European Annals of Otorhinolaryngology, Head and Neck diseases 133 (2016) 113–118

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Review

Olfactory exploration: State of the art

D.T. Nguyen ∗ , C. Rumeau , P. Gallet , R. Jankowski
Service d’ORL et chirurgie cervico-faciale, hôpitaux de Brabois, CHRU de Nancy, rue du Morvan, 54500 Vandœuvre-lès-Nancy, France

a r t i c l e i n f o a b s t r a c t

Keywords: Olfactory disorders are fairly common in the general population. Exploration, on the other hand, is seldom
Olfaction performed by ENT specialists, even in reference centers. There may be three reasons for this: this particular
Self-assessment sensory modality may seem unimportant to patients and/or physicians; available treatments may be
Psychophysical test
underestimated, although admittedly much yet remains to be done; and olfactory exploration is not
Olfactory bulb
covered by the national health insurance scheme in France. Advances in research in recent decades have
Olfactory evoked potentials
Functional MRI shed light on olfactory system functioning. At the same time, several techniques have been developed
to allow maximally objective olfactory assessment, as olfactory disorder is sometimes the first sign of
neurodegenerative pathology. Moreover, objective olfactory assessment may be needed in a medico-legal
context. The present paper updates the techniques currently available for olfactory exploration.
© 2015 Elsevier Masson SAS. All rights reserved.

1. Why test olfaction? Fluctuation in the olfactory disorder should be investigated,

as it is often associated with inflammatory pathology, either
About 1 in 15 adults has an olfactory disorder [1,2]. The propor- nasal (allergic rhinitis), ethmoid (nasal polyposis) or, more rarely,
tion increases with age, reaching 30% or more in over 70-year-olds sinus (maxillary, frontal or sphenoidal sinus pathology). Olfac-
[1]. Age-related olfactory impairment seems to implicate reduced tory distortion is often reported in post-infectious anosmia or
regeneration of olfactory cells during life: the loss is progressive, hyposmia, and by certain women around the age of 50; in
and most people fail to notice it [3]. Younger hypo/anosmic patients younger patients (1st and 2nd decade), on the other hand,
often report diminished quality of life, loss of libido, depression and metabolic etiology should be explored [12]. The interview also
elevated risk of domestic accidents [4–10]. assesses impact on quality of life (depression, libidinal disorder)
Exploration of olfactory disorder is essential, firstly to plan treat- and may identify a domestic accident that led to the olfactory
ment when possible, and secondly for medico-legal reasons. Once impairment.
diagnosis has been established, the physician should inform the
patient and family and provide advice to help overcome the dis-
ability and in particular to avoid domestic accidents.
3. Clinical examination

2. Interview Rigid or fiber-optic endoscopy of the nasal cavities, and of the

olfactory clefts in particular, should be attempted, with or with-
The interview is primordial in establishing etiology and clas- out local anesthesia. Endoscopy, however, is sometimes hindered
sifying dysosmia. It should focus on onset circumstances (cranial in consultation by septal deviation, chondrovomeral spur, narrow
trauma, infection, medication), occupational or personal toxic cavity or poor patient cooperation preventing visualization of the
exposure (wood dust increasing the risk of olfactory cleft cancer olfactory clefts. If possible, the examination should assess olfac-
[11], exposure to chemicals, tobacco smoke, etc.) and personal and tory cleft mucosal status (edematous or not), presence of polyps, of
familial history (Parkinson’s or Alzheimer’s disease, schizophrenia, respiratory epithelial adenomatoid hamartoma [13,14] or any neo-
etc.). plastic lesion, pathological discharge, obstructive septal deviation,
and hypertrophy of the respiratory and/or olfactory nasal mucosa.
When ENT examination fails to identify any nasal etiology, a neuro-
∗ Corresponding author. logical or sometimes psychiatric opinion may be sought, depending
E-mail address: [email protected] (D.T. Nguyen). on the findings of the interview.

http://dx.doi.org/10.1016/j.anorl.2015.08.038
1879-7296/© 2015 Elsevier Masson SAS. All rights reserved.
114 D.T. Nguyen et al. / European Annals of Otorhinolaryngology, Head and Neck diseases 133 (2016) 113–118

