Chemical Senses Vol. 30 No. suppl 1 © Oxford University
Press 2005; all rights reserved
Clinical Studies of Olfaction
Smell & Taste Center, University of Pennsylvania Medical Center, Philadelphia, PA, USA
Correspondence to be sent to: Richard L. Doty, e-mail: doty{at}mail.med.upenn.edu
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Introduction |
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 Top Introduction Disorders associated with...Causes of chemosensory lossAcknowledgements and disclosuresReferences |
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Disorders of the senses of taste and smell are not uncommon, occurring in over three million adults in the United States alone. Olfactory dysfunction occurs in about half of the population between the ages of 65 and 80 years and in about three-quarters of those 80 years of age and older (Figure 1). Although rarely appreciated, taste and smell disorders have significant consequences for the patient, including (i) impaired quality of life; (ii) increased health or safety risks from spoiled foods and dangerous vapors (e.g. leaking natural gas); (iii) compromised vocational abilities; and (iv) altered food choices and consumption patterns that can adversely impact health or worsen underlying illnesses (e.g. decreased body weight, impaired immunity, overuse of salt in hypertension or sugar in diabetes mellitus).
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A major focus of our Center over the last 25 years has been on the development of reliable, valid and easy-to-use tests for evaluating the senses of taste and smell. Quantitative testing is needed to (i) determine what specific cranial nerves are affected; (ii) accurately assess function (patient subjective reports can be misleading); (iii) communicate valid information to patients regarding the level of dysfunction and whether it is normal for their age and sex; (iv) monitor disease progression; (v) determine treatment efficacy; (vi) provide objective information regarding worker’s compensation and other insurance or legal claims; (vii) detect early signs of tumors and neurological disorders that may not be discerned otherwise; (viii) maximize efficacy of intervention or treatment; (ix) detect malingering; and (x) provide state-of-the-art medical surveillance and care. Most of the olfactory tests we have developed, including tests of odor detection, identification and memory, are commercially available and some, such as the University of Pennsylvania Smell Identification Test (UPSIT), have been translated into multiple languages and administered to hundreds of thousands of persons. Among the findings of our Center is the close relationship between a test’s length (e.g. number of items) and its reliability, a key index of its sensitivity (Figure 2).
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Disorders associated with olfactory loss |
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TopIntroductionDisorders associated with...Causes of chemosensory lossAcknowledgements and disclosuresReferences |
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Although there are numerous diseases, disorders, drugs and interventions that can adversely influence smell function, nearly two-thirds of chronic anosmia or hyposmia cases (i.e. those which are presumably permanent) are due to prior upper respiratory infections, head trauma and nasal and paranasal sinus disease (Deems et al., 1991
). Fewer instances of olfactory
dysfunction are associated with iatrogenic interventions (e.g. septoplasty, rhinoplasty,
turbinectomy, radiation therapy, medications), intranasal neoplasms (e.g. inverting
papilloma, hemangioma and esthesioneuroblastoma), intracranial tumors or lesions (e.g.
Foster Kennedy syndrome, olfactory groove meningiomas, frontal lobe gliomas,
epilepsy-related lesions), neurodegenerative diseases, toxic agents, psychiatric
disorders and endocrine and metabolic disorders.
Common colds or influenzas seem to be the most frequent disorders associated with
permanent smell loss in the adult human (Deems
et al., 1991). Rhinosinusitis and head trauma are the next most
common disorders associated with such loss. In the case of head trauma, blows to the back
of the head are more likely to cause greater olfactory loss than blows to the front of
the head (Doty et al.,
1997). The prevalence of olfactory dysfunction in patients with head trauma
is usually 15% or less and the dysfunction is roughly proportional to the severity
of the injury (Levin et al.,
1985;
Deems et al., 1991). Of 268
head trauma patients complaining of smell loss who were evaluated at our center,
66.8% had anosmia and 20.5% hyposmia. Of the 66 patients who were retested
over intervals ranging from 1 month to 13 years, only three, none of who initially had
anosmia, regained normal olfactory function. Dysosmia prevalence decreased from 41.1 to
15.4% over post-trauma periods averaging several years (Doty et al., 1997).
