Cambridge University Press 978-0-521-13062-2 — Smell and Taste Disorders Christopher H. Hawkes , Richard L. Doty Frontmatter More Information Smell and Taste Disorders © in this web service Cambridge University Press www.cambridge.org Cambridge University Press 978-0-521-13062-2 — Smell and Taste Disorders Christopher H. Hawkes , Richard L. Doty Frontmatter More Information Smell and Taste Disorders Christopher H. Hawkes, MD FRCP HonoraryProfessorofNeurologyandHonoraryConsultantNeurologist,NeuroscienceCentre,BlizardInstitute, BartsandtheLondonSchoolofMedicineandDentistry,London,UK Richard L. Doty, PhD FAAN Professor,DepartmentofOtorhinolaryngology:HeadandNeckSurgery,andDirector,SmellandTasteCenter, PerelmanSchoolofMedicine,UniversityofPennsylvania,Philadelphia,Pennsylvania,USA © in this web service Cambridge University Press www.cambridge.org Cambridge University Press 978-0-521-13062-2 — Smell and Taste Disorders Christopher H. Hawkes , Richard L. 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Doty Frontmatter More Information Contents Preface vii Acknowledgments ix 1 AnatomyandPhysiologyof 7 NeurodegenerativeChemosensory Olfaction 1 Disorders 293 2 AnatomyandPhysiologyof 8 Assessment,Treatment,and Gustation 46 MedicolegalAspectsof ChemosensoryDisorders 387 3 MeasurementofOlfaction 80 4 MeasurementofGustation 138 5 Non-neurodegenerativeDisordersof Olfaction 182 Index 406 6 Non-neurodegenerativeDisordersof Colorplatesaretobefoundbetween Gustation 248 pp.214and215. v © in this web service Cambridge University Press www.cambridge.org Cambridge University Press 978-0-521-13062-2 — Smell and Taste Disorders Christopher H. Hawkes , Richard L. Doty Frontmatter More Information Preface This smell and taste disorders aims to provide neuroscientists, physicians, dentists, and psychologists with concise, practical, and authoritative information for understanding, testing, and managing disorders of taste and smell. Nearly 3 percent of Americans under the age of 65 suffer from some form of chronic olfactory or gustatory dysfunction – apercentagethatrisestomorethan50percentofthoseover65yearsofage andislikely muchhigherinareasoftheworldwhereairandwaterpollutionareprevalent.Despitesuch statistics, the chemical senses remain neglected by the majority of medical practitioners. Such oversight stems from a number of sources, not least of which is the lack of under- standingortrivializationofthesesensesandthebeliefthattheiraccurateassessmentcannot bemadeintheclinic.Less-than-totaldysfunctionisrarelybroughttotheattentionofthe physicianand,whenaberrationsarefound,manyareunsureofhowtoproceed. Although practical quantitative tests of smell function are now widely available, the majorityofneurologiststestonlycranialnervesIIthroughXII.Thiscontinues,despitethe fact that olfactory testing has been recommended by the Quality Standards Committee of theAmericanAcademyofNeurologyforinclusioninthediagnosticcriteriaforParkinson’s disease(Suchowerskyetal.,2006).Similarsuggestionshavebeenmadeforinclusionofsmell testingasanaidinthediagnosisofAlzheimer’sdisease(Fosteretal.,2008).Thereisevidence thatsmelltestscanbeusefulindifferentialdiagnosisofseveraldisorders(e.g.,depressionvs. Alzheimer’s disease; Parkinson’s disease vs. progressive supranuclear palsy and essential tremor).Moreover, they may assist thedetection ofmalingering. Loss ofsmell or tastehas considerablemedico-legalimportance,commandingmajorfinancialcompensationforthose who are victims of head injury or exposure to toxic agents, particularly for the young and personswhoselivelihoodsdependuponchemosensation.Asthisbookemphasizes,thereare