Premiere Publications from The Triological Society Read all three of our prestigious publications, each offering high-quality content to keep you informed with the latest developments in the field. iF anieiN el ig Laryngoscope Editor-in-Chief: Michael G. Stewart, MD, MPH The leading source for information in head and neck disorders. Laryngoscope.com ramos ita Laryngoscope Investigative Otolaryngology G Editor-in-Chief: D. Bradley Welling, MD, PhD, FACS. Rapid dissemination of the science and practice of otolaryngology-head and neck surgery. InvestigativeOto.com ENTtoday Editor-in-Chief: Alexander Chiu, MD Must-have timely information that Otolaryngologist- head and neck surgeons can use in daily practice. Enttoday.org WILEY‘arngncop 8 January 1088, EVALUATION OF OLFACTORY DYSFUNCTION IN THE CONNECTICUT CHEMOSENSORY CLINICAL RESEARCH CENTER*} ‘WiLuam 8, Cam, PHD RONALD B, GoopsPRED, MD JANNBANE F. Gent, PHD GepaLD LeonaRD, MD New Haven, CT ASTRACT "The olfactory test administored to patients at the Connecticut Chemovensory Clinical Research Center combines stability of outcome with sensitivity to variables known to affect olfaction (age, sex). The test, which pairs am dor Lureshold component with an odor identification component, readily reealves differences in function between. jon of functioning for various probable caus [postupper respiratory infection, and head trauma), proves sensitive to improvemonts in functio fand controle. t reveals differences in the distrib Intervention (othmoidgctomy, se Evaluation of olfaction has typically relied on ther threshold determination or odor identification, or both. Whereas the threshold places functioning on a quantitative continuum,!? odor identification has often offered only an impressionistic, semiquantita- tive view.*# Suitably constructed tests of odor iden- tification can, however, place functioning on a con- tinuum.* The University of Pennsylvania Smell Identification Test (UPSIT), which employs microen- capsulated fragrance labels, is an example.” Cain and Krause* devised various brief quantita tive tests of odor identification with either natural items or microeneapsulated fragrances. A version that comprises natural items became one component. of a two-part test administered to patients at the Connecticut Chemosensory Clinical Research Center (CCRC). Its companion component, a threshold test, employs n-butyl aleohol (I-butanol} as the odorant. Desirable attributes of butyl alcohol include: solubility, low toxicity, ready availability in high purity, and neutral odor quality. Ithas attained wide acceptance as a reference odorant in various applied settings because of these same attributes.” The two- ‘component CCCRC test is portable, inexpensive to create, and can be administered in an ordinary room. ‘The CCORC has evaluated the olfactory function- ing of hundreds of patients over the last few years. ‘The olfactory tost has been shown to be effective in distinguishing patients with complaints from those with no deficits."° The present report extends the ‘—Wiventh JB, Perce Foundation Laborairy ued Yale Univeriy Seheatef Mectne (WSC), New Haven the Deparnont of Paine Dendy, Sena! o Donat Medios, Univesity e Conca Health Cente 9.6 the Department fee, Shel of Modo, Univer iy Connetat Hens Contar(2.8.;end the Dien of Orage fy, Doparnnt ef Surgery, Schon of Man, Univers of Conca $k Genter(O). ‘his stay was eopporel by NIH grants NSI6GOS and NS2IE4, glo“ Nt: This anak wen eld fr pity 14 ‘Sond Roprint Roguuts to Dr, Willa 5, Calo deh Pleo Found ‘ion abartry, 290 Congress Aven, Now Haven, POSSI 83 ised by therapeutic ‘administration for nnsaVsinue disease), and correlaten with objective signs of ‘nsal/sinus disease (visual exam, xray). The two components of te t ‘component soos somewhat more sensitive than the threshold component ‘agreo well, though the odor identification ‘currenlly designed. comparison to a group of 670 patients and controls, and considers how porformance varies with age, sex, probable cause, and therapeutic intervention, and how well the two components of the test agree. ‘METHOD Subjecte Testing was porformed on 229 paldveluntoorawithot olfactory complaints, Thoso parsons roorultad through «varity of char holy rangod from 6 a 64 years of ago, median 86, Ratio of