TardiveSyndromes

EoinMulroy1,BettinaBalint1,2,KailashPBhatia11DepartmentofClinicalandMovementNeurosciences,UCLQueenSquare

InstituteofNeurology,LondonWC1N,3BG2DepartmentofNeurology,UniversityHospital,Heidelberg,Germany

CorrespondingAuthor:

EoinMulroy

eoin.mulroy@nhs.net

DepartmentofClinicalandMovementNeurosciences,UCLQueenSquare

InstituteofNeurology,LondonWC1N3BG

Phone:02034567890

Wordcount:4141

Abstract

Dopaminereceptorblockingantipsychotics,firstintroducedtoclinicalpractice

in1952,werehailedasapanaceainthetreatmentofanumberofpsychiatric

disorders.Within5yearshowever,thisnotionwastobeshatteredbythe

recognitionofbothacuteandchronicdrug-inducedmovementdisorderswhich

canaccompanytheiradministration.Tardivesyndromes,denotingthedelayed

onsetofmovementdisordersfollowingadministrationofdopaminereceptor

blocking(andalsoother)drugs,comprisediversemanifestationsrangingfrom

theclassicoro-bucco-lingualdyskinesia,throughdystoniccraniocervicaland

trunkposturingtoabnormalbreathingpatterns.

Despitehavingbeenanimportantpartofclinicalmovementdisorderpracticefor

over60years,thepathophysiologicbasisoftardivesyndromesremainspoorly

understoodandtheoptimaltreatmentapproachremainsunclear.Thisreview

summarisesthecurrentstateofknowledgerelatingtotardivesyndromes,and

providesclinicianswithpragmatic,clinicallyfocusedguidancewithwhichto

tacklethedisorder.

Introduction

Movementdisordersoccurringasadirectiatrogenicconsequenceofthe

administrationofdopaminereceptorblockingneurolepticdrugswerefirst

reportedin1957,fiveyearsaftertheirintroductionintopsychiatricpractice.The

year1964sawtheirfirstcollectivedescriptionasa‘tardive’(drawnfromthe

latintardus,meaninglate)phenomenon[1],reflectingtheirdelayedonset

followingmedicationadministration,incontrastto‘acute’dystonicreactions,

whichcanalsooccurfollowingdopaminergicblockade.Thistermwasrapidly

adopted,andinthefollowingdecades,aflurryofpublicationsweretoexpand

thephenotypicspectrumofthedisorder.Concurrently,theoriesaimingto

explaindiseasepathogenesisbegantoemerge,andanumberoftherapeutic

strategieswereexplored.Thisreviewprovidesphysicianswithapragmatic,

clinically-basedplatformwithwhichtoapproachtardivesyndromes.Inaddition,

weexploresomerecentdevelopmentsinourunderstandingofdisease

pathophysiology,discusshowtoapproachtreatmentoftardivesyndromesand

trytodispelsomecommonlyheldmythsalongtheway.

Anecessarypreambletothisreviewisabriefforayintonosology.Indeed,

tardivesyndromes(TS)areplaguedbyinconsistentuseofdescriptivelanguage.

Theterm‘Tardivedyskinesia’,whenfirstintroduced,wasintendedtosubsume

therangeofdiversemovementswhichcanemergeinadelayedfashionfollowing

long-termneurolepticadministration.However,morerecently,alessconfusing

approachwhichclassifiestardivemovementsaccordingtotheirindividual

clinicalphenomenologies,hasbeenpromoted,andwillbeusedinthisreview.

Accordingly,‘Tardivesyndrome’isemployedastheumbrellatermforany/all

potentialtardivemovementdisorders.Meanwhile,‘Tardivedyskinesia’is

reservedasadescriptorofaspecificclinicalentity,namelythatofthe

characteristicoro-bucco-lingualchoreiformmovements(seebelow).

Thescaleoftheproblem

Tardivesyndromes(TS)areapredictable,sometimespermanent,disabling

consequenceofmedicationadministration.Theyarepredominantlyencountered

inthepsychiatricpopulation,wheretheyexacerbatetheburdenofsocialstigma

andarelinkedtopoorerqualityoflifeandincreasedmorbidityand

mortality[2,3].Antipsychoticsarebyfarthemostcommonoffenders,though

numerousotherdrugshavealsobeenimplicated(table1).

