BotulinumToxinTypeA:AdverseEventsand Management
MaurizioCavallini,MD
1
2
MarcoPapagni,MD
1 OperativeUnitofDermatologyandDermato-Surgery,Centro DiagnosticoItalianoHospital,Milan,Italy
2 ItalianScienti fi cSocietyofAestheticMedicine,Milan,Italy
3 ItalianScienti fi cSocietyofAestheticMedicine,Milan,Italy
4 AcademyofAestheticSciences,Naples,Italy
FacialPlastSurg
Abstract
Keywords
► botulinumtoxin
► depressorangulioris
► adverseevents
► safety
► OnabotulinumtoxinA
RiccardoLazzari,MD
3 AdrianoSantorelli,MD 4
Addressforcorrespondence MarcoPapagni,MD,ItalianScienti fi c SocietyofAestheticMedicine,Milan,Italy (e-mail:dottmarcopapagni@gmail.com).
Aestheticmedicineiswitnessinganincreasin gexploitationofalltheprocedures.The demandhasneverbeenhigherthanitistoday.Thenumberofpractitionersisalso increasingyearbyyear.Consequentlycomplicationsandotherkindsofrelatedtroubles andproceduresarealsorising.Neverliketodayisfundamental,incaseoftroubles,how toproperlymanagewiththemostfrequentissues.Inaestheticmedicine fi eld, botulinumtoxinproceduresarethesafest.Lotofpatientsareworriedaboutbotulinum toxindespitetheavailablescienti fi cliterature.Rareshort-termcomplicationsare observed.Inthemostofcases,nothingsevereoccursiftheinternationalrecommendationsandthemostrecentguidelinesarecloselyfollowed,themajorityofthemare injectionrelated.Thisstudyisareviewofrareorcommonproblemsthatcanoccurand howtomanageorsolvethesituations.
Aestheticmedicineiswitnessinganincreasingexploitationof botulinumtoxinwithmillionsofproceduresperformedinthe worldeveryyear sevenmillionintheUnitedStatesalone, accordingtotheAmericanSocietyofPlasticSurgeons.1 Exploitationofthebotulinumtoxinpropertiesextendsbeyond aestheticmedicinetoclinicalapplicationsindifferentanatomicaldistrictswithmanytherapeuticgoals.2
Analreadyextensiveandsteadilyincreasinginternational literatureunanimouslydescribesbotulinumtoxinassafe andeffective.Theinternationalagreementamongusers, bothintheliteratureandincongresses,isbroadalsoon currentbotulinumtoxinadministrationprotocolsandnew administrationprotocolrefi nements.
SevereBotulinumToxinAdverseEventsAre Rare
Thecurrentconsensusisthatthebotulinumtoxinsafetyprofi le ishighwithclinicalseverityofadverseeffects,complications, orsecondaryeffectsinverselyrelatedtoincidence.Perilous situationsareusuallyuniquemorethanrare.Noseverityoccurs
iftheinternationalrecommendationsandthemostrecent guidelinesinelectronicdatabases(MEDLINE/PubMed)are closelyfollowed.3–5 Transientandmilduntowardeffects,althoughlessuncommon,arealwaysrare.
AChinesesubjectrecentlysufferedabotulismepisodewith severesystemicconsequencesafterself-administeringan uncharacterizedbotulinumtoxin-basedproductbought fromtheblackmarket.6 Similarclinicalproblemsarepossible afterinappropriateadministrationofbotulinumtoxinby unqualifi edoperatorswithoutrespectforcorrectdosesand inareasotherthantheface.6–8 Occasionalasymmetries,headaches,andpossiblyedemasaremorefrequentthansevere events,althoughalwaysinalowpercentageofsubjects.
Thebotulinumtoxinsiteofactionistheneuromuscular junction,andalmostallfacemusclesmayundergotreatment.2 Precisionandmeasureinactionandeffectsareparamount.They requireadeepknowledgeofthefaceanatomyanddilutionlogic andrationale,andasoundappreciationoftheoverallclinical situation.2 Associatingsuccesswithsafetymeansplanningtreatmentsbasedonacarefulassessmentofindividualcharacteristics andthemostrecentupdatesoftheinternationalliterature.
