Visual hallucinations in neurological and ophthalmological ...

Visual hallucination – visual percept not associated with a real object. · Complex visual hallucination – subtype of visual hallucination whose content is a ... Skiptomaincontent YouarehereHome Archive Volume91, Issue5 Visualhallucinationsinneurologicalandophthalmologicaldisease:pathophysiologyandmanagement Emailalerts ArticleText Articlemenu ArticleText Articleinfo CitationTools Share RapidResponses Articlemetrics Alerts PDF XML Neurodegeneration Review Visualhallucinationsinneurologicalandophthalmologicaldisease:pathophysiologyandmanagement http://orcid.org/0000-0002-0837-5080JohnO'Brien1,http://orcid.org/0000-0001-7958-6558JohnPaulTaylor2,CliveBallard3,RogerABarker4,ClareBradley5,6,AlistairBurns7,DanielCollerton2,SonaliDave8,RobDudley9,PaulFrancis3,8,AndreaGibbons6,http://orcid.org/0000-0002-6683-4337KateHarris4,VanessaLawrence8,IracemaLeroi10,IanMcKeith2,MichelMichaelides11,12,ChaitaliNaik11,ClaireO'Callaghan13,KirstyOlsen2,MarcoOnofrj14,RebeccaPinto8,GregorRussell15,PeterSwann1,AlanThomas2,PrabithaUrwyler16,17,http://orcid.org/0000-0002-5092-6325RimonaSharonWeil18,http://orcid.org/0000-0002-4214-9642Dominicffytche8 1 DepartmentofPsychiatry,UniversityofCambridgeSchoolofClinicalMedicine,Cambridge,Cambridgeshire,UK 2 TranslationalandClinicalResearchInstitute,NewcastleUniversity,NewcastleuponTyne,UK 3 UniversityofExeterMedicalSchool,MedicalSchoolBuilding,StLuke’sCampus,Exeter,UK 4 DepartmentofClinicalNeurosciences,WT-MRCCambridgeStemCellInstitute,UniversityofCambridgeSchoolofClinicalMedicine,Cambridge,Cambridgeshire,UK 5 HealthPsychologyResearchLtd,Egham,Surrey,UK 6 HealthPsychologyResearchUnit,RoyalHollowayUniversityofLondon,Egham,Surrey,UK 7 FacultyofMedicalandHumanSciences,TheUniversityofManchester,Manchester,UnitedKingdom 8 InstituteofPsychiatry,PsychologyandNeuroscience,King'sCollegeLondon,London,London,UK 9 GatesheadEarlyInterventioninPsychosisService,Cumbria,Northumberland,Tyne&WearNHSFoundationTrust,Gateshead,UK 10 GlobalBrainHealthInstitute,DepartmentofPsychiatry,SchoolofMedicine,TrinityCollegeDublin,Dublin,Ireland 11 MoorfieldsEyeHospitalNHSFoundationTrust,London,UK 12 InstituteofOphthalmology,UniversityCollegeLondon,London,UK 13 BrainandMindCentreandCentralClinicalSchool,FacultyofMedicineandHealth,UniversityofSydney,Sydney,NewSouthWales,Australia 14 ClinicalNeurologica,DipartimentodiNeuroscienze,ImagingeScienzeCliniche,UniversitàG.D’Annunzio,Chieti-Pescara,Italy 15 BradfordDistrictCareNHSFoundationTrust,LynfieldMountHospital,Bradford,UK 16 GerontechnologyandRehabilitationGroup,ARTORGCenterforBiomedicalEngineeringResearch,UniversityofBern,Bern,Switzerland 17 UniversityNeurorehabilitationUnit,DepartmentofNeurology,UniversityHospitalInselspital,Bern,Switzerland 18 DementiaResearchCentre,UniversityCollegeLondon,London,UK Correspondenceto ProfessorJohnO'Brien,DepartmentofPsychiatry,UniversityofCambridgeSchoolofClinicalMedicine,Box189,LevelE4,CambridgeCB20SP,UK;john.obrien{at}medschl.cam.ac.uk AbstractVisualhallucinationsarecommoninolderpeopleandareespeciallyassociatedwithophthalmologicalandneurologicaldisorders,includingdementiaandParkinson’sdisease.Uncertaintiesremainwhetherthereisasingleunderlyingmechanismforvisualhallucinationsortheyhavedifferentdisease-dependentcauses.However,irrespectiveofmechanism,visualhallucinationsaredifficulttotreat.TheNationalInstituteforHealthResearch(NIHR)fundedaresearchprogrammetoinvestigatevisualhallucinationsinthekeyandhighburdenareasofeyedisease,dementiaandParkinson’sdisease,culminatinginaworkshoptodevelopaunifiedframeworkfortheirclinicalmanagement.Herewesummarisetheevidencebase,currentpracticeandconsensusguidelinesthatemergedfromtheworkshop.Irrespectiveofclinicalcondition,caseascertainmentstrategiesarerequiredtoovercomereportingstigma.Oncehallucinationsareidentified,physical,cognitiveandophthalmologicalhealthshouldbereviewed,witheducationandself-helptechniquesprovided.Notallhallucinationsrequireinterventionbutforthosethatareclinicallysignificant,currentevidencesupportspharmacologicalmodificationofcholinergic,GABAergic,serotonergicordopaminergicsystems,orreductionofcorticalexcitability.Abroadtreatmentperspectiveisneeded,includingcarersupport.Despitetheirfrequencyandclinicalsignificance,thereisapaucityofrandomised,placebo-controlledclinicaltrialevidencewheretheprimaryoutcomeisanimprovementinvisualhallucinations.Keyareasforfutureresearchincludethedevelopmentofvalidandreliableassessmenttoolsforuseinmechanisticstudiesandclinicaltrials,transdiagnosticstudiesofsharedanddistinctmechanismsandwhenandhowtotreatvisualhallucinations.parkinson'sdiseasedementiahallucinationshttps://creativecommons.org/licenses/by/4.0/ThisisanopenaccessarticledistributedinaccordancewiththeCreativeCommonsAttribution4.0Unported(CCBY4.0)license,whichpermitsotherstocopy,redistribute,remix,transformandbuilduponthisworkforanypurpose,providedtheoriginalworkisproperlycited,alinktothelicenceisgiven,andindicationofwhetherchangesweremade.See: https://creativecommons.org/licenses/by/4.0/. http://dx.doi.org/10.1136/jnnp-2019-322702 StatisticsfromAltmetric.com parkinson'sdiseasedementiahallucinationsIntroductionVisualhallucinations(VH)andclosely-relatedvisualperceptualsymptoms(box1)arecommonindegenerativediseasesofthebrainandeye,andtheirprevalencevariesdependingontheconditionandsymptomtype.ThethreepredominantclinicalcontextsinwhichVHoccurasrepeatedepisodesoveraprolongedcoursearethe(i)dementias,(ii)Parkinson’sdisease(PD),bothinitsearlystagesandafterprogressiontoPDdementia(PDD)and(iii)eyeorvisualpathwaydisease.Prevalencevariesacrossdifferentdementiasubtypeswithrecentestimatesof55%to78%indementiawithLewybodies(DLB),32%to63%inPDD,11%to17%inAlzheimer’sdisease(AD)and5%to14%invasculardementia.1InDLB,well-formedanddetailedVHareacorefeatureandincorporatedintodiagnosticcriteria.2ThetermCharlesBonnetsyndromeisusedtodescribeVHinvisualimpairmentduetoeyeorvisualpathwaydisease,withprevalencerangingfrom15%to60%dependingonthedegreeofvisualloss.3InPD,prevalenceofVHislinkedtodiseasedurationanddopaminemedication,withamorethan80%cumulativeprevalenceovertime.4 