Table1:ExamplesofMedicationsknowntocauseTardivesyndromes[4–11]

Antipsychotics

Risk of Tardive Syndrome*

· 'Typical' Haloperidol High Droperidol High

Loxapine High Chlorpromazine High Fluphenazine High Thioridazine High Trifluoperazine High Sulpiride High Zuclopenthixol High Perphenazine Moderate Molindone Moderate

· 'Atypical' Quetiapine Low

Olanzapine Low Risperidone Low Paliperidone Low Clozapine Very Low Amisulpiride Low Ziprasidone Low/Moderate Aripiprazole Very Low Lurasidone Moderate

Antidepressants • MAOIs

o Phenylzine Low/moderate • SSRIs

o Citalopram Low o Escitalopram Low o Fluoxetine Low o Fluvoxamine Low o

• SNRIs o Venlafaxine Low o Duloxetine Low

• TCAs o Amitryptiline Low o Imipramine Low

Antiemetics • Metoclopramide Low/Moderate • Prochlorperazine Low/Moderate

Anticholinergics • Benzhexol Low • Orphenadrine Low • Procyclidine Low

Antiepileptics • Carbamazepine Low • Phenytoin Low • Ethosuximide Low

MoodStabilisers

• Lithium Low/moderate

Antimalarials

• Chloroquine Low • Amodiaquine Low

Antihistamines • Hydroxyzine Low

Anxiolytics

• Alprazolam Low

CalciumChannelblockers

• Amlodipine Low

Stimulants • Amphetamines Low • Methylphenidate Low

DopamineDepletors • Tetrabenazine Verylow

* The risk of developing tardive syndromes, as they relate to individual medication administration is a complex issue. It depends not only on the medication itself, but on a variety of other factors including medication dosage and duration of administration, co-administration with other medications capable of producing tardive syndromes, patient comorbidities and critically, the age of the patient. As such, this expression of 'risk' is intended purely as a general guide, and each case must be assessed on its merits.

Theconditionaffectsbetween20-50%ofpatientsreceivingneuroleptic

drugs[12].Advancingageisthemostrobustrisk-factorforthedevelopmentof

TS,withyearlyincidenceratesincreasingfrom5%inthoseunder40yearsof

ageto12%orhigherinolderagegroups[12–14].Riskincreasescumulatively

withdurationofexposureandcumulativedose,culminatinginanincidenceof

20-25%after5yearsofexposure[15,16].[17].Thesestatisticsmustalsobe

interpretedintheknowledgethatmedicationcomplianceratesamongthe

schizophrenicpopulationarearound50%,sothesefiguresmaywellbean

underestimate[18].

Numerousotherfactorsmayincreaseone’sriskfurther,includinghistoryofan

affectivedisorder,previousorganicbraindamage,diabetesmellitus,femalesex

(oestrogenperhapsbeingprotectivepre-menopausally)andrace[19].Indeed,

Asianshaveonaveragehavelower(roughly20%)andAfricanAmericanson

averagehigherdiseaseprevalenceascomparedtoCaucasians[19–21].

DiseasePathophysiology

Thepathophysiologicbasisoftardivesyndromesremainspoorlyunderstood.

Thisuncertaintyisreflectedinthegreatnumberoftheorieswhichpurportto

explainthedelayeddevelopmentofthesemovementdisorders.

Theearliesttheorytogainpopularacceptancewastheso-calleddopamine

receptorhypersensitivitytheory.Thissuggestedthatadministrationof

dopamineblockingneurolepticsledtocompensatoryup-regulationand/or

hypersensitivityofpost-synapticdopamine(particularlyD2)receptors[22,23].

Hypersensitivityofthesereceptors,whichareexpressedonindirectpathway

mediumspinyneuronsandareinhibitory,wouldhavetheneteffectofpallidal

andsubthalamicnucleusdis-inhibition,producingabnormalhyperkinetic

movements[22].Thishypothesiswaslargelybasedonclinicalobservations,such

asthegreaterlikelihoodofTSinpatientsreceivingpotentD2blockersandthe

apparentimprovementintardivedyskinesiawithadditionaldopaminergic

blockade,aswellasonsomeanimalstudies[22,23].However,evidencein

humansforsuchalterationsislacking.Thereisnocorrelationbetweenin-vivo

striatalD2receptorligandbindingassessedbyPETandTDseverity.Equally,

post-mortemstudieshavenotdemonstratedsignificantdifferencesinD2

receptornumbersinthosewithandwithoutTS[22].Moreover,thistheoryfails

toexplainwhymanypatientsfailtorecoverfollowingcessationoftheoffending

medication-iftheonlyproblemwasreceptorup-regulation/hypersensitivity,

onewouldexpectthistonormalizefollowingdrugwithdrawal.

