesubbasalplexusofcornealnervesbut lesstothe deeper stromal nerves than that seen in LASIK.[13] Due to thedamagetocornealnervessecondarytotheseprocedures,there is adecrease in corneal sensitivity and reduction inreflextearsecretion.ThisisoneofthemainmechanismsforDEDpost-refractivesurgery.[11,14]Theverticalsidecutofthecornea inSMILE is shorter than that in aLASIKflap, thustheremaybe less disruption of the normal corneal nerveanatomy [Fig.1aand1b].Thishasbeenevaluatedinanumberofstudieswithsomereportinglesscornealnervedamageanddry eye in SMILE than LASIK[15]andnosignificantdifferencein others.[16,17]Moreover therewasno significantdifferenceincornealreinnervationandsensitivitybetweenSMILEandLASIK at 6monthspostoperatively.[18] Even in PRK there havebeendiffering resultswith some studies claiming lessreductionintearsecretion,cornealsensitivityanddecreasedDEDinPRKcomparedtoLASIK.[13,19,20]whichwasnotprovedin other studies.[21,22]The locationof thehinge inLASIK, isanother importantpointwhich issaid tohaveabearingonthedry eye after refractive surgery. FengYF et al. in their metanalysisstatedthatahorizontalhingeledtolesscornealsensorydisturbance anddry eyeas compared to averticallocationinearlypostoperativeperiod,however,therewasnostatisticallysignificantdifferencebetweenthetwogroupsattheendof6monthspost-surgery.[23]

Thesechangestothecornealnervescanbestudiedintheeyeby invivoconfocalmicroscopy (IVCM).This techniquecanbeusedtodemonstratethetransectionofcornealnervespost-refractivesurgeryandserialimagingcanalsodemonstratetheslowregenerationofnervefibers,whichusuallytakes3–6months.[14]However,insomepatientsthenervefiberregeneration

canbesignificantlylowereven1-yearpost-surgery.[24] Tests using theCochet-Bonnetesthesiometer tocheckcorneal sensitivityshow that corneal sensation recovers topre-operative levelsbyaround6monthspost-surgery.However,somepatientsdoexperiencethesymptomsforalongerduration.[13]

Reduced blink rateThedecreasedcornealsensitivitymayaffectthecorneal-blinkreflex-lacrimalglandpathwayresultinginareducedblinkrateanddecreasedreflexaqueoustearsecretion.[11]Sinceblinkingcontributestotheexpressionofmeibumfromthemeibomianglands (MG) in theeye lids, the lipid layersecretion isalsodependenton theblink.Reduction in theblink rateandanincompleteblinkmayresult insubsequent reduction in theMGlipidsecretionandevaporativeDED.[24]

Corneal curvature change associated tear film instabilityChangesincornealcurvaturemayalterthefrictionencounteredbetweenthecorneaandlid,leadingtoanunstabletearfilmand dry eye.[25]

Mucin associated tear film instabilityThe pressure exerted due to the suction applied duringtherefractivesurgerycandamageconjunctivalgobletcellsresulting in reducedmucin secretion.[26] In addition, thecorneal nerve disruption alters themembrane-associatedmucinexpressionontheepithelium,leadingtoanunstabletearfilm.[27]

Pain without stainPostrefractivedryeyecanalsobeduetoneuropathiccornealpain(NCP)whichisalsotermedascornealallodynia,cornealneuralgia,cornealneuropathyorkeratoneuralgia.[28] This has nowbeenincludedintheTFOSDEWSIIreportasaseparatecondition needing special care.[3] The symptoms ofNCPandDED can overlapwithpatients complaining of pain,discomfort,burning,irritationandgrittinessintheeyes.[1] It canbetriggeredbyanocularsurgeryorinfectioninsomecasesorberelatedtonon-ocularcauses,neurological,orpsychiatricconditions.[29]CornealrefractivesurgerylikeLASIK,SMILEorPRKcanbeacauseforneuropathicpain.Oneclassicalfeatureis thedisproportionately increasedsymptomsascomparedto signs.

Variouspossibleetiopathogenesisofpost-refractiveDEDhavebeensummarizedinFig.2.Inaddition,patientsmayalsosufferfromaqueousdeficiencyandevaporativedryeyenotrelatedtotherefractivesurgery.AroutinescreeningforDEDisimportantbeforeplanningrefractivesurgeryonapatientasthesepatientscanhaveasignificantworseningofthediseasepostoperativelyifundiagnosedandnotmanagedadequately.PatientsarescreenedforDEDaspernormalprotocolDEDintheout-patientdepartment.Therearenoadditional specialtestsforcheckingdryeyebeforerefractivesurgery.

