smell and olfactory disorders, how to diagnose and how to manage?

By
Dr. Mohammed Moustafa Alashmawy

‫الرحيم‬‫الرحمن‬‫هللا‬‫بسم‬
ِ‫إ‬ ْ‫م‬ُ‫وه‬ُ‫ب‬َ‫ا‬ َ
‫ال‬َ‫ق‬ ُ‫ير‬ ِ‫ع‬
ْ
‫ال‬ ِ
‫ت‬َ‫ل‬َ‫ص‬َ‫ف‬‫ا‬َّ‫م‬
َ
‫ل‬َ‫و‬
َ
‫ل‬ َ
‫ف‬ُ‫وس‬ُ‫ي‬ َ‫يح‬ِ‫ر‬ ُ‫د‬ ِ
‫ج‬َ‫أل‬‫ي‬ِ‫ن‬
‫ن‬َ‫ا‬ َ‫أل‬ْ‫و‬
ِ
‫ون‬ ُ‫د‬ِ‫ن‬َ‫ف‬ُ‫ت‬
{
94
}
َ‫ل‬َ‫ض‬‫ي‬ِ‫ف‬
َ
‫ل‬ َ
‫ك‬َّ‫ن‬ِ‫إ‬ ِ‫اّلل‬َ‫ت‬
ْ
‫وا‬
ُ
‫ال‬َ‫ق‬
َ
‫ك‬ِ‫ل‬
ِ
‫يم‬ ِ‫د‬َ‫ق‬
ْ
‫ال‬
{
95
}
‫اء‬َ‫ج‬‫ن‬َ‫ا‬‫ا‬َّ‫م‬َ‫ل‬َ‫ف‬
ُ‫اه‬َ‫ق‬
ْ
‫ل‬َ‫ا‬ ُ‫ير‬ ِ
‫ش‬َ‫ب‬
ْ
‫ال‬
‫ا‬ً‫ير‬ ِ
‫ص‬َ‫ب‬ َّ‫د‬َ‫ت‬ْ‫ار‬َ‫ف‬ ِ‫ه‬ِ‫ه‬ْ‫ج‬َ‫و‬ ‫ى‬َ‫ل‬َ‫ع‬
ِ‫إ‬ ْ‫م‬ُ‫ك‬
َّ
‫ل‬‫ل‬ُ‫ق‬َ‫ا‬ ْ‫م‬
َ
‫ل‬َ‫ا‬ َ
‫ال‬َ‫ق‬
ُ‫م‬َ‫ل‬ْ‫ع‬َ‫ا‬‫ي‬ِ‫ن‬
َ
‫ن‬ِ‫م‬
َ
‫ون‬ُ‫م‬َ‫ل‬ ْ‫ع‬َ‫ت‬ َ‫أل‬‫ا‬َ‫م‬ ِ‫اّلل‬
{
96
}
(
‫يوسف‬
:
94
،
95
،
96
)

Sense of smell provides people with valuable input from
the chemical environment around them. When this input is
decreased or distorted, disability and decreased quality of
life are reported (Miwa et al., 2001).
• Food & drink:
• Flavor is mostly due to Smell
• Safety:
• Smoke & explosive gases
• Spoiled Foods
• Quality of Life:
• Relaxation
• Beauty
• It is important in…

Anatomy of the Olfactory
Nervous System
The olfactory nervous system consists
of three main stations:
 olfactory epithelium
 olfactory bulb
 olfactory cortex

olfactory epithelium
Site:
 superior aspect of the nasal vault in the cribriform plate
 superior turbinate
 anterior and middle parts of the middle turbinate
 dorsoposterior region of the septum

Ultrastructure:
• The olfactory epithelium
is a pseudostratified
columnar ciliated
epithelium that rests on a
highly cellular lamina
propria that contains the
Bowman's glands.
• It contains four major cell
types: ciliated bipolar
olfactory receptors
(ORNs), microvillar cells,
sustentacular cells and
basal cells (Meredith, 2001;
Jafek et al., 2002).

Each bipolar receptor
cell sends up to 50 cilia
from its dendritic knob
into the overlying
mucus, thus enhancing
the effective surface
area for odorant
binding. Also each
bipolar neuron sends a
single axon through
the cribriform plate to
the olfactory bulb.

olfactory bulb
The olfactory bulbs are
composed of six
concentric layers:
 glomerular nerve cell
layer
 the external plexiform
layer
 tufted cell layer
 mitral cell layer
 internal plexiform
layer
 granule cell layer

The mitral cells are the biggest neurons in the bulb, project to the olfactory
cortex via the lateral olfactory tract (LOT). Thus the LOT is a major central
olfactory pathway connecting the olfactory bulb to the olfactory cortex

olfactory cortex
 the anterior olfactory
nucleus
 the olfactory tubercle
 the piriform cortex
(gyrus ambiens)
 the periamygdaloid
cortex
 the lateral entorhinal
cortex (Brodmann's area
28)
 the corticomedial
amygdaloid nuclei (gyrus
semilunaris)
• Composed of six areas:

The olfactory
cortex. a: olfactory
bulb, b: olfactory
tract, c: olfactory
trigone, d: lateral
olfactory stria, e:
amygdalar sulcus, f:
rhinal fissure, g:
hippocampal
fissure, h: collateral
fissure, i:
prehippocampal
rudiment, j: medial
olfactory stria, k:
cortical amygdaloid
nucleus (gyrus
semilunaris), l:
uncus (see
contralateral side
for subdivisions), m:
parahippocampal
gyrus, OT:
Olfactory tubercle,
APS: Anterior
perforated
substance, DBB:
Diagonal band of
Broca, IG: the
intralimbic gyrus,
BG: Band of
Giacomini, UG:
uncinate gyrus, GS:
gyrus semilunaris,
GA: gyrus ambiens,
EA: Entorhinal area

Embryology of the olfactory system
The human fetus has a well developed ciliated olfactory epithelium by 9 weeks of
age but Completely differentiated olfactory cells are observed by 11 weeks, while
adult-like lamination of the olfactory bulb and a clearly-defined glomerular layer are
present by 18.5 weeks.

Physiology of the Olfactory
Nervous System
In the nasal cavity, volatile molecules reach the olfactory epithelium and interact
with odorant receptors in the fine cilia of the olfactory sensory neurons.
Humans have ~1000 genes encoding different types of odorant receptors, although a large
fraction of them appear to be pseudogenes and only between 300 and 400 are functional
genes (Dulac and Axel, 1995).
The axons of the
olfactory sensory
neurons expressing
the same type of
odorant receptor
converge to the
same glomerulus in
the olfactory bulb.

