Imaging of the Olfactory System

David M. Yousem, Kader Karli Oguz, and Cheng Li

The olfactory system consists of the primary olfactory nerves in the nasal cavity, the olfactory bulbs and tracts, and
numerous intracranial connections and pathways. Diseases affecting the sense of smell can be located both
extracranially and intracranially. Many sinonasal inflammatory and neoplastic processes may affect olfaction.
Intracranially congenital, traumatic, and neurodegenerative disorders are usually to blame for olfactory dysfunc-
tion. The breadth of diseases that affect the sense of smell is astounding, yet the imaging ramifications have barely
been explored.
Copyright © 2001 by W,B. Saunders Company

HE ANATOMY AND PHYSIOLOGY of ol-
T faction have rarely been the subject of arti-
cles in the radiologic literature, in part because this
special sense is the least appreciated one in the
neurosciences. All too often the olfactory system
is ignored in the usual clinical evaluation of a
patient, hence, the common recording that "cranial
nerves II to XII are intact." Nonetheless, to the
astute clinician and conscientious neuroradiologist,
knowledge of the ramifications of olfactory dys-
function is very rewarding. Therefore, this article
initially focuses on the functional anatomy of the
sense of smell and then addresses those protean
entities that affect cranial nerve I (see Table 1).
Both peripheral and central diseases that impact on
the sense of smell are explored.
ANATOMIC IMAGING (NORMAL)
Smells are perceived in the upper nasal cavity by
olfactory neuroepithelial receptors. The primary
olfactory nerves pierce the cribriform plate to stim-
ulate and synapse with olfactory bulb nuclei. In
truth, the true olfactory nerves are located in the
nasal cavity and these should be termed cranial
nerves I (CN I). Instead, the olfactory bulb and
tract, which is a secondary neuron, is usually
referred to as the first cranial nerve (Fig 1).
From the olfactory bulb, fibers travel in the
From the Russell H. Morgan Department of Radiology and
Radiological Sciences, Johns Hopkins Hospital, Baltimore,
MD; and the Smell and Taste Center, Department of Otorhi-
nolaryngology, Head and Neck Surgery, Hospital of the Uni-
versity of Pennsylvania, Philadelphia, PA.
Address reprint requests to David M. Yousem, MD, Director
of Neuroradiology, The Russell H. Morgan Department of
Radiology and Radiological Sciences, Johns Hopkins Hospital,
600 North Wolfe Street, Phipps B-112, Baltimore, MD 21287;
e-mail: yousem@rad.jhu.edu
Copyright © 2001 by W.B. Saunders Company
0887-2171/01/2206-0001535.00/0
doi:l O.1053/sult.2001.28800
olfactory tract to enter the brain just lateral and
anterior to the optic chiasm. Fibers continue into
medial and lateral olfactory striae to septal nuclei
at the base of the brain just inferior and anterior to
the rostrum of the corpus callosum. Axons from
mitral and tufted cells project to central brain
limbic system components including the pyriform
and entorhinal cortex and adjacent corticomedial
amygdala (which together form the uncus), the
ventral striatum, the parahippocampus area, and
the anterior olfactory nuclei. From these areas
there are widespread interconnections with many
parts of the brain, including the mediodorsal thal-
amus, hypothalamus, orbitofrontal and dorsolateral
frontal cortex, temporal cortex, and other areas of
the limbic system (Fig 2).
The sizes of the olfactory bulbs and tracts
(OBTs) have recently been reported in the litera-
ture. 1 The left and right OBT volumes peak in the
fourth decade of life, but show considerable vari-
ation within each subject group (see Table 2).
The mean left and fight OBT volumes and the
mean combined volume show a decline in the
seventh and eighth decade that parallels a decline
in scores by the patients on the University of
Pennsylvania Smell Identification Test (UPSIT)
scores. Thus, as the volume declines, function
declines. A Kruskal-Wallis test, performed to de-
tect differences between the means of OBT vol-
umes between decades showed borderline signifi-
cance at P = .05 for the left OBT, but not the right.
The biggest differences noted were between the
fourth and seventh decade for fight and left OBTs.
By using regression analysis based on the gener-
alized estimating equations model, a OBT volumes
show significant decreases between decades of life
(P = .027).
As measured in large population studies by us-
ing the UPSIT, there is an initial increase in odor
identification capability to the third decade of life,
at which time the UPSIT scores plateau? At about

