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or K
+
channels (30,31).
The amount of adenylate cyclase activity produced by various odorants in a frog ciliary
preparation (32) is positively correlated with the magnitude of the frog's
electroolfactogram (EOG; a surface potential associated with the number of receptors
activated) (29) and with the perceived intensity of these same odorants to humans (33).
Some odorants also activate cGMP, which is believed to play a role in the modulation of
the sensitivity of olfactory receptor neurons, such as during adaptation (34). Although G
proteins other than G
olf
(e.g., G
i2
and G
o
) have been identified in olfactory receptor cells,
they appear not to be involved in early transduction events, likely assisting in such
processes as axonal signal propagation, axon sorting, and target innervation (35).
OLFACTORY DISORDERS
Terminology
Anosmia refers to loss of the ability to smell, whereas hyposmia or microsmia refers to
decreased ability to smell. Total anosmia denotes an inability to smell all odorants on
both sides of the nose. Partial anosmia implies an inability to smell certain odorants. In
some cases, partial anosmia is indicative of decreased sensitivity to a broad spectrum of
odorants (general hyposmia), with the decrement exceeding the absolute threshold for
only some odorants. Specific anosmia, the lack of ability to smell one or a few odorants
in the presence of an otherwise normal sense of smell, is rarely a reason for medical
consultation. Hyperosmia reflects abnormally acute smell function. This condition occurs
only rarely (e.g., in some unmedicated epileptic patients). Olfactory dysfunction can be
either bilateral or unilateral (sometimes termed binasal or uninasal). Loss of olfaction on
both sides of the nose is referred to as bilateral anosmia or, as noted above, total anosmia.
Dysosmia is distorted or perverted smell perception, with parosmia and cacosmia
denoting a change in the quality of an olfactory cue (e.g., a flower smelling rancid) and
phantosmia denoting odor perception in the absence of an olfactory stimulus (e.g.,
olfactory hallucinations).
Causes of Olfactory Loss (Anosmia and Hyposmia)
Chemosensory disorders originate from a multitude of causes (Table 22.1) and may be
the consequence of normal aging. When damage to the olfactory receptors or to central
neural structures involved in olfactory transduction is the basis of the dysfunction, the
problem is due to sensorineural factors. This occurs, for example, when contre-coup
movement of the brain in trauma sheers the olfactory axons at the level of the cribriform
plate. When intranasal problems, such as blockage from nasal polyps, are the basis of the
olfactory dysfunction, the condition is due to conductive factors (36,37). In some cases, it
is difficult to classify an olfactory disorder into these two mutually exclusive categories,
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. Although many
cases of olfactory dysfunction due to conductive factors are treatable, most olfactory
disorders due to sensorineural factors are untreatable.
TABLE 22.1. EXAMPLES OF REPORTED
ETIOLOGIES FOR OLFACTORY DYSFUNCTION
Numerous factors can produce decrements in olfactory function. Nearly two thirds of
cases of chronic anosmia or hyposmia (i.e., those presumably permanent) are due to prior
upper respiratory infections, head trauma, and nasal and paranasal sinus disease, and
most reflect permanent damage to the olfactory neuroepithelium (2). Other causes include
iatrogenic interventions (e.g., septoplasty, rhinoplasty, turbinectomy, radiation therapy),
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, psychiatric disorders,
exposure to environmental chemicals, and hypothyroidism. According to Finelli and Mair
(38), the single most egregious error of neurologists is failure to recognize the symptom
of anosmia as the principal or sole feature of an olfactory groove neoplasm. Importantly,
5% to 10% of head trauma cases exhibit olfactory dysfunction, with most having anosmia
(36,37).
Causes of Olfactory Distortions (Dysosmia)
Most dysosmias reflect dynamic elements associated with degeneration (or, more rarely,
regeneration) of the olfactory epithelium and remit over time. Thus, it is common for
patients with anosmia from such causes as head trauma and upper respiratory infections
to report that before onset of their anosmia they experienced a period of weeks or months
when dysosmia was present. Some cases of extremely debilitating chronic dysosmia
(usually of a number of years duration and often unilateral), where weight loss is marked
or daily functioning is markedly impaired, are amenable to surgical intervention (e.g.,
ablation of regions of the olfactory epithelium or olfactory bulb removal). Of the surgical
approaches, intranasal ablation or stripping of tissue from the olfactory epithelium on the
affected side is more conservative and less invasive than removal of the olfactory bulb
and/or tract via a craniotomy (39). If the dysosmia reappears after such surgery,
additional intranasal ablations can be performed. In most cases, demonstrable smell loss
does not accompany the dysosmic condition, implying a requirement for a relatively
intact sensory system for expression.