The binding of odorants to odorant receptors in the cilia causes production of a
cyclic nucleotide, cAMP, which directly opens ionic channels in the plasma
membrane. An inward transduction current is carried by Na+ and Ca+2 ions.
The increase in the internal concentration of Ca+2 causes the opening of Ca+2-
activated Cl– channels that produce an efflux of Cl– from the cilia, contributing
to the olfactory neuron depolarization. The depolarization spreads passively to
the dendrite and soma of the olfactory neuron, triggering action potentials that
are conducted along the axon to the olfactory bulb (Menini, 1999; Firestein, 2001).

Mitral and tufted cells transmit signals from the
glomeruli in the olfactory bulb to pyramidal neurons in
the olfactory cortex.

Disorders of the sense of smell
are not uncommon, occurring 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
(Doty et al., 1984a; Doty, 2005).
Olfactory disorders

Classification of olfactory disorders
• anosmia (absence of smell function)
• hyposmia or microsmia (decreased
sensitivity to odorants)
• partial anosmia (ability to perceive
some but not all odorants)
• hyperosmia (abnormally acute smell
function).
• Presbyosmia (age related
impairment of smell perception)
• Olfactory agnosia (inability to recognize
an odor sensation, even though olfactory
processing and general intellectual functions are
essentially intact, as in some stroke patients).
Quantitative disorders Qualitative disorders
(dysosmia)
• Parosmia or troposmia (the
perceived distortion when there is an
odorant stimulus present). Euosmia is
a pleasant parosmia to selected
odorants.
• Phantosmia (lasting longer than a
few minutes) and olfactory
hallucination (lasting only a few
seconds) describe the perception of an
odor (usually unpleasant) when there is
no odorant stimulus present. Cacosmia
(unpleasant phantosmia).

Etiology of olfactory disorders
Conductive Sensorineural and/or Central
• Benign:
Enlarged adenoids, allergic rhinitis, atrophic
rhinitis, bronchial asthma, nasal deformity, nasal
polyposis, sinusitis, vasomotor rhinitis, rhinitis
medicamentosa, Sjoegren’s syndrome, leprosy.
• Malignant:
Tumours of paranasal sinus or nasopharynx
extending in nasal cavities, primary tumours of
nasal cavities.

Sensorineural and/or Central
• Upper respiratory infection: (e.g. viral infection of olfactory epithelium)
• Nasal or sinus disease (SND).
• Head injury
• Idiopathic
• Endocrine disease:
• Congenital:
• Neurological disorders:
• Anterior skull base space occupying lesions:
Diabetes mellitus, adrenocortical insufficiency, Cushing’s syndrome, primary
amenorrhoea, hypothyroidism, pseudohypoparathyroidism, Turner’s syndrome.
Kallmann's syndrome (olfactory dysplasia, which is characterized by
hypogonadotropic hypogonadism and anosmia) in which there is agenesis of
both olfactory bulbs
Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple
sclerosis, Down’s syndrome, infarction, temporal lobe epilepsy
frontal lobe glioma, olfactory neuroblastoma, suprasellar meningioma, suprasellar
cholesteatoma, sphenoid ridge meningioma, aneurysms of anterior communicating
bifurcations, internal carotid aneurysms extending over pituitary fossa, pituitary
tumours (esp. adenomas), craniopharyngioma, osteomas.

• Psychiatric disorders:
Depression, schizophrenia,
anorexia nervosa (severe
stage), hysteria,
malingering, olfactory
reference syndrome,
seasonal affective
disorders.
• Organic disorders:
Chronic liver disease
(cirrhosis), chronic renal
failure, vitamin deficiency
(A, B6, B12), trace metal
deficiency (copper, zinc),
Wernike’s-Korsakoff
syndrome, gout, chronic
alcoholism.
• Toxic exposure:
Drugs, industrial dusts, metals
and volatiles.

Diagnosis of olfactory disorders
History
Examination
ENT neurological
investigations
Subjective Objective

History
 Define the complaint. Is it a taste complaint (as most will say) or is it an
olfactory problem (as is more often the case)?
 Whether the complaint is a decreased sense of smell, a distorted sense
of smell or both. If there is a distortion, is it only to inhaled odorants (troposmia)
or does it exist when no odorants are in the environment (phantosmia).
 If it is hyposmia or anosmia, it should be ascertained if the smell function is
diminished or completely lost, localized to the right or left nostril, or both, and
whether the dysfunction is for all odorants or only a few.
 Onset, course and duration should be noted, as well as the general health,
including endocrinal status, hospital admissions, surgical interventions,
radiotherapy and medications received, associated events such as viral or
bacterial respiratory infections, head trauma, exposure to toxic fumes, and
systemic diseases.
 Smoking history since olfactory ability is known to decrease as a function of
cumulative smoking dose, and cessation of smoking can result in improvement
in smell over time.

Examination
• complete otolaryngological examination:
Including cranial nerves and orbital contents (to direct attention to lesions of the skull
base), as well as general evaluation of the upper respiratory tract and ears (A hearing
problem reflecting viral or bacterial otitis media may alter taste function in the anterior
tongue via chorda tympani nerve damage or inflammation). Nasal endoscopy is
preferred over routine anterior rhinoscopy for better visualization of the nasal mucosa.
The olfactory neuroepithelium should be directly visualized when possible and a
determination made as to whether the airflow access to it is blocked or not.
• Neurological Examination:
• Dementia with olfactory deficit …… a possibility of Alzheimer’s disease.
• Blackouts, disorientation, seizure activity and mood changes ...... temporal lobe
epilepsy.
• Assessment of motor system, reflexes, cerebellar and gait functions are important while
considering early Parkinson’s disease.
• Assessment of position sense, vibration, temperature and pain for consideration of
various neuropathies as diabetes, pernicious anemia, neuropathy of renal disease, liver
failure and many other toxic neuropathies.

investigations
1) Subjective measures (Psychophysical Tests):
• Tests of absolute olfactory sensitivity (odor detection and
recognition thresholds)
• Tests of suprathreshold olfactory function (odor discrimination,
odor recognition, odor identification, odor intensity discrimination, odor
memory, and suprathreshold scaling of odor intensity and
pleasantness)
2) Objective measures:
• Psychophysiologic measures (electro-olfactogram &
chemosensory event-related potentials).
• Imaging techniques (CT, MRI and functional imaging).
• Measures of respiration