IssueTheme EndonasalRhinoplasty; GuestEditor:Dr.MichaelCarron ©2022.Thieme.Allrightsreserved. ThiemeMedicalPublishers,Inc., 333SeventhAvenue,18thFloor, NewYork,NY10001,USA
DOI https://doi.org/ 10.1055/s-0041-1741531. ISSN 0736-6825.
injectionsites,inabsolutetermsorrelativetothesubject,is whatleadstosuchanunfavorableoutcome.18,19
Thecandidatesubjectswithsomedegreeofupperdermatochalasisoreyebrowptosisatbaselinedeservespecial attention.Increasingthesafetymarginintheseindividuals needstoleaveamorecomprehensivesectionofthecaudal frontalismusclefreetocontract.Thelowerfrontalwrinkles neartheeyebrowwillbeimpossibletocorrect:informingthe candidatesubjectbeforetheprocedureisunavoidable.
Anotherpossiblytroublingprocedureisthecombined correctionofthecorrugatorsuperciliiandfrontalismuscles becauseofthedynamicinteractionbetweenthelatterandits antagonist mimicmus cles.Suchinteractioncruciallycontributestotheaestheticbalanceoftheforehead.20 Cautionis paramountsincenothingisavailabletocounteractthis adverseevent waitingformuscletonerestorationisall wecancurrentlydo.20
Palpebralptosis:Thediffusionofthebotulinumtoxin solutiontothepalpebralsegmentoftheorbicularisoculi muscleisresponsibleforeyelidlowering.Thiseventmay followthetreatmentofglabellarwrinkles.Mistakesinthe injectiontechniqueandexaggeratedvolumesorproduct concentrationaretheculpritforthebotulinumtoxindiffusionbeyondthetargetmuscle.21
Thepalpebralptosisistransitory,fromsomeweeksuptoa coupleofmonths,steadilydisappearingwiththeprogressive functionalrecoverybytheorbicularisoculimuscleneuromuscularjunctions.Instillingapraclonidineeyedropswith caretoavoidthesympathomimeticadverseeffectsmay acceleratefunctionalandaestheticrecovery.22
Asymmetries: theseadverseeffectsmayhappenwith nearlyallbotulinumtoxintreatmentsinallthreeface sections.Selectingasymmetricinjectionpointsordifferent dosesbetweenthetwofacesidesisthecauseofthisproblem insubjectswithoutpre-existingasymmetries.23 Conversely, insubjectswithoutpre-existingasymmetries,theproblemis fi ne-tuningthedifferencesininjectedunitstomodulatethe differentialmusclecontractionbetweenthetwofacesides. Thepreconditiontocorrectinducedasymmetriesisto identifythemusclesectionswithsomeresidualcontractile activityandinjectabouttwounitsinthetargetarea,with somevariationsaccordingtothespeci fi csituation.
Headache:asideeffectduetotheinjectionandnottothe injectedbotulinumtoxin.Currentevidenceshowsthat,in subjectsliabletoheadaches,theheadpaincouldoriginate fromtheneedlestimulationofthefrontalepicranialaponeurosisorthemuscularspasmthatoccursjustbeforethe block. 24 Thetreatedsubjectsreportasensationlikeaweight ontheforeheadthatwanesaftersomehoursandresponds welltocommonanalgesics.
Lackofresponse:atreatmentshortcomingthatmayoccur inallareasduetomistakesintheplanningofinjectionsites fortheindication.Theanatomicaldifferencesofmany muscleslikethecorrugatorsupercilii,thefrontalis,andthe orbicularisoculi inshape,insertion,andcontractileactivity mayrequirethattheoperatordeviatesfromhishabitual procedures.Suchdeviationsfromtheusualmimicmuscle anatomicalstandard,therelatedpeculiaritiesoffacialex-
pression,andtheabilitytorecognizethemarecrucialto individualizetheinjectionpointscorrectly.Afurthertouchupandrefi nementsessionmayalsobehelpful.
Preliminaryassessmentmistakesareacommoncauseof lackofimprovementsafterperiocularwrinkles(crow’sfeet) treatment.Thecauseofsuchwrinklesisthecontractionof theorbicularisoculilateral fi bersandthesmilemuscles, especiallythegreaterzygomaticmuscle.Anyeffectivecrow’s feettreatmentplanrequiresidentifyingwhichmimiccontractileactivityprevails.Thelateralperioculartreatment willbepoorlyorwhollyineffectivewhentheorbicularis oculilateral fi bersdonotexertthemostactivecontractility.