nolongerexcusesforneglectingthechemicalsensesinmedicalpractice. Smellandtasteareregularlylumpedtogether,particularlybylaypeople.Whilebothare chemicalsensesandcontributetotheflavoroffoodsandbeverages,intheembryothesetwo systemsdevelopindependentlyandarecompletelyseparateatsubcorticallevelandmerge onlyattheanteriorinsula.Olfactionisseeminglymoreancient,developingfirstphylogen- etically; taste, as an oral chemosensory system, is a relatively new thalamic-dependent system. It is important to recognize, however, that both olfactory and gustatory receptor proteins are found outside of the nose and oral cavity, suggesting that these proteins are ubiquitous and have functions beyond those of transducing the conscious perception of tastesandsmells.Forexample,olfactoryreceptorproteinshavebeenfoundinthetongue, brain,prostate,enterochromaffincells,pulmonaryneuroendocrinecells,andspermatozoa. Taste receptors have now been reported in the epiglottis, larynx, respiratory epithelium, stomach,pancreas,andcolon,where theyinfluencesuchprocesses asdigestion,chemical absorption, insulin release, and protection of the epithelium from xenobiotic agents. Olfaction is more plastic than taste, and it is damaged more readily from head trauma, viruses,andexposuretoxenobiotics.Inbornmechanismslargelydeterminethemeaningof taste experiences, whereas learning plays a much greater role for the sense of smell. Nonetheless, these primary sensory modalities intermingle both with each other and othersensorysystemsatthecorticallevel–interactionsthatinsomecasesareinfluenced greatlybylearning.Suchinterplayisonlyjustbeginningtobeunderstood. vii © in this web service Cambridge University Press www.cambridge.org Cambridge University Press 978-0-521-13062-2 — Smell and Taste Disorders Christopher H. Hawkes , Richard L. Doty Frontmatter More Information viii Preface Many chemosensory systems have evolved in mammals, including the vomeronasal system,butthesensesoftasteandsmellarethemostprominentinhumans.InChapters1 and 2 we emphasize the anatomy and physiology of these two modalities, beginning with olfaction, which as noted above is typically more compromised than taste by injury and disease.Insubsequent chapterswereviewmethods tomeasuresmell(Chapter3)andtaste (Chapter 4), what factors influence these modalities, and, from a clinical perspective, the nature and major causes of their dysfunction with an emphasis on neurological disorders (Chapters5,6,and7).Ourgoalistoprovideup-to-dateinformationaboutthesesensesin healthanddisease,andtoguidethepractitionerintheassessment,treatment,andmanage- mentofpatientswithchemosensorydisturbances(Chapter8). WeexpressourgratitudetotheeditorsofCambridgeUniversityPresswhoagreedtoan update of our earlier work The Neurology of Olfaction (2009) and to include taste com- plaints.Wehopethatthiscompendiumwillservetheneedsofabroadarrayofclinicians andscientistswhorecognizetheuniquerolethatthechemicalsensesplayinmedicineand everydaylife. References Suchowersky,O.,Reich,S.,Perlmutter,J., Foster,J.,Sohrabi,H.,Verdile,G.andMartins,R., Zesiewicz,T.,Gronseth,G.,Weiner,W.J.,2006. 