Preoperative Evaluation for DED in Patients Undergoing Refractive SurgeryHistory and slit-lamp examinationA detailed history preoperatively is essential and should includehistoryofcontactlensintolerance,allergy,medicationuse,previouschemicalinjury,long-termuseofantiglaucomamedicationsandassociatedsystemicdiseaseslikerheumatoid

Figure 1: (a) Diagrammatic representation of the normal corneal nerve anatomy with distribution at various levels. (b) Diagrammatic representation of differences in nerve transection in LASIK v/s SMILE

b

a

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arthritis, Sjogren’s syndrome, rosacea, systemic lupuserythematosus.[30]Ifsuspectingunderlyingsystemicdisease,a timely referral to an immunologist/rheumatologistwillhelpinthemanagementofthesystemicconditionandbettermanagement of theDED.Overlapping demographics ofpatientsopting for a refractive surgeryand those sufferingfrom theabove-mentioned conditions emphasizes theneedforcarefulhistorytakingandevaluation.[31,32]

Patient questionnairesValidated questionnaires like theOcular SurfaceDiseaseIndex (OSDI),DryEyeQuestionnaire (DEQ-5) and Impactof Dry Eye on Everyday Living (IDEEL) are useful topreoperativelypickup symptomatology suggestiveofdryeye.[33,34]

Examination – ocular surface assessmentEvaluationoftheface,eyelidsincludingmeibomianglands,blinkpatterns,tearfilm,conjunctivaandcorneaareessentialinDED.Meibomianglanddysfunction(MGD)isgradedusingdifferentclassificationsandscales.[35]

Routine tests for Dry eye evaluation including tearmeniscus height,[36] schirmers test with and withoutanesthesia,[37,38]tearbreaktime[21]andocularsurfacestainingusingfluorescein, roseBengal or lissaminegreen formarean important part of the preoperative evaluation,[39] and the same testsmust be repeatedpostoperatively if patientdevelops symptoms suggestiveofdry eye.Care shouldbetaken tonot touch the strip to the ocular surface to avoidfalse staining while instilling the dye. It is important to look foracharacteristicpatternofcornealstainingtermedLASIKinducedneuroepitheliopathy (LINE) seen inpostrefractivesurgerypatientsiftheyaresymptomatic[Fig. 3].[40]

Advanced Diagnostic Modalities can be Added to the Evaluation Preoperatively if Suspecting Dry EyeInterferometryTear film interferometry is one of the newer modalities ofdry eye assessment. Itmeasures thenature, lipid layerthickness (LLT) and lipid layerbreakupusing interferencepatterns.TheLipiView(TearScienceInc.,Morrisville,NC,USA)andIDRA(SBISistemiInc,StradaTorino,Italy)aresomeofthecommerciallyavailableinterferometers.[41]

Meibographycanbeusedtoassessthe morphology of the meibomianglandsandlossasthiscanbeacontributortothedry eye.[42]

Confocal microscopyIn vivo confocalmicroscopy (IVCM) is a non-invasive,high-resolution imaging tool that images the cornea at thedifferent levels anddelineates cellular changes. It isusefulin followingup nerve and inflammation-related changesseen in the corneapostrefractive surgeryand inDED.Thenumberanddensityof sub-basalandstromalnervecells isderangedinDEDrelatedconditions.[43]Bead-likeformation,micro-neuromas, tortuosity and irregular branching andincreasedcornealdendriticcelldensity[cDCD]arealsoseenonIVCMinpatientsofDED[Fig.4a].[43,44]Changesinkeratocytecount,stromalchangesandnervedensityhavebeenshowntooccurafterrefractivesurgery.[45,46]IVCMcanalsodemonstratethecornealnerve-relatedchangespostrefractivesurgery,andnerve regeneration on serial follow up [Fig.4b].InasubsetofpatientswhohaveNCP, in vivo confocalmicroscopy(IVCM)demonstrateddecreased corneal nerves and the presence

Figure 2: Flow chart of the probable pathophysiology of post‑refractive surgery DED

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ofmicroneuromas indicativeof the swellingof the injurednerve terminal.[47,48]Thesefindingscouldaidindiagnosisandplanning management.