Box1GlossaryoftermsVisualhallucination–visualperceptnotassociatedwitharealobject.Complexvisualhallucination–subtypeofvisualhallucinationwhosecontentisaformedobject,face,animal,figure,etc.Visualillusion–realobjectperceivedincorrectly.Traditionallyusedtorefertoerrorsofcategoryidentity(eg,pileofclothsseenasacat).Pareidolia–specificsubtypeofillusioninwhichfaces,objects,etc,areperceivedwhenviewingformlessvisualstimulisuchasclouds,tree-bark,flamesorinpatternedvisualstimulisuchascarpets,wallpaper.Metamorphopsia–asubtypeofillusionusedtorefertoerrorsofspatial,temporalperception(eg,seeingarealobjectdistorted,seeingarealobjectpersistintimeoratthewrongspatiallocation).Passagehallucination–animalorpersonpassing(enpassage),typicallybriefandinperipheralvisualfield.CharacteristicofParkinson’sdiseasepsychosis.Presencehallucination–senseofsomeonebeingclosebyorbesidewithoutanassociatedvisual,auditoryortactileexperience.CharacteristicofParkinson’sdiseasepsychosis.Minorhallucination–collectivetermusedinParkinson’sdiseasetodescribeillusions,passagehallucinationsandpresencehallucinations.Multimodalityhallucination–visualhallucinationcombinedwithhallucinationsinothersenses.Contentindifferentmodalitiesmaybeperceptuallyrelated(eg,figuretalkingtoyou)orperceptuallyunrelated(disembodiedvoicewithcontentunrelatedtofigure).Pseudohallucination–inneurologicalliterature,ahallucinationwithinsight.Inpsychiatricliterature,ahallucinationinthemind’seyeratherthanexternallyprojectedandrelatedtoimagery.Fullinsight–inthecontextofvisualhallucinations,anunderstandingthattheexperienceisnotreal.Insightmaybeabsentonthefirstoccasionahallucinationoccursbecauseofitscompellingnaturebutwithrepeatedinstancestheexperienceisrecognisedasfalse.Partialorfluctuatinginsight–inthecontextofvisualhallucinations,insightisvariableandfrequentlyabsentatthetimethehallucinationoccurs.Insightmayberestoredinretrospect.Secondarydelusion–afalsebeliefrelatedtothevisualhallucination(eg,peoplehavebeenletintothehouse).Secondarydelusionsimplyimpairedinsight.Todate,researchintothemechanismandtreatmentofVHhasfocussedpredominantlyonthesethreeclinicalcontexts,withtheemergenceofparallel,oftencontradictory,literature.LittleconsiderationhasbeengiventofactorscommontoeachconditionorhowmechanismsmightinteractwheneyediseasecombineswithdementiaorPD.TheNationalInstituteforHealthResearch(NIHR)fundeda5 yearresearchprogramme(SHAPED:StudyofvisualHallucinationsinParkinson’sdisease,EyediseaseandDementia)toexamineVHfromatransdiagnosticperspectivefocussingontheseconditionsandtodevelopaunifiedframeworkforclinicalmanagementbasedoncombinedcurrentbestpracticeandtreatmentevidence.Aspartofthisprogramme,weundertookanexpert-ledreviewprocessofrecentliteratureandcurrentpractice,culminatinginaworkshopheldinApril2018toformulateconsensusguidelinesfortheclinicalmanagementofVH.TheunderlyingmechanismofvisualhallucinationsTheworkgrouphighlightedtworelatedbutdistinctaspectsofVHmechanismthatmightinformtreatment.OnewaswhatbrainchangesoccuratthetimeofVH(thehallucinatingstate);theotherbeingwhatbrainchangesareassociatedwithasusceptibilitytoVH(thehallucinationtrait).Studiesofthehallucinatingstateideallyrequiretheexaminationofreal-timebrainchangescoincidentwithVH.TransientactivationofthevisualassociationcortexhasbeenfoundinCharlesBonnetsyndromearoundthetimeofonsetofVH,5whilemorewidespreadchangeshavebeenfoundinPDwithde-activationofthevisualassociationcortexandactivationofthefrontalcortex.6DifferencesinmethodologymakeitdifficulttoconcludewhetherthisreflectsadifferenceinthemechanismunderlyingtheVHstateinthesedisorders.However,mostattentionhasbeenonbrainchangesassociatedwithsusceptibilitytoVH.Therearethreemechanisticmodels:(i)disturbedbalancesbetweentop-downandbottom-upaspectsofvisualperception,(ii)chronicdeafferentationcausinghyperexcitabilitytothecorticalstructuresinvolvedinvisionand(iii)misattributionofinternalimagery.Thefirstmechanism,thePerceptionAttentionalDysfunction(PAD)modelorrelatedvariants,7–9highlightscombinedimpairmentindistributedperceptualandattentionalnetworksleadingtodisturbedbalancesbetweentop-downandbottom-upprocesses(orpriorsandsensoryevidence).ThishasespeciallybeenimplicatedintheaetiologyofhallucinationsindementiaorPDandproposesthat,incombinationwithpoorvisualperception,continuousperceptualactivityisunderconstrainedbyimpairedattentionalfocusandthatthehallucinatoryelementofasceneisnotdisconfirmedbydiscrepantvisualinput.Incontrast,thesecond,deafferentation-hyperexcitability,modelisbelievedtounderlieCharlesBonnetsyndrome,andproposeshyperexcitabilitysecondarytochronicfunctionalvisualdeafferentation,resultinginincreasedspontaneousactivitywithinthehighervisualcorticalareasleadingtoVH.10Thethirdmodel,derivedfrompsychoticdisorders,issimilartoPADinitsemphasisonunbalancedgenerativeperceptionbutproposesthathallucinations,whatevertheirmodality,resultfromafailuretocorrectlyattributeinternaleventsasinternalduetofailuresinsourcemonitoring.11 Eachmodelissupportedbyarangeofevidenceincluding:cognitive/highervisualfunctiondeficits,functionalimagingoftask-relatedactivity,restingstatemetabolismorbloodflow,cortical/whitematterchangesandalteredstructuralandfunctionalconnectivityandpostmortemneuropathology.ThefunctionalandstructuralchangesdifferbetweenstudiesofVH,bothwithinagivenconditionandacrossconditions,butmayallformpartofadistributednetwork.1213PathologyinvolvinganypartofthenetworkmayresultindysfunctionthatleadstoVH,asshownforanatomicallydistinctlesionsitescausingpeduncularhallucinations13andVHinPD.14 PostmortemevidencehasthecomplicationthatchangesidentifiedmayhavefollowedtheonsetofVHandreflectlaterdiseaseprogressionratherthantheprimarycauseofVH.Nevertheless,VHduringlifeinpatientswithdementiaisastrongpredictorofLewybody(LB)pathologyatautopsy.1516InpatientswithVHassociatedwithPDandDLB,LBpathologyisfoundintheamygdalaandparahippocampalgyrus,17superiorandlateralfrontalcortex(Brodmannarea8/9),inferior/lateraltemporalcortex(Brodmannarea20,21),inferiorparietalcortex(Brodmannarea39,40)andcingulatecortex(Brodmannarea24)(regionspooledfrom.1819)UnlikepatientswithVHinthecontextofPDwithdementia,patientswithVH,PDandrelativepreservationofcognitiondonothaveprominentcorticalorhippocampalLBinvolvement.20VHarealsolinkedtohigheramyloidandtaupathologyinfrontal,parietalandhippocampalareas,21andpatientswithPDwhogoontodevelopVHhavecerebrospinalfluid(CSF)amyloidchangesthatsuggestearlyADpathology.22InPDwithoutdementia,theoccipitallobeisrelativelyfreeofpathologywithabsentLBandtaupathologyandmildamyloidburdenirrespectiveofwhetherpatientsexperienceVH.23 