456 Seminars in Ultrasound, CT, and MRI, Vol 22, No 6 (December), 2001: pp 456-472
IMAGING OF THE OLFACTORY SYSTEM
Table 1, Causes of Olfactory Dysfunction
Primary Olfactory Apparatus
Conductive Disorders Lesions
Sinusitis Sinusitis
Polyposis Traumatic injury
Sinonasal cavity neoplasms Congenital aplasia, hypoplasia
Olfactory neuroblastoma
Cocaine
Toxins
Viral infections
age 60, however, a decline in median UPSIT
scores begins to be seen across patients to the point
that nearly 75% of individuals over 80 years old
score 19 or less on the 40-item UPSIT test. 4 These
patients are severely hyposmic or anosmic. Similar
changes in odor threshold values for phenyl ethyl
alcohol are noted, however, the drop-off starts to
be seen at about age 40 in men and 60 in women. 5
Smokers and men tend to have higher thresholds
than nonsmokers and women, respectively. A
change in the perception of pleasantness of taste
also occurs with age. 6'7 This effect can be elimi-
nated when the nostrils are occluded and the olfac-
tory influence on taste is nullified.*
Several theories have been espoused as to why
the sense of smell declines with age and include:
(1) reduction in volume of the sensory neuroepi-
thelium caused by cumulative effects of viral in-
fections, (2) replacement of the olfactory neuro-
epithelium with nonsensory columnar epithelium
in the olfactory clefts of the nose, (3) diminution in
central neurotransmitters (eg, norepinephrine), (4)
reduction in patency of the airway, (5) variations in
the nasal cycle with age, or (6) reduction in resis-
tance of the olfactory neuroepithelium to infectious
or toxic insults. 4"5'9-a5
The finding of a decline in the human OBT
volume with advancing age lends credence to the
idea of a reduced amount of afferent input to the
olfactory bulbs and tracts from the olfactory neu-
roepithelium and ciliated nerves that pierce the
cribriform plate. A decrease in central neurotrans-
mitters is a less plausible explanation for the quan-
titative findings because the predominant effect
seen is at the bulb and tract level, not at the cortical
level.
FUNCTIONAL IMAGING (NORMAL)
Functional magnetic resonance imaging (fMRI)
has been used in an attempt to localize regions of
457
NeurodegenerativeDisorders Miscellaneous
Alzheimer's disease Vasculitis
Parkinson's disease infarction
Huntington's disease Surgery
Schizophrenia
Multiple sclerosis
Temporal lobe epilepsy
Korsakoff's disease
Amyotropic lateral sclerosis
the brain associated with olfaction. Koizuka et a116
have noted bilateral increased cerebral blood flow
in the inferior frontal lobes, piriform cortex, and
orbitofrontal regions after phenyl ethyl alcohol
olfactory stimulation. Wexler et al t7 showed sim-
ilar areas of activation in these and other limbic
structures when odors were presented to normal
volunteers.
Yousem et a118 have performed olfactory-stim-
ulated functional magnetic resonance imaging
(OSfMRI) in 18 normal subjects between 29 and
43 years of age by using a homemade olfactometer
in which odors from 3 sources were alternated at
5-second intervals for 30 seconds during the on
stimulus and room air was used for 30 seconds for
the off stimulus. They found that odorants that
stimulated only CN I had extensive activation that
was localized to the orbitofrontal region (Brod-
mann area 11) and the cerebellum. The volume of
activation was greater in the right orbitofrontal
region than the left (Table 3, Fig 3).
Some odorants not only stimulate the olfactory
system but also activate trigeminal neurons that
abound in the nasal cavity. Stimulants such as
carbon dioxide that "sting or burn the nose" tend to
have more fifth-cranial nerve input. When Yousem
et a118 applied an fMRI paradigm with odorants
that also induce trigelmnal nerve stimulation they
found wider activation of many different areas,
including visual and cingulate areas (Table 4, Fig
4). Yousem et al ~8 found that there was accommo-
dation (diminution of brain activation) to pleasant
olfactory nerve-mediated odors, but amplification
(an increase in brain activation) to repeated testing
with trigeminally mediated odors.
Fulbright et a119 reported that pleasant odors
lateralized to the left insula region whereas the
unpleasant odors were more left frontal.
In a study of the effects of age on fMRI, 2° 5
older right-handed patients (mean age 73.2 years)
458 YOUSEM, OGUZ, AND LI

Fig 1. Normal olfactory bulb and tract. (A) The olfactory bulbs (open arrows), olfactory sulci (arrowheads), and gyri rectus (g)
are well seen on coronal Tl-weighted surface coil images (e, ethmoid sinuses). (B) A t a more posterior cut, the open arrows now
show the olfactory tracts sitting in the olfactory sulci (arrowheads). (C) Even more posteriorly, normal small tracts (arrows) are
seen in the sulci.

and 5 younger right-handed patients (mean age of ized to a standard atlas, and individual and group
23.8 years) underwent blood oxygenation level statistical parametric maps (SPMs) were generated
dependent (BOLD) fMRI scans that used binasal for each task. The SPMs (P < .01) of volumes of
olfactory nerve stimulation. The data were normal- activation and distribution of cluster maxima were
IMAGING OF THE OLFACTORY SYSTEM 459

A B

C D
Olfactory Olfactory
tract

bulb

Olfactory

Fig 2. Connections to cortex from the olfactory system (diagram or graph). Organization of the human olfactory system. (A)
Peripheral and central components of the olfactory pathway. (B) Enlargement of region boxed in (A) showing the relationship
between the olfactory epithelium, containing the olfactory receptor neurons, and the olfactory bulb (the central target of olfactory
receptor neurons). (C) Diagram of the basic pathways for processing olfactory information. (D) Central components of the olfactory
system. (Reprinted with permission. 92)

Table 2. OBT Volumes Versus Decade of Life

Mean LOBT Standard Mean ROBT Standard Mean OBT
Decade Volume (ILL) Deviation Volume (F.L) Deviation Volume (/~L)
3rd 122.7 17.1 129,1 9.8 125.9
4th 158.7 21.1 145,5 27.8 152.1
5th 140.1 41.7 131,6 29.9 135.9
6th 127.9 27.9 130,7 26.8 129.3
7th 108.5 29.4 123,9 22.5 116,2
8th 114.5 31.0 124,7 15.0 119.6
Abbreviations: R, right; L, left.
Reprinted with permission from Yousem et al. 1
460 YOUSEM, OGUZ, AND LI