Inflammatory biomarkersOneoftheimportantunderlyingfactorsinthepathogenesisofDEDisocularsurface inflammation.[49] IdentificationandquantificationoftheinflammatorymarkersinDEDcanhelptheclinicianstocustomizeDEDmanagementespeciallyifitisdetectedinapre-refractivesurgerypatientastheassociatedinflammationcanhavean impactonhealingandoutcomespostrefractivesurgery.[49-51]Matrixmetalloproteinase9(MMP9)isoneofthecommonlystudiedinflammatorymarkersandcannowbemeasuredusinganoutpatientpointofcarediagnostictest called the InflammaDry (Rapid Pathogen Screening,QuidelCorporation).[33]However,aneasydiagnostickitwhichcouldmeasurealargerrangeofinflammatoryfactorsknowntobeassociatedwith this condition couldgivemuchmoreinformationandhelpcustomizetreatment.[49]

Management of dry eye related to refractive surgeryTheTFOSDEWSIIhasgivenverycomprehensiverecommendationsformanagementofDED. It elaborateson treatmentaspectsrangingfromeducationofthepatientregardingenvironmentalmodificationsanddiseaseprognosticationtotreatmentoptionsavailable fordifferent typesofDED. It also talksabout thenewerthermalandlight-basedtherapies forMGDandroleofanti-inflammatoryagents,autologousserumandoralsecretagoguesacrossdisease severity.[52] Thepostrefractive surgeryDEDmanagementremainsthesame,exceptthatpostoperativelythetopicalanti-inflammatoryandimmunomodulatorymedicationslikecyclosporinemayneedtobecontinuedforlongerduration(upto4months)dependingoncertainpreoperativecharacteristics.[53]

Post-operative topical medications to treat and prevent dry eyeTear substitutesTear substitutes help in lubricating the surface and alsorelievepatientsymptomatologyprotectingthesurfaceagainstdesiccationandpromotingtearretention.[52,54]Alargenumberoftopicalformulationsareavailablecontainingcarboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC),sodiumhyaluronate,polyvinylalcohol,polyvinylpyrrolidoneandpolyethyleneglycol.SodiumHyaluronate(HA)inaddition

hasbeenshowntobindwelltoocularsurfaceandhaspotentialwound healing properties.[55]Lubricatingeyedropsareselectedbasedon themechanismof action, composition, viscosity,osmolarity/osmolality,pHandpreservativeagents.

Preservativeintearscanincreaseinflammationandhencepreservative-freemedicationsarepreferred,especiallywhenthedropshavetobeinstilledmorethan4timesadayoverlongperiods of time.[54,56]Benzalkoniumchlorideandchlorobutanolpreservatives in excess candamage the corneal epitheliumresulting in symptomsmimicking theDED itself.Newerpreservativeslikepurite(sodiumchlorite)sodiumperborate,areshowntocauselessharmtotheocularsurface.[57,58]Thus,preservative-freeeyedropsshouldberecommendedtopatientswhorequiremorefrequentinstillationofeyedropsinordertoprevent thepreservative relateddamage to corneal andconjunctivalsurfacehealth.

Anti‑inflammatory treatmentsInflammationisaknownunderlyingfeatureofvarioustypesofDEDandisfurtherincreasedpost-refractivesurgery.Useof anti-inflammatorymedications like topical steroids andcyclosporinemayhavean important role inpost-operativecare.Thishelpsinreducingandbreakingtheinflammatorycascadewhich iskey to alleviating symptomsand treatingthe disease.[10,52]

Topical steroids - Steroids act on the inflammatorycascade, byblocking cyclooxygenase. They alsohave localimmuno-modulatoryactivitybyinhibitingcertaintranscriptionfactors.[59]Topicalcorticosteroidusedecreasesocularirritationand inflammation.[52] Since they are a part of the normalpost-operative regime in refractive surgery, theyarekey toreducingtheincidenceofdryeyesymptomsinthesepatientsintheearlypost-operativeperiodandcanbeusedfor4-6weeksin tapering doses.[52] The strength of steroid used would depend ontheseverityofinflammationintheeye.Patientsprescribedtopical corticosteroids fordry eye shouldbemonitored foradverseeffectslikeraisedintraocularpressureandcataract.[52]