NeurotransmittersystemsandVHInbothADandDLB,thereisstrongevidenceforreducedcholinergicfunctionassociatedwithmorefrequentVH.24–27ThisisconsistentwithevidencefromcaseseriesinPDandPDDsuggestingimprovementinVHwithcholinesteraseinhibitors28–30andimprovementinVH,amongotherneuropsychiatricsymptoms,inthesecondaryanalysisofalarge-scaleclinicaltrialexaminingtheeffectofcholinesteraseinhibitorsoncognition.31 NeurochemicalstudiesofCSFmetabolitessuggestanegativecorrelationbetweenthedopaminemetabolitehomovanillicacid(HVA)andVHinasmallnumberofLBDpatientsandweaknegativecorrelationswithaspartateandtaurineinAD.32OnesuggestionisthatVHsusceptibilityislinkedtoaspecific3,4-dihydro-xyphenylaceticacid-HVAmetabolicdeficit,possiblyasaresultofacommonpolymorphisminthecatechol-O-methyltransferase(COMT)gene.ThereisalsoevidenceofreducedstriataldopaminetransporterbindinginpatientswithPDwhogoontodevelopVH,thoughttoreflectdysfunctionalfrontostriatalcircuitryandalteredinhibitoryexecutivefunction33–36consistentwiththePADmodel.ThismayalsohelpexplainwhyVHinsomepatientswithPD/PDDimprovewhentheirdopaminergicloadisdroppedorpartiallyblockedwithdrugssuchasclozapineorquetiapine.PostmortemstudiesalsohighlightreductionsincholinergicandGABAactivityintheabsenceofmajorneuronalorsynapticloss,suggestingfunctionalratherthanstructuralchangesmaycontributetoVH.37InPD,increased5HT2abindinghasbeenlinkedtoVHinpostmortem38andinvivoneurotransmitterbindingstudies.39Thismayalsohelpexplainwhythe5HT2ainverseagonistpimavanseriniseffectivetreatmentforhallucinationsinPD.Insummary,researchonthemechanismofVHhaslargelybeenconfinedtostudieswithinagivenclinicalcondition,withapaucityoftransdiagnosticresearchonthewiderapplicabilityofmechanismsorinteractionsbetweenthem.ItalsoremainsunclearwhethermechanismsproposedforcomplexVHalsoapplytorelatedperceptualsymptoms(eg,illusions,presencehallucinations),orphenomenologicalvariantsofcomplexVHwithfull,partial/fluctuatingandabsentinsight.VisualhallucinationsandtheirmanagementEyediseaseCharlesBonnetsyndromeVHareassociatedwithdiseasesaffectingtheretina,lighttransmissionwithintheeye(eg,cataract,cornealopacity)orvisualpathwaysandvisualcortex.Theydonotrelatetoaspecificocularpathologysubtype40andcanoccurinmonoculardisease.Typicalphenomenologyincludessimplehallucinations(coloursandelementaryshapes)geometricalpatterns,disembodiedfacesandcostumedfigures.41CharlesBonnetsyndromeriskincreasesinpatientswithsevereimpairmentofvisualacuity.3ThefrequencyofVHoccurrenceinCharlesBonnetsyndromereducesovertime,butmorethan75%ofpatientswillcontinuetoexperiencehallucinationsbeyond5yearsaftertheironset.42Clinicalimpression,supportedbypatientsurveys43isthatCharlesBonnetsyndromeisunder-recognisedwiththefearofstigmareducingself-report.AroundathirdofCharlesBonnetsyndromepatientshavesymptomsrequiringclinicalinterventionbeyondreassuranceandeducation(negativeoutcomeCharlesBonnetsyndrome).42ComparedwithpatientswitheyediseasebutnoVH,CharlesBonnetsyndromeadverselyaffectsqualityoflife.44 CurrentpracticeForCharlesBonnetsyndrome,ophthalmologyserviceswillexplainsymptoms,reassureandsignpostforfurthersupportandself-helptechniques,withlimitedevidencefromacaseseriesthatthismayreduceVHinsomepeople.45Theself-helptechniquesaimtostophallucinationsatthetimetheyoccurandincludeeye-movements,changinglightinglevelstoincreasevisualinputandalerting/distractionstrategies.Ifclinicallysignificantthroughcausingdistress,referraltootherspecialitiesmayoccur.Astagedapproachtotreatmentisusedwithahealthscreenandmedicationreviewandoptimisationofvision(eg,cataractremoval).46ForpeoplewithVHassociatedwithacutevisuallossduetomaculardegeneration,astudyofranibizumabfoundimprovementin23%,withanassociationwithimprovedvisualacuity.47Thereiscase-reportevidencefortreatmentwithanticonvulsants,4849cholinesteraseinhibitors,505HTantagonists(ondansetron),51selectiveserotoninreuptakeinhibitors,52atypicalneuroleptics,53Yi-GanSan(aChinesetraditionalmedicinewithmultipleneurotransmittereffects)54andrepetitivetranscranialmagneticstimulation.55However,nonecanberecommendedforroutineclinicalusewithoutfurtherevidencefortheirefficacy.Parkinson’sdiseaseVHinPDformpartofaprogressivespectrumofsymptoms(PDpsychosis)thatstartwithillusions,presencehallucinationsandpassagehallucinationsandprogresstoformedhallucinations,typicallyofpeopleandanimals.56TheyareaparticularchallengeinPD,astreatmentformotorsymptomscantriggerandworsenVH.Theyareassociatedwithhighermortality,57whichmaybelinkedtoantipsychoticuse,58andareastrongerpredictorofnursinghomeplacementthancognitiveormotorsymptoms.59Thestigmaofmentalillnessmayleadtounder-reporting.60VHinPDhaveasignificantnegativeimpactoncarers,withincreasingcarerdistressasinsightintotheVHbecomesimpaired.60ComparedwithPDpatientswithoutVH,patientswithVHhavereducedqualityoflife.61 CurrentpracticeTheNICE(NationalInstituteforHealthandCareExcellence)2017guidelinesforPD62recommendastagedapproachtotreatment,typicallyundertakenwithinaPDservice.Thestartingpointisareviewofmedicalorpharmacologicaltriggersandadeliriumscreenwithadviceongeneralcopingstrategies.6364AreductioninPDmedicationmaybenecessarywhilemonitoringforworseningmotorsymptoms,dopaminewithdrawalsyndromeorneurolepticmalignantsyndrome.Medicationsshouldbewithdrawn,startingwiththosemostlikelytoprovokeVH,thatis,anticholinergics,amantadineandMAO-Binhibitors,followedbydopamineagonistsandCOMTinhibitors.IfVHpersist,thecautiouswithdrawaloflevodopamayhelp.6566Ifthesestrategiesarenoteffective,antipsychoticmedicationsmaybeconsidered.67Severalrandomisedcontrolledtrials(RCTs)haveshownclozapinetobeefficacious,withbenefitforVHwithoutworseningmotorsymptoms.6869Quetiapineismorewidelyusedthanclozapine,butthereislessevidenceofefficacy.70–73Pimavanserin,anovelantipsychoticwithpotentinverseagonistactivityonthe5HT2Areceptor,hasemergedasanewpotentialtherapy,withtwopositiveRCTs.Meltzeretal 74reportedreducedVH,andCummingsetal 75reportedimprovementsonpsychosisscoresandcaregiverstress.PimavanserinislicensedasatreatmentforPDpsychosisintheUSA.RivastigmineanddonepezilareusedtotreatcognitiveimpairmentinPDandmayalsohelpreduceVH,28–30althoughtodatetherearenoRCTsofcholinesteraseinhibitorsusingVHasaprimaryendpoint.DementiaVHindementiatendtobeofpeople/children,animalsorobjects.76Around50%ofpatientsaresignificantlydistressedbytheirexperiences,withfearandangerbeingthemostcommonresponses.77AscoredefiningfeaturesofDLB,theyarelikelytobepresentatthepointofdiagnosis,contrastingwithADwhereVHoccurinlaterstagesofcognitivedecline,5to6yearsaftertheonsetofdementia.78VHareassociatedwithincreasedlikelihoodofnursinghomeplacement.79AsinPD,carerimpactincreaseswhenpatientinsightbecomesimpaired.60 