Somesubjectsaresimplynon-responders 25;othersshow aprogressivereductionofbotulinumtoxinef fi cacy.The causativeroleofautoimmunityandtheproductionofautoantibodiesarestillopenissues. 26
BotulinumToxinandtheFacialMiddleThird
Diplopia:theunderlyingmechanismofthisadverseeventis thesamethatcausespalpebralptosis anabnormalmigrationofthebotulinumtoxinsolutiontonon-targetmuscles liketheextraocularones.Notherapiesareavailableforthis veryinfrequenteventbutwaitingforitsspontaneousremission.27 Thetemporaryuseofprismaticlensesmaybehelpful. Lagophthalmos:theincompleteordefectiveclosureof eyelidswithalackoftotaleyeocclusionandsecondary oculardrynessfollowstheparalysisoftheorbicularorbital musclewiththeassociateddif fi cultiesinmaintainingproper musclefunction.Managementiswitheyedropsandlubricatinggels.14
Ectropionandoutwardeversionofthelowereyelidconjunctivalsac:Palpebralectropion,occurringinsubjectswith palpebrallaxity,maybeaconsequenceofbotulinumtoxin injectionsinthepretarsalregionnearthemarginoflower eyelids.Theenhancedorbicularmusclelaxitycausesthe outwardprojectionoffatcollections,ultimatelyleadingto theprominenceofpalpebralbags.Lymphaticdrainageinthis regionmaybeaco-actorifimpairedandcauseseyelid edema,especiallyinsubjectswithsubstantialorbicular musclelaxityandlongwrinklesthatextendtothemalar area.14
Eyelidedema:Arareandself-limitingbotulinumtoxin typeAadverseeventoccurringwhenlocallymphaticreabsorptiondecreasesduetoreducedlymphaticdrainage.Eyelidedemadisappearstypicallywithin2to4weekswithout medicaltreatment.Theriskofeyelidedema,bestmanaged withhalf-dosebotulinumtoxininjections,isnotablyhighfor candidatesubjectsofAsianethnicityorpreviousdermatochalasisorpoorperiocularmuscletone.Assessmentofthe functionandtoneoftheorbicularisoculiandlevatorpalpebraesuperiorismusclesbeforetreatmentisparamountin subjectsatrisk.Applicatinghotpadsovertheeyes,frequent blinkinginthemorning,andself-massageofaffectedareasto increasevenousreturnallshowedtoimproveoutcome.28
Derangedsmile:somesmileandmouthmobilityabnormalitiesmayoccurafterbotulinumtoxintreatmentofthe upperandlowerfacethird.Adversesmileeventsmayoccur
duringtreatmentofthehyperactiveupperlipofgummy smile,thesmallverticalwrinklesabovetheupperlipthatrun verticallydownwardintothelipandareknownas “barcode ” lines,andwhentryingtoinduceadepressorangulioris (DAO)musclerelaxation.29
Thegummysmileistypicallyduetotheenhancedcontractionoranatomicalshortnessofoneormoredeepsmile muscles,namelythelevatorlabiisuperioris,thelevatorlabii superiorisalaequenasi,thezygomaticusminorandmajor, andtheorbicularisoris.
Alltheseconditionsmaybechallengingtoidentifyand treat;thebilateralinjectionoftoomanybotulinumtoxin units,leadingtooveralllackofallsmilemusclemovements, isoneofthemistakesleadingtoderangedsmiles.Other reasonsareawrongpreparatoryinjectionplanoraproceduralmistakeintheinjectionsymmetry,withonlyafraction ofmuscletreatedonafaceside.
Waitingforspontaneousresolutionistheonlyoptionin caseofoverallorexcessivemonolateralsmilemuscleblock;a furthertouch-uptreatmentsessiongenerallyisenoughto solveasymmetriesduetoinadequatetreatmentofamuscle segment.30
Aderangedsmilemayalsofollowthebotulinumtoxin treatmentof “barcode” lineswhenthemuscleinhibitionis toopotentormotilitysuppressionisnothomogenousdueto excessivetoxindilution,injectionoftoomanyunits,orlackof acorrectinjectionsymmetry.Thereisnoeffectivecorrection forthecompletemuscleblockbutwaitinguntilthetoxin actionwanes;touch-upsessionsmayhelpincaseof asymmetries.31
BotulinumToxinandtheFacialLowerThird
DAO:marionettelinesaremainlycausedbytheptosisofsoft cheektissues.TheDAOmuscleiscausallyimportantwhen themuscletoneisexcessivebecausethismuscledepresses theoralcommissures thetypicallysadfacialexpressionis theoutcome.
Toxintreatmentrequiresinsertingone-thirdofa 30G 1/2¢¢needleperpendicularlytotheskin;therecommendeddoseis2to4unitspersideforbothmenandwomen. Thecorrectinjectionsiteis1cmabovethejawlowermargin and1cmlaterallytothelabiomentalfold.