Table 3. Pleasant Olfactory Nerve fMRI Stimulation Values Table 4. Trigeminal Odor fMRI Stimulation Values
Size of Activation FPQ Brodmann Size of Activation FPQ Brodmann
(FPQ* Units) Value Area No. Location (FPQ* Units) Value Area No. Location

43, 16 2.5, 2.1 11 Right orbitofrontal 68 2.5 19 Left primary visual

4 2.0 11 Left orbitofrontal cortex
10 2.1 Not described Cerebellum 58 2.2 30 Retrosplenial cortex
53 2.8 19 Right primary visual
Abbreviation: FPQ, fundamental power quotient.
cortex
*FPQ over 2.0 considered statistically significant.
49 2.1 23 Posterior cingulate
24 2.5 6 Premotor and S M A
22 2.1 7 Precuneus
22 2.1 Not provided Cerebellum
compared for the 2 patient groups. Analysis of the 21 2.2 11 Orbitofrontal cortex
group SPMs revealed activation in the frontal
*FPQs over 2.0 considered statistically significant.
lobes, perisylvian regions, and cingulate gyri.
More voxels were activated in the younger group
than the older group (Fig 5). The right inferior
frontal, right perisylvian, and right and left cingu- deviation 6.5 years) given the same olfactory stim-
lum had the largest number of voxels activated. uli in an fMRI experiment at 1.5 T.
The most common sites of activation on individual The women's group averaged activation maps
maps in both groups were the right inferior frontal showed up to 8 times more activated voxels than
regions and the right and left superior frontal and did those of men for specific regions of the brain
perisylvian zones. Young patients activated these (Table 6, Fig 6). In all sites, women showed
regions more frequently than older patients and the more activated voxels than men. The difference
younger patients activated more voxels (Table 5). was most striking in the right temporal (peri-
On standardized tests of odor identification and insular) regions. When individual patients were
odor detection in nearly all age groups, women studied, Yousem et a121 found that all women
score better than men. 4 Yousem et a121 studied and 7 of 8 men showed some degree of activa-
whether these findings would translate to differ- tion, but that the sites of activation varied
ences between the sexes in the volume of activated widely. Six of 8 men activated the right superior
brain with odor-stimulated fMRI. The activation frontal region and the right perisylvian region.
maps of 8 right-handed women (mean age 25.3 Half of the men activated the left perisylvian and
years, range 2 0 - 4 4 years, standard deviation 8.3 right inferomedial temporal zone. All other sites
years) were compared with those of 8 right-handed showed activated voxels in fewer than half of the
men (mean age 30.5, range 18-37 years, standard men.

Fig 3. Orbitofrontal activation

with fMRI. Note the perisylvian
(curved arrow) and orbitofrontal
(straight arrow) activation of the
brain in this group map of pa-
tients who were presented with a
combination of hydrogen sulfide
and rose oil (phenylethyl alcohol),
pure olfactory nerve stimulants.
Right more than left activation is
seen.
 Fig 4. Trigeminal stimulation
with fMRI. With carbon dioxide, a
trigeminal nerve stimulant, peri-
cingulate, perisylvian (curved ar-
row, black arrow), inferior frontal
(straight arrows), and brain stem
activation becomes more appar-
ent.

Fig 5. Results of fMRI of

young patients compared with
older patients. (A) Young pa-
tients show greater perisylvian
and frontal activation (arrows),
given a cranial nerve I stimulant,
than (B) older subjects.
462 YOUSEM, OGUZ, AND LI

Table 5. Olfactory fMR| Data: Young Versus Old

Patient Group RIF LIF RIMT LIMT RP LP RC LC RSF LSF

No. patients who activated

in each region (P = .05)
Young 5 2 2 2 4 5 4 1 4 4
Old 4 3 1 2 5 3 2 1 4 4
No. voxels activated in each
region (P = .01)
Young 12 0 0 0 12 4 11 18 3 4
Old 1 0 0 0 9 0 0 0 3 1

Abbreviations: R, right; L, left; I, inferior; S, superior; F, frontal; M, medial; T, temporal; P, perisylvian; C, cingulate.

DISEASE STATES (PERIPHERAL) tive surgery to restore olfactory ability and normal
Sinonasal Inflammatory Disease mucociliary clearance.