In rare instances dysosmias present as auralike hallucinations presumably associated with
central (e.g., temporal lobe) dysfunction. In many such cases, no seizure activity can be
documented, and no evidence of central nervous system lesions or tumors is apparent.
Nonetheless, low doses of anticonvulsant medication may be effective in mitigating the
frequency and severity of some of these dysosmias. Dysosmias also occur in a wide range
of psychiatric disturbances that usually are diagnosed on other grounds (e.g., psychosis).
Infrequently, dysosmia may be due to the perception of foul odors produced by the body,
such as those from purulent nasal secretions in sinusitis or from exhalations in halitosis or
uremia. Other disorders that may present as dysosmia include trimethylaminuria (fish
odor syndrome) and cat odor syndromea pediatric neurologic disorder associated with
a -methyl-crotonyl-CoA carboxylase deficiency. Such rare disorders usually exist in the
presence of a normally functioning olfactory system.
Causes of Heightened Smell Function (Hyperosmia)
In contrast to cases of anosmia, hyposmia, and dysosmia, cases of hyperosmia
(heightened smell function) are rare if, indeed, existent. Although untreated adrenal
cortical insufficiency has been reported to produce hyperosmia in humans, this has not
been confirmed, and animal studies have found no evidence for hypersensitivity after
adrenalectomy (40). There have been suggestions of hyperosmia in syndromes such as
multiple chemical sensitivity, but the limited data available also fail to support this notion
(41). Hyperosmia reportedly occurs in some cases of epilepsy during the interictal period,
although, as noted above, most patients with long-term epilepsy and intractable seizure
activity, such as candidates for temporal lobe resection, are hyposmic (42).
Influences of Aging on the Ability to Smell
It is important to realize that disorders of smell function, particularly loss or decreased
smell ability, are not uncommon in the general population and increase with age (Fig.
22.2). Unfortunately, such losses often go unnoticed, and physicians rarely assess smell
ability quantitatively in the same way that they assess visual or auditory acuity. Under the
age of 65 years, approximately 1% of the population has major difficulty smelling.
Between 65 and 80 years, this increases remarkably, with about half of the population
experiencing significant decrement in the ability to smell. Over the age of 80, this figure
rises to nearly 75% (43). It is significant that smell dysfunction is not only a potential
early sign of nasal sinus disease but of such debilitating neurodegenerative diseases as
AD and idiopathic PD.
FIGURE 22.2. University of Pennsylvania Smell
Identification Test (UPSIT) scores as a function of age
and gender. Numbers by data points represent sample
sizes. (From Doty RL, et al. Smell identification ability:
changes with age. Science 1984;226:14411443, with
permission.)
Dementia-related Olfactory Dysfunction
Considerable research has been devoted to the study of olfactory dysfunction in
dementia-related diseases. Of particular interest is the observation that olfactory
dysfunction may be the first sign of AD and idiopathic PD (44). In the case of AD, limbic
brain regions that receive the olfactory bulb mitral and tufted cell projections tend to be
the brain regions with the highest concentration of neurofibrillary tangles and neuritic
plaques (45). In PD, bilateral olfactory deficits occur before the onset of most of the
classic neurologic signs and symptoms and are unrelated to disease stage, use of
antiparkinson medications, duration of illness, and symptom severity, such as masked
faces, tremor, rigidity, bradykinesa, or gait disturbance (46,47 and 48).
Although the olfactory loss in AD and PD is pervasive and marked, this is not true of a
number of other neurodegenerative disorders, and olfactory testing can be helpful in
establishing a differential diagnosis. For example, patients with essential tremor and
those with progressive supranuclear palsyconditions that share many motor symptoms
with PDhave little or no olfactory dysfunction (49). Similarly, patients with
parkinsonism secondary to intravenous exposure to the proneurotoxin, 1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine, appear to have relatively normal olfactory function
(50). Recently, it has been shown that the olfactory loss associated with multiple sclerosis
is directly proportional to the number of multiple sclerosis-related plaques in central brain
regions associated with olfactory processing (i.e., inferior middle temporal lobe and
periorbital frontal cortex) (51).