TopicalCyclosporineA(CsA)-TopicaladministrationofCyclosporineA(CsA)hasanimportantrole intreatmentofDEDpost-refractivesurgery.]ItactsbypreventingactivationofT-cellsandproductionofinflammatorycytokines.[60] It has also shownsomeeffectonincreasingtearsecretionandimproveboththesymptomsandsignsofDEDinseveralstudies.[60,61] Sincethepathophysiologyofdryeyepost-refractivesurgeryisslightlydifferentfromregulardryeye,itisimportanttocontroltheinflammationwhichmayimprovepatientsymptomseven

Figure 3: Clinical photograph of LASIK induced neurotrophic epitheliopathy staining (LINE)

Figure 4: (a) Beading of nerves , increased tortuosity of corneal nerves (arrow), increased dendritic cells (star) seen on IVCM in patients of DED. (b) Early nerve regeneration post LASIK seen on IVCM

ba

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without signs. Topical cyclosporine is usually prescribedfor aminimumdurationof 3monthsbecause theonset ofactionisslowerthansteroids,andcanalsobestarted1monthpreoperatively if patient is having dry eye preoperatively.[53,62]

Treatment of meibomian gland dysfunctionIfthepatienthaschronicMGDpreoperatively,itisadvisableto treat this before planning refractive surgery to avoidpostoperative complications.Thegoal of all treatments forMGDistoimprovetheflowofmeibomianglandsecretionsand reduce inflammation thus leading tonormal tearfilmstability.Thiscanbedonebyconventionalmethodslikelidhygiene,warmcompress,glandexpression,oralandtopicalmedicationsornewerprocedural therapies like the thermalpulsation system[63,64] and Intense pulsed light[65,66] if the

patientisnonresponsiveorfasterresolutionisrequired.Theseprocedureshaveshowngoodeffecteveninpostrefractivedryeye,butcaremustbetakennottoperformthermalpulsationinearlypostoperativeperiodtoavoidflaprelatedissues.

Essentialfattyacids- Usage of oral Omega-3fattyacidslikeeicosapentaenoicacid[EPA]anddocosahexaenoicacid[DHA]andplant-basedsources5-aminolevulinate[ALA]havebeenshowntoimprovesymptomsanddecreaseinflammationandocularsurfacestaininginsomestudies,[67]butnotinothers.[68]

RoleofVitaminDinDED-AsignificantassociationhasbeenfoundbetweenDEDandvitaminDandaprotectiveroleofVitaminDhasalsobeenpostulated.[69] It has an important role inwoundhealingandanassociationhasalsobeenfoundwiththecornealdendriticcelldensityandinflammatoryfactorsin

Figure 5: Algorithmic approach to evaluation and management of DED pre and post refractive surgery with emphasis on subdivision by type and grade of disease

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tears,[70,71]ItcanbeusedasadjuvanttherapyforpatientswithDEDnon-responsivetoconventionaltherapy.

Fig.5summarizesthealgorithmicapproachtodiagnosingandmanagingDEDrelatedtorefractivesurgery.Inadditiontothefeaturesspecifictopostrefractivedryeye,itisimportantnottomisseasilydiagnosablecausesforDEDpreoperatively.AsdiscussedintheTFOSDEWSIIreport,sinceDEDcanhavealotofoverlapbetweenaqueousandevaporativedisease,itisusefultoplantherapybasedontheseverityofdiseaseaswell as the symptoms and signs.[52]Thishastobedonebothpreoperativelyandpostoperativelyifpatientissymptomatic.

ConclusionThe management of DED is evolving and the treatment of post refractivedryeyeneedsacomprehensiveunderstandingofthepossiblepathomechanisms.Inthisarticlewedetailthedifferentaspectsofpostrefractivedryeyeandpresentanalgorithmicapproach for it’smanagement.A combinationofdetailedhistory,simpletestsandneweradvancesinunderstandingwillhelpoptimizeoutcomesinthesepatients.Duetothevariedpathophysiology in thepostrefractiveDED, this algorithmmaybefurthercustomizedforoptimalresults.Asystematicapproachtothediseasewithabalanceoftestsanddiagnosticsasdiscussed,followedbyappropriatemedicationsforadequatedurationwillgivethebestoutcomes.

Financial support and sponsorshipNil.

Conflicts of interestTherearenoconflictsofinterest.

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