Subjective measures (Psychophysical Tests)
I. Measurement of absolute olfactory sensitivity:
1. Classic Olfactory Detection Threshold Measurement:
2. Signal Detection Measurement of Olfactory Sensitivity
• Detection threshold: the lowest concentration of an odor that can be perceived.
• Recognition threshold: the lowest concentration of an odorant that has a
recognizable quality, is typically higher than the detection threshold.
There are three psychophysical methods which are the most popular for measuring basal
detection olfactory thresholds:
• The method of constant stimuli (method of right and wrong cases )
• The method of limits (Single ascending series butanol odor detection threshold test)
• The staircase or up-down method (Smell Threshold Test™ ):
more accurate and reliable test of threshold than the popular single series ascending
method of limits, since it is less dependent upon early test trials in which practice or "warm-
up" effects are present, and it uses a number of points within the perithreshold region to
bracket the threshold value, thereby resulting in a threshold estimate based upon a sample
of more than a single category change

“Smell Threshold Test™(STT)”
It is a compact, portable smell
testing kit housed in a light weight,
attractive aluminum carrying case
(2.72 kg) that can serve as a test
table.
Odorants are contained within
stimulus bottles which provide
consistent output.
The pure CN I stimulant “phenyl
ethyl alcohol” is provided in 17
concentration steps. It can be
used to test 50 subjects before
new refills are needed.
The kit costs ~ $1,295.00.

II. Measurement of suprathreshold
olfactory function:
A. Odor Quality Discrimination test
B. Odor Quality Recognition tests
C. Odor Quality Identification tests
D. Odor memory test (OMT)

A. Odor Quality Discrimination test:
• Odor quality discrimination is the ability to distinguish among odors,
not to recognize, identify, or remember them.
• 4 methods are used:
1) A number of same- and different-odorant pairs are presented, and the
proportion of the pairings that are correctly identified as same or different can
be used as the measure of discrimination (Potter and Butters, 1980).
2) “Triangle test" : the subject is required to choose an odd stimulus from a set
of stimuli which are identical to one another except for the odd stimulus (i.e.,
orders A AB, BAA, ABA, BBA, ABB, BAB). When only one of the stimuli
serves as the odd sample e.g., A AB, ABA, BAA, the test is called “a three
alternative forced-choice test” (Frijters, 1980; Frijters et al., 1980).
3) "odor confusion matrix" : each odorant of a set is presented in
counterbalanced order to a subject. The subject's task is to determine which
one of a set of codes previously assigned to each of the odorants best
describes the odor sensation on a given trial (Wright, 1987).
4) "Sniffin' Sticks" test: The subject is presented with three odorants and the task
was to identify the sample that had a different smell (Kobal et al., 1996).

B. Odor Quality Recognition test:
 The subject is presented on a given trial with a "target"
odorant and provided with a set of several odorants which
includes the target stimulus. The subject's task is to report
which odor of the set is the same as the previously
presented target.
 A variant of this general theme is termed “odor matching
test” in which four odors are contained in eight vials (two
vials per odorant). The subject is simply required to pair up
the equivalent two-vial containers, demonstrating the
ability to match the odors. Scoring consists of giving a
single point to each pair correctly matched (0 to 4). This
test was found to be sensitive to lesions of the right
temporal lobe (Abraham and Matha, 1983).

C. Odor Quality Identification tests:
(1) Odor naming test:
It requires a subject to provide a name for each of a set of odors.
Despite the fact that this test have found use in clinical settings,
many normal persons have difficulty in naming or identifying
even familiar odors without cues. This has been called "the tip of
the nose" phenomenon. Therefore, response alternatives are
most commonly provided (Lawless and Engen, 1977; Gregson et al.,
1981).
(2) Yes/no odor identification test:
It is relatively simple, in that the subject is required only to report
whether or not each stimulus smells like that described by a
target word supplied by the examiner (Doty, 1992a).

(3) University of Pennsylvania Smell Identification
Test (UPSIT):
 Tests the ability of the subject to
identify each of 40 "scratch and sniff"
odorants (Doty, 1989a).
 It consists of four envelope-sized
booklets, each containing 10 odorants.
The odorants are positioned on brown
strips at the bottom of the pages of the
test booklets. The stimuli are released
by scratching the strips with a pencil
tip in a standardized manner.
 Above each odorant strip is a four-
alternative multiple-choice question.
The test is forced-choice i.e., the
subject have to mark one of the four
alternatives even if no smell is
perceived (Doty et al., 1984a).
 The most widely used psychophysical test.

(4) The Brief Smell Identification Test (B-SIT) or the
12-item Cross-Cultural Smell Identification Test
(CC-SIT):
The 12-item self-administered odor identification test is analogous to
the UPSIT and can be administered in less than 5 minutes. This test
incorporates multicultural odorant items selected from the UPSIT. The
following odorants from the UPSIT items are included in the CC-SIT:
banana, chocolate, cinnamon, lemon, onion, pineapple, gasoline, paint
thinner, rose, soap, smoke, and turpentine. Thus, the final CC-SIT was
composed of six food-related and six nonfood-related odorants.
The CC-SIT is applicable not only to the clinical setting but also
to situations in which a very rapid measure of olfactory function
is required, such as in surveys.
The small number of items limits the usefulness of this test as it is
impossible to determine whether a low score on the CC-SIT is due to
olfactory dysfunction or to malingering.

(5) The Quick Smell Identification Test "Q-SIT"
The test consists of individual tear out cards, each of which contains three
microencapsulated odorant strips. Beside each strip is a multiple-choice
question with five alternatives (e.g. Banana, Peanut, Rose, Paint Thinner,
None/other).
The Q-SIT can be administered in less than a minute. It costs less than
$2.00/patient and because it is compact, it easily fits into a pocket and
can be used on hospital rounds or in examination rooms.
It cannot detect
malingering because
it comprises only
three test items and
a response of
"None/Other" can
be made.

(6) The Pocket Smell Test (PST):
The PST is a three-item microencapsulated "scratch and sniff" test.
On each item, the examiner releases an odor by scratching the
encapsulated odor patch with a pencil; the patient then smells the
odor and chooses one of the four response alternatives, i.e. it is a
forced-choice screening test.
This self-administered 3-item test provides a very brief screen of
gross olfactory dysfunction. If the subject misses one or more of the
three items on this test, then a detailed Smell Identification Test
should be administered.
The test is available in 3 versions:
Gas Company Version (odors:
apple, natural gas, rose), American
Version (lemon, lilac, smoke), and
Universal Version (peanut, mint,
paint thinner).