4. How to assess olfaction? represents peripheral olfactory receptor sensitivity, and completes
the more advanced and complex assessment of odor identification
4.1. Self-assessment and discrimination, which also involve central olfactory functions.
High concentrations (suprathreshold) are often used in the odor
Olfaction can be self-assessed subjectively, on a binary question- identification and discrimination sub-tests. Odor identification is
naire (Do you have olfactory disorder? yes/no), a 3-, 5- or 11-point often defined by the ability to name an odor: the subject has to
numerical scale [15–17], or certain quality of life questionnaires detect and then recognize the exact odor and finally retrieve the
(e.g., DyNaChron) [9,18]. These are the simplest and quickest means appropriate verbal label from semantic memory. Odor discrimi-
of assessing olfaction at a point or over a given period of time. They nation is less complex, the subject detecting then differentiating
are, however, entirely subjective and require perfect cooperation between odors.
and confidence in the subject’s responses. Performing just one sub-test leads to much lower specificity
Self-assessment proves unreliable in normosmic patients with- and sensitivity than the full test, which is the reference procedure
out prior training [19], as they may have no idea what olfaction [57]. It is recommended to associate detection threshold testing
loss is like, or before surgery for nasal polyposis [20], where the to at least one of the other sub-tests (odor identification and/or
patient is liable to exaggerate his or her impairment so as to justify discrimination), either combination being equally reliable [36].
the operation. In contrast, there is a strong correlation between
self-assessment and psychophysical assessment of olfaction in 4.3. Electrophysiological recording
hyposmic and anosmic patients [19,20]. There is also a strong cor-
relation between olfactory self-assessment and nasal permeability Electrophysiological recording reveals presence or absence of
in healthy subjects [19] and patients with septal deviation and/or olfaction objectively. It may be required for medico-legal purposes,
inferior turbinate hypertrophy [21]. Self-assessed olfactory disor- especially in case of post-traumatic anosmia. This method is rarely
der seems to correlate with self-assessed nasal obstruction when used in practice, as it is complex to perform and the apparatus is
the two symptoms are associated or absent [20], but not when they expensive.
are dissociated [20].
Certain specific questionnaires, such as the QOD (Questionnaire 4.3.1. Electro-olfactogram
for Olfactory Dysfunction) [22], may be useful in assessing qualita- Each odorous stimulation depolarizes the olfactory receptors,
tive olfactory disorders, such as parosmia or phantosmia, for which and the sum of these depolarizing currents induces a negative
there are no objective assessment tools. potential on the surface of the olfactory epithelium. Recording this
Finally, combined self-assessment and psychophysical testing is signal, however, requires an electrode positioned under endoscopy
recommended in current practice, as it is more precise, especially in direct contact with the sensorineural epithelium: i.e., in the olfac-
in fluctuating disorders of smell [20]. tory cleft [58]. The procedure is little used in humans, except in
research laboratories.
4.2. Psychophysical tests
4.3.2. Contingent negative variation (CNV) [59]
Psychophysical olfactory assessment tests are widely used, CNV corresponds to cognitive information processing, cortical
being easy to perform and more reliable than self-assessment. alertness, attention level, perception, and motor task readiness
They are considered semi-objective, as they require the cooper- [60,61]. It shows as a slow negative deflexion wave on the elec-
ation of the subject. They can only be used to assess quantitative troencephalogram, appearing after the first stimulus to be detected
disorder. (S1) and before the second stimulus (S2) [59], whence the name
Some 200 psychophysical tests have been developed; Table 1 “S1–S2 paradigm”. It was first described by Gerull et al. in 1984
presents only those that have been validated [23–52]. The most [62] as a clinical investigation tool to confirm perception of an
widely used are the UPSIT, CCCRC and Sniffin’ Sticks tests. Reliabil- odorant. Following odorant stimulus S1, CNV appears ahead of S2
ity depends on the composition of each test battery, the number (which may, for example, be an acoustic stimulus), disappearing at
of odors tested and the number of subjects involved in validation. S2 onset. If the subject fails to detect the odorant, no CNV appears
Whichever test is used, interfering factors, such as age, gender, on the electroencephalogram. However, the technique appears not
culture, geography, etc. must be taken into account. to be reliable, the CNV onset depending on a range of psychological
Olfactory measurement may be conducted orthonasally (as in variables [63].
most tests) or retronasally. Orthonasal olfaction is tested by pre-
senting olfactory stimuli below the nasal vestibules, and retronasal 4.3.3. Olfactory event-related potentials (OERP)
olfaction by delivering olfactory stimuli (liquid [53], spray [43], Since Gert Kobal’s pioneering work in 1981 [64], electroen-
or powder [49]) to the mouth (on the tongue), so that the stimu- cephalographic OERPs have been widely used in many countries
lus reaches the olfactory mucosa via the rhinopharynx. Retronasal to explore olfactory system functioning. Recording is via elec-
assessment is more precise in case of mechanical or inflamma- trodes positioned at the vertex, under rigorous stimulus control.
tory obstruction of the anterior nasal cavity [54,55]. The Japanese The principle consists in repeating 16 to 80 olfactory stimuli of
developed another method of retronasal assessment, measuring 200-millisecond duration and with 7–8 L/min airflow at 30–40 s
the latency between intravenous injection of prosultiamine (garlic intervals to avoid olfactory system adaptation. The OERP is a
odor), which is eliminated via the lung, and the moment at which biphasic potential with negative deflexion, N1, showing 200to
the subject reports smelling the odor [56]. 700 ms’ latency after olfactory stimulation, followed by a posi-
Psychophysical tests are mainly based on three principles: the tive wave, P2, with 300–800 ms latency [65]. The P2 component
odor detection threshold for an odorant stimulating only olfac- is often described as a complex of two distinct components (P2
tory receptors (often n-butanol or 2-PEA (2-phenylethyl alcohol)), and P3) [66]. There is from time to time an initial positive P1 peak
odor identification (with or without the help of an odor list), and with 250–320 ms latency before N1 [66]. The final OERP is the
odor discrimination; the combination of these varies from test mean value for all stimulations, to highlight variations synchro-
to test (Table 1). The odor detection threshold is defined as the nized with stimulus onset and reduce non-synchronized activity
lowest concentration of odorant detected by the subject in a proce- [67]. The purely olfactory molecules used are vanillin, 2-PEA (rose),
dure presenting increasing or decreasing concentrations. It mainly hydrogen sulfate (H2 S: rotten egg), or amyl acetate (banana); CO2
 D.T. Nguyen et al. / European Annals of Otorhinolaryngology, Head and Neck diseases 133 (2016) 113–118 115