AnalternativehypothesisisthatTSactuallyrepresentsaneurodegenerative

disorderofstriatalinterneuronsinducedbyoxidativestress.Thistheory,which

issupportedsomewhatbyanimalandhumanneuropathologicalstudies[24,25],

holdsthatdopaminergicreceptorblockadecausesincreaseddopamineturnover

andoxygenfreeradicalproductionbymonoamineoxidase[22].Thesefree

radicalsarethoughttobetoxictostriatalinterneurons,causinggliosiswithinthe

basalganglia,explainingthepersistenceofsymptomsaftermedication

discontinuation.Thesignificantandsustainedimprovementsometimes

observedfollowingdeepbrainstimulationforTSmayarguesomewhatagainst

thisideahowever.

AfurthertheoryimplicatesdamagedordysfunctionalstriatalGABAergic

neuronsinthepathogenesisofTD.Theseneuronssynapseonthesomaof

mediumspinyneurons,providingpotentfeedforwardinhibition,balancing

activityinthedirectandindirectbasalgangliapathwaysandprovidingsurround

inhibition[22,23].Selectivelesioningoftheseneuronshasbeenshownto

producedyskinesia[26].Long-termD2agonism,intheory,hasthepotentialto

damageGABAergicinterneuronsviaglutamate-mediatedexcitotoxicityand

increasedoxidativestressfromdopamineturnover[27].

Finally,alteredNMDA-mediatedsynapticplasticityhasbeensuggestedasa

somewhatunifyingtheory.AntipsychoticsareknowntoinfluenceNMDA

receptormediatedsynapticplasticity.Inthissetting,patternsofabnormal

neurotransmissione.g.secondarytoD2receptorhypersensitisationcouldbe

abnormallypotentiated,perpetuatingacycleofabnormalsensorimotor

integrationandabnormaltardivemovements[22].

Ofcourse,noteveryonewhoisexposedtoneurolepticdrugswilldevelopa

tardivesyndrome,implyingthatother,possiblygeneticfactorsareatplay,

conferringincreasedvulnerabilitytoTS.Genomewideassociationstudieshave

identifiedsomepotentialcandidategenes,thoughtheirrelevancetoclinical

practiceremainstobedetermined[28].

Makingthediagnosis-thedevilisinthedetail

Thefollowingsectiondescribesboththetypical(orperhapssimplybetter

recognized!)andlesstypicalpresentationsofTS.Onemustbemindfulhowever

thatindividualcomponentsofthesyndromerarelyoccurinisolation.Rather,

theygenerallycoexisttogreaterorlesserdegrees(thoughonemaybe

dominant),anditisoftentheidentificationofmultiplemovement

phenomenologiescompatiblewithTSwhichallowsaconfidentdiagnosistobe

made.Avitalpartoftheevaluationisthereforenotonlyidentificationofa

movementwhichispotentiallytardiveinaetiology,butactivelysearchingforthe

presenceofothercompatibleabnormalities.Failingnoticecluessuchasafidgety

patient(akathisia)whosighsdeeply(respiratorydyskinesia)andmoveshislegs

backandforthduringtheconsultation(stereotypies),canrapidlyleadonedown

thewrongdiagnosticpath.

ThoughdiagnosticcriteriaforTShavebeendeveloped(table2),inclinical

practice,therearereallyonlytwoquestionswhichmatter:

1. Isthereahistoryofdopaminereceptorblocking(orotherTS-causing)

drugadministration(eitherprescriptionmedication,overthe

counter/traditionalremedies,orpoisoning),andwhatisthetemporal

relationshipofthistotheonsetofthemovementdisorder?

2. Istheclinicalphenomenologycompatiblewithatardivesyndrome(see

below)?

Table2:DiagnosticandStatisticalManualofMentalDisorders,fifthedition

(DSM-5)definitionoftardivesyndromes

Tardivesyndromesaremovementdisordersdistinguishedbytheirlate

emergenceinthecourseoftreatmentandtheirpotentialpersistenceformonths

toyears,eveninthefaceofneurolepticdiscontinuationordosagereduction.

Symptomsdevelopinassociationwiththeuseofaneurolepticmedicationforat

leastafewmonths.

Symptomsmaydevelopafterashorterperiodofmedicationuseinolder

persons.

The‘typical’tardivesyndrome

‘Classic’tardivedyskinesiainvolvesstereotypedchoreoathetoidmovements

predominantlyinvolvingthelips,tongueandperioralregion.Themovements

tendtopredominateinthelowerface,withfrontalisinvolvementbeingunusual.