It is now well established that smell loss is associated with a number of
neurodegenerative diseases (for recent reviews, see
Mesholam et al., 1998;
Doty, 2003;
Hawkes, 2003). In the case of
Parkinson’s disease (PD), the prevalence of such loss is greater than that of
tremor and, by a number of accounts, essentially equivalent to that of the other cardinal
signs of the disease (Hawkes et al.,
1999). Medications commonly used to mitigate PD symptoms (e.g.
L-dopa, dopamine agonists, anticholinergic compounds) have no influence on the
smell deficit, which is as severe in non-medicated or never-medicated patients as in
those who are medicated (Quinn et al.,
1987;
Doty et al., 1992b;
Roth et al., 1998). In PD,
Alzheimer’s disease (AD) and the Parkinsonism-dementia complex of Guam (PDCG),
severe bilateral loss, but rarely total anosmia, appears in the earliest disease stages
(Doty et al., 1987;
Hawkes et al., 1997, 1999;
Bacon et al., 1998;
Graves et al., 1999;
Devanand et al., 2000;
Royall et al., 2002;
Schiffman et al., 2002;
Swan and Carmelli, 2002). This is in
contrast to diffuse Lewy body disease (DLBD) and dementia with Lewy bodies (DLB), where
anosmia is the norm, as well as to progressive supranuclear palsy (PSP), corticobasal
degeneration (CBD), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine-induced Parkinsonism
(MPTP-P), where smell function is normal or only marginally altered (Doty et al., 1992a, 1993;
Wenning et al., 1995).
Moderate loss of olfactory function is most commonly present in Huntington disease (HD)
and multiple system atrophy (Wenning et
al., 1995;
Bylsma et al., 1997;
Moberg and Doty, 1997). This
heterogeneity of dysfunction among diseases makes it possible to use olfactory tests as
an aid in differential diagnosis [e.g. in distinguishing PD from PSP (Hawkes, 2003) and AD from dementia (McCaffrey et al., 2000)] and
provides a comparative means for better understanding the pathophysiological substrate
responsible for the underlying olfactory anomalies.
Smell testing has also been found useful in predicting the onset of AD and PD. In one
study, for example, the 12-item version of the UPSIT was administered to 1604
non-demented community-dwelling senior citizens 65 years of age or older (Graves et al., 1999). Over a subsequent 2 year
time period, the olfactory test scores were a better predictor of cognitive decline than
scores on a global cognitive test. Anosmics who had at least one APOE-4 allele had 4.9
times the risk of having cognitive decline than normosmics not having this allele. This
contrasts with the 1.23 times greater risk for cognitive decline in normosmics with at
least one such APOE allele. When the data were stratified by sex, women who were anosmic
and possessed at least one APOE-4 allele had an odds ratio of 9.71, compared to an odds
ratio of 1.90 for women who were normosmic and possessed at least one allele. The
corresponding odds ratios for men were 3.18 and 0.67, respectively. In a recent study,
tests of odor detection, identification and discrimination were administered to 250
relatives of PD patients (
84% children, 16% siblings, one parent;
Berendse, 2001). In the 25 hyposmic
relatives and in 23 normosmics sampled from this group, nigrostriatal dopaminergic
function was assessed using single photon emission computer tomography (SPECT) with
[125I] ß-CIT as a dopamine transporter ligand. An abnormal
reduction in striatal dopamine transporter binding was present in 4 of the 25
(16%) hyposmic relatives, two of whom subsequently developed clinical
parkinsonism, and in none of the 23 normosmic relatives. This implies that the olfactory
dysfunction likely occurs before the development of classical motor signs.
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Causes of chemosensory loss |
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TopIntroductionDisorders associated with...Causes of chemosensory lossAcknowledgements and disclosuresReferences |
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Most cases of chemosensory dysfunction reflect damage to the olfactory, rather than the taste, system. The latter system is less vulnerable to head trauma and regional insults than the olfactory system, reflecting, to some degree, redundancy of taste bud innervation (i.e. involvement of the paired CN VII, IX and X nerves). The most common taste aberrations arise from systemic causes, such as side effects of antilipid, antibiotic and antifungal medications.