Sinonasal tract disease is one of the common Allergic Reaction

causes of olfactory disturbance. The Cause of the
olfactory deficits among patients with nasal and
paranasal sinus disease is most likely caused by
nasal airway obstruction. Recently, the influence of
nasal obstruction on olfaction has been compre-
hensively reviewed. 22 Any cause of bilateral ob-
struction can lead to decreased smell sensations by
limiting airflow to the olfactory receptors. Besides
the obstructive effect, lesions that are located in the
upper nasal vault and/or cribriform plate region
may also directly damage the olfactory epithelium
and olfactory neurons.
Paranasal sinusitis (Fig 7) is a relatively com-
mon disorder affecting approximately 30% of the
population at some time in their lives. 23-26 One of
the common symptoms of acute and chronic para-
nasal sinusitis is decreased smell sensation, which
is generally reversible. The prompt diagnosis and
treatment of sinusitis are important for restoring
olfactory function. Though the exact cause of che-
mosensory dysfunction secondary to sinusitis is
elusive, alterations in nasal air flow and mucocili-
ary clearance or obstruction from secretory prod-
ucts, polyps, or retention cysts may contribute to
olfactory dysfunction. At present, high-resolution
computed tomography (CT) is the preferred imag-
ing technique to evaluate for sinusitis, preceded by
nasal endoscopic examination. CT helps the func-
tional endoscopic sinus surgeons in planning effec-
Allergic rhinitis is a common upper-airway con-
dition affecting about 30 million Americans with
peak prevalence in the age group from 35 to 54
years. Hyposmia or anosmia is common with al-
lergic rhinitis, mainly caused by nasal obstruction
by polyps or inflamed mucosa, which limit access
of inspired air to the roof of the nasal vault. The
diagnostic work-up begins with a careful history
that attempts to identify offending allergens. Skin
testing of specific antigens is often used to confirm
the diagnosis. Medical imaging studies play a sup-
plementary role in the evaluation of sinonasal air-
way status and differential diagnosis. CT and MRI
are also important for detecting any complications
such as sinusitis, mucoceles, and aggressive polyps
in patients with allergic rhinitis. Rounded excres-
cences and enlargement of ostia are seen in the
airway of patients with polyposis.
Trauma
The incidence of posttraumatic anosmia ranges
from 24% to 30% for severe head injuries, 15% to
19% for moderate head injuries, and 0% to 16% for
mild head injuries. 27 Blows to the frontal region or
the occiput are commonly associated with post-
traumatic anosmia. Sumner 2s found that a blow to
the occiput has 5 times the chance of inducing
anosmia than a blow to the forehead if posttrau-
matic amnesia is present (indicating a severe head

Table 6. Analysis of Activation With Group-Averaged Maps Between Men ,and Women Thresholded at P < ,05
Left Frontal Right Frontal Left Temporal Right Temporal
Patient Group Voxels Activated Voxels Activated Voxels Activated Voxels Activated

Women 157 730 303 465

Men 19 152 55 31
Ratio of women to men 8.3 4.8 5.5 15.0
IMAGING OF THE OLFACTORY SYSTEM 463

Fig 6. Women versus men

fMRI results. (A) Women show
more activation than (B) men,
especially in the perisylvian re-
gions and frontal (arrows). Note
right-sided dominance.