CurrentpracticeVHaremanagedwithindementiaservicesinthewidercontextofneuropsychiatricsymptoms.Astagedapproachisusedwithaphysicalhealthreview,excludingdeliriumandothermedicalconditionsthatcancauseVH,andmedicationreviewtoreduce/stopdrugswhichmaycauseorexacerbateVH.Antipsychoticsmayhavebenefit80butpotentialadverseeffectsofsevereantipsychoticsensitivityandmortalitymeanthattheyshouldbeusedcautiouslyinLBD.Thereissomeevidencecholinesteraseinhibitorsreduceneuropsychiatricsymptoms,includingVH.263181HighdosecholinesteraseinhibitorshavebeenshowntoreducethefrequencyofVHinLBDbutwithincreasedsideeffects,needingcarefultitrationunderexpertsupervision.82Astudyofmemantinefoundreducedhallucinations(which,althoughnotsubdividedbyhallucinationmodality,wouldhavemainlybeenVH)inDLBafter24weekstreatment.83TranscranialmagneticstimulationandtranscranialdirectstimulationhavebeensuggestedasapproachesforVHinLBD,butstudiestodatehavenotshownbenefit.84 ComorbiddiseaseStudiesofVHinPDordementiatypicallyexcludepatientswitheyediseasesothereislimiteddataontheprevalence,phenomenologyormanagementofVHinthecontextofcomorbideyedisease.EyediseasemayresultinanearlieronsetofVHindementia,resultinginthemisdiagnosisofADasDLB.85InPD,eyediseasedetectablebygeneralophthalmologicalexaminationisnotassociatedwithVH;1886however,moredetailedtestingwithretinalimaginghasfoundreducedretinalnervefibrelayerthicknessinPDpatientswithVH.86SomepatientspresentingwithCharlesBonnetsyndrometoophthalmologyclinicsmayhaveunrecogniseddementiacharacterisedbypartialorfluctuatinginsightintoVH.87CasereportevidencesuggeststhatoptimisingvisionmayhelpreduceVHindementia.88 DiscussionTheabsenceofanoverarchingmodelforVHindifferentdisordersorevidence-basedtreatmentslimitedthescopeoftherecommendationstheworkgroupcouldmake.ThefocusoftheNIHRprogrammeonPD,dementiaandeyediseasealsomeantthatVHinotherclinicalandnon-clinicalcontextswerenotcovered(schizophrenia/bipolardisorder(s1);bereavement(s2);delirium(s3);sleep-related,medication,36hallucinogenuse(s4);peduncularhallucinations(s5);epilepsy(s6tos7);migraine(s8);visualsnowsyndrome(s9)-seetable1).However,theconsensusviewwasthatwheretreatmentwasindicatedfortheseotherconditions,similaritiesincurrentpracticeacrossthecoredisorderscouldlogicallybeextendedtoallconditions.Belowwehighlightkeyconsiderations,thegeneralframeworkformanagingVHandrelatedsymptoms,andareasforfutureresearch.Viewthistable:Viewinline Viewpopup Table1Visualhallucinationsinwiderclinicalandnon-clinicalcontextCaseidentificationWhatevertheunderlyingcondition,helpcanonlybeprovidedforpatientswithVHifthesesymptomshavebeenidentifiedbytheirclinicalteam.Theworkgroupidentifiedtheneedtoaddresscontinuingstigmaofself-reportingsymptomsperceivedasindicatorsofmentalillnessordementia.Evidencefromeyediseasethatpre-emptivewarningmaybeeffectiveinreducingdistressoremotionalimpactatVHonset42suggeststhatlow-levelinformationaboutthepossiblefutureoccurrenceofVHshouldbeprovidedatthepointofeyedisease,dementiaorPDdiagnosis,withsignpostingtomoredetailedinformationwhichcanbeaccessedatalaterstage.SystematicenquiryabouttheoccurrenceofVHshouldbepartofroutinefollow-uptohelpshareresponsibilityforidentifyingVHbetweenthepatientandcareteam.ThresholdforspecifictreatmentinterventionTheworkgroupnotedthatVHthatarenotdistressingforthepatientorcarerdonotneedtreatmentbeyondgeneralmeasures,psychoeducationandhelpinadapting,acceptingandlivingwellwithsymptoms.Typically,thisbenignVHphaseoccursearlyinthedisease,highlightingtheimportanceofkeepingVHunderreview.Animportantfactordefiningthethresholdatwhichinterventionisrequiredmaybethetransitionfromfullinsighttopartialorfluctuatinginsight,wherethepatientrespondstoVHasiftheyarerealatthetimetheyoccur,evenifinsightisrestoredaftertheevent.Thisinsight-relatedphenomenologicaldistinctioncorrespondstothatintheneurologicalliteraturebetweenpseudohallucinations(definedbyintactinsight)andhallucinationswithoutinsight.Theterminologyisunsatisfactoryaspseudohallucinationscarrydifferentimplicationsinthepsychiatricliterature;however,theconceptualdistinctionbetweenVHwithinsightintactincontrasttopartial,fluctuatingandabsentinsightstatesisworthrevisitingasithelpsmarkatransitionpointfortreatmentneedinallconditions.Theworkgroupalsonotedexceptionstotheassociationbetweeninsightandtreatmentneed,forexample,interventionmightberequiredinthepresenceoffull,continuousinsightwhereVHcontentisitselfdistressingorVHbecomesointrusivetheylimitfunction.CarersandVHAnotherfeatureofVHcommontodifferentconditionsistheneedtoalsoconsidertheirimpactoncarers.FactorsmediatingtheincreasedriskofcarehomeplacementwithVHareunclearbutmayincludecarerdistresscausedindirectlybyVH.TheconsensusviewwasthatthetreatmentofVHshouldextendbeyondthepatienttoprovidesupportandadviceforthecarer.ConsensusframeworkforthemanagementofVHThegeneralframeworkformanagingVHandrelatedsymptomsissummarisedinfigure1.Itbeginsbeforetheonsetofhallucinationswithforewarningandpre-emptivequestioningtoencouragetheirreporting.OnceVHareidentified,astagedapproachissuggestedwithareviewofcognitiveandophthalmologicalhealthaswellasaphysicalhealth/deliriumscreen.Medicationshouldbereviewed,focussingonanti-muscarinicandopiatedrugsand,inPD,dopaminergictherapy.Supportincludingreassurance,psychoeducation,normalisation(explainingVHarepartofadiseaseandhaveabasisinbrainfunction)andoptimisationofvisualfunctioningshouldbeoffered.Thisshouldbeperson-centred,identifyingtheparticulartriggersandsettingsthatincreasetheriskofVHandavoidingthesesituationsbyplanningalternativemeaningfulandrewardingactivities.Downloadfigure Openinnewtab Downloadpowerpoint