Patientsoftenmovethetongueinawrithingmotioninsidethemouth,areprone

tofrequentrapidtongueprotrusion(‘flycatchertongue’),andpushingofthe

tongueagainsttheinsideofthecheek,creatingabulge(‘bonbonsign’).Chewing

and/orgrimacingmovements,lipsmackingandpuckeringaretypical.Thismay

beaccompaniedbylowamplitudechoreiformmovementsofthedistallimbs,the

so-called‘pianoplayer’dyskinesia,duetotheirresemblancetofinger

movementsonpianokeys[29].Patientsareoftenunawareoftheseinvoluntary

movements,thoughthoseinvolvingthelipsandtonguemaycauseproblems

withfeeding.

Tardivedyskinesiaisusuallyaccompaniedbyoneormoreofthefollowing

tardivephenomena:

-Tardiveakathisia,whichisanuncomfortablesenseofinnerrestlessness,

requiringtheaffectedindividualtorepeatedlymoveaboutinordertoeasethis

unpleasantsensation.Thiscanincluderockinginplacewhenseated,marching

whenstanding,repetitivescratchingorrubbingorindeedjustappearing

generally‘fidgety’duringtheconsultation.

-Tardivestereotypies:thesearepatterned,purposeless,repetitiveandsomewhat

ritualisticmovementswhichmayappearastruncalrocking,pelvicthrusting,to-

and-frolegmovements,handwringingorcrossing/uncrossingofthelegs.They

mayresembleakathisiabutincontrast,stereotypiesarenotaccompaniedby

innerrestlessness.

-Tardivedystonia:Aswithmosttardivesyndromes,tardivedystoniaadopts

distinctphenomenologicalcharacteristicswhichareeasilyidentifiedbythe

trainedobserver.Thedisorderfrequentlyinvolvesthecraniocervicalregion,

oftenmanifestingasretrocollis.Dystoniamayextendtothetrunk,as

opisthotonicposturing,whileinthearms,abduction,internalrotationandwrist

flexionistheclassicallyadoptedposture[29].Blepharospasmmayalsoemerge.

IncontrasttootherTS,tardivedystoniaappearsparticularlyprevalentinyoung

menaroundtheageof40years[24].Remissionisalsolesslikelythanwith

tardivedyskinesia,particularlywithdrugexposurebeyond10years[24].

Thefollowingtardivedisordersarelesswelldefined,withonlyahandfulof

casesreportedintheliterature.

-TardiveTourettismisararedisordercharacterizedbytheemergenceof

multiplemotorandverbalticsfollowingexposuretodopaminereceptor

blockingdrugs.Theticsaregenerallysimilartothoseofprimaryticdisorders,

exhibitingsuppressibility,buildupoftensionpriortotheticandreleaseof

tensionuponperformanceofsame[30,31].

-Tardivetremor

Theentityoftardivetremorwasfirstproposedina1992reportoffivepatients

witha3-5Hzposturalandactiongreaterthanresttremorwithoutcoexistent

parkinsonism[32].Thoughbearingsomesimilaritiestoparkinsoniantremor,

tardivetremorissaidtobedifferentiatedfromtheformerbyitsposturaland

kinetic(ratherthanrest)predominance,itscoarsedisablingnature,itslackof

responsivenesstolevodopaanditsoccasionalimprovementwithfurther

dopaminergicblockadeortetrabenazine[32,33].Thesyndromegenerally

persistsdespiteDRBAwithdrawal.

-Tardivemyoclonus

Tardivemyoclonusdescribesbrief,upper-limbpredominantposturalmyoclonic

movementswhicharesaidtobeaconsequenceoflong-termdopaminergic

blockade[34,35].Theliteratureonthisentityishighlylimitedhowever,and

thereforeshouldbeinterpretedwithcaution.

-ThephenomenonofTardiveGaithasalsobeendescribed.Thoughpoorly

characterizedandnotuniform,gaitdisturbanceshavebeendescribedas

‘dancing’(multipleshortstepsfollowedbyalongstep)or‘duck-like’(broad

basedwithshortstridelengthandsomesteppagefeatures).Otherabnormalities

includeinitialfloorcontactwithtoesratherthanheels,spasticqualitiesand

abnormalarmswing[36].

Somerather‘atypical’presentations

PatientswithTSnotinfrequentlyexhibitotherlessrecognized,butnonetheless

characteristicfeatureswhichpointtowardsthediagnosis.Amongthese,

respiratoryphenomena,tardivepisasyndromeandwithdrawalemergent

dyskinesiaareparticularlyimportanttobeawareof.