injury). This may be caused by contra coup shear-

ing effects at the cribriform plate and inferior
frontal lobe region. Side impact injuries also can
cause olfactory dysfunction at a high rate. 29 None-
theless, because frontal injuries are more common
than occipital or lateral blows, posttraumatic anos-
mia is most often seen in the setting of a frontal
contact injury. 28-3° Fractures of the skull or face
are seen in 45% to 68% of individuals with bilat-
eral posttraumatic anosmia. 3°'31
Of 268 patients with head trauma who presented
to the University of Pennsylvania Smell and Taste
Center evaluated by Doty et al, 29 66.8% had anos- Fig 7. Sinusitis/polyps. Complete opacification of the up-
mia, 20.5% had microsmia, 15.4% had persistent per nasal cavity, maxillary antra, and ethmoid sinuses is seen
paraosmia, and 12.7% had normosmia. On retest- in this patient with sinonasal polyposis and postobstructive
sinusitis. Depending on the chronicity of the disease, the
ing, less than 2% recovered olfactory function patient may sustain permanent smell loss.
464
completely, 36% improved slightly, 45% had no
change, and 18% worsened.
Retention of the sense of smell in one nostril is
uncommon (< 11% of patients) in posttraumatic
patients evaluated for chemosensory abnormalities.
In patients who have partial or incomplete loss of
olfactory function, the deficit may go completely
unnoticed.
Recovery of olfactory function after head
trauma is variable. Return of olfactory function can
occur in 14% to 39% of patients initially anos-
mic 2am'3z especially if the interval of posttrau-
matic amnesia is less than 24 hours. Although 74%
of patients recovering olfactory function do so
within 12 weeks, 1 study reported that an addi-
tional 22% will regain function by the second year
after the injury. 28 Despite the fact that reports of
return of olfactory function as long as 7 years after
injury have been published, few studies have used
quantitative tests of olfactory function. Olfactory
neurons have the capacity for neurogenesis allow-
ing new receptor growth, so it is surmised that the
late return of function may be related to a periph-
eral (olfactory nerves-bulbs-tracts) mechanism
rather than a more central one. In humans it is
YOUSEM, OGUZ, AND LI
believed that there may be fibrotic scarring that
occurs at the cribriform plate that may prevent
regenerating axons from connecting to the second-
ary neurons of the olfactory bulb. 33
To evaluate the sites of injury in patients with
posttraumatic olfactory deficits, Yousem et a134
studied 25 patients with posttraumatic smell dys-
function by using olfactory testing and MR. Quan-
titative and qualitative gradings for olfactory bulb,
tract, subfrontal region, hippocampus, and tempo-
ral lobe damage were correlated with olfactory test
results. Twelve patients were anosmic, 8 had se-
vere impairment, and 5 were mildly impaired.
Olfactory bulb and tract (88% of patients), sub-
frontal (60%), and temporal lobe (32%) injuries
were found (Fig 8), but did not correlate well with
the UPSIT scores. Odor discrimination deficits
correlated best with frontal injury and odor mem-
ory correlated best with temporal lobe damage.
These relationships did not achieve statistical sig-
nificance. The finding that the OBT volumes in
patients with posttraumatic anosmia are smaller
than those of patients with residual smell function
or control subjects suggests that the source of the
olfactory deficit after trauma may be at the OBT
Fig 8. Posttraumatic injury to the olfactory apparatus. (A)
There is complete wipe-out of this patient's inferior frontal
lobes on this coronal T1-weighted image, The patient was in
a severe motor vehicle accident. He was anosmic. (B) Al-
though olfactory tracts (arrows) are seen in this patient, there
is inferior frontal encephalomalacia. The patient was micros-
mic. (C) This patient with posttraumatic anosmia had no OBT
on the left and only a piece of a tract (arrow) on the right, The
frontal lobes were sheared bilaterally,
IMAGING OF THE OLFACTORY SYSTEM
level or even more proximally in the olfactory
neurons. Shearing of nerves at the cribriform plate
is the most plausible explanation.
CONGENITAL
Congenital anosmia is said to exist when a
patient has no recall of smell sensation dating to
early childhood. Some patients report a reduced
sense of smell since birth (congenital hyposmia)
and still others who claim to have no sense of smell
may show some residual or normal function on
laboratory testing. Although the etiology of early
anosmia or hyposmia may include such entities as
viral infections, posttraumatic injury to the ol-
factory epithelium, choanal atresia, holoprosen-
cephaly, septo-optic dysplasia, meningoencephalo-
celes that affect the frontoethmoidal region, or
Kallmann's syndrome (anosmia with hypogo-
nadotropic hypogonadism), 35 studies conducted by
Jafek et a136 and Leopold et a137 suggest that
congenital anosmia usually does not occur in as-
sociation with other anomalies.
Kallmann's syndrome was extensively de-
scribed in 194435 and has been the focus of a
number of clinical, genetic, and pathologic studies.
The disorder appears to be found most commonly
as an x-linked disorder, but can be inherited
through autosomal transmission as well. 38 Patients
are eunuchoid and may have coexistent renal
anomalies, cleft lips or palates, infertility, spastic
paraplegia, cerebellar dysfunction, nystagmus, or
hearing loss. 38 Although most initial reports noted
the absence of olfactory bulbs and tracts in Kall-
mann's syndrome macroscopically, 35'39 the pres-
ence or absence of olfactory neuroepithelium in
Fig 9. Congenital anosmia. (A) No olfactory bulbs or tracts can be seen in this individual with congenital anosmia. Note also the
absence of well-formed olfactory sulci (compare with Fig 1). (B) The same findings are seen in this patient who has never smelled
the scent of a flower.
465
patients with congenital anosmia and/or Kall-
mann's syndrome is still being debated. Thus, 2
camps have developed; those that believe that
Kallmann's syndrome patients have no epithelium
and those that believe that the olfactory axons
simply fail to reach the prosencephalon and hence
do not connect intracranially. The hypogonadism