(7) "Sniffin' Sticks" test (TDI score):
 It is one of the most widely used olfactory tests in Europe.
 It comprises three tests of olfactory function:
 odor threshold (n-butanol, testing by means of a staircase method)
 odor discrimination (16 pairs of odorants, triple forced choice)
 odor identification (16 common odorants, multiple forced choice)
So the TDI score is the sum of the scores of these 3 tests.
 For odor identification, odorants are presented in
commercially available felt-tip pens. The tampon of the pen
is filled with liquid odorants or odorants dissolved in
propylene glycol. For odor presentation, the cap is removed
by the experimenter for ~3 s and the pen's tip is placed ~2
cm in front of both nostrils.
Identification of odorants is performed as a multiple forced
choice from a list of 4 descriptors. The subject's scores
from 0 to 16 (Hummel et al., 1997).

(8) The four-minute odor identification test "12-
item test":
 It is extracted from the
"Sniffin' Sticks" test.
 The screening takes
approximately 4 minutes to
be administered by
selecting only 12 items
from the 16 items of the
"Sniffin' Sticks" test.
 The 4 excluded items
were garlic, turpentine,
apple and anise.

(9) The Connecticut test (Connecticut Chemosensory
Clinical Research Center ‹‹CCCRC››):
• It is composed of two components:
 odor identification test
 detection threshold test (single ascending series butanol odor
detection threshold test).
• For the odor identification test,
a kit comprised ten opaque plastic
jars containing sachet-like packets
of stimuli. These stimuli are 7
olfactory stimuli (Johnson's baby
powder, chocolate, cinnamon,
coffee, mothballs, peanut butter
and Ivory bar soap) and three
trigeminal stimuli (ammonia, Vicks
Vapo-Steam and wintergreen).
The ten items are presented in
irregular order for monorhinic
smelling.

When presented with an item, the participant seeks its name from a
20-item list placed against a screen that separates participant from
the examiner. The list contains the names of the ten test items and
of ten distracters. In addition to the names on the list, response of
"no sensation" and "don't know" are permitted.

(10) Smell diskettes as screening test of olfaction:
It was designed using 8 diskettes containing different odorants. They
are made of polyester and can be opened to release the odors and are
closed after testing.
The application of odors by diskettes is easy and fast, and eliminates
the risk of contaminating the hands of the investigator or the test
person with the odorant. In most situations the whole test could be
done in less than 5 minutes.

The test was designed as a triple forced multiple choice test,
resulting in a score from 0 to 8 correct answers. The answers were
presented on a questionnaire with illustrations.
One odorant (acetic acid) also stimulates the fibers of the trigeminal
nerve. Patients with anosmia should be able to identify this odor, so
this item allows to identify possible malingerers.

(11) The Sniff Magnitude Test (SMT):
Assesses a person’s olfactory ability by comparing sniffs to non-
odorized air with sniffs to odors. The test is based on the observation
that people with a normal sense of smell reduce the size of their sniff
when they encounter an odor stimulus while people with an impaired
sense of smell do not reduce the size of their sniff.
It is easy, rapid, reliable and relatively
unaffected by the variations in memory,
attention and linguistic skills.
The test allows for multiple odor stimuli to
be delivered using several canisters. These
canisters contain either no odor or they
contain an odor stimulus diluted in mineral
oil. During testing, the participant wears a
bilateral nasal cannula of the type used to
provide oxygen to patients with limited
respiratory capacity.

A participant’s sniff creates a negative pressure that is sensed by a pressure
transducer connected to the cannula and a processing board located within a
laptop computer. Within milliseconds of detecting a sniff, the computer also
opens the lid of the testing canister attached to sniff apparatus, thereby
exposing the participant to any odor stimulus within the canister. This all
occurs very rapidly so that the participant’s impression is that his or her sniff
resulted in the immediate opening of the canister lid and exposure to the
odor.
Four stimulus canisters were used in the test; one was a no odor stimulus
(air blank) and the others contain methylthiobutyrate (MTB) in 2
concentrations and Ethyl 3-mercaptoproprionate (EMP). MTB is described as
having a fecal odor while EMP is described as urinous odor.

(12) Jet Stream Olfactometer (JSO):
It includes three (A, B, C) odorants:
• Odorant A is a dilution of phenyl
ethyl alcohol (smells like a rose)
• Odorant B is a dilution of
cyclotene (smells like burning)
• Odorant C is a dilution of
isovaleric acid (smells like sweat).
These odorants can be sprayed into
the nasal cavity using a special
device to stimulate the olfactory
epithelium and patients do not need
to breathe.

(13) Odor Stick Identification Test (OSIT):
This test includes 13 odorants. These odorants are packed in
microcapsules and then mixed in paste. Each paste is hardened in the
form of a lipstick, which is called the ‘odor stick’.
Each odor stick is painted in a 2 cm
circle on a thin paraffin paper by the
examiner. The examiner folds this
paper in half and rubs it to grind the
microcapsules and then passes it to
the patient. The patient next opens
and sniffs the paper.
The patient is then given six
alternatives: four odor names,
including one correct name in
principle, ‘not detected’ and
‘unknown’. ‘Unknown’ indicates that
the presented odorant was detected
but not recognized.

(14) The Alinamin test (The intravenous olfaction test):
A dose of 10 mg (2 ml) Alinamin® is injected slowly into the median
cubital vein of the left arm at a constant rate over 20 s, then the
latency interval and the duration are measured. The latency interval
is the time from injection until recognition of the smell. Duration is
the time from recognition until disappearance of the smell. In
normal cases, the latency interval is 7-8 s, and the duration is 1-2
min.
This may be due to:
• Exposure of the receptors to odorized lung air.
• Diffusion of the stimulus from nasal capillaries
to the olfactory receptors.
Alinamin is a thiol-type derivative of vitamin B1
(thiamine propyldisulfide). It smells like garlic.

D. Odor memory test (OMT) :
The odor memory test is a 12-item, four-alternative, forced-choice
test with 10, 30 and 60 s delay intervals. The test administrator must
simply scratch a set of microencapsulated odors with a pencil for the
subject to sample at the appropriate time points.
Following the smelling of an inspection odor, four alternatives are
presented after a given delay interval, and the subject is required to
identify which one corresponds to the inspection odor.