CLINICAL ASSESSMENT AND PATIENT MANAGEMENT
Clinical History
To understand chemosensory dysfunction, it is imperative that the clinician decipher a
basic confusion that can confound accurate diagnosis. In an evaluation of 750 patients
with chemosensory dysfunction, it was demonstrated that although most patients present
with complaints of both smell and taste loss, few (less than 5%) have identifiable whole-
mouth gustatory deficits. This is due largely to a descriptive confusion between taste
(i.e., true gustation) and flavor, which reflects to a large degree the olfactory-derived
sensations from foods. Specifically, the perception of poor ability to taste during
deglutition usually reflects loss of flavor sensations derived from retronasal olfactory
stimulation rather than to loss of taste-bud mediated sensations, per se (52). Thus, such
flavors as chocolate, coffee, vanilla, strawberry, pizza, licorice, steak sauce, root beer,
and cola disappear when CN I is damaged, leaving intact only sweet, sour, salty, bitter,
and perhaps umami (monosodium glutamate-like) sensations. Whole-mouth taste
function is much more resistent to injury than olfactory function, largely due to the
redundancy of innervation of the gustatory system (i.e., CN VII, IX, and X). Although
seemingly a simplistic concept, this is the first consideration in the decision tree for
diagnosis and treatment of olfactory disorders.
The semantic confusion between taste and flavor can also be expanded to include certain
dysosmias, in that patients may confuse dysgeusia (taste distortion) with dysosmia,
perceived as flavor distortion. For example, a foul taste may represent a retronasal
dysosmia that occurs during deglutition. To differentiate, the clinician must know that the
taste (an actual dysosmia) typically is described using terms such as chemical-like or
rancid rather than terms reflecting distortion of a true gustatory quality (e.g., bitter). In
other words, patients with true dysgeusias generally can assign a distinct taste quality to
the sensory distortion (e.g., salty or bitter) (2,53).
A patient's description of the nature and onset of the chemosensory problem is essential
to the clinical history. The same is true of an assessment of the patient's past medical and
surgical histories, with an emphasis on such areas as endocrinologic state, history of
radiation therapy, and medications taken before symptom onset (such as thyroid
supplementation, high doses of antibiotics, antihypertensive medications, or
antineoplastic agents). Delayed puberty in association with anosmia (with or without
midline craniofacial abnormalities, deafness, and renal anomalies) suggests the
possibility of Kallmann syndrome. Importantly, associated events are critical for
establishing an etiologic diagnosis (e.g., viral or bacterial respiratory tract infections,
head trauma, exposure to toxic fumes, systemic diseases, and signs of early dementia,
parkinsonism, or central tumors). Information about or signs or symptoms of toxic
chemical exposure and seizure activity (e.g., automatisms, occurrence of black outs, deja
vu, etc.) should be sought, particularly in cases where heightened sensitivity is a
complaint. Decreased olfactory function has been observed in some persons infected with
the human immunodeficiency virus.
In patients complaining of anosmia or hyposmia, it is useful to ask whether smell
function is diminished or completely absent, localized to one or the other nasal chamber
(or both), and whether the dysfunction is for all odorants or only a few. Patients with loss
due to nasal or paranasal sinus disease are more likely to indicate a gradual loss of
function than those whose loss is due to a prior upper respiratory infection or to head
trauma (2). Some patients with olfactory dysfunction secondary to nasal or paranasal
sinus disease report temporary recovery of function under circumstances in which nasal
patency is increased. For example, function may return during warm days, exercise,
showering, or treatment with topical or systemic corticosteroids, implying a deficit in
stimulus delivery to the olfactory cleft (as in allergic rhinitis) rather than solely a
sensorineural problem.
Smoking history should be explored, in light of evidence that olfactory ability decreases
as a function of cumulative smoking dose and that cessation of smoking can result in
improvement in olfactory function over time (54). A history of allergy should be sought,
as should a history of current or past nasal or paranasal sinus infection. Inquiry should be
made about previous nasal or paranasal sinus surgery, although olfactory deficit after
such surgery has been shown to be rare (55). Importantly, the association of nasal
obstruction, headache, facial pain, postnasal discharge, purulent or clear rhinorrhea,
otologic symptoms, and throat symptoms should be sought with specific questioning.