-Firstdescribedin1964,RespiratoryDyskinesiainvolvesperiodicdisturbancesof

respiratoryrate,rhythmandamplitude,sometimesaccompaniedbyrespiratory

pausesorforcedinspirationagainstaclosedglottis[37].Patientsmaycomplain

ofdyspnoea,dysphonia,ormaybeseentohuff,grunt,gasportakeshort,rapid

breaths[38].Theserespiratoryphenomenaoftenaccompanyothermoreclassic

tardivemotorfeatures.

-TardivePisasyndrome

Predominantlyaffectingolderwomen,tardivepisasyndromedescribesadrug-

inducedpersistenttruncaldystoniamanifestingastoniclateralflexion,

occasionallyaccompaniedbyslightrotation[39].The‘laterallyleaningpatient’is

animportantcluetoatardiveaetiology.

-Withdrawalemergentdyskinesiaisconsideredavariantoftardivedyskinesia

whichisgenerallyobservedfollowingeitherabruptdiscontinuationor

significantdosereductionsinneurolepticmedications[40].Thesyndrome

predominantlyaffectschildren,andusuallymanifestsasgeneralizedchorea(as

opposedtothefacial-predominantmovementsobservedinclassicTD).Itis

usuallyself-limitingafterdaystoweeks[40].

-Tardiveoculogyriccrises

Originallydescribedasacharacteristicfeatureofencephalitislethargicaand

nowmorecommonlyassociatedwithmedication-relatedacutedystonic

reactions(aswellasdopaminesynthesispathwaydefects),oculogyriccrisescan

rarelyoccurasatardivephenomenoninpatientschronicallyexposedto

antipsychoticmedications[41,42].Tardiveoculogyriccrisesoftenaccompany

othertardivemotorphenomenaandmaygounrecognized.Theyarenot

infrequentlyassociatedwithtransientrecurrencesofpsychiatricsymptoms

rangingfromanxiety,hallucinationsandbizarrebehaviortoauditory

hallucinations[41].

-Avarietyoftardivepainsyndromeshavealsobeendescribed,temporally

associatedwithneurolepticuseandoftenrespondingtostandardTStreatments.

Examplesincludetardiveoralpain,whichdescribesanuncomfortable,often

burningsensationinthemouthandlips,andpainfulgenitalsyndrome,with

similarafflictionofthegenitalregion[43].

-Tardivebruxism

Bruxism,ofeitherthegrindingormixedgrinding-clenchingtypehasbeen

describedasaside-effectoflong-termneurolepticexposure.Itlikelyrepresents

aformefrusteoftardiveoromandibulardystonia[44].Noiseproductionisoften

astrikingfeatureofthesyndrome,attimessosevereastoannoyroommates.

Themovementsdisappearduringsleep.

AssessingTSseverity

Priortoinitiatingapatientondopaminereceptorblockingdrugs,clinicians

shouldstrivetodocumentthepresenceofabsenceofabnormalinvoluntary

movements.Whilebothphysicianandnurse-ledstandardizedassessmenttools

(suchastheabnormalinvoluntarymovementscale(AIMS)andScanmove

instrument,respectively)maynotalwaysbepracticalinthebusyclinical

setting[45,46],afocusedexaminationisneverthelessimportant.Itwas

recognizedover140yearsagothatpsychiatricpatientsmayexhibitstereotypies,

choreaorabnormalfacialgrimacingasaresultoftheirdisease-failureto

documentthispriortotreatmentmayleadtotheselaterbeingmis-attributedto

adrugeffect[47,48].

Therehavealsobeenpublicationssuggestingthatacertainnumberofolder

peopledevelopspontaneousmovementsofthefaceaspartofnormalageing.

Whetherthisistrueormerelyrepresentstheemergenceoffacialorcranio-

cervicaldystonicsyndromeswithageisyettoberesolved.

Factsandfallacies

Mythno.1:Secondgenerationantipsychotics,withtheirlowerD2binding

affinity,havereducedtheincidenceoftardivesyndromes

Thishasbeenaparticularlycontentiousissueandmakingadefinitestatementin

eitherdirectionisdifficult.Whatcanbesaidwithcertaintyisthatthe

introductionofsecond-generationantipsychoticshasnotdoneawaywithTS.

Rather,duetorapiduptakeintheirprescription,includingoff-labeluseformood

disordersandsleep,theymayironicallyhavecontributedfurthertotheproblem.

WhilesomestudiessuggestthattheincidenceofTSwithsecondgeneration

antipsychoticsisnotvastlydissimilarfromthatoftheirfirstgeneration

counterparts[10,49],thelargestliteraturereviewto-dateinvolving34,555

patientstreatedwithantipsychoticsacross56studiesfoundanannualized

incidencerateof2.98%withsecond-generationantipsychoticsversus7.7%with

first-generationantipsychotics,supportingtheclaimthatSGAmayindeedcarry

alowerrisk[50].Thisisalsosupportedbyarecentlargemeta-analysisof57

studiesonTS[9].