ales to females equated 3.06, Patients ‘Tho test was givon to 441 patients at the CCCRC between ‘August 1881 and December 1964, Those poaons ranged frm 17 {685 years a ag, modion 5. Rao of female fo male equalled EBighty-nino porcont of tho pationts complained ofan olfactory Aisordor, 96% ofthese of a pallor completo ibility ta eral ‘Average doration of complaint equalloa 8 youre. Half tho patients hned previously sought modal trntment fer thelr compat." ‘eating Procedure Routine evaluation ofa patient ineiaded oterhinalaryngoogial (ORD), nauralogial, physesl, and dental (optional) exams ‘nutrition interview, linia! laboratory sreoning tat, and vel ‘tion of smell and fasta" The ovalsaion of sell tok pln st but alwaysheforethe ORL elved tho all teat elthor ‘Threshold Teeting ‘The threshold test employed aqueous dilutions of 1-butanal where succossve dilations dered bya factor of three. Tho highest aqueous eancontratln equalled 4% (vapor phase of ap. proximately 3,000 ppm. Tho numberof dilution steps ranged from ‘St013 depending upon ereurastancas of tstlog. ‘Thotest solutions were presented for smalling In 250-ml eapas- lay squeezablepalyethylone bates containing 00 ml af aoltion™ ‘Tao botl laste had a pop-up spout that Gitd inte the nostri. ‘Te sample a both, tho person placed the epout into the epecfied ost, Chen squecre end anid sisleaneoualy. ‘A tos hit contain an ompty bottle used to demonstrate the ssucesing and vllingtehque, twa bettas at each tat concen. ‘ation, and sb blanks of deionized water Pig. 1). Testing bogan ‘with te lowest concentration. The tet participa resivd the atte with thiseoncontration along with ablank andliad ta decide84 CCAIN, ET AL: EVALUATION OF OLFACTORY DYSFUNCTION ter Names 1. Squentble ots sor or tenons and riers for threshold testing, jars used ‘of odor choces to which patient Which smeled strongor. If lator, the parilpant reclvod ‘nothor blank paired with the next higher ebneontration. Herons {riguored ineromoatsin concentration, whoreas correc choices|ed {o anothor presentation of tho samo concentration (in tho other bottle) anda blank Four correct choles In raw led to cessation ‘testing The ensentration at which this ceurred marked the ‘Threshold ig. 2) Aftor dotcrminaton ofthe threshold the lot nostril toting awitehod to tho ight ast, Hentfcation Testing ‘The participant recalved the idoatiiestion tat aftr tho thresh. cldttat Ait comprised ton 180ml opaque plastiejarscontciag fachot-like pockota of stil. asod onthe performance af naa: fale pation, wo cen sty tat oven simul appeajed exciosivey, fr almost a0, to tho sonte of sell Gohason'sbaby powder, thocolat, cinnamon, ele, mathbals, peanut butter, en Teary® {uarscap)andtnreeappealodtofhocommen chemical sonreas well (Gmmonte, Vicks Vapo Steam, and wintargroan). The ton itoms ‘wore prosonted in irogular order for monorhlaie smelling. Zo ttriet the stimslse to one nostril, eho participant hold the Frrlovant nstell cls ‘Whoa proaonied with anitom, th patiipant sought is name from a3 ltr list placed against x seoon that scparated part pant from examiner. The it contelned tne name of tho on toot. Remsandotten lstracors (Pig 1) Ta edltlan othe namasonthe lis responses ono seneaton® and “don't know” wore pormited. ‘The exami gave corroctive feedback whenevor the parteipant, tented tiated items a tecond timo st some forrest answer upoa soond prosentetion canclled & provious ‘ror. This llowods partiipant to realy mistakes and thereby ‘crease tne posit of cognitive crrora.ta such cages, thelist le point A lela! with en item sorved as training. The score for tho tast ‘amprised the number af elfeclary items out of sevan corecly Hontifed and e notation regarding ability to parelve trigeminal imolation Pig. 2). RESULTS ‘Threshold: Normals ‘Thresholds for normal volunteers followed a roughly normal distribution with a mode at dilution 8.0 and a mean at 7.7 (SE=0.12) (Fig. 3). The range of concentration for persons under 65 years exceeded 500 to 1. Such a large range is not uncommon in et fa Die vu oses sy 2 ow te | ee 7T [RTT = tex Text bis ST] 2, Seoro shoot for odor ta Laftsido shows typical hres results fore hyponle patient Tho treabalgouelled 4 in thoieh ontrl (EN) nd fie Fight ostil (RN): Righe side awe ‘onincaton rosalts, The sere of iatoret is