• Psychophysiologic measures:
 Electro-olfactogram (EOG)
 Chemosensory event-related potentials (CSERP)
• Imaging techniques:
 CT
 MRI
 functional imaging (PET, SPECT, fMRI)
• Measures of respiration.

(1) The electro-olfactogram (EOG) or the evoked
potential of the olfactory epithelium:
It the summated generator potential of the olfactory receptor cells and
therefore represents peripheral olfactory events (no reflection of the
central events).
The EOG is recorded using intranasal electrodes. The subjects slowly
introduce the intranasal electrode themselves into the left nostril till
reaching the position of the olfactory epithelium. Electrode position is
checked using nasoendoscope.
The electrode is connected to the input of the electroencephalography
(EEG) machine and referred to the earth electrode on the forehead.
The odorants used are androstenone (with urinous or sweaty odor)
and amyl acetate (with an apple-/banana-like odor).

The odorants are delivered by an olfactometer. A constant airflow is
delivered to the nostril via a teflon nasal cannula inserted through a
self-expanding bung approximately 1.5 cm into the nostril. The self-
expanding bung closes off the stimulated nostril, ensuring a
unidirectional, constant airflow.

The technical difficulties associated with placement of the electrode
limits the use of EOG. So Wang et al., studied the possibility of
recording the EOG using external electrodes placed on the root of
the nose on either side of the bridge and at the medial termination
of the eyebrows.
The ability to record the
EOG non-invasively by
use of external
electrodes opens the
way to routine
measurement of
olfactory function in the
clinic, the laboratory and
in the design and
development of drugs for
olfactory pathologies.
Intranasal
electrode

(2) Chemosensory event-related potential (CSERP) or
the olfactory event-related potential (OERP):
In contrast to EOG, the OERP reflects the activity of both peripheral
and central elements of the olfactory system. It is recorded using the
EEG. The electrodes are silver chloride cup electrodes, attached to the
scalp using a water soluble conductance paste.
The electrodes can be placed on
any position on the scalp.
Usually, the recording sites
follow the International 10-20
system with origin points from
nasion, inion and preauriculars.
These electrodes are referenced
to the electrode placed behind
the right ear and an earth
electrode is placed on the
forehead.

 Correlation between EOG and OERP:
A simple exponential
relationship appears
between EOG and
OERP. Thus the larger
the peripheral
(receptor) potential
(EOG), the larger was
the corresponding
central potential
(OERP). However,
towards the higher
values of the OERP,
there is a decreasing
increment for
increasing values of
the EOG.

 electro-olfactogram (EOG)
 chemosensory event-related potentials (CSERP)
 CT
 MRI
 functional imaging (PET, SPECT, fMRI)
• Measures of respiration.

 Computed Tomography (CT):
• CT is well suited to the investigation of the sinonasal cavities.
• To study soft tissue, the window widths range from 150 to 400 HU. Conversely,
the bony detail is best observed at wide window settings from 2000 to 4000 HU.
• Slice thicknesses of 3-5 mm are often employed.
• Intravenous contrast is usually reserved for the identification of vascular lesions,
tumors, meningeal or parameningeal processes, and abscess cavities.

 Magnetic Resonance Imaging (MRI):
• MRI is less sensitive for the detection of bony abnormalities but soft
tissue discrimination is more clearly illustrated by MRI than by CT.
• MRI is the study of choice to evaluate the olfactory bulbs, olfactory
tracts, and intracranial causes of olfactory dysfunction.

 Functional imaging (radionuclide imaging):
• Functional imaging studies are valuable in detecting alterations of
regional brain function and biochemistry.
(a) Positron Emission Tomography (PET):
• PET commonly measures local changes in blood flow. When a
specific area is more activated there is an increase of regional
cerebral blood flow (rCBF), and this increase in rCBF is measured by
a tracer, such as 15O.
(b) Functional Magnetic Resonance Imaging (fMRI):
• fMRI is also an indirect index of neural activity that measures blood
flow. It doesn't depend on an introduced tracer or contrast agent but
on an intrinsic contrast—hemoglobin so it is non-invasive and less
expensive. Changes in rCBF are studied through differences in blood
oxygenation, and the so-called blood oxygen level dependent (BOLD)
signal is measured by a magnetic resonance scanner.

Group-averaged map of 19
individuals following (A)
olfactory stimulation with H2S
and PEA, or (B) trigeminal
stimulation with CO2. Areas of
activation are indicated by
red/yellow colors (inactivation is
indicated by blue colors)

Neural activations. A, Piriform cortex. i, normalized T1-weighted scan showing bilateral activations in
posterior piriform cortex. Note in this and all subsequent figures that the left side of the brain
corresponds to the left side of the figure (neurological convention). The region bounded by the rectangle
in (i) is shown magnified in (ii) for comparison with a high-resolution anatomical image of posterior
piriform cortex (iii). Fp, Frontal piriform cortex; Tp, temporal piriform cortex; A, amygdala; C, caudate;
P, putamen, I, insula. B, Amygdala. Neural responses in bilateral dorsomedial amygdala are shown. C,
Orbitofrontal cortex. Caudal central regions of orbitofrontal cortex were bilaterally activated by all odors.
D, Contrasts of parameter estimates.

Clinical associations with
olfactory disorders
 Neurological diseases
 Head trauma and skull base surgery
 Hormonal disorders

 Neurological diseases
Olfactory dysfunction has been observed in a wide range of
neurological disorders as:
While there is no or mild alteration of the smell
function in essential tremor, PSP, MPTP-P, depression,
and panic disorder.
• early-stage Alzheimer's disease (AD)
• idiopathic Parkinson's disease (PD)
• parkinsonism- dementia complex of
Guam (PDCG)
• schizophrenia (SZ)
• epilepsy
• multiple sclerosis
• Down syndrome (DS)
• Huntington’s disease (HD)
• amyotrophic lateral sclerosis (ALS)
• multi-infarct dementia
• Korsakoff's psychosis
• alcoholism
• seasonal affective disorder
• attention-deficit hyperactivity disorder
• stroke

Alzheimer's disease (AD(
 Bilateral
 Occurs in the earliest stages of the disease, including some
cases of questionable AD.
 The loss appears to progress with time.
 Olfactory testing is useful in the differential diagnosis of AD
from other disorders commonly misdiagnosed as AD, such as
depression.
 Olfactory dysfunction is a predictor of subsequent
development of AD in older persons. Increased olfactory
thresholds and UPSIT scores of 30-35 showed a moderate to
strong sensitivity and specificity for diagnosis of AD at follow-
up.