Figure1Theconsensusframeworkforthemanagementofvisualhallucinationsindifferentconditions.Recommendationsnotsupportedbymeta-analysisareindicatedinwhite.Orangeboxesindicatehallucinationcharacteristicsandtherapeutictargets.AD,Alzheimer’sdisease;CBS,CharlesBonnetsyndrome;CBT,cognitivebehaviouraltherapy;DLB,dementiawithLewybodies;PD,Parkinson’sdisease;PDD,PDdementia.VHthatbecomeclinicallysignificantbycausingdistresstothepatientortheircarersrequirefurtherintervention.Giventhecurrentlimitationsinbothourunderstandingoftheunderlyingmechanism(s)ofVHsusceptibilityortheneurophysiologicalchangescoincidentwithVHandtheclinicaltrialevidencebase,theworkgroupwereunabletomakedefinitivemedicationrecommendations.Thereisatheoreticalbasisforpharmacologicalinterventionstargetingcholinergic,GABAergic,serotonergicordopaminergicsystemsandforreducingcorticalexcitabilitythroughnon-invasivestimulationoranticonvulsantmedication.Treatmentmightaimtoreverselong-termchangesassociatedwithVHsusceptibilityortoreducethefrequencyordurationoftransientchangescoincidentwithVH.FuturedirectionsTheworkinggroupnotedanimportantmethodologicalchallengeforclinicaltrialsormechanisticstudiesisthelackofaccepted,validated,ratingscalesforVHorrelatedsymptoms.Thereisaclearneedtodevelopbettermetricswhichextendbeyondretrospectivecollectionofquestionnaireorscaledatatoreal-worldcollectionofVHastheyoccurusing,forexample,newmobiletechnologyorreal-timefunctionaldatathroughdevelopmentsinelectroencephalogramtelemetry.MeasuresofVHsusceptibilityarealsorequired,suchaspareidoliatestsdevelopedforDLB.8990Giventheimportanceofinsightanditscontinuityatthedecisionpointforspecificintervention,bettermeasuresofinsightwhicharesensitivetopartialorfluctuatingstatesarerequired,aswellasstudiesofthecognitivecontextinwhichinsightbecomesimpaired,forexample,generalisedcognitivedeclineordeclineinspecificcognitivefunctionssuchasself-monitoringorsymptom-awareness.91 Forclinicaltrials,theworkgrouphighlightedthelackofstandardisationofVH-relatedoutcomemeasuresandtheneedfortrialstakingatransdiagnostic,mechanism-basedperspectivetocomplementevidencefromthetraditionalcondition-specifictrials.ItremainstobeestablishedwhetherasingletreatmentapproachwillbeeffectiveinallconditionsorwhetherdifferenttreatmentswillberequiredwithfurtherstudiesneededtoelucidatetheunderlyingmechanismofVHfromatransdiagnosticperspectiveandtheroleofdysfunctionaldistributedbrainnetworks.Clinicaltrialsfornon-pharmacologicalapproachesarealsorequired,inparticulartheroleofpsychologicaltherapiessuchasrescripting,imagerytransformation,desensitisation,cognitivebehaviouraltherapytargetingpatient-carerdyadsandnon-invasivebrainstimulation.Bothmedicationandnon-pharmacologicaltrialsmighttargetlonger-termsusceptibilityortransientchanges,eitherseparatelyorincombination.ConclusionsAlthoughtheclinicalimportanceofVHandrelatedsymptomshaslongbeenrecognised,theevidence-basefortheirpathophysiologyortreatmentislimitedandfocussesonsingleconditions.Awiderperspectiveisrequired,highlightingkeysimilaritiesanddifferencesbetweenconditionsandtakingintoaccountbrainchangesconferringsusceptibilitytosuchsymptomsaswellasthosecoincidentwiththeiroccurrence.Inadvanceofsuchdevelopments,theworkgroupconcludedthattreatmentofVH,irrespectiveoftheirclinicalcontext,wouldbenefitfromacommonmanagementframeworkandsharedprioritiesforfutureresearch.Additionalreferencesarepresentinonlinesupplementaryfile1.Supplementalmaterial [jnnp-2019-322702supp001.pdf] AcknowledgmentsWethanktheNIHRNewcastle,Cambridge,UCLHandSLAMBiomedicalResearchCentres;JOBandRABaresupportedbyanNIHRSeniorInvestigatorawardandtheCambridgeCentreforParkinson’sPlusdisorders.References↵ CummingsJ , BallardC , TariotP ,etal .Pimavanserin:potentialtreatmentforDementia-Relatedpsychosis.JPrevAlzheimersDis2018;5:253–8.doi:10.14283/jpad.2018.29 OpenUrl↵ McKeithIG , BoeveBF , DicksonDW ,etal .DiagnosisandmanagementofdementiawithLewybodies:fourthconsensusreportoftheDLBConsortium.Neurology2017;89:88–100.doi:10.1212/WNL.0000000000004058 OpenUrl↵ ffytcheDH .Visualhallucinationsineyedisease.CurrOpinNeurol2009;22:28–35.doi:10.1097/WCO.0b013e32831f1b3f OpenUrlCrossRefPubMed↵ GibsonG , MottramPG , BurnDJ ,etal .Frequency,prevalence,incidenceandriskfactorsassociatedwithvisualhallucinationsinasampleofpatientswithParkinson'sdisease:alongitudinal4-yearstudy.IntJGeriatrPsychiatry2013;28:626–31.doi:10.1002/gps.3869 OpenUrlPubMed↵ ffytcheDH , HowardRJ , BrammerMJ ,etal .Theanatomyofconsciousvision:anfMRIstudyofvisualhallucinations.NatNeurosci1998;1:738–42.doi:10.1038/3738 OpenUrlCrossRefPubMedWebofScience↵ StebbinsGT , GoetzCG , CarrilloMC ,etal .AlteredcorticalvisualprocessinginPDwithhallucinations:anfMRIstudy.Neurology2004;63:1409–16.doi:10.1212/01.WNL.0000141853.27081.BD OpenUrlCrossRefPubMed↵ CollertonD , PerryE , McKeithI .Whypeopleseethingsthatarenotthere:anovelperceptionandattentiondeficitmodelforrecurrentcomplexvisualhallucinations.BehavBrainSci2005;28:737–57.doi:10.1017/S0140525X05000130 OpenUrlPubMedWebofScience↵ ShineJM , O'CallaghanC , HallidayGM ,etal .Tricksofthemind:visualhallucinationsasdisordersofattention.ProgNeurobiol2014;116:58–65.doi:10.1016/j.pneurobio.2014.01.004 OpenUrlCrossRefPubMed↵ ZarkaliA , AdamsRA , PsarrasS ,etal .IncreasedweightingonpriorknowledgeinLewybody-associatedvisualhallucinations.BrainCommun2019;1:fcz007.doi:10.1093/braincomms/fcz007 OpenUrl↵ BurkeW .TheneuralbasisofCharlesBonnethallucinations:ahypothesis.JNeurolNeurosurgPsychiatry2002;73:535–41.doi:10.1136/jnnp.73.5.535 OpenUrlAbstract/FREEFullText↵ AllenP , LarøiF , McGuirePK ,etal .Thehallucinatingbrain:areviewofstructuralandfunctionalneuroimagingstudiesofhallucinations.NeurosciBiobehavRev2008;32:175–91.doi:10.1016/j.neubiorev.2007.07.012 OpenUrlCrossRefPubMedWebofScience↵ CarterR , ffytcheDH .Onvisualhallucinationsandcorticalnetworks:atrans-diagnosticreview.JNeurol2015;262:1780–90.doi:10.1007/s00415-015-7687-6 OpenUrl↵ BoesAD , PrasadS , LiuH ,etal .Networklocalizationofneurologicalsymptomsfromfocalbrainlesions.Brain2015;138:3061–75.doi:10.1093/brain/awv228 OpenUrlCrossRefPubMed↵ WeilRS , HsuJK , DarbyRR ,etal .NeuroimaginginParkinson'sdiseasedementia:connectingthedots.BrainCommun2019;1:fcz006.doi:10.1093/braincomms/fcz006 OpenUrl↵ TiraboschiP , SalmonDP , HansenLA ,etal .WhatbestdifferentiatesLewybodyfromAlzheimer'sdiseaseinearly-stagedementia?Brain2006;129:729–35.doi:10.1093/brain/awh725 OpenUrlCrossRefPubMedWebofScience↵ ToledoJB , CairnsNJ , DaX ,etal .ClinicalandmultimodalbiomarkercorrelatesofADNIneuropathologicalfindings.ActaNeuropatholCommun2013;1:65.doi:10.1186/2051-5960-1-65 OpenUrl↵ HardingAJ , BroeGA , HallidayGM .VisualhallucinationsinLewybodydiseaserelatetoLewybodiesinthetemporallobe.Brain2002;125:391–403.doi:10.1093/brain/awf033 OpenUrlCrossRefPubMedWebofScience↵ GallagherDA , ParkkinenL , O'SullivanSS ,etal .TestinganaetiologicalmodelofvisualhallucinationsinParkinson'sdisease.Brain2011;134:3299–309.doi:10.1093/brain/awr225 OpenUrlCrossRefPubMed↵ PapapetropoulosS , McCorquodaleDS , GonzalezJ ,etal .CorticalandamygdalarLewybodyburdeninParkinson'sdiseasepatientswithvisualhallucinations.ParkinsonismRelatDisord2006;12:253–6.doi:10.1016/j.parkreldis.2005.10.005 OpenUrlCrossRefPubMedWebofScience↵ HardingAJ , StimsonE , HendersonJM ,etal .ClinicalcorrelatesofselectivepathologyintheamygdalaofpatientswithParkinson'sdisease.Brain2002;125:2431–45.doi:10.1093/brain/awf251 OpenUrlCrossRefPubMedWebofScience↵ JacobsonSA , MorshedT , DuggerBN ,etal .PlaquesandtanglesaswellasLewy-typealphasynucleinopathyareassociatedwithformedvisualhallucinations.ParkinsonismRelatDisord2014;20:1009–14.doi:10.1016/j.parkreldis.2014.06.018 OpenUrl↵ ffytcheDH , PereiraJB , BallardC ,etal .RiskfactorsforearlypsychosisinPD:insightsfromtheParkinson'sprogressionmarkersinitiative.JNeurolNeurosurgPsychiatry2017;88:325–31.doi:10.1136/jnnp-2016-314832 OpenUrlAbstract/FREEFullText↵ KalaitzakisME , ChristianLM , MoranLB ,etal .DementiaandvisualhallucinationsassociatedwithlimbicpathologyinParkinson'sdisease.ParkinsonismRelatDisord2009;15:196–204.doi:10.1016/j.parkreldis.2008.05.007 OpenUrlCrossRefPubMedWebofScience↵ CourtJA , BallardCG , PiggottMA ,etal .VisualhallucinationsareassociatedwithloweralphabungarotoxinbindingindementiawithLewybodies.PharmacolBiochemBehav2001;70:571–9.doi:10.1016/S0091-3057(01)00644-X OpenUrlCrossRefPubMed↵ HeppDH , RuiterAM , GalisY ,etal .PedunculopontinecholinergiccelllossinhallucinatingParkinsondiseasepatientsbutnotindementiawithLewybodiespatients.JNeuropatholExpNeurol2013;72:1162–70.doi:10.1097/NEN.0000000000000014 OpenUrlCrossRefPubMed↵ SatohM , IshikawaH , MeguroK ,etal .ImprovedvisualhallucinationbydonepezilandoccipitalglucosemetabolismindementiawithLewybodies:theOsaki-Tajiriproject.EurNeurol2010;64:337–44.doi:10.1159/000322121 OpenUrlCrossRefPubMed↵ TeaktongT , PiggottMA , MckeithIG ,etal .MuscarinicM2andM4receptorsinanteriorcingulatecortex:relationtoneuropsychiatricsymptomsindementiawithLewybodies.BehavBrainRes2005;161:299–305.doi:10.1016/j.bbr.2005.02.019 OpenUrlPubMed↵ BullockR , CameronA .RivastigmineforthetreatmentofdementiaandvisualhallucinationsassociatedwithParkinson'sdisease:acaseseries.CurrMedResOpin2002;18:258–64.doi:10.1185/030079902125000813 OpenUrlCrossRefPubMedWebofScience↵ SobowT .Parkinson'sdisease-relatedvisualhallucinationsunresponsivetoatypicalantipsychoticstreatedwithcholinesteraseinhibitors:acaseseries.NeurolNeurochirPol2007;41:276–9.OpenUrlPubMed↵ KuritaA , OchiaiY , KonoY ,etal .ThebeneficialeffectofdonepezilonvisualhallucinationsinthreepatientswithParkinson'sdisease.JGeriatrPsychiatryNeurol2003;16:184–8.doi:10.1177/0891988703256054 OpenUrlCrossRefPubMedWebofScience↵ BurnD , EmreM , McKeithI ,etal .EffectsofrivastigmineinpatientswithandwithoutvisualhallucinationsindementiaassociatedwithParkinson'sdisease.MovDisord2006;21:1899–907.doi:10.1002/mds.21077 OpenUrlCrossRefPubMedWebofScience↵ VermeirenY , LeBastardN , VanHemelrijckA ,etal .Behavioralcorrelatesofcerebrospinalfluidaminoacidandbiogenicamineneurotransmitteralterationsindementia.AlzheimersDement2013;9:488–98.doi:10.1016/j.jalz.2012.06.010 OpenUrl↵ RavinaB , MarekK , EberlyS ,etal .Dopaminetransporterimagingisassociatedwithlong-termoutcomesinParkinson'sdisease.MovDisord2012;27:1392–7.doi:10.1002/mds.25157 OpenUrlCrossRefPubMed↵ JaakkolaE , JoutsaJ , MäkinenE ,etal .VentralstriataldopaminergicdefectisassociatedwithhallucinationsinParkinson'sdisease.EurJNeurol2017;24:1341–7.doi:10.1111/ene.13390 OpenUrl↵ KiferleL , CeravoloR , GiuntiniM ,etal .Caudatedopaminergicdenervationandvisualhallucinations:evidencefroma¹²³I-FP-CITSPECTstudy.ParkinsonismRelatDisord2014;20:761–5.doi:10.1016/j.parkreldis.2014.04.006 OpenUrl↵ DaveS , WeintraubD , AarslandD ,etal .DruganddiseaseeffectsinParkinson'spsychosis:revisitingtheroleofdopamine.MovDisordClinPract2020;7:32–6.doi:10.1002/mdc3.12851 OpenUrl↵ KhundakarAA , HansonPS , ErskineD ,etal .AnalysisofprimaryvisualcortexindementiawithLewybodiesindicatesGABAergicinvolvementassociatedwithrecurrentcomplexvisualhallucinations.ActaNeuropatholCommun2016;4:66.doi:10.1186/s40478-016-0334-3 OpenUrl↵ HuotP , JohnstonTH , DarrT ,etal .Increased5-HT2Areceptorsinthetemporalcortexofparkinsonianpatientswithvisualhallucinations.MovDisord2010;25:1399–408.doi:10.1002/mds.23083 OpenUrlCrossRefPubMedWebofScience↵ BallangerB , StrafellaAP , vanEimerenT ,etal .Serotonin2AreceptorsandvisualhallucinationsinParkinsondisease.ArchNeurol2010;67:416–21.doi:10.1001/archneurol.2010.35 OpenUrlCrossRefPubMedWebofScience↵ AbbottEJ , ConnorGB , ArtesPH ,etal .Visuallossandvisualhallucinationsinpatientswithage-relatedmaculardegeneration(CharlesBonnetsyndrome).InvestOphthalmolVisSci2007;48:1416–23.doi:10.1167/iovs.06-0942 OpenUrlAbstract/FREEFullText↵ SanthouseAM , HowardRJ , ffytcheDH .Visualhallucinatorysyndromesandtheanatomyofthevisualbrain.Brain2000;123:2055–64.doi:10.1093/brain/123.10.2055 OpenUrlCrossRefPubMedWebofScience↵ CoxTM , ffytcheDH .NegativeoutcomeCharlesBonnetsyndrome.BrJOphthalmol2014;98:1236–9.doi:10.1136/bjophthalmol-2014-304920 OpenUrlAbstract/FREEFullText↵ MenonGJ .Complexvisualhallucinationsinthevisuallyimpaired:astructuredhistory-takingapproach.ArchOphthalmol2005;123:349–55.doi:10.1001/archopht.123.3.349 OpenUrlCrossRefPubMedWebofScience↵ ScottIU , ScheinOD , FeuerWJ ,etal .Visualhallucinationsinpatientswithretinaldisease.AmJOphthalmol2001;131:590–8.doi:10.1016/S0002-9394(01)00833-9 OpenUrlCrossRefPubMedWebofScience↵ CrumblissKE , TaussigMJ , JayWM .VisionrehabilitationandCharlesBonnetsyndrome.SeminOphthalmol2008;23:121–6.doi:10.1080/08820530801888170 OpenUrlCrossRefPubMed↵ JefferisJM , ClarkeMP , TaylorJ-P .Effectofcataractsurgeryoncognition,mood,andvisualhallucinationsinolderadults.JCataractRefractSurg2015;41:1241–7.doi:10.1016/j.jcrs.2014.09.044 OpenUrl↵ SinghA , SørensenTL .CharlesBonnetsyndromeimproveswhentreatmentiseffectiveinage-relatedmaculardegeneration.BrJOphthalmol2011;95:291–2.doi:10.1136/bjo.2010.179465 OpenUrlFREEFullText↵ HolroydS , SabeenS .Successfultreatmentofhallucinationsassociatedwithsensoryimpairmentusinggabapentin.JNeuropsychiatryClinNeurosci2008;20)::364–6.doi:10.1176/jnp.2008.20.3.364 