The order in which symptoms appeared and regressed is at times helpful. The duration of
the problem is of importance in relation to the possibility of spontaneous recovery, which
is generally assumed to be minimal after 6 months if damage to the olfactory epithelium
is implicated. In the case of conductive olfactory loss, if olfactory function returns
intermittently, then olfactory receptors are present, regardless of the disease duration
(56). The patient should be queried also about olfactory distortions and whether they
seem bilateral or unilateral. If the problem is present while the patient is being examined,
have the patient hold shut both sides of the nose and the left and right sides separately to
ascertain if the problem requires airflow to the receptors and, if so, whether the problem
is localized to the left or to the right. If such localization exists, then the rhinologist can
focus attention on the involved side of the nose. Exploring a complaint of taste loss is
very important, because this usually reflects an olfactory disorder. It is useful to have the
patient distinguish between the loss of the perception of flavor of food or beverages and
the loss of the perception of sweet, sour, bitter, and salty stimuli. Inquiring as to whether
the patient can perceive saltiness in potato chips, sourness in lemonade, or sweetness in
sugar on cereal can help in this differentiation. An anosmic will be able to taste the
sweetness of an apple or a pear but will be unable to distinguish between their flavors or
to taste chocolate.
Physical Examination
Essential components of the physical examination include a complete otolaryngologic
examination with an emphasis on anterior rhinoscopy and nasal endoscopy, both flexible
and rigid, allowing for a thorough assessment of the olfactory cleft. The nasal mucus
membranes should be examined for color, surface texture, swelling, inflammation,
exudate, ulceration, epithelial metaplasia, erosion, and atrophy. When pansinusitis is
present, the anosmic etiology is obvious. However, very minor polypoid disease at the
olfactory cleft can also account for major olfactory dysfunction (56). Helpful on nasal
endoscopy is the finding of mucopus above the eustachian tube orifice, suggesting
posterior ethmoid and/or sphenoid disease, whereas mucopus below the eustachian tube
suggests disease involving elements of the osteomeatal complex. The presence of polyps,
masses, adhesions of the turbinates to the septum, and marked deviations of the septum
all have the potential for adversely influencing airflow to the olfactory epithelium,
because a mere 15% of inspired air typically traverses the olfactory cleft in the
unobstructed state (57). Importantly, there is a false-negative rate of nearly 50% with
anterior rhinoscopy when compared with nasal endoscopy (56). Allergy is suggested if
the mucous membrane is pale, usually as a result of edema within the lamina propria.
Chronic or acute exposure to environmental or industrial pollutants is suggested by
metaplasia within the epithelium and by swelling, inflammation, exudate, erosion, and
ulceration. Atrophy of the lamina propria is suggested by unusual spaciousness, dryness,
and crusting, as is seen in atrophic rhinitis.
Complete neurologic evaluation is also necessary, emphasizing cranial nerve function
and attention to possible skull base and intracranial lesions. Optic disk examination
should be performed to determine the presence of increased intracranial pressure
(papilledema), particularly in cases of unilateral olfactory dysfunction, because tumors of
the olfactory groove or sphenoidal ridge (e.g., meningiomas) can cause Foster Kennedy
syndrome, comprised of ipsilateral anosmia or hyposmia, ipsilateral optic atrophy, and
central papilledema.
Olfactory Testing
Accurate assessment of olfactory function is essential to establish the validity of a
patient's complaint, characterize the specific nature of the problem, reliably monitor
changes in function over time (including those of iatrogenic etiology), detect
malingering, and establish compensation for permanent disability. It should be noted that
many patients complaining of anosmia or hyposmia actually have normal function
relative to their age and gender. Others may be unaware of their deficits. For example,
approximately 90% of patients with idiopathic PD have a demonstrable smell loss, yet
less than 15% are aware of their problem until tested objectively (46).
Olfactory evaluation often has both medical and legal consequences. As stated earlier,
anosmia or hyposmia is common in head injury (2,37) and often is the only residual
neurologic impairment from falls and motor vehicle accidents. Importantly, malingering
is commonly detected using olfactory tests with malingering scales, such as the
University of Pennsylvania Smell Identification Test (UPSIT; see next section), that
should be administered in cases where litigation is involved. In Great Britain, disability
benefits for anosmia resulting from an injury are available under the National Insurance
Act and under private accident insurance policies. In the United States, disability
compensation is provided for under the 1963 amendment to the Workman's
Compensation Law when decreased future earning power is apparent. Whereas the
Veterans Administration awards a 10% whole body disability for total anosmia, the
Guides to the Evaluation of Permanent Impairment published by the American Medical
Association suggests only a 3% compensation, a figure we consider woefully inadequate.