tho cumulative ‘amber af correct reopones tothe seven ited lat odar, Which qunlod 4 nnd 3 forthe Teh and right nostri, resecivly. {beret responses on rat were carved over taal (Phe ikes ‘smmonia and wintergreen, mentined in the txt, are sometimes replaced by tel eens, auch nd guile and emo ic, which 60 Bat figurela the scoring hela of choices elteredactordlngl) ‘eating af bath nostra to optional and doos not igure In the ‘coring. Trigeminal response wes teatod with Vicks single-session olfactory testing." Persons over 65 showed an even greater rangeand ahigher threshold, mode and mean of 6.0 (SH=0.32) ((6648)=4.91, <0.0001), ‘Age took a gradual toll on threshold sensitivity beginning in about the sixth decade (Pig. 4). A ten- dency toward female superiority, seen in theresults of younger participants, became more pronounced in the results of older participants, Analysis of variance (ANOVA) confirmed the reliability of age and sex as significant factors (FI7,211}=7.83, p<0.0001 for age; FUL,211}+5.88, p<0.021 for sex) Identification: Normals Modal performance of normals in identification occurred at seven items correct (ie., perfect perfor- mance) with a sharp reduction in frequency from seven to four items correct (Fig. 3). Women performed better here also, and the influence of age on perform- ance looked much like that seen in the threshold test, ie, stable average performance throughout the younger decades in both sexes followed by a grad- ual fall (Fig. 4) (F17,203]=14.39, p<0.0001 for age; FUL,2031-6.18, p<0.014 for sex). ‘Threshold: Patients The threshola distribution for patients differed dramatically from that of normals (ig. 8). The modal threshold occurred at a point equal to or greater than the highest available concentration (dilution step 0) andonly 3%had thresholds equalto or better than the average normal person. Age bore no relation to ‘Hreshold among patients, where frank clinical prob-‘CAIN, BY AL: EVALUATION OF OLPACTORY DYSFUNCTION 85 -Butonat Theshols Threshold Score ee Fig 2. Distribution ofthresbol Odor Identification Composite Scare Rei 1 stop) threshold score(seala of to), odardenteation (Ot), and composite score (average of odor idcntiiation and threshld sara) for patents and controls undor ago 6B lems predominated. Average threshold equalled 2.0 (SB=0.10) below age 65 and 2.5 (SE=0.24) above 65, Identification: Patients ‘The patients also produced a markedly abnormal distribution in the identification test (Fig. 3). More than half the patients scored zero and only 7% scored ‘as many as seven items correct. ‘The correlation between the threshold and identifi- cation tests equalled +0.77, which indicated that the score on one test predicted 60% of the variance on the other. Both tests presumably measure largely the ‘same property: sensitivity. Composite Score ‘The outcome of the threshold and identification tests was combined into a composite seore. Under the assumption thata person whoobtaineda thresholdat step 7 or better had normal threshold functioning, re was no further need to discriminate among steps 7, 8, 9, and so on, The distribution of threshold fter this foreshortening looked much like that of the identification scores (Fig, 3). The foreshorten- ing had no deleterious effect on the correlation be- tween the tests (+0.78 vs, +0.77). This recoding of ‘norma? thresholds also led to considerable similarity in the picture of how age influenced the two types of tests (Pig. 4) To combine the threshold and identifi- cation scores into a single score, we averaged the two (Fig, 3). The advantage ofso combining the two scores, can be decided from a comparison of scores across nostrils in the control population. The correlation coefficient between nostrils equalled +0.72 for the threshold score, +0.68 forthe identification score, and. +0.79 or the composite. Hence, the use ofthe compos- ite sore increased the variance accounted for by 37% over the use of the identification score alone and 23% over the use of the threshold score alone. The infla-86 Ase ‘CAIN, BT AL: EVALUATION OP OLPACTORY DYSFUNCTION (years Pig. 4 Showing how performance inthe threshold and identifintion componenta varied with ago and sox in controls, ence of age on composite score looked much like that seen in previous examples (Fig. 