Table 1
Olfaction tests.

Test Year Method

Country

CCCRC (Connecticut Chemosensory 1983 and 1988 1/Threshold test: n-butanol. Forced choice, 2 alternatives (odor vs. odorless)
Clinical Research Center) [23,24] USA 4-correct-in-row-method. Odorsin flasks
2/Identification: 10 odors in jars. Forced choice, 20 alternatives. Feedback
UPSIT (University of Pennsylvania 1984 Identification of 40 encapsulated odors. Forced choice, 4 alternatives. Technique:
Smell Identification Test) [25,26] USA scratch and sniff
OCM (Odorant Confusion Matrix) [27] 1987 Identification of 10 odors presented 10 times each (100 stimuli, or 121 if blanks are
USA added). Forced choice, 10 alternatives
Identification vs. misidentification
T&T Olfactometer (Toyoda and Takagi 1987 5 odors. Detection threshold: lowest detected concentration; recognition threshold,
Olfactometer) [28] Japan lowest identifiable concentration. Odors are presented on filter paper
GITU (Geur Identification Test Utrecht) 1988 Identification of 18 or 36 odors in pots. Forced choice, either 4 alternatives, or a list of
Dutch Odour Identification Test [29] Netherlands 24 for 18 odors to be identified
Everyday life odors
SDOIT (San Diego Odor Identification 1992 Identification of 100 odors in pots. Forced choice with a table of 20 visual stimuli
Test) [30] USA
Computer-assisted olfactory test [31] 1994 Odors in bottles
France 1/Threshold determination for 5 odorants
2/Identification of 6 odorants
CC-SIT (Cross-Cultural Smell 1995, 1996 Identification de 12 encapsulated odors. Forced choice, 4 alternatives. Technique:
Identification Test) USA scratch and sniff
MOD-SIT (Modular Europe
SmellIdentificationTest) [32,33] Asia
Combined olfactory test [35] 1996 1/n-Butanol threshold test. Plastic recipients
UK and New Zealand 2/Identification of 9 odors in pots. Forced choice, 4 alternatives
Sniffin’ Sticks [36–38] 1997, 2000, 2007 Odors in pens
Germany Switzerland 1/n-Butanol threshold test. Forced choice, 16 triplets. Single staircase method
Austria Australia 2/Discrimination: 16 odorant triplets. Identification of pen with different odor. Forced
Greece Italy choice
USA 3/Identification: 16 odors. Forced choice, 4 alternatives
AST (Alcohol Sniff Test) [39] 1997 Isopropanol detection. Measurement of distance from nose
USA
CA-UPSIT (Culturally Adjusted 1998 Identification of 20 encapsulated odors. Forced choice, 4 alternatives. Technique:
olfactory test, derived from UPSIT) USA scratch and sniff
[40] Guam
SOIT (Scandinavian Odor Identification 1998, 2001 Identification of16 odors in flasks. Forced choice, 4 alternatives
Test) [41,42] Sweden
Finland
Smell diskette [44] 1999 Identification of 8 odors. Forced choice, 4 alternatives
Switzerland
“Random” test [45] 2001 Labeling 16 concentrations of 2 odorants presented randomly
Germany
“Four-minute odor identification test” 2001 Identification of12 odors in pens. Forced choice, 4 alternatives
[37] Germany
Biolfa olfactory test [47,48] 2002, 2004 2 seriesof flasks with different odors:
France – threshold test (3 odors: eugenol, aldehyde C14, phenylethyl alcohol (PEA))
– identification test: 8 odors at 4 concentrations each, forced choice with 6
alternatives
Retronasal smell test “taste powders” 2002 Retronasal olfaction test
[49] Germany Identification test: 20 odors. Forced choice, 4 alternatives
Powders applied to tongue
ETOC (European Test of Olfactory 2003 16 bottles of different odors, in 2 steps:
Capabilities) [50] France, Switzerland, – Detection
Netherlands – Identification: forced choice, 4 alternatives
Composite score taking account of chance answers
BAST-24 (Barcelona Smell Test–24) 2006 24 odors: 20 olfactory, 4 trigeminal
[51] Spain 3 questions to:
– detect odor (“Can you smell something?”)
– spontaneously identify odor (“Do you recognize this odor?”)
– identify odor on forced choice (“Which of these 4 odors do you smell?”)
OM (Odourized Markers) [52] 2007 6 colored odorized pens. 2 steps:
Czech Republic – name odor without guidance
– identify odor on forced choice with 4 alternatives