OpenUrlCrossRefPubMed↵ HostyG .CharlesBonnetsyndrome:adescriptionoftwocases.ActaPsychiatrScand1990;82:316–7.doi:10.1111/j.1600-0447.1990.tb01392.x OpenUrlPubMedWebofScience↵ BurkeWJ , RoccaforteWH , WengelSP .Treatingvisualhallucinationswithdonepezil.AmJPsychiatry1999;156:1117–8.doi:10.1176/ajp.156.7.1117a OpenUrlPubMedWebofScience↵ NevinsM .CharlesBonnetsyndrome.JAmGeriatrSoc1997;45:894–5.doi:10.1111/j.1532-5415.1997.tb01526.x OpenUrlPubMedWebofScience↵ BergmanY , BarakY .Escitalopramforantipsychoticnonresponsivevisualhallucinosis:eightpatientssufferingfromCharlesBonnetsyndrome.IntPsychogeriatr2013;25:1433–6.doi:10.1017/S1041610213000719 OpenUrl↵ MaedaK , ShirayamaY , NukinaS ,etal .CharlesBonnetsyndromewithvisualhallucinationsofchildhoodexperience:successfultreatmentof1patientwithrisperidone.JClinPsychiatry2003;64:1131–2.OpenUrlPubMedWebofScience↵ MiyaokaT , FuruyaM , KristianL ,etal .Yi-ganSanfortreatmentofCharlesBonnetsyndrome(visualhallucinationduetovisionloss):anopen-labelstudy.ClinNeuropharmacol2011;34:24–7.doi:10.1097/WNF.0b013e318206785a OpenUrlPubMed↵ MerabetLB , KobayashiM , BartonJ ,etal .Suppressionofcomplexvisualhallucinatoryexperiencesbyoccipitaltranscranialmagneticstimulation:acasereport.Neurocase2003;9:436–40.doi:10.1076/neur.9.5.436.16557 OpenUrlCrossRefPubMedWebofScience↵ ffytcheDH , CreeseB , PolitisM ,etal .ThepsychosisspectruminParkinsondisease.NatRevNeurol2017;13:81–95.doi:10.1038/nrneurol.2016.200 OpenUrl↵ GoetzCG , StebbinsGT .MortalityandhallucinationsinnursinghomepatientswithadvancedParkinson'sdisease.Neurology1995;45:669–71.doi:10.1212/WNL.45.4.669 OpenUrlCrossRefPubMed↵ WeintraubD , ChiangC , KimHM ,etal .AssociationofantipsychoticusewithmortalityriskinpatientswithParkinsondisease.JAMANeurol2016;73:535–41.doi:10.1001/jamaneurol.2016.0031 OpenUrl↵ GoetzCG , StebbinsGT .RiskfactorsfornursinghomeplacementinadvancedParkinson'sdisease.Neurology1993;43:2227–9.doi:10.1212/WNL.43.11.2227 OpenUrlCrossRefPubMed↵ RenoufS , FfytcheD , PintoR ,etal .VisualhallucinationsindementiaandParkinson'sdisease:aqualitativeexplorationofpatientandcaregiverexperiences.IntJGeriatrPsychiatry2018;33:1327–34.doi:10.1002/gps.4929 pmid:http://www.ncbi.nlm.nih.gov/pubmed/29953689 OpenUrlPubMed↵ McKinlayA , GraceRC , Dalrymple-AlfordJC ,etal .AprofileofneuropsychiatricproblemsandtheirrelationshiptoqualityoflifeforParkinson'sdiseasepatientswithoutdementia.ParkinsonismRelatDisord2008;14:37–42.doi:10.1016/j.parkreldis.2007.05.009 OpenUrlCrossRefPubMedWebofScience↵NICE.Parkinson'sdiseaseinadults2017.↵ DiederichNJ , PieriV , GoetzCG .CopingstrategiesforvisualhallucinationsinParkinson'sdisease.MovDisord2003;18:831–2.doi:10.1002/mds.10450 OpenUrlCrossRefPubMedWebofScience↵ MuellerC , RajkumarAP , WanYM ,etal .AssessmentandmanagementofneuropsychiatricsymptomsinParkinson'sdisease.CNSDrugs2018;32:621–35.doi:10.1007/s40263-018-0540-6 OpenUrl↵ ConnollyBS , LangAE .PharmacologicaltreatmentofParkinsondisease:areview.JAMA2014;311:1670–83.doi:10.1001/jama.2014.3654 OpenUrlCrossRefPubMedWebofScience↵ DiederichNJ , FénelonG , StebbinsG ,etal .HallucinationsinParkinsondisease.NatRevNeurol2009;5:331–42.doi:10.1038/nrneurol.2009.62 OpenUrlCrossRefPubMed↵ WilbyKJ , JohnsonEG , JohnsonHE ,etal .Evidence-BasedreviewofpharmacotherapyusedforParkinson'sdiseasepsychosis.AnnPharmacother2017;51:682–95.doi:10.1177/1060028017703992 OpenUrl↵ PollakP , TisonF , RascolO ,etal .ClozapineindruginducedpsychosisinParkinson'sdisease:arandomised,placebocontrolledstudywithopenfollowup.JNeurolNeurosurgPsychiatry2004;75:689–95.doi:10.1136/jnnp.2003.029868 OpenUrlAbstract/FREEFullText↵ParkinsonStudyGroup.Low-Doseclozapineforthetreatmentofdrug-inducedpsychosisinParkinson'sdisease.NEnglJMed1999;340:757–63.doi:10.1056/NEJM199903113401003 OpenUrlCrossRefPubMedWebofScience↵ OndoWG , TintnerR , VoungKD ,etal .Double-Blind,placebo-controlled,unforcedtitrationparalleltrialofquetiapinefordopaminergic-inducedhallucinationsinParkinson'sdisease.MovDisord2005;20:958–63.doi:10.1002/mds.20474 OpenUrlCrossRefPubMedWebofScience↵ ShotboltP , SamuelM , FoxC ,etal .ArandomizedcontrolledtrialofquetiapineforpsychosisinParkinson'sdisease.NeuropsychiatrDisTreat2009;5:327–32.doi:10.2147/NDT.S5335 OpenUrlPubMed↵ RabeyJM , ProkhorovT , MiniovitzA ,etal .EffectofquetiapineinpsychoticParkinson'sdiseasepatients:adouble-blindlabeledstudyof3months'duration.MovDisord2007;22:313–8.doi:10.1002/mds.21116 OpenUrlCrossRefPubMedWebofScience↵ FernandezHH , OkunMS , RodriguezRL ,etal .QuetiapineimprovesvisualhallucinationsinParkinsondiseasebutnotthroughnormalizationofsleeparchitecture:resultsfromadouble-blindclinical-polysomnographystudy.IntJNeurosci2009;119:2196–205.doi:10.3109/00207450903222758 OpenUrlCrossRefPubMed↵ MeltzerHY , MillsR , RevellS ,etal .Pimavanserin,aserotonin(2A)receptorinverseagonist,forthetreatmentofparkinson'sdiseasepsychosis.Neuropsychopharmacology2010;35:881–92.doi:10.1038/npp.2009.176 OpenUrlCrossRefPubMedWebofScience↵ CummingsJ , IsaacsonS , MillsR ,etal .PimavanserinforpatientswithParkinson'sdiseasepsychosis:arandomised,placebo-controlledphase3trial.Lancet2014;383:533–40.doi:10.1016/S0140-6736(13)62106-6 OpenUrlCrossRefPubMed↵ UrwylerP , NefT , MüriR ,etal .VisualhallucinationsineyediseaseandLewybodydisease.AmJGeriatrPsychiatry2016;24:350–8.doi:10.1016/j.jagp.2015.10.007 OpenUrl↵ CollertonD , TaylorJ-P .Advancesinthetreatmentofvisualhallucinationsinneurodegenerativediseases.FutureNeurol2013;8:433–44.doi:10.2217/fnl.13.19 OpenUrl↵ HopeT , KeeneJ , FairburnCG ,etal .NaturalhistoryofbehaviouralchangesandpsychiatricsymptomsinAlzheimer'sdisease.Alongitudinalstudy.BrJPsychiatry1999;174:39–44.doi:10.1192/bjp.174.1.39 OpenUrlAbstract/FREEFullText↵ SternY , TangMX , AlbertMS ,etal .PredictingtimetonursinghomecareanddeathinindividualswithAlzheimerdisease.JAMA1997;277:806–12.doi:10.1001/jama.1997.03540340040030 OpenUrlCrossRefPubMedWebofScience↵ TampiRR , TampiDJ , BalachandranS ,etal .Antipsychoticuseindementia:asystematicreviewofbenefitsandrisksfrommeta-analyses.TherAdvChronicDis2016;7:229–45.doi:10.1177/2040622316658463 OpenUrlCrossRef↵ MoriT , IkedaM , FukuharaR ,etal .CorrelationofvisualhallucinationswithoccipitalrCBFchangesbydonepezilinDLB.Neurology2006;66:935–7.doi:10.1212/01.wnl.0000203114.03976.b0 OpenUrl↵ PakrasiS , ThomasA , MosimannUP ,etal .CholinesteraseinhibitorsinadvanceddementiawithLewybodies:increaseorstop?IntJGeriatrPsychiatry2006;21:719–21.doi:10.1002/gps.1547 OpenUrlPubMed↵ EmreM , TsolakiM , BonuccelliU ,etal .MemantineforpatientswithParkinson'sdiseasedementiaordementiawithLewybodies:arandomised,double-blind,placebo-controlledtrial.LancetNeurol2010;9:969–77.doi:10.1016/S1474-4422(10)70194-0 OpenUrlCrossRefPubMedWebofScience↵ ElderGJ , CollobySJ , FirbankMJ ,etal .ConsecutivesessionsoftranscranialdirectcurrentstimulationdonotremediatevisualhallucinationsinLewybodydementia:arandomisedcontrolledtrial.AlzheimersResTher2019;11:9.doi:10.1186/s13195-018-0465-9 OpenUrl↵ SkogsethR , HortobágyiT , SoennesynH ,etal .AccuracyofclinicaldiagnosisofdementiawithLewybodiesversusneuropathology.JAlzheimersDis2017;59:1139–52.doi:10.3233/JAD-170274 OpenUrl↵ LeeJ-Y , KimJM , AhnJ ,etal .RetinalnervefiberlayerthicknessandvisualhallucinationsinParkinson'sdisease.MovDisord2014;29:61–7.doi:10.1002/mds.25543 OpenUrlCrossRefPubMed↵ RussellG , BurnsA .CharlesBonnetsyndromeandcognitiveimpairment:asystematicreview.IntPsychogeriatr2014;26:1431–43.doi:10.1017/S1041610214000763 OpenUrl↵ ChapmanFM , DickinsonJ , McKeithI ,etal .Associationamongvisualhallucinations,visualacuity,andspecificeyepathologiesinAlzheimer'sdisease:treatmentimplications.AmJPsychiatry1999;156:1983–5.doi:10.1176/ajp.156.12.1983 OpenUrlPubMedWebofScience↵ YokoiK , NishioY , UchiyamaM ,etal .Hallucinatorsfindmeaninginnoises:pareidolicillusionsindementiawithLewybodies.Neuropsychologia2014;56:245–54.doi:10.1016/j.neuropsychologia.2014.01.017 OpenUrlCrossRefPubMedWebofScience↵ UchiyamaM , NishioY , YokoiK ,etal .Pareidolias:complexvisualillusionsindementiawithLewybodies.Brain2012;135:2458–69.doi:10.1093/brain/aws126 OpenUrlCrossRefPubMedWebofScience↵ ShadMU , KeshavanMS , TammingaCA ,etal .Neurobiologicalunderpinningsofinsightdeficitsinschizophrenia.IntRevPsychiatry2007;19:437–46.doi:10.1080/09540260701486324 OpenUrlCrossRefPubMed FootnotesTwitter@CambridgePsychiatry:@psychiatry_ucam.OldAgePsychiatryKing'sCollegeLondon:@KCL_OAPNIHR.NewcastleBRC:@NIHRNewcBRC.LewyBodyLab:@LewyBodyLab,@rimonaweilContributorsJOBco-convenedtheSHAPEDGuidelinegroupandwrotethefirstandsubsequentdraftsofthepaper.Hetakesresponsibilityforthewholecontentasguarantor.JPTco-convenedtheSHAPEDGuidelinegroupandcontributedtothewritingofthefirstandsubsequentdrafts.CB,RAB,CB,AB,DC,SD,RD,PF,AG,KH,VL,IL,IMcK,MM,CN,CO’C,KO,MO,RP,GR,PS,AT,PU,RWprovidedevidencefortheGuidelinegroupandthispaper,commentedondraftsandapprovedthefinalversion.DfwasChiefInvestigatoroftheSHAPEDstudy,co-convenedtheSHAPEDGuidelinegroupandcontributedtothewritingofthefirstandsubsequentdraftsofthepaper.FundingThisstudyisfundedbytheNationalInstituteforHealthResearch(NIHR)(ProgrammeGrantsforAppliedResearch(GrantReferenceNumber(RP-PG-0610-10100)).ThisstudywasalsosupportedbygrantsfromtheNewcastleBiomedicalResearchCentreandCambridgeBiomedicalResearchCentre.COissupportedbyaNationalHealthandMedicalResearchCouncilNeilHamiltonFairleyFellowship(1091310).SupportedbygrantsfromtheNationalInstituteforHealthResearchBiomedicalResearchCentreatMoorfieldsEyeHospitalNHSFoundationTrustandUCLInstituteofOphthalmology(Michaelides,MandNaik,C).DisclaimerTheviewsexpressedarethoseoftheauthorsandnotnecessarilythoseoftheNIHRortheDepartmentofHealthandSocialCare.CompetinginterestsRogerABarkerhasactedasaconsultanttoUCB,LivingCellTechnologies,BlueRockTherapeutics,SanaBiotechnology,FCDI,NovoNordiskandCellino.ClareBradleyisdirectorandmajorityshareholderofHealthPsychologyResearchLtd,whichlicencesherpatient-reportedoutcomemeasuresforotherstouseandmanagestheirlinguisticvalidationintootherlanguages.Shereceivesroyaltieswhenexistinglanguageversionsofherquestionnairesarelicensedtocommercialcompanies.HerCollegecurrentlyreceivesresearchgrantstosupportherresearchfromViiVHealthCareandfromMedtronic.ShehasrecentlyreceivedspeakerfeesfromAstellasandroutinelyadvisesmanypharmaceuticalcompaniesandcontractresearchorganisationsontheuseofherquestionnairesintheirclinicaltrials.RobertDudleyreportsdeliveringtrainingworkshopsandhaswrittenbooksaboutCBT,forwhichhehasreceivedfees,andreportsdeliveringCBTintheNationalHealthService(NHS).PaulFrancishasreceivedspeakingfeesfromSuvenandNutricia.IracemaLeroihasreceivedspeakingfeesfromEisai,BoehringerIngelheim,GEHealthcare,GlaxoSmithKline,ShireandLundbeck.IanMcKeithhasactedasaconsultantforGEHealthcare,SumitomoDainipponPharma,SanofiandEisai.JohnO’BrienhasactedasaconsultantforTauRx,Axon,GEHealthcareandEisai.MarcoOnofrjhasservedonthescientificadvisoryboardsofGlaxoSmithKline,Novartis,Lundbeck,Eisai,Valeant,MedtronicandNewron;hasreceivedspeakerhonorariafromZambon,theWorldParkinsonCongress,theMovementDisorderSocietyandtheAtypicalDementiascongress;wasaninvitedguestandlecturerfortheMentalDisordersinParkinsonDiseaseCongress;servesontheeditorialboardofMedicine(Baltimore);hasbeenemployedasaspeakerforBoehringerIngelheim,GlaxoSmithKline,UCBandZambonandhasreceivedresearchsupportfromtheItalianMinistryofHealthandtheItalianMinistryofEducation.RimonaSWeilhasreceivedspeakerfeesfromGEHealthcare.John-PaulTaylorhasreceivedspeakerfeesfromGEHealthcareandactedasaconsultantforHeptares-Sosei.Nootherauthorsdeclaredanyconflicts.PatientconsentforpublicationNotrequired.ProvenanceandpeerreviewNotcommissioned;externallypeerreviewed. RequestPermissions IfyouwishtoreuseanyorallofthisarticlepleaseusethelinkbelowwhichwilltakeyoutotheCopyrightClearanceCenter’sRightsLinkservice.Youwillbeabletogetaquickpriceandinstantpermissiontoreusethecontentinmanydifferentways. Copyrightinformation: ©Author(s)(ortheiremployer(s))2020.Re-usepermittedunderCCBY.PublishedbyBMJ.https://creativecommons.org/licenses/by/4.0/ThisisanopenaccessarticledistributedinaccordancewiththeCreativeCommonsAttribution4.0Unported(CCBY4.0)license,whichpermitsotherstocopy,redistribute,remix,transformandbuilduponthisworkforanypurpose,providedtheoriginalworkisproperlycited,alinktothelicenceisgiven,andindicationofwhetherchangesweremade.See: https://creativecommons.org/licenses/by/4.0/. ReadthefulltextordownloadthePDF: Subscribe Login LoginviaInstitutionLoginviaOpenAthens Loginusingyourusernameandpassword ForpersonalaccountsORmanagersofinstitutionalaccounts Username* Password* Forgotyourlogindetails?Registeranewaccount?Forgotyourusernameorpassword?