4). Sex, however, disappeared as a relevant variable. A composite sco:e of 6 or better accounted for approximately 90% ofthe distribution of normals, as did an identification score of 6, and a threshold of 6 ig. 2). This level, which represents the intersection point between the distribution of controls and the Aistribution of patients, was defined as the lower ‘boundary of thezone of normosmia, Composite sores of at least 5, but less than 6 were designated mild hhyposmia, Scores of at least 4, but less than 5 were designated moderate hyposmia. Scores of at least 2, Datlessthan 3 were designated sovere hyposmia. And scores below 2 wore designated anosmia. (For persons, ‘over 65 years, the upper boundary of zone ofhyposmia, was set at 8 and the boundary between mild and moderate hyposmia was shifted down by one point.) Distribution of Functioning for Various Probable Causes Common causes of olfactory dysfunction in CCCRC patients included: J. nasal/sinus disease (e.g., poly- posis, pansinusitis) (30.2%), 2. postupper respiratory illness (post-URD (18.6%), 3, head trauma 8.6%), and 4, idiopathic hyposmia/anosmia (21.0%)." Among Tmt eran [“ rn ig. 5, Dlsrbution of performance (compos score) for pax tion of three etiola these eategories, the distribution of scoresin the post- URI and idiopathic eategories differed from those in the nasaV/sinus disease and head trauma categories ig. 5). Whereas the distributions for nasal/sinus disease and head trauma displayed a majority of scores of anosmia (scores less than 2), those for post- URL and idiopathic conditions displayed a majority of scores of hyposmia (scores of 2 or more). The finding that patients with nasal/sinus disease exhibit three times the frequency of anosmia as patients with post. ‘URI ean have diagnostic significance. An outeome of anosmia on the olfactory test should increase efforis to look for signs of nasal disease, even though the patient may claim that the smell problem began after an upper respiratory infeetion.!* ‘The difforencos in distributions among etiological categories held true for both the threshold and the identification components ofthe olfactory test Never- theless, the identification component consistently yielded a higher frequency of anosmic scores (85% us. ‘72% for nasal/sinus disease, 42% vs. 34% for post- ‘URI, 78% vs. 62% for head trauma, and 56% vs. 39% 06; Patients 8 | a a Disparity Score (Threshold Score ~10 Seore) Distribution of dapertybotween th Useshold score and ton sare in patients, veel‘CAIN, BT AL.: EVALUATION OF OLFACTORY DYSFUNCTION 87 Exam + X-ray positive Exam or X-ray positive Nelther positive ores 45 67 Composite Score Fig. 1. Avorago compute scare (41 patignts with varying dagrocs of evidence a {for idiopathic). This component may therefore have higher sensitivity than the threshold component. The distribution of difference scores betwoen the compo- nents (threshold score minus identification score) emphasizes that conclusion (Fig. 6). Although the two components yielded scores within one point of each other in two thirds of cases, positive deviations of a ‘magnitude greater than one exceeded corresponding negative seores by 3:1. Hence, the threshold task made pationts appear more normal than the identifi- cation tal ‘We may ask whether the score on the olfactory test shows any association with objective indices of di ease. Figure 7 shows such an association in 200 patients who received both a nasal airway examina- tion (with a nasopharyngoscope) and x-rays of the sinuses.*The composite score for the 181 individual nostrils with postive signs of nasalsinus disease by both nasal exam and x-ray fall significantly below that of the 74 nostrils with only one positive sign, which in turn fell below that ofthe 196 nostrils with no positive signs (Scheffés's Multiple Range lest, 1<0.08). Two positive signs suggest more serious dis fase than one and lower functioning falls in register with that finding. Improvement of Scores with Therapy: Case Studies ‘Figure Biillustrates how the test reflected improve- ‘ment of functioning after transantral ethmeidectomy for diseased sinus tissue. The patient's olfactory fune- tion rose from anosmia presurgery to normosmia postsurgery. Figure 9 displays function scores for 30 patients with various