can also be used to stimulate the trigeminal nerve. If an OERP is Electrophysiological olfactory recording gives objective assess-
evoked, the olfactory system is functional [65]. Absence of OERP, ment of olfactory function, but does not shed light on the etiology
however, does not demonstrate absence of olfactory function, as of olfactory disorder [55].
30% of subjects without olfactory deficit show no OERP [68]. One OERPs are used clinically when the origin of olfactory disorder
hypothesis for absence of OERP is temporal variation in signal onset is unclear [66]. Recording takes about 45 min in all for twenty 2-
over successive sequences, thus failing to emerge in the mean value PEA stimuli followed by twenty trigeminal CO2 stimuli. Absence of
[69,70]. For this reason, time-frequency wavelet analysis, moni- olfactory with presence of trigeminal potentials (even with sub-
toring signal frequency over time, has been recommended [70]. tle changes) is a strong indicator of olfactory dysfunction: e.g.,
116 D.T. Nguyen et al. / European Annals of Otorhinolaryngology, Head and Neck diseases 133 (2016) 113–118

congenital or post-traumatic anosmia [66]. OEPs can also con- and dispersed, inter-subject variation in a given observational set-
tribute to early diagnosis of Parkinson’s and Alzheimer’s disease, up is great [88], activated areas depend on the complexity of the
multiple sclerosis, etc. [66]. cognitive task associated to sniffing [89], and certain random acti-
vations may occur in anosmic subjects [65]. Consequently, fMRI
4.4. Investigation of reactions to olfactory stimulation data are to be used with caution in diagnosing olfactory disorder.
The technique should nevertheless be further studied, so that one
Based on the change in respiratory rate following olfactory stim- day it may provide a reliable diagnostic tool.
ulation, the Sniff Magnitude test (CompuSniff) was developed to
complete the odor detection and identification tests, overcoming
5. Conclusion
certain limitations of traditional psychophysical tests [71]. It can
be used in uncooperative patients and children.
Olfactory exploration methods have greatly developed over
Assessment of the pupillary reflex and blink induced by olfactory
recent decades. Even so, interview and clinical examination remain
stimulation remains restricted to research applications and is not
essential to diagnosis. Psychophysical tests are easy to imple-
yet used clinically [65].
ment in everyday practice, but are time-consuming, and should
be interpreted with caution in the light of their limitations. Finally,
4.5. Olfactory bulb volume
objective methods of olfactory exploration, such as evoked sen-
sorineural potentials and functional MRI are being developed and
Olfactory bulb plasticity depends on peripheral olfactory neu-
perfected, and may be available for everyday use in coming years.
ronal activity [72]. It has been suggested that there is a close
relation between structure and function, as there is a correlation
between olfactory function and olfactory bulb volume in subjects Disclosure of interest
with healthy olfaction [73]. Olfactory bulb volume has also been
shown to correlate with olfactory dysfunction [74] and with psy- The authors declare that they have no conflicts of interest con-
chophysical and electrophysiological results [75]. Olfactory bulb cerning this article.
volume can be measured by contouring ≥ 1.5 Tesla MRI images
[76]. The depth of the frontal lobe olfactory sulcus, which seems
to depend on the presence of the olfactory bulb [77] and shows References
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