Olfactory dysfunction can be attributed to one of three causes: (i) conductive or transport impairments from obstruction of the nasal passages (e.g. by chronic nasal inflammation, polyposis, etc.); (ii) sensorineural impairment from damage to the olfactory neuroepithelium (e.g. by viruses, airborne toxins, etc.); or (iii) central olfactory impairment from damage to central olfactory structures and/or connections (e.g. tumors, masses impacting on olfactory tract, etc.). In some cases, it is difficult to classify an olfactory disorder into one or another of these classes, as both blockage of airflow to the receptors and damage to the receptors and/or more central elements of the olfactory system can be simultaneously present. In the case of chronic rhinosinusitis, for example, damage to the olfactory membrane in addition to blockage of airflow can occur. Although many cases of olfactory dysfunction due to conductive factors and to well-defined tumors or hematomas are treatable, most olfactory disorders due to sensorineural factors are not.
There is clear histological evidence that upper respiratory infections adversely
influence the olfactory neuroepithelium. Thus, on intranasal olfactory biopsy of four
patients with anosmia and 11 patients with hyposmia following a viral illness, patients
with anosmia were found to have markedly reduced number of receptors and those receptors
were abnormal compared to those patients with hyposmia (Jafek et al., 1990). Although spontaneous recovery
in these patients is possible to some degree given the propensity of olfactory neurons to
regenerate, such recovery, when it occurs, is rarely marked and may take years. Topical
and oral steroids have not proven effective for post-viral smell loss.
Theoretically, any inflammatory or obstructive process in the nose can disturb smell
function, including allergic rhinitis, rhinosinusitis, nasal polyposis, intranasal tumors
and previous nasal surgery. Although medical (e.g. administration of topical or systemic
steroids) or surgical (e.g. excision of polyps) treatment can improve olfactory function
in some of these cases, return of function to normal levels is not the norm (Doty and Mishra, 2001). In the case of
rhinosinusitis, for example, factors other than, or in addition to, nasal airflow
blockage are responsible for the loss and chronic inflammation is likely toxic to
olfactory neurons. Hence, many cases of rhinosinusitis also have a sensorineural
component. The severity of mucosal histopathological changes of patients with chronic
rhinosinusitis is positively related to the magnitude of olfactory loss (Kern, 2000). Biopsies from the neuroepithelial
region of patients with nasal disease are less likely to yield olfactory related tissue
than biopsies from controls (Feron et
al., 1998). The same is true for anosmic versus non-anosmic
rhinosinusitis patients, the former of whom exhibit a generally more pathological
epithelium (e.g. disordered arrangement of cells, more islands of respiratory-like
epithelium) (Lee et al.,
2000).
Smell disturbance following head trauma usually reflects rapid acceleration/deceleration of the brain (i.e. coup/contrecoup injury). The most common mechanisms include disruption of the sinonasal tract from shearing forces and direct contusion and ischemia to the olfactory bulb and frontal and temporal poles. Although cribriform plate fractures can occur in some cases, they are not a prerequisite for dysfunction. Most head trauma-related loss is perceived soon after the injury, although damage to the olfactory receptors may lead to delayed cell death in some cases and to a delay in the onset of dysfunction.
The weight of the evidence implicates central olfactory structures as the most likely
entities that harbor the pathology responsible for the olfactory dysfunction of AD and
PD, including the anterior olfactory nucleus and the olfactory bulb (Esiri and Wilcock, 1984;
Hyman et al., 1991;
Davies et al., 1993;
Kovacs et al., 1999;
Tsuboi et al., 2003).
Although there is considerable evidence that the pathology of AD begins in olfactory
regions within the medial temporal lobe, most notably layer II of the entorhinal cortex
(Brouillet et al., 1994;
Gomez-Isla et al., 1996),
and progresses from there to neocortical regions, there is some evidence that the
olfactory bulbs are the first structures to exhibit pathology (Braak and Braak, 1998;
Kovacs et al., 2001).
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Acknowledgements and disclosures |
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TopIntroductionDisorders associated with...Causes of chemosensory lossAcknowledgements and disclosuresReferences |
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This contribution was supported, in part, by the following grants from the National Institutes of Health, Bethesda, MD: PO1 DC 00161, RO1 DC 04278, RO1 DC 02974 and RO1 AG 17496. This article is a brief synopsis of an invited presentation made at the 14th International Symposium on Olfaction and Taste held on Kyoto, Japan, on 9 July 2004. I wish to thank Drs Takashi Yamamoto and Masafumi Sakagami for their kind invitation to make this presentation. Disclosure: Dr Doty is a major shareholder in Sensonics Inc., the manufacturer and distributor of tests and taste and smell.
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TopIntroductionDisorders associated with...Causes of chemosensory lossAcknowledgements and disclosuresReferences |
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