Mythno.2:Prolongedexposuretoacausativedrugisnecessaryinorderto

beatriskofTS.

Though,asdetailedabove,thecumulativeriskofTSincreasesyear-on-yearand

mostpatientsdevelopthedisorderafteratleast1-2yearsofdrug

exposure[23,24],therearereportsofitsoccurrenceafterjustasingledoseof

neuroleptic.Prolongeddrugexposureisthereforenotanecessarypre-requisite.

MythNo.3Someneurolepticsaresafe

Therecognitionthatfirstgeneration(‘typical’)antipsychoticswereassociated

withanumberofextrapyramidalside-effectspromptedthedevelopmentof

newercompounds,termed‘atypical’antipsychotics,whichweresupposedly

definedbytheabsenceofextrapyramidalsymptomsattherapeuticdoses.

Numerousmechanisticdifferencesofthesenewercompounds,includingeffects

onserotonergicsignaling,morerapiddissociationfromtheD2receptor,limbic

selectivity,andinthecaseofaripiprazole,partialdopaminergicagonismwere

positedasthereasonbehindtheirmorefavourablesideeffectprofiles.

Whileitistruethatnoteveryneuroleptichasthesamepropensitytocause

tardivesyndromes,nonearedevoidofrisk.Allclassesofantipsychoticscan

producetardivesyndromes[20,51].Nevertheless,newer‘atypical’agents

probablycarryabouthalftheriskofproducinglaterTSascomparedtotheir

‘typical’counterparts[9].Furthermore,itisimportanttorememberthatitisnot

justneurolepticswhichareimplicatedinthedevelopmentoftardivesyndromes

(table1).

Differentialdiagnosesnottomiss,andhowtospotthem:

Differentiatingspontaneousfromdrug-inducedmovementdisordersinpatients

withpsychiatricillnesscanbeachallengingendeavor.Itisnonetheless

imperativetoensurethatadequatethoughthasbeengiventoexcludeimportant

differentialdiagnoseswhichcanpresentwiththecombinationofpsychiatric

diseaseandabnormalmovements[29].Thefollowingconditionsareimportant

tokeepinmind:

1. Huntington’sdisease

Asatrinucleotiderepeatexpansiondisorderwiththecardinalmanifestationsof

chorea,psychiatricdiseaseandcognitivedecline,HDisoneofthemost

importantdifferentialdiagnosesoftardivedyskinesia.Psychiatricdisease(often

requiringneuroleptictreatment),canprecedethedevelopmentofhyperkinetic

movementsinHDbyanumberofyears.Theemergenceofthelattercan

thereforeeasilybemis-diagnosedastardivebytheinexperiencedobserver.

Inthissetting,someclinicalcluescanbeparticularlyhelpful[52].Theseinclude:

a. Thenatureofthehyperkineticmovements:hyperkineticmovements

intardivedyskinesiatendtobestereotypedandsemi-purposeful,as

opposedtotherandom,flowingmovementsofchoreawhichtypify

HD.

b. Topographicaldistribution:inTS,movementstendtopredominate

aroundthelowerfaceandaxially(manifestingasretrocollisand

opisthotonus).Incontrast,HDpatientsoftenhavesignificantlimb

chorea,whichisunusualinTS.Hyperkineticmovementsofthe

frontalismusclearealsocommoninHD,butuncommoninTS

c. Eyemovements:Eyemovementdisordersareoftenaprominent,early

featureofHD.Theycaninvolvedisordersofsaccadicinitiation,

brokenpursuitsandgazeimpersistence.Eyemovementsaregenerally

normalinTD,makingacarefuloculomotorexaminationanimportant

partoftheevaluationofalltardivesyndromes.

d. Motorimpersistence(ofgrip,tongueprotrusionorgazefixation)isa

classicfeatureofHD,butisveryuncommoninTD,andthereforea

valuableclinicalsign.

e. Otherfeaturesoftardivesyndromessuchasakathisiaand

opisthotonusarehighlysuggestiveofTS.Conversely,afamilyhistory

suggestingdominantinheritanceandcaudateatrophyonMRIwould

pointtoadiagnosisofHD.

2. Anti-NMDAreceptorencephalitis

Anumberofautoimmunemovementdisorderscanhaveco-existent

neurobehaviouralfeatures-theseareextensivelyreviewedelsewhere[53].