Parkinson's disease (PD)
 Bilateral
 Male > female
 appears in both familial and sporadic forms of parkinsonism.
 no progression in olfactory dysfunction with the disease progression.
 Olfactory testing is useful in the DD of idiopathic PD from a number
of other neurodegenerative diseases with motor symptoms, including
disorders often misdiagnosed as PD (e.g., PSP, MPTP-P, and essential
tremor).
 Anti-PD medications (e.g., L-dopa, dopamine agonists,
anticholinergic compounds) have no influence on the smell deficit.
 Some asymptomatic first–degree relatives of patients with either
familial or sporadic forms of PD appear to exhibit olfactory dysfunction.
So olfactory testing is likely useful in the early detection of PD.

Schizophrenia (SZ)
 Bilateral (although some left:right differences may be
present)
 There is progression in olfactory dysfunction with the disease
progression.
 Appears to occur early in the disease process and is found in
many patients who may be prone to SZ, such as those with
family histories positive for significant mental illness.
 Antipsychotic medications have no obvious influence on smell
function in SZ. However, drugs that alter dopaminergic pathways
can influence the ability to smell e.g., d-amphetamine which
enhances the odor-detection performance at low doses and
depresses such performance at somewhat higher doses

Down syndrome (DS)
 Smell loss observed in DS is very close to
that observed in AD (i.e., UPSIT scores 20)
and DS patients who live into early
adulthood develop the clinical features of
AD.
 Deposition of amyloid in cortical brain
regions associated with olfactory processing
(entorhinal cortex) as early as the age of 19
years is the cause of olfactory deficit.

 Head trauma and skull
base surgery
 Head trauma:
• Incidence: anosmia >>> 60% in cases of severe
head injury.
Parosmia >>> 25-33% of patients.
• The likelihood of anosmia is dependent on the
severity of the injury.
• UPSIT testing revealed that only 5% of patients with
head trauma regained normal olfactory function on
retesting.

• Mechanisms of injury in head trauma:
(1) Sinonasal tract alterations:
• Mucosal hematoma or edema within the
olfactory cleft with direct injury to the olfactory
neuroepithelium.
• Scarring with synechia formation or fractures
of the nasal skeleton or septum with
subsequent airflow alterations that prevent
odorants from reaching the olfactory cleft.
• Post-traumatic rhinosinusitis with resultant
alterations in nasal airflow or mucus quantity
and viscosity.
This mechanism is potentially treatable. Often reduction of mucosal
edema, repair of nasal or septal fractures with relief of airway
obstruction, or the treatment of sinusitis can improve olfaction.

(2) Shear Injuries:
• Tearing or shearing of the axons
while traversing the foramina of
the cribriform plate due to:
• Fractures of the naso-orbito-
ethmoid region involving the
cribriform plate
• Rapid translational shifts in
the brain secondary to coup or
contra-coup forces generated
by blunt head trauma
Regenerating axons apparently fail to reach the olfactory bulb due
to scar formation and obliteration of the foramina in the cribriform
plate so improvement is less likely to occur.

(3) Brain contusion and hemorrhage:
• Head trauma often results in traumatic brain injury in the form of
cortical contusion or intraparenchymal hemorrhage.
• Behavior disturbances and memory disorders frequently accompany
impaired olfactory recognition.

 Skull base surgery
Patients undergoing transorbital craniotomy via the suprabrow approach
(for benign lesions such as meningiomas, craniopharyngiomas and
pituitary adenomas), complain of smell loss on one or both sides of their
nose.
Localized frontal subcranial approaches to the skull base have been
described which minimize frontal lobe retraction and conserve
olfaction on the uninvolved side.
Loss of olfaction may result from:
• Frontal lobe retraction with shearing of the olfactory axons as they
traverse the cribriform plate
• Direct mechanical injury (i.e. retraction, compression or excision) to
the olfactory axons or olfactory bulb,
• Compromise of the vascular supply to the olfactory system
• Injury to the central olfactory pathways.

 Hormonal disorders
 Sex differences
 Influence of the menstrual cycle on
olfactory perception
 Changes in olfactory function during
pregnancy

 Sex differences
 Women are more
sensitive than men
to a wide variety of
odorants.
 Women maintain
their smell function
to an older age
than do men.

 Influence of the menstrual cycle
on olfactory perception
 Olfactory sensitivity peaks are noted mid-cycle, mid-
luteally, and during the second half of menses.
 These peaks are noted in both women taking and not
taking oral contraceptives, suggesting that gonadal
hormones may not be the primary basis for these sensory
changes but it may result from peripheral mechanisms
limiting the access of odorant molecules to the olfactory
receptors.
 women perceive olfactory stimuli with a higher
sensitivity during ovulation and also some body odors
tend to be more pleasant (e.g. vaginal odors).

 Changes in olfactory function
during pregnancy
 Women experience food cravings and food aversions during
pregnancy. These dietary changes are related to olfactory
perception as abnormal smell sensitivity was reported by
majority of women at the early stage of pregnancy while
decreased considerably at the late stage and approached
absence after pregnancy (9–12 weeks post partum).
 Nausea and vomiting during pregnancy serves a protective
function for the embryo by inducing aversions against certain
foods that contain teratogenic and abortifacient chemicals,
this is called the ‘embryo protection’ hypothesis.

Occupational and environmental aspects
influencing olfactory function
Among the causes of damage to the olfactory system is exposure to
toxic chemicals. This exposure may be:
 Acute exposure:
With exposure to high concentrations of the chemicals that cause rapid
physical damage to the olfactory epithelium and related tissues. This
always occurs by accident.
 Chronic exposure:
With exposure to relatively low levels of compounds that produce no
noticeable irritation. In such cases, the pathological changes may be so
gradual that inferences of causality are difficult to make.