probable causes of dysfunction (L4nasal/ sinus disease, 5 post-URI, 7 idiopathic, and 4 ‘other, excluding head trauma) before and during a 1-week course of systemic corticosteroid administration (60 mg of prednisone daily). As a group, only the nasal/sinus disease patients showed reliable im- provement. Funetioning fell in the anosmie range (a score of 1 or below) prior to steroid administration, but rose to moderate hyposmia (between three and five) after 7 days on the medication, a significant improvement (paired ¢ = 4.52; d/13; p<0,001). Post- URL and idiopathic patients started and finished the ‘week of medication with severe hyposmia, Patientsin the “other” category started and finished with anos- mia, Temporary reversal of anosmis/hyposmia via TT Patient #226 L a4 3 5 3 3] = ct surgery re ' “mt ttt, Time post-surgery (weeks) ig 8, Showinghow measured olfactory functioning varied over no nire and ster staged surgery eR se thon Sight sida) {he etimotd sinus steroid therapy has long been known (though only by subjective report) in eases of nasal polyposis. DISCUSSION ‘The two-component CCCRC olfactory test seoms to perform satisfactorily for the various issues posed s0 farin the chemosensory clinic. The two components of the test yielded similar outcomes when scored on the seven point scoring system. Among normals, each component uncovered a gradual decline with age beginning in late middle age and a slight advantage for women. Inthisregard, theresults agree with those 7 _ 7 NORMOSHIA NASAL walle Sh sinus moderate DISEASE 4] 1b ne nyPosia| Composite Score WAT WAT U7 UAT Day Fig. . Showing how clfutory sores i for goo ‘arid on daye 4, and 7 ofa day cures of rl som UF predasone (6 ing). Text om ‘ediation, 5 patients itrtion ‘T'precoded the use af the88 (CAIN, BT AL: EVALUATION OF OLPACTORY DYSFUNCTION on the UPSIT"s# and with other tests of odor identi fieation'* and odor threshold. Each component also offered good resolution between the patient with fn olfactory complaint and the normal, though the identification component offered slightly better reso- lution. This difference between components could reflect the stringency of the criterion used to decide threshold, A criterion of four eorrect choices in a row may yield some unrealistically low thresholds. A. more stringent criterion, such as five correctin a row, ‘might bring the two components into alignment. Insofar as the two components might measure the same propery, then one component, might seem superfluous. On the grounds of ease of use, speed of administration, and resolution between patients and controls, the identifieation component might seem the more desirable, Indeed, if circumstances permit- ted use of only one component, the identification component would generally be the choiee. Ibis, how ‘ever, too early to decide to use only one component, routinely. In the two-component test, the threshold eompo- nent has particular value in lability eases. Whereas the malingerer could merely claim not to detect the items in the identification component, he must make achoice on each trial in the threshold test. Whenever applied in a liability ease, the usual threshold testing, procedure where errors trigger increases in concen- tration is abandoned. Instead, all concentrations are given four times until two successive concentrations are detected four times out of four or until the highest concentration is reached without consistent detec- tion, This strategy allows inspection of the data for departures from randomness that mighteharacterize apatient who tries to simulate anosmia, ‘The ease of construction and simplicity of adminis- tration of the CCCRC test will, we hope, encourageits use beyond the clinic specializing in chemosensory disorders. In routine ORL practice, the test couldhelp bboth to establish the initial severity of olfactory disor- ders and to chart the course of changes after surgery, during and after medication, or simply over time. Such use would decrease sole reliance an the subjec tive impressions of the patient and could assist in appropriate and timely decision making. BIBLIOGRAPHY : Olfacton in Human Disease, In: Loose Lea layngology. G. M. English (BA). Harper and Row, [New York, pp. 139, 1082 2. 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