of Kallmann's syndrome is thought to be caused by
either a lack of cells that can express luteinizing
hormone releasing hormone (LHRH) or by abnor-
mal migration of the LHRH neurons from the
olfactory placode in the nose to the hypothala-
mus. 37 Truwit et al4° support the neuronal migra-
tional anomaly theory. They believe that soft tissue
seen by MR in the region below the expected
location of the olfactory bulbs represents arrested
neurons.
In a study of 24 individuals with congenital
anosmia, Yousem et a141'42 showed absence of the
olfactory bulbs and tracts in 16 patients, hypoplasia
of bulbs and tracts in 4 patients, and absent bulbs
but hypoplastic tracts in 4 patients (Fig 9). Three
individuals could smell, though with severe deficits
(UPSITS 18-24 of a possible 40), and 2 of the 3
had intact small bulbs and tracts. 41"42 Vogl et a143
also documented the ability of MR to show abnor-
malities of the olfactory pathway in patients with
congenital anosmia. Eighteen patients diagnosed
with Kallmann's syndrome and 10 patients with
idiopathic hypogonadatrophic hypogonadism were
included in this study, which used a head coil.
Seventeen of the 18 patients with Kallmann's syn-
drome showed absence of the olfactory bulbs and
tracts and 8 of these individuals had normal olfac-
tory sulci adjacent to the gyms rectus. Olfactory
466
bulbs and tracts were present in all 10 patients who
had idiopathic hypogonadotropic hypogonadism,
though 3 showed some degree of hypoplasia. In
3 other studies of patients with Kallmann's syn-
drome, complete absence or hypoplasia of the
olfactory bulbs and tracts was the predominant
finding. 38'4°'44'45 The olfactory sulci may be vari-
ably aplastic, hypoplastic, or normal.
TUMORS OF THE NASAL CAVITY AND
PARANASAL SINUSES
Neoplasms of the sinonasal tract are uncommon.
Malignant tumors of the nasal cavity and paranasal
sinuses account for only 0.2% to 0.8% of all
human malignancies. 46-49 Early symptoms of si-
nonasal tract tumors, nasal discharge, unilateral
nasal obstruction, and minor intermittent epistaxis
may simulate low-grade chronic infection. Almost
all sinonasal tract tumors and tumor-like condi-
tions that grow to a large size may cause a decline
in olfactory acuity by interfering with patency of
the nasal airway or directly destroying the olfac-
tory receptors. The most common malignancies of
the sinonasal system are squamous cell carcinoma
and adenocarcinoma, but lymphoma, melanoma,
adenoid cystic carcinoma, and chondrosarcomas
also populate the nasal cavity. Two examples of
intrinsic sinonasal tract tumors relatively unique to
the sinuses (the olfactory neuroblastoma and the
inverted papilloma, both of which often cause
hyposmia or anosmia) may serve as prototypes for
masses in this region.
OLFACTORY NEUROBLASTOMA
Olfactory neuroblastoma, or esthesioneuroblas-
toma, is a rare nasal tumor originating from the
olfactory neuroepithelium lining the roof of the
nasal vault and in close proximity to the cribriform
plate. There have been less than 300 reported cases
in literature worldwide. Olfactory neuroblastomas
occur in all age groups with a peak incidence in the
11 to 20 and 51 to 60 years age groups. There is a
slight preponderance of the tumor in women. The
incidence of olfactory neuroblastoma has been es-
timated to range from 2% to 3% of all malignant
intranasal neoplasms. The most common symp-
toms are unilateral nasal obstruction and recurrent
epistaxis. Hyposmia and rhinorrhea are not un-
usual. Extension into the orbit, paranasal sinuses,
or anterior cranial fossa may cause vision distur-
bances and headache. In the detection and staging
of olfactory neuroblastoma, CT and/or MRI play
YOUSEM, OGUZ, AND LI
an important role. Generally speaking, MRI is
more accurate than CT in showing the tumor's
intracranial extent. MRI is also exquisitely useful
for differentiating neoplasm from postobstructive
secretions because of the difference in the signal
intensity (secretions are bright on T2, tumor inter-
mediate) and gadolinium enhancement. Unfortu-
nately, signal intensity characteristics of various
sinonasal tract tumors overlap each other, so MRI
cannot usually predict specific tumor histology.
However, a recently described imaging finding
characteristic of olfactory neuroblastomas is the
presence of peripheral peritumoral cysts along the
intracranial portion of the tumor. If stippled calci-
fications are also seen on CT, the diagnosis is
relatively assured. 5°'51
INVERTED PAPILLOMA
The inverted papilloma is a relatively rare and
locally aggressive sinonasal tumor. It constitutes
0.5% to 4% of primary nasal tumors and occurs in
all age groups and in men more than women. The
most common presenting symptoms are nasal ob-
struction, epistaxis, and hyposmia. Subsequent si-
nusitis and tumor extension into the sinuses and
orbits can cause purulent nasal discharge, pain, and
diplopia. Radiographic findings of inverted papil-
loma can vary from a small nasal polypoid nodule
to an expansile large mass, which may remodel the
nasal vault and extend into the sinuses, orbits, or
even the anterior skull base. CT and MRI are very
useful in defining the location and extension of the
tumor. 52 Yousem et al52 have shown that this
tumor can be separated from obstructed secretions
based on lower T2-weighted (T2W) signal inten-
sity and solid enhancement in inverted papillomas.
However squamous cell carcinoma and inverted
papillomas look alike (Fig 10), which is important
because coincidental carcinomas occur in up to
15% of patients with inverted papillomas.
Other benign neoplasms to affect the sinonasal
cavity include osteomas, enchondromas, schwan-
nomas, and juvenile angiofibromas.
Malignant Neoplasms
Squamous cell carcinomas account for 80% of
the malignancies that affect the paranasal sinuses
and 80% occur in the maxillary sinus. The hall-
mark of malignancies of the sinonasal cavity is
bony destruction, which is seen in approximately
80% of CT scans of sinonasal squamous cells
carcinoma at initial presentation. The lesion is
IMAGING OF THE OLFACTORY SYSTEM
Fig 10. Inverted papilloma. Separating the low-intensity
inverted papilloma (*) from the high-intensity secretions (S) is