Exposure to irritants often causes a reflexive
depression in respiratory rate, and this reflexive
response has frequently been used as a guide in
establishing permissible exposure limits (PELs)
and threshold limit values (TLVs). The TLV, much
like the PEL, reflects limits to airborne concentrations
of substances “under which it is believed that
nearly all workers may be repeatedly exposed day
after day without adverse effect”.
TLVs

 Mechanisms of toxic insult:
Toxic compounds can affect olfactory function:
 Indirectly:
By causing irritation in the nasal passage or blocking the flow
of air to the olfactory epithelium.
 Directly:
By altering the viability of the sensory epithelium. Some
olfactotoxins act immediately (e.g., methyl bromide ) causing
the sloughing of the olfactory epithelium down to the
basement membrane within 24 hours of exposure. Others
(e.g., dimethylamine) act only after being metabolized into
reactive intermediates.

 Defense mechanisms against toxic insult:
 First line of defense:
Free nerve endings of the trigeminal nerve detect the airborne
sensory irritants. If escape is not possible, the breathing rate
and/or pattern are altered in an attempt to minimize the entry
of the irritant into the airways.
 Second line of defense:
The nasal passages actively participate in the metabolism of
these compounds through the presence of phase I and phase
II enzymes which are found in concentrations greater than in
the liver or lungs.
The nasal mucosa is also capable of secreting antibodies, as
well as antimicrobial proteins such as lactoferrin and lysozyme,
to deal with inhaled pathogens

Recovery of the epithelium is in part related to the degree of damage
and in part to the cell types that have been damaged. In cases of
complete damage to the olfactory epithelium, save the basal cell layer,
regeneration may begin within 24 hours, with the covering of the naked
basement membrane with squamous cells from surrounding areas. By 4
days this epithelium becomes more cuboidal, and by 30 days it increases
in differentiation and thickness to become a more or less mature
olfactory epithelium.
when there is a loss of
Bowman's glands beneath the
olfactory epithelium, the
regeneration is considerably
slower. The participation of
Bowman's glands and ducts
appears to be critical in the
efficient and complete
regeneration of the epithelium

Substances affecting olfaction
(for which there are some supportive scientific data)

 Toxic metals:
A. Cadmium:
• Cadmium is often cited as the "textbook' example of a
toxic compound to which exposure results in anosmia.
• Workers exposed to cadmium fumes were evaluated.
They showed moderate to severe hyposmia, but not
anosmia, with no deficits in odor discrimination. This might
indicate that the peripheral olfactory receptor neurons were
damaged but the more central components of the system
were not.
• Cigarette smoking may intensify the dysfunction with
occupational cadmium exposure.

B. Chromium:
• Chromium is reported to cause anosmia and elevation of the smell
thresholds.
• Septal perforation is a common symptom associated with chromium
exposure.
• The degree of olfactory dysfunction is not related to the presence of
the septal perforation but related to the duration of employment in the
factory.
C. Mercury:
• Exposure to high levels of organic mercury in utero, as in Minamata
disease, both raises detection thresholds and decreases olfactory
identification ability.
• At autopsy in these patients, some gliosis and neuronal degeneration
are evident in the bulb

 Irritant
gases:
• The effects of exposure to SO2 and/or ammonia on olfactory function
proved to affect 25% of the workers. The deficit is assumed to be
peripheral in nature and more or less permanent in nature.
• Exposure to ozone results in an initial increase in the olfactory
threshold. However, thresholds have returned to normal within few
days, suggesting that the system may have compensated for the initial
insult.
• Exposure to acrylic acid causes olfactory dysfunction that increases
with cumulative exposure. The effects appeared to be reversible and
the highest relative risk of olfactory dysfunction occurred in the group
of workers who had never smoked.
Smoking induces metabolic enzymes in the nasal
mucosa that may provide protection against the
toxic effects of these gases

 Solvents:
• Due to their lipophilic nature, most solvents readily
penetrate the underlying cellular membranes after traversing
the mucus leading to decreased olfactory function.
• Workers exposed to petroleum products (fuel oil vapors) are
found to be less able to detect decreasing concentrations of
n-butanol and fuel oil. This is termed "industrial anosmia”
the phenomenon whereby exposure to strong odors in the
workplace results in a reduction in sensitivity for those
specific odors, while sensitivity to other odors remain the
same. These effects are transient and reversible which
suggests that it is due to short-term effects such as olfactory
fatigue or adaptation, rather than to toxic insult to the
olfactory receptor neurons.

 Multiple Chemical Sensitivity
(MCS)
• The olfactory system may play a role in triggering a group
of symptoms collectively known as idiopathic environmental
intolerances. These symptoms include autonomic arousal
(light-headedness, nausea, anxiety, tachycardia), upper and
lower respiratory tract irritation, neurological symptoms
(short-term memory loss), and others. A more limited version
of this phenomenon with a well-defined set of criteria is
known generally as multiple chemical sensitivity (MCS).
• In individuals experiencing MCS, exposure to many airborne
contaminants including solvents, perfumes, cleaning agents,
gasoline, pesticides, and paint, called “triggers”, elicits the
multimodal symptoms.

(MCS)
• Etiology:
 Biological theory (odor-related aversive conditioning):
Involves a traumatic exposure episode.
 Psychogenic theory (odor-related, stress-induced illness):
Represents the conditioning of an odor cue with autonomic
arousal symptoms resulting from stress. The stress is usually
chronic in nature and may result from the workplace
environment (job pressures, employment insecurity, etc.) or
from perceived dangers, such as working with "unknown
chemicals" or living near a toxic waste site.

(MCS)
Boxer (1990) stated, "It has been observed clinically that
psychologic reactions to exposure to neurotoxins can be
more serious than the direct neurotoxic effects".
 Other theories:
• Increased limbic System reactivity resulting from time-
dependent sensitization.
• Neurogenic inflammation arising from stimulation of chemical
irritant receptors.
• Toxic porphyria may be the basis for MCS.