In practice, both the Veterans Administration and the American Medical Association
impairment guidelines are exceeded in many legal settlements for anosmia. It should be
noted that occupation should be taken into account in disability issues, as loss or
decreased smell function is particularly significant for persons in some occupations (e.g.,
chefs, plumbers, wine tasters, municipal gas workers).
Traditionally, physicians have examined the ability to smell by asking a patient to sniff a
few odorous items (e.g., coffee, cinnamon, or tobacco in small vials) and to report
whether or not an odor is perceived. Unfortunately, this procedure is analogous to testing
vision by shining a flashlight into each eye and asking whether or not a light is seen.
Asking the patient to identify the odor does not correct the situation, because even normal
subjects have difficulty identifying some odors without cueing. Despite the fact that most
olfactory disorders are discernible using various nominally distinct olfactory tests (e.g.,
tests of odor detection, discrimination, identification, and memory), the interpretation of
the findings of such tests must be made conservatively. For example, all such tests are
influenced by damage to the olfactory neuroepithelium, making it dangerous to assume,
in any given case, that poor performance on a specific type of test (e.g., odor memory)
has anything to do with damage to neural circuits underlying the name of the test (e.g.,
odor memory circuits) (58). Presently, there is no way to distinguish between central and
peripheral deficits on the basis of psychophysical or electrophysiological testing. The fact
that the reliability (and hence sensitivity) of a number of olfactory tests is low or
unknown adds further difficulty in attempts to establish differential function.
Although most olfactory problems are bilateral and bilateral testing reflects the better
functioning side of the nose, in some instances unilateral testing is warranted. To
accurately assess olfaction unilaterally, the naris contralateral to the tested side should be
occluded without distorting the patent nasal valve region to prevent or minimize crossing
of inhaled or exhaled air at the rear of the nasopharynx to the opposite side (so-called
retronasal stimulation). An easy way of doing this is to seal the contralateral naris using a
piece of Microfoam tape (3M Corporation, Minneapolis, MN) cut to fit the naris borders.
The patient is instructed to sniff the stimulus normally and to exhale through the mouth.
Psychophysical Tests
Despite the fact that a wide range of psychophysical olfactory tests are available for
accurately assessing olfactory function, most are of unknown reliability and validity,
cumbersome, and suffer for lack of normative data. Fortunately, during the last few years
a handful of standardized and practical psychophysical tests have been developed,
including several brief self-administered screening tests (e.g., 59,60,61 and 62). The most
widely used of these tests is the UPSIT, known commercially as the Smell Identification
Test (Sensonics, Inc., Haddonfield, NJ) (59,60) (Fig. 22.3). This test, which is available
in English, Spanish, French, and German language versions, has been administered to
nearly 200,000 patients since its invention in the early 1980s. The UPSIT can be self-
administered in 10 to 15 minutes by most patients in the waiting room and scored in less
than a minute by nonmedical personnel. This test consists of four booklets containing 10
odorants apiece. The stimuli are embedded in 10- to 50-m diameter microencapsulated
crystals located on scratch and sniff strips on the bottom of the pages of the test
booklets. Above each strip is a multiple choice question with four response alternatives.
The patient is required to choose an answer, even if none seems appropriate or no odor is
perceived (i.e., the test is forced choice). This encourages the patient to carefully sample
all of the stimuli and provides a means for detecting malingering; because chance
performance is 10 of 40, very low scores reflect avoidance, and hence recognition, of the
correct answer. Norms based on the administration of this test to nearly 4,000 people are
provided and an individual's percentile rank established relative to persons of the same
age and gender. This test also makes it possible to classify an individual's function, on an
absolute basis, into one of six categories: normosmia, mild microsmia, moderate
microsmia, severe microsmia, anosmia , and probable malingering. The reliability of this
test is very high (test-retest Pearson r = 0.94).
FIGURE 22.3. University of Pennsylvania Smell
Identification Test (UPSIT; commercially known as the
Smell Identification Test