easy on the T2-weighted scan in this patient.
confined to the maxillary antrum in only 25% of
cases at presentation. 49 In most series, the lesion is
characterized by a low-signal intensity on T2W
scans. This is why differentiation with obstructed
secretions that are typically bright in signal inten-
sity on T2W scans is so easy on MRI.
Minor salivary gland tumors and melanoma are
the next most common malignancies to affect the
sinonasal cavity after squamous cell carcinoma. 49
The minor salivary gland tumors represent a wide
variety of histologic types including adenocarci-
noma, adenoid cystic carcinoma, mucoepidermoid
carcinoma, and sinonasal undifferentiated carci-
noma. Of all minor salivary gland tumors, adenoid
cystic carcinoma is the most common variety. Its
signal intensity may be high or low on T2W scans,
possibly related to the degree of tubular or cribri-
form histologic pattern as well as cystic spaces,
necrosis, and tumor cell density. 53 Tissue specific-
ity is not readily achievable with MRI or CT.
Gadolinium is of particular use with adenoid cystic
carcinomas, which have propensity for perineural
spread. 54 Enhancing cranial nerves may be present.
With sinonasal cavity malignancies one should
always attempt to trace back the branches of the
fifth cranial nerve via the pterygopalatine fossa,
foramen rotundum, foramen ovale, and orbital fis-
sures to identify perineural neoplastic spread.
Adenocarcinomas of the paranasal sinuses have
a predilection for the ethmoid sinuses and appear
more commonly in woodworkers. This tumor also
tends to have low-signal intensity on T2W MRI
images, but may have high-signal intensity in a
small percentage of patients.
467
Sarcomas of the sinonasal cavities are very rare,
with chondrosarcoma the most common. Again,
the histologic diagnosis is probably better sug-
gested by CT based on the characteristic whorls of
calcification. However, for staging, MRI is com-
petitive with CT and, particularly if repeat exami-
nations are going to be required, follow-up with
MRI to avoid the radiation exposure of CT is
recommended.
Melanoma is a tumor that is usually identified in
the nasal cavity as opposed to the paranasal si-
nuses. It has been associated with melanosis in
which there is field deposition of melanin along the
mucosal surface of the sinonasal cavity. Therefore,
multiplicity of lesions becomes a problem when
dealing with melanomas. Neither CT nor MRI is
particularly helpful in identifying the microscopic
field cancerization of melanoma. When melanoma
contains melanin there is paramagnetism that
causes T1 and T2 shortening (Fig 11), accounting
for high-signal intensity on T l W scans and low-
signal intensity on T2W scans. 55 However, an
amelanotic melanoma may have bright signal in-
tensity on T2W scans. The presence of hemorrhage
associated with the melanoma, a common occur-
rence because of the coincidence of epistaxis, may
further obfuscate the signal intensity pattern.
Lymphoma does occur in the paranasal sinuses
and may have variable signal intensity as well. It is
characterized by homogeneous signal intensity
without necrosis and is associated with cervical
lymphadenopathy.
Metastatic disease to the paranasal sinuses is
extremely rare. Of the primary causes of metasta-
ses to the sinuses, renal cell carcinoma is probably
the most common. This is a tumor that also has a
propensity for hemorrhage and that may also have
a variable signal intensity depending on the stage
of hemorrhage.
MISCELLANEOUS PERIPHERAL CAUSES
It is estimated that 30 million Americans have
used cocaine and 5 million use it regularly. 56
Intranasal use of cocaine and heroin has reached
epidemic proportions in the United States. Al-
though hyposmia or anosmia has been suggested to
occur often in cocaine abusers, few studies that
used quantitative measures of olfactory function
have confirmed such reports. A recent study re-
ported that, of t 1 cocaine abusers who underwent
detailed olfactory testing, only 1 was found to be
anosmic and another had mild olfactory discrimi-
468
nation dysfunction. 57 These investigators note that
most cocaine abusers do not develop permanent
olfactory dysfunction. If, in fact, olfactory distur-
bance occurs as a result of heavy cocaine use, it
could be caused by associated conductive disor-
ders, nasal airway obstruction, alteration in sinona-
sal aerodynamics, damage to the olfactory epithe-
lium, damage to the central olfactory system, or
osteolysis of the cribriform plate. 5s
Within the differential diagnosis for nasal sep-
turn cartilaginous destruction, one should include
Wegener's granulomatosis, syphilis, leprosy, lym-
phoma, rhinoscleroma (a klebsiella infection), and
fungal invasion.
Hyposmia or anosmia induced by occupational
or accidental exposure to toxins has been tradition-
ally thought to be caused by damage to the periph-
eral pathways. However, one study has suggested
that olfactory deficits caused by occupational ex-
posure to toxins (acrylates or methylacrylates)
have both peripheral toxic and central nervous
YOUSEM, OGUZ, AND LI
Fig 11. Melanoma. (A) Sagittal Tl-weighted scan shows a
mass (*) in the frontoethmoidal region with postobstructive
high-intensity secretions (S). (B) The lesion (arrows) is dark on
T2-weighted images. (C) CT shows involvement of the lamina
papyracea (arrows). Many melanomas will not be bright on
Tl-weighted scans because some are amelanotic and some
do not have sufficient deposition of melanin paramagnetism
to shorten T1.
system (CNS) effects. 59 One report of anosmia as
a sequela of hydrogen sulfide (H2S) inhalation
suggested the loss to be caused by central brain
damage. 6°
DISEASE STATES (CENTRAL)
Neurodegenerative Disorders
Dementia of the Alzheimer' s type. From a clin-
ical perspective, one of the earliest manifestations
of dementia of the Alzheimer's type (DAT) is a
loss of odor perception. 61-63 This is accounted for
pathologically by the presence of neurofibrillary
tangles, neuritic plaques, and cholinergic neuronal
loss in olfactory eloquent regions of the brain: the
entorhinal cortex, the olfactory bulbs, the hip-
pocampi, the olfactory nuclei, and the piriform
cortex (Fig 12). It appears that the olfactory system
is damaged early in DAT, with spread of neurofi-
