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Home , Olfactory bulb, Olfactory nerve, Olfactory system, Olfactory tract, Sense of smell

Imaging of the

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

The olfactory system consists of the primary olfactory in the , the olfactory bulbs and tracts, and numerous intracranial connections and pathways. Diseases affecting the 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 is astounding, yet the imaging ramifications have barely been explored. Copyright © 2001 by W,B. Saunders Company

HE ANATOMY AND of ol- to enter the just lateral and T faction have rarely been the subject of arti- anterior to the optic . Fibers continue into cles in the radiologic literature, in part because this medial and lateral olfactory striae to septal nuclei special sense is the least appreciated one in the at the base of the brain just inferior and anterior to . All too often the olfactory system the rostrum of the corpus callosum. from is ignored in the usual clinical evaluation of a mitral and tufted cells project to central brain patient, hence, the common recording that "cranial components including the pyriform nerves II to XII are intact." Nonetheless, to the and and adjacent corticomedial astute clinician and conscientious neuroradiologist, (which together form the ), the knowledge of the ramifications of olfactory dys- ventral , the parahippocampus area, and function is very rewarding. Therefore, this article the anterior olfactory nuclei. From these areas initially focuses on the functional anatomy of the there are widespread interconnections with many sense of smell and then addresses those protean parts of the brain, including the mediodorsal thal- entities that affect cranial I (see Table 1). amus, , orbitofrontal and dorsolateral Both peripheral and central diseases that impact on frontal cortex, temporal cortex, and other areas of the sense of smell are explored. the limbic system (Fig 2). The sizes of the olfactory bulbs and tracts ANATOMIC IMAGING (NORMAL) (OBTs) have recently been reported in the litera- Smells are perceived in the upper nasal cavity by ture. 1 The left and right OBT volumes peak in the olfactory neuroepithelial receptors. The primary fourth decade of life, but show considerable vari- olfactory nerves pierce the to stim- ation within each subject group (see Table 2). ulate and with nuclei. In The mean left and fight OBT volumes and the truth, the true olfactory nerves are located in the mean combined volume show a decline in the nasal cavity and these should be termed cranial seventh and eighth decade that parallels a decline nerves I (CN I). Instead, the olfactory bulb and in scores by the patients on the University of tract, which is a secondary neuron, is usually Pennsylvania Smell Identification Test (UPSIT) referred to as the first cranial nerve (Fig 1). scores. Thus, as the volume declines, function From the olfactory bulb, fibers travel in the declines. A Kruskal-Wallis test, performed to de- tect differences between the means of OBT vol- umes between decades showed borderline signifi- From the Russell H. Morgan Department of Radiology and cance at P = .05 for the left OBT, but not the right. Radiological Sciences, Johns Hopkins Hospital, Baltimore, The biggest differences noted were between the MD; and the Smell and Center, Department of Otorhi- fourth and seventh decade for fight and left OBTs. nolaryngology, and Surgery, Hospital of the Uni- By using regression analysis based on the gener- versity of Pennsylvania, Philadelphia, PA. Address reprint requests to David M. Yousem, MD, Director alized estimating equations model, a OBT volumes of Neuroradiology, The Russell H. Morgan Department of show significant decreases between decades of life Radiology and Radiological Sciences, Johns Hopkins Hospital, (P = .027). 600 North Wolfe Street, Phipps B-112, Baltimore, MD 21287; As measured in large population studies by us- e-mail: [email protected] ing the UPSIT, there is an initial increase in Copyright © 2001 by W.B. Saunders Company 0887-2171/01/2206-0001535.00/0 identification capability to the third decade of life, doi: l O.1053/sult.2001.28800 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 457

Table 1, Causes of Olfactory Dysfunction Primary Olfactory Apparatus Conductive Disorders Lesions NeurodegenerativeDisorders Miscellaneous Sinusitis Alzheimer's disease Vasculitis Polyposis Traumatic injury Parkinson's disease infarction Sinonasal cavity neoplasms Congenital aplasia, hypoplasia Huntington's disease Surgery Olfactory neuroblastoma Cocaine Multiple sclerosis Toxins Temporal lobe epilepsy Viral infections Korsakoff's disease Amyotropic lateral sclerosis

age 60, however, a decline in median UPSIT the brain associated with olfaction. Koizuka et a116 scores begins to be seen across patients to the point have noted bilateral increased cerebral blood flow that nearly 75% of individuals over 80 years old in the inferior frontal lobes, , and score 19 or less on the 40-item UPSIT test. 4 These orbitofrontal regions after phenyl ethyl alcohol patients are severely hyposmic or anosmic. Similar olfactory stimulation. Wexler et al t7 showed sim- changes in odor threshold values for phenyl ethyl ilar areas of activation in these and other limbic alcohol are noted, however, the drop-off starts to structures when were presented to normal be seen at about age 40 in men and 60 in women. 5 volunteers. Smokers and men tend to have higher thresholds Yousem et a118 have performed olfactory-stim- than nonsmokers and women, respectively. A ulated functional magnetic resonance imaging change in the of pleasantness of taste (OSfMRI) in 18 normal subjects between 29 and also occurs with age. 6'7 This effect can be elimi- 43 years of age by using a homemade nated when the are occluded and the olfac- in which odors from 3 sources were alternated at tory influence on taste is nullified.* 5-second intervals for 30 seconds during the on Several theories have been espoused as to why and room air was used for 30 seconds for the sense of smell declines with age and include: the off stimulus. They found that odorants that (1) reduction in volume of the sensory neuroepi- stimulated only CN I had extensive activation that thelium caused by cumulative effects of viral in- was localized to the orbitofrontal region (Brod- fections, (2) replacement of the olfactory neuro- mann area 11) and the cerebellum. The volume of with nonsensory columnar epithelium activation was greater in the right orbitofrontal in the olfactory clefts of the , (3) diminution in region than the left (Table 3, Fig 3). central (eg, ), (4) Some odorants not only stimulate the olfactory reduction in patency of the airway, (5) variations in system but also activate trigeminal neurons that the nasal cycle with age, or (6) reduction in resis- abound in the nasal cavity. Stimulants such as tance of the olfactory neuroepithelium to infectious carbon dioxide that "sting or burn the nose" tend to or toxic insults. 4"5'9-a5 have more fifth-cranial nerve input. When Yousem The finding of a decline in the OBT et a118 applied an fMRI paradigm with odorants volume with advancing age lends credence to the that also induce trigelmnal nerve stimulation they idea of a reduced amount of afferent input