Anti-NMDAreceptorencephalitisinparticularhowever,couldbe

confusedwithtardivedyskinesia,duetotheprominentstereotyped

perioraldyskinesiawhichtypifiesthedisorder.Theconditionpresents

differentlydependingonage,withchildrenhavingmore‘neurological’

(seizures,movementdisorders)phenotypes,whileadultstendtopresent

withneurobehaviouralsyndromes,whichcanbemistakenfor

psychosis[54].Sometimes,theneuropsychiatricfeaturesrequire

neuroleptictreatment,creatinganadditionalpitfallinthediagnostic

pathway.A‘fullhouse’ofsymptoms,includingautonomicdysfunction,

generallydevelopswithin1month[54].Clinicalsuspicionshouldleadto

testingforthecausativeantibodyinserumandcerebrospinalfluid.

3. Wilson’sdiseaseshouldalwaysbekeptinthedifferentialdiagnosisofany

movementdisorder,especiallyinpatientsundertheageof40years

(thoughlatepresentationsarereported).Psychiatricsymptomsare

commoninWilson’sdisease,andperioralmovementsarealsoclassic.

However,theytendtoassumeamoredystonicquality,frequently

producingrisussardonicus.Dysarthriaanddroolingarealsocommonin

WD,butunusualintardivedyskinesia.

4. Edentulousdyskinesiaisahyperkineticmovementdisorderaffecting15%

oftheedentulouspopulation[55]inwhichstereotyped,choreiform

perioralandlipmovementsbearstrikingresemblancetothetardiveoro-

bucco-lingualdyskinesia.Thedisorderispresentunderconditionsof

partialorcompleteedentulism,andoftenresolvesorsignificantly

improveswiththeintroductionofdenturestothemouth.Itspathogenesis

isthoughttorelatetoalteredsensoryfeedbackfromoralstructuresasa

resultofmalocclusion.

5. Meigesyndromeisaprimarydystonicdisordermostlyaffectingwomenin

their50sand60s,characterizedbythecombinationofblepharospasm

andoromandibulardystonia.Differentiationfromtardiveconditionson

purelyclinicalgroundscanbeparticularlydifficult,henceahistoryof

exposuretodopaminereceptorblockingagentsiscriticaltothoroughly

exploreinthehistory.

Treatment

Managementoftardivesyndromesshouldincorporatethreekeyaspects.

First,preventionisalwaysbetterthancure.Assuch,medicationswith

documentedpotentialforinducingTSshouldbeusedatthelowestpossibledose

fortheshortestperiodoftimepossible.Thismayofcoursenotalwaysbe

possible.

Secondcomesthequestionofmedicationwithdrawal.Inactualfact,theevidence

thatwithdrawingtheoffendingdrugsignificantlyaltersthenaturalhistoryof

tardivesyndromesisnotasstrongasonemightthink[56].Nevertheless,thisis

anintuitivemoveinclinicalmedicine-removethethingwhichiscausingthe

problem.Mostmovementdisorderphysicianswouldthereforeadvocate

stoppingtheoffendingDRBA,oratleastchangingtoadrugwithlesspotential

fortardivephenomena,ifpossible.Thealternativedrugofchoiceinthissetting

isoftenclozapine,bothduetoitsprovenefficacyinthetreatmentof,andits

lowerriskofinducingTS[57–59].Closeconsultationwiththepsychiatric

servicesisnecessarypriortoembarkingonsuchacourseofaction.Itisalso

importanttorealizethattardivesymptomsmayinitiallyworsenfollowing

neurolepticdrugwithdrawal,andthatequallythesymptomsmaybesuppressed

byswitchingtoamorepotentdopaminereceptorblockingagent[60].

Finallycomesthequestionofsymptomatictreatmentsfortardivesyndromes.

Numerousagentshavebeentrialledinthisregard,withvaryingevidencefor

theireffectiveness.

Asmentionedbefore,TSareoftenacomplexmedleyofdifferentmovement

disorders,andapproacheswhichmaybeeffectiveforonemovementmay

worsenanother.Atailoredapproach,focusedonaddressingtheissuewhichis

primarilybothersomeforthepatientisthereforeparamount;generally,thiswill

beeithertardivedyskinesiaortardivedystonia.

Concerningtardivedyskinesia,themainstayofmedicaltreatmentresides

aroundtheadministrationofvesicularmonoaminetransporter-2(VMAT-2)

inhibitors(tetrabenazine,deutetrabenazine,valbenazine-thelattertwobeingthe

onlyFDAapproveddrugsforthetreatmentofTD),whichactthroughpre-

synapticdopaminedepletion.Themainsideeffectsofthesemedicationsarethe

developmentofreversibleparkinsonism,aswellasdose-dependentmood

changes,particularlyintheelderly;theside-effectprofilesofdeutetrabenazine

andvalbenazineappearsignificantlymorefavourable[61].