2008.Researchcriteriaforthediagnosisof Practiceparameter:Diagnosisandprognosisof Alzheimer’sdisease:Geneticriskfactors,blood newonsetParkinsondisease(anevidence-based biomarkersandolfactorydysfunction. review).Reportofthequalitystandards InternationalPsychogeriatrics20(4),853–855. subcommitteeoftheAmericanAcademyof Hawkes,C.H.,Doty,R.L.,2009.TheNeurologyof Neurology.Neurology66(7),968–975. Olfaction.Cambridge,UK:CambridgeUniversity Press. © in this web service Cambridge University Press www.cambridge.org Cambridge University Press 978-0-521-13062-2 — Smell and Taste Disorders Christopher H. Hawkes , Richard L. Doty Frontmatter More Information Acknowledgments Weoweadebtofgratitudetothefollowingwhohavehelpedwithvarioussectionsofthis volume: ProfessorKailashBhatia,NationalHospitalforNeurologyandNeurosurgery,Queen Square,London ProfessorJayGottfried,PerelmanSchoolofMedicine,UniversityofPennsylvania, Philadelphia,Pennsylvania ProfessorJohnHardy,NationalHospitalforNeurologyandNeurosurgery,QueenSquare, London Dr.IsabelUbeda-Banon,UniversidaddeCastilla-LaMancha,Avda.deMoledoress/n,13071, CiudadReal,Spain. ProfessorJasonWarren,NationalHospitalforNeurologyandNeurosurgery,Queen Square,London ix © in this web service Cambridge University Press www.cambridge.org Chapte1r Anatomy and Physiology of Olfaction Introduction Theevolutionofliferequiredorganismstosensechemicalssuspendedordissolvedinwater. Someofthesechemicalsprovidednourishment,whereasothersweredestructiveandhadto beavoided.Single-celledorganisms,suchasEscherichiacoli,developedmultiplechemical receptors critical for such survival. The rotatory direction of their flagellae – whip-like appendages used to propel them through their environment – is altered by the type of chemical encountered. Thus, chemicals important for sustenance induce a counterclock- wise rotation of the flagella, facilitating a smooth and somewhat linear swimming path, whereas toxic chemicals provoke a clockwise flagellar rotation, resulting in tumbling and turningawayfromtheoffendingstimulus(Larsenetal.,1974). Thesenseofsmellisoneofnature’struewonders,beingubiquitouswithintheanimal kingdomandcapableofdetectinganddifferentiatingthousandsofdiverseodorantsatvery lowconcentrations.Humanspossessfarmoreodorantreceptortypesthananyothersensory system,whichexplains,inpart,theirabilitytoperceivesuchalargenumberofstimuli.Itis now well established, as described in subsequent chapters of this book, that the olfactory systemprovidesauniqueprobeintothegeneralhealthofthebrain.Thus,smelllossisamong thefirstsignsofneurodegenerativediseasessuchasAlzheimer’sorParkinson’sdiseaseand providesinsight into elements ofbrain development.Importantly, smell loss is one of the best predictors of future mortality in older populations, being a stronger predictor than cognitivedeficits,cancer,stroke,lungdisease,orhypertensionevenaftercontrollingforthe effects of age, sex, race, education, socioeconomic status, smoking behavior, alcohol use, cardiovasculardisease,diabetes,andliverdamage(Wilsonetal.,2011;Gopinathetal.,2012; Pintoetal.,2014;Devanandetal.,2015).Inthefuture,screeningforarangeofneurological disorders by olfactory biomarkers may be commonplace and may encourage the develop- ment of protective measures that delay or prevent central nervous system (CNS) degeneration. Wenowdescribethedetailedanatomy,physiology,andpharmacologyoftheolfactory pathway,followedbyfactorsthatinfluenceolfactoryinputanditsinterpretation. Nasal Cavity During normal inspiration, only 5–10 percent of inhaled airreaches the olfactory epithe- lium.Thisspecializedpseudostratifiedneuroepitheliumharborstheolfactoryreceptors.Itis foundhighwithinthenasalvault,liningsectorsoftheuppernasalseptum,cribriformplate, superior turbinates, and, to a lesser extent, the anterior aspect of the middle turbinates 1 14:54:42 02 2 SmellandTasteDisorders Olfactory bulb Cribriform plate Olfactory epithelium Superior Middle al s na Inferior o h OrOtdoraNntostril TuPrbailnaatetes NasoOdRoreatnrotnasal p h ar y n x Figure1.1 Thisfigureshowsthehumannasalcavityandextentoftheolfactoryepithelium.Notetheextensionof theepitheliumontotheanteriorpartofthemiddleturbinate.Odorantsaccesstheolfactoryepitheliumeither directlythroughtheorthonasalroute(anteriorarrow)orindirectlythroughtheretronasalrouteasinchewingor swallowing(posteriorarrow).ReproducedwithpermissionfromRawson,N.