Treatment of the Olfactory
disorders
 Treatment of the olfactory loss
(anosmia and hyposmia)
 Treatment of the olfactory distortion
(parosmia and phantosmia)

 Treatment of the olfactory
loss:
i) Medical therapy:
• Corticosteroids
• Antibiotics
• Theophylline
• Zinc sulphate
• Vitamin A
• Caroverine
• α-lipoic acid
ii) Surgical therapy

i) Medical therapy:
• Corticosteroids:
 Act as anti-inflammatory drugs that reduce submucosal edema and
mucosal hypersecretion and thereby increase nasal patency.
 Directly improve olfactory function by modulating the function of
olfactory receptor neurons through effects on olfactory Na,K-ATPase.
 Systemic steroids have a higher therapeutic efficacy compared with
topical steroids ………… Why ???
 Only a small volume of nasally applied sprays reach the olfactory
epithelium, which is situated in an effectively protected area of the nasal
cavity. This situation can be improved by the application of sprays in a
`head-down forward position' (HDF) or "Mecca position“.
 The site of inflammation relevant to olfactory loss may not always be in
the mucosa but in the area of the cribriform plate or the olfactory bulb.

i) Medical therapy:
• Corticosteroids:
 A new method—local injection of
steroids have been suggested. The
advantage of this method is the need for
only a small amount of steroids,
additionally, the steroid was certainly
administered. Suspended steroid was used
for this method because the steroid
suspension should be slowly spread in the
nasal mucosa near the olfactory cleft, thus
being effective at the local area.
Dexamethasone acetate suspension or
betamethasone sodium acetate
suspension (5 mg/2 weeks) were used in
this therapy. The steroid was injected
eight to ten times at intervals of 2 weeks.

• Antibiotics:
 Antibiotic therapy should only be started after the bacteria have
been identified and tested for resistance to antibiotics.
 Macrolides (e.g. roxithromycin) may have anti-inflammatory effects
and shrinkage of nasal polyps with low dose long-term macrolide
treatment has been reported.
 The tetracycline analogue,
minocycline, has been demonstrated
to inhibit neuronal apoptosis. It
stimulates expression of the anti-
apoptotic protein Bcl-2, inhibiting the
mitochondrial pathway of apoptosis.
It also possesses inherent anti-
infective properties so it may become
the drug of choice for treatment of
sinusitis and smell loss.

• Theophylline
 It is a nonselective phosphodiesterase (PDE) inhibitor
which have been proposed, as a therapeutic approach for
relieving symptoms of hyposmia.
 It acts by blocking the PDE involved in the
transduction process, therefore preventing cAMP
metabolizing into AMP.
 Whether it can be considered as an effective
therapeutic agent is controversial because toxic side
effects have been reported at doses which are very close
to therapeutic ranges.

• Zinc sulphate  Zinc is believed to play
an important role in the
regeneration of the OSNs.
Therefore, zinc sulphate
supplementation appears
to be therapeutically useful
for post-traumatic olfactory
disorder as the blast cells
are still intact and
regenerative capacity is
retained in the olfactory
epithelium while in post-
URTI, there is a loss of the
regenerative capacity as a
result of damage of the
OSNs and blast cells.

• Vitamin A
 Treatment involving vitamin A is not generally
supported. It was suggested that it acts by regenerating
the olfactory cells.
• Caroverine
 It is N-methyl-D-aspartate (NMDA) antagonist which
leads to decrease of the feedback inhibition in the
olfactory bulb.
 It significantly improves odor identification ability (i.e.
it may be effective in the treatment of sensorineural or
central disorders of smell).

• α-lipoic acid
 The potential therapeutic effects of α-lipoic acid
in olfactory loss following URTI have been
reported.
 Possible mechanisms of actions include the
release of nerve growth factor and antioxidative
effects, both of which may be helpful in the
regeneration of olfactory receptor neurons. It also
enhances motor nerve conduction velocity as well
as microcirculation.
 It is safe and is used in the treatment of
diabetic neuropathy.

 Aims at both reduction of nasal obstruction and
removal of inflamed mucosa or polyps.
 Performed endonasally under endoscopic or
microscopic control. Post-operative improvement of
olfactory function has been reported.
 Surgery is beneficial in most cases but it may also
pose a certain risk to olfactory function. Formation of
synechiae (mucosal adhesions), crusting or damage to
the olfactory epithelium may all compromise the success
of the intervention. There is a risk of 1.1% of becoming
anosmic after nasal surgery.

 Treatment of the olfactory
distortion:
i) Medical therapy:
• reassurance & watchful waiting
• topical nasal saline or oxymetazoline drops
• sedatives & antidepressants drugs
• anticonvulsants drugs "Gabapentin”
• antiepileptic drugs "sodium valproate, phenytoin”
• neuroleptics “Haloperidol”
• topical cocaine Hcl

• reassurance & watchful waiting
 Patients need to be reassured that they do not have a
malignant disease or an infection. It may help to explain
the neural etiology.
 Most patients will note a gradual decrease in the
symptom with time, and this can occur over several years.
Thus, `watchful waiting' is an appropriate course to take.
• topical nasal saline or oxymetazoline drops
 Aiming at blocking the involved nostril. These can be
placed in limitless quantity every few hours in the HDF
(`Mecca') position.
 Oxymetazoline HCl nasal drops give the patient rhinitis
medicamentosum which is useful in preventing the air flow
from reaching the olfactory cleft

• topical cocaine Hcl
 It can temporarily block most distortions by
anesthetizing the neurons, and is useful in the diagnosis of
these individuals. It is an excellent vasoconstrictor so the
effect may be to deprive the neuron of blood supply.
 The drug is applied as a drop into the nostril of the
supine patient while their neck is fully extended. Care must
be exercised when using it because undesired effects can
occur. Some patients with a temporary troposmia suddenly
have a permanent phantosmia after its use. Also some
individuals lose all their olfactory ability in one nostril after
its application. So extensive informed consent must be
obtained from the patient before its use.

 Bifrontal craniotomy:
To remove the olfactory bulbs or nerves. It result in bilateral
permanent anosmia and include the risks associated with a
craniotomy.
 Stereotaxic amygdalotomy:
for the treatment of olfactory hallucinations.
 Endoscopic intranasal excision of the olfactory
epithelium followed by temporalis fascia grafting:

 Endoscopic intranasal excision of the olfactory
epithelium followed by temporalis fascia grafting:
• This procedure is successful in eliminating the phantosmia and
also the patient returns his olfactory ability again.
• indications:
Unilateral phantosmia that has been present for more than 2
years and can be eliminated with intranasal cocaine anesthesia
of the ipsilateral olfactory mucosa.
• procedure:
cut all the fila olfactoria and destroy all connections between
the nasal cavity neurons and the olfactory bulb in the operated
nostril.
• Carries the risk of CSF rhinorrhea.

Pioneers in olfaction
Doty, R.L.
Hummel, T.
Leopold, D.A.
Buck, L.
Axel, R.

AMERICAN SOCIETY
FOR BIOCHEMISTRY
AND MOLECULAR
BIOLOGY

Dream
Egyptian Olfactory Test


“Smell is a sense whose value
seems to be only really
appreciated after it is lost”
(Toller et al., 1999)

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