OthercompoundswhichareworthamentionincludeAmantadine,whichhas

shownantidyskineticpropertiesinmultiplecontrolledanduncontrolledstudies,

andissupportedbyAANguidelinesforshort-termtreatmentoftardive

dyskinesia.Propranololhassurprisinglygooddatatosupportitsuse,thoughthis

islikelyduetoitseffectofincreasingneurolepticdruglevels[47].Clonazepam

alsoappearseffective,thoughintherandomizedcontrolledtrialsettingit

appearedtoloseitsefficacyafter5-8monthsandthuscanonlybetentatively

recommendedforshort-termuse.Anumberofantioxidantshavealsobeen

trialled.Datasurroundingtheirefficacyislargelyinconclusive[60].Otheroptions

suchasadditionaldopaminergicblockadee.g.withhaloperidol,haveproven

efficacyinreducingtardivedyskinesia,atleastintheshort-term.Thishowever

comesatthecostofanincreaseinakineticrigidsyndromes.Furthermore,there

isinsufficientdataonthelong-termeffectsofsuchapproaches,andgiventhat

theseagentshavegreatpropensitytocauseTS,additionalpotentdopaminergic

blockadeisnotrecommendedasatreatmentstrategyinTS[60].

Fortardivedystonia,botulinumtoxinisaneffectiveoption[23].Trihexyphenidyl

canalsoimprovedystonicsyndromes,thoughoccasionallyatthecostof

worseningdyskinesia.

Forbothtardivedyskinesiaanddystonia,anapproachwhichisgaining

increasingrecognitionisthatoffunctionalneurosurgery.Indeed,pallidaldeep

brainstimulationcanbegreatlybeneficial,andearlyreferraltoacentrewith

experienceinthisprocedureshouldbeencouragedinrefractoryordebilitating

cases[62].Physiciansmaybereluctanttorecommendthisprocedureduetothe

riskofworseningunderlyingpsychiatriccomorbidity,thoughinpractice,thisis

seldomanissue,especiallywithpallidaltargets[62].Pallidotomycanalsobeen

consideredinpoorsurgicalcandidates.

Tardiveakathisiacanbeequallybothersome,butthereisadearthofevidence

regardingitsoptimaltreatment.Clonidine,moclobemide,benzodiazepinesand

evenelectroconvulsivetherapy(ECT)hasbeenusedinsomeinstances,with

varyingdegreesofsuccess[63–66].Tardivepainsyndromesoftenrespondto

VMAT-2inhibitors,thoughotheroptionssuchasECThavebeenused[43].

Withdrawalemergentdyskinesiaoftensettlesspontaneouslyoverafewweeks

withouttreatment.Severesymptomscanhoweverbemanagedby

reintroductionoftheoffendingdrug,followedbyaslowertaper.

Patientoutcomes

Inanidealworld,patientsdevelopingTSwouldhavetheircausativeneuroleptic

treatmentstopped.Then,andonlythen,couldthetruereversibilityofthe

syndromebeassessed.Thenatureofpsychiatricdiseasehowevermeansthat

ongoingtreatmentisoftennecessary,makingassessmentofTSoutcomes

difficult.PredictorsofpooroutcomeappearsimilartothoseofdevelopingTSin

thefirstplace,andincludeadvancedage,longerdurationofantipsychotic

treatmentandgreatercumulativedose[67].Onceestablished,TSseverityoften

fluctuatesovertime,thoughinasignificantproportion,theTSfailsto

resolve[56,68].

Keypoints

• Tardivesyndromesoftencompriseamultitudeofcharacteristic

movementdisorders.Eachoftheseshouldbecarefullyexaminedforin

suspectcases.

• ClozapineisthedrugofchoiceforpatientswithTSwhorequireongoing

neuroleptictreatment

• VMAT-2inhibitorssuchastetrabenazine,deutetrabenazineand

valbenazinearethebestmedicaltreatmentoptionsfortardivedyskinesia

• Pallidaldeepbrainstimulationisaneffectivetreatmentoptionin

refractoryordebilitatingtardivesyndromes

Acknowledgments

Nil

CompetingInterests

Nil

Fundingdeclaration

Thisresearchreceivednospecificgrantfromanyfundingagencyinthepublic,

commercialornot-for-profitsectors

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