(2000),Chapter11,Humanolfaction. (Figure1.1).Theexistenceofolfactoryreceptorneurons(ORN)onthemiddleturbinateisa usefulaspectofappliedanatomyforthosewishingtobiopsyolfactoryreceptorcells(ORC) forculture,histology,orpatchclampstudies,asitismoreaccessibleandlessriskytosample thanthemainolfactoryarea. Sniffing.Althoughsniffingassistssmellrecognitionandidentification,thefirstawarenessofa newodorcanbepassive;sniffingthenfollowsinanattempttoanalyzetheodorfurtherand assessitsbehavioralsignificance.Sniffingredirectsupto15percentoftheinhaledairthrough theolfactorymeatus,a~1mm-wideopeningleadingtotheuppermostsectorofthenosethat containsmostoftheolfactoryepithelium.Sniffinghelpstoincreasethenumberofodorous moleculesthatultimatelyreachthisregion.However,moleculesmustabsorbintothemucus thatformsacrossthenasalmucosatomakecontactwiththeolfactoryreceptorcells.Insome cases–particularlyinthecaseofhydrophobicodorants–stimulimaybecarriedthroughthis mucusbyspecialized“odorantcarrier”proteinstothereceptors(Pelosietal.,1990).Itshould beemphasizedthatwithoutamoistmucosalsurface,detectionofodorsislargelyimpossible. AsmentionedinChapter5,diseaseswithexcessivenasaldrynesssuchasSjögren’ssyndrome areoftenaccompaniedbysmelldysfunction. NasalTurbinates.Thenasalturbinatesarehighlyvascularizedstructuresthatextendintothe nasalcavityfromitslateralwall(Figure1.2).Theycanrapidlyexpandorcontract,depending uponautonomicnervoussystemtoneandstimulation.Exercise,hypercapnia,andincreased sympathetic tone constrict their engorgement, whereas cold air, irritants, hypocapnia, and 14:54:42 02 AnatomyandPhysiologyofOlfaction 3 Figure1.2 CoronalT1–weightedMRIscantoshowthemainstructuresaroundthenose. increasedparasympathetictonecaninducesuchengorgement.Turbinateengorgementcan beinfluencedbypressureonsectorsofthebody,bodyposition,orambienttemperature.Left- to-rightfluctuationsinrelativeengorgement,termedthenasalcycle,occurinmanypeople overtime,althoughthesechangewithageandreciprocityisfrequentlytheexceptionrather thantherule(Mirzaetal.,1997).Thesefluctuationsrelatetochangesinlateralizedbloodflow tovariouspairedorgans,includingthetwobrainhemispheres,andbelongtothebasicrest- activity cycle, a continuation of the REM/non-REM sleep cycle that occurs during the daytime.Althoughtheturbinateshaveneverbeenthoughtrelevanttotheclinicalneurologist, thisconceptmay needtochange giventhe recentsuggestionthatrhinorrhea, secondaryto relative parasympathetic overactivity, may be a prodromal sign of Parkinson’s disease (see Chapter7andBoweretal.,2006). InnervationoftheNasalCavity.Incommonwiththenasalandoralmucosae,theolfactory epithelium also contains free nerve endings from the trigeminal nerve (CN V). Non- olfactory elements of nasal chemosensation, e.g., sharpness, coolness, warmth, and pun- gency, are mediated via free nerve endings of this nerve (Figure 1.3). These free nerve endings are supplied to the upper part of the nasal cavity by the anterior and posterior ethmoidnerves–branchesofthenasociliarynervewhichcomefromtheophthalmic(first division)ofthetrigeminalnerve.Thenasopalatinenerve,abranchofthemaxillarynerve (seconddivisionofthe trigeminalnerve)is thesourceoftheCNVfibersinnervatingthe posteriornasalcavity.MostodorouscompoundsstimulateCNIandCNV,atleastathigher 14:54:42 02