Themainriskofbotulinumtoxininjectionsinthisarea focusesuponthedepressorlabiiinferiorismuscleimmediatelybelowtheDAO·veryvisibly,andaestheticallyunacceptablederangedsmilesaretheoutcome.Animpairmentoflip functionmaybeassociatedtoo,increasingpatient discomfort.13
Masseter:Botulinumtoxinmasseterinjectionsareroutinaryprocedures,generallywithgoodresultsandsafety pro fi les.Mostcomplicationsappearwithin2to4weeksof injectionanddisappearwithin12weeks.However,temporary,thesecomplicationsdecreasepatientconfi dence. Appreciatingtheinjectionsafetyzonesrequiresknowing theregionalanatomyandleveragingultrasoundsupport.32 Theultrasoundvisualizationofthedeepinferiortendonand themasseterbodyduringinjectionsmaypreventthepara-
doxicalmassetericbulging,afrequentoccurrenceofblind injections,andincreasetheoveralleffectiveness.33
Conclusion
Threeconsiderationsmaysummarizethecurrentevidence aboutbotulinumtoxinsafetyandeaseofuse:
• Sideeffectshaveanoveralllowincidence,andthebotulinumtoxinsafetypro fi lecompareswellwiththatofother aestheticmedicineprocedures.
• Complicationsaretemporaryandclinicalreversal,strictly relatedtotheperiodofpharmacologicalactivityofbotulinumtoxin,isalwayscomplete.
• Almostalladverseeventsareduetotechnicalmistakesby theoperator.
Inafewwords,thankstothelowerincidenceoftransitory localandsystemicadverseevents,botulinumtoxinproceduresqualifyasverysafeandeffective.
Con fl ictofInterest
Nonedeclared
References
1 DoverJS,MonheitG,GreenerM,PickettA.Botulinumtoxinin aestheticmedicine:mythsandrealities.DermatolSurg2018;44 (02):249–260
2 ParkMY,AhnKY.Scientifi creviewoftheaestheticusesof botulinumtoxintypeA.ArchCraniofacSurg2021;22(01):1–10
3 ZargaranD,ZollerFE,ZargaranA,MosahebiA.Complicationsof facialcosmeticbotulinumtoxinAinjection:analysisoftheUK Medicines&HealthcareProductsRegulatoryAgencyregistryand literaturereview.JPlastReconstrAesthetSurg.2021Jun17; S1748-6815(21):00332–00336.Doi:10.1016/j.bjps.2021.05.074
4 KroumpouzosG,KassirM,GuptaM,PatilA,GoldustM.Complicationsofbotulinumtoxina:anupdatereview.JCosmetDermatol2021;20(06):1585–1590
5 SethiN,SinghS,DeBoulleK,RahmanE.Areviewofcomplications duetotheuseofbotulinumtoxinAforcosmeticindications. AestheticPlastSurg2021;45(03):1210–1220
6 TianX,GaoL,FuG,etal.Ararecaseofseveresystemiclifethreateningbotulismcausedbyalocalbotulinumtoxin-Ainjection.JAADCaseRep2020;6(09):854–857
7 ChertowDS,TanET,MaslankaSE,etal.Botulismin4adults followingcosmeticinjectionswithanunlicensed,highlyconcentratedbotulinumpreparation.JAMA2006;296(20):2476–2479
8 FanKL,WangYL,ChuG,LeungLP.Delayedantitoxintreatmentof twoadultpatientswithbotulismaftercosmeticinjectionof botulinumtypeAtoxin.JEmergMed2016;51(06):677–679
9 FoissacR,BenatarMJ.Infl uenceofbotulinumtoxintypeAesthetic injectionsonfacialexpressions.JCosmetDermatol2021;20(05): 1405–1410
10 RaspaldoH,BaspeyrasM,BellityP,etal;ConsensusGroup.Upperandmid-faceanti-agingtreatmentandpreventionusingonabotulinumtoxinA:the2010multidisciplinaryFrenchconsensus part1. JCosmetDermatol2011;10(01):36–50
11 LorencZP,KenkelJM,FagienS,etal.Consensuspanel’sassessment andrecommendationsontheuseof3botulinumtoxintype Aproductsinfacialaesthetics.AesthetSurgJ2013;33 (supplI):35S–40S
12 KrasilnikovaO,PozdnyakovaM.Innovativeapproachtoaestheticalmedicineservicesqualityassessment.JCosmetDermatol 2021;20(02):636 –646