brillary tangles from the entorhinal cortex to the
limbic system, then to neocortical areas. Primary
IMAGING OF THE OLFACTORY SYSTEM
Fig 12. Alzheimer's disease. The dilatation of the temporal
horns (arrows) and the atrophy of the temporal lobes {T),
as well as dilation of parahippocampal fissures, would sug-
gest the diagnosis of Alzheimer's disease in a demented
individual.
olfactory cortices are involved in more advanced
stages of the disease. 64 A theory espousing the
possibility that DAT is a transmissible disease
spread through the nasal passages has emphasized
the early involvement of the olfactory system with
DAT. 65"66 The investigators note that (1) neurofi-
brillary tangles are seen in olfactory eloquent areas
including the bulbs, (2) olfactory dysfunction is
invariably seen in patients with DAT, (3) olfactory
deficits are present early in the disease, predating
cognitive decline, (4) patients may be unaware of
deficits, (5) the olfactory deficits appear to be
unrelated to cognitive deficits both anatomically
and functionally, (6) the olfactory dysfunction
mimics that in Parkinson's disease and Hunting-
ton's disease, and (7) DAT progression can be
followed through olfactory testing. 67 Nonetheless,
the volumes of the OBTs in DAT have not been
shown to be reduced in a preliminary study com-
paring OBT volume and age-matched controls
(D.M. Yousem, unpublished data, 1991). Clearly,
however, temporal lobe volume loss is apparent in
DAT.
Multiple sclerosis. Multiple sclerosis (MS) af-
fects millions of Americans in the prime of their
lives. Though the influence of MS on the sense of
smell has long been controversial, recent MRI
studies have showed that the olfactory function in
patients with MS has closely correlated with the
load of demyelinating plaques within central olfac-
tory processing areas of the brain. 68-v° In 1997,
Doty et al68 found a strong negative relationship
(Spearman r = - . 9 4 ) between the UPSIT scores
469
and the number of MRI-determined plaques within
the inferior frontal and temporal lobe regions of the
brain. Another study has also shown a close asso-
ciation, longitudinally, between the remission and
exacerbation of plaque numbers and UPSIT scores,
with more plaques in the brain olfactory processing
areas reflecting lower UPSIT scores. 7°
Parkinson's disease. Odor detection and iden-
tification are significantly impaired in patients with
Parkinson's disease (PD). 66'71'72 Research into the
cause of smell dysfunction in patients with PD has
focused on dopaminergic changes. Patients with
PD show significantly reduced mean uptake of
~sF-dopa in the caudate nuclei and putamen, a
reduction of striatal dopamine storage, and reduced
activity in basal ganglia. However, the olfactory
deficit is unrelated to the severity of motor or
cognitive symptoms, and is not improved by L-
dopa therapy. Olfaction in parkinsonism-dementia
complex (PDC) of Guam is similarly affected, but
in patients with progressive supranuclear palsy and
patients with 1-methyl-4-phenyl-l,2,3,6-tetrahy-
dropyridine (MPTP)-induced parkinsonism, olfac-
tory function is normal. This may be a differential
point.
Acquired immune deficiency syndrome. Olfac-
tory deficits of patients with human immunodefi-
ciency virus (HIV) infection have been recently
reported. 73 Patients with acquired immune defi-
ciency syndrome (AIDS) dementia score lower on
UPSIT tests than those who have clinical disease
without dementia who, in turn, score worse than
those who are seropositive without disease who
still perform worse than normal controls. Everall et
a174-77 have found that the neuronal numeric den-
sity in the frontal cortex is significantly lower in
the HIV group than in a control group, with a loss
of about 38% of neurons in the superior frontal
gyms. This may account for the olfactory deficits
in these patients. Patients with AIDS also develop
sinusitis more frequently.
A number of other neurodegenerative disorders
including Huntington's disease, Korsakoff's psycho-
sis, and multisystem atrophy show significant olfac-
tory function loss during the course of the diseases.
Schizophrenia. Impaired olfactory function
has been reported in schizophrenic patients, espe-
cially men. 78-86 These olfactory deficits, which are
not of the same magnitude as those seen in patients
with AD and PD, are perhaps not unexpected,
given the occurrence of olfactory hallucinations as
symptoms in a number of patients with schizophre-
470
nia, and the evidence linking both to temporal lobe
dysfunction. Kopala et als5 studied olfactory iden-
tification ability in pre- and postmenopausal pa-
tients with schizophrenia as well as control sub-
jects. Olfactory deficits were present in all
schizophrenic patients, but at a more pronounced
level in postmenopausal ones. The investigators
stated that estrogen deficiency aggravates the con-
dition originating from schizophrenia.
Neuropathologic studies in schizophrenic pa-
tients have reported neuronal loss in the entorhinal
region and prefrontal cortex, gliosis in the basal
limbic structures of the forebrain, and atrophy in
temporolimbic structures. Neurophysiologic stud-
ies (including regional cerebral blood flow, brain
electrical activity mapping, and regional metabolic
activity in the brain) in patients with schizophrenia
have shown prefrontal cortex and temporal lobe
dysfunction, s7 Functional imaging, such as pos-
itron emission tomography (PET) or single photon
emission computed tomography (SPECT), has pro-
vided some evidence that certain schizophrenic
patients have decreased blood flow and metabo-
lism in the frontal lobes (hypofrontality).
Anatomic imaging findings have basically paral-
leled the neuropathologic changes in the brains of
patients with schizophrenia. The most consistent
finding (on both CT and MRI) is an increase in the
size of the cerebral ventricular system, especially in
the frontal and temporal horns, and corresponding
decreases in cerebral tissue, especially in the prefron-
tal cortex and in medial temporolimbic structures, s7
Suddath et a188 evaluated the volume of the temporal
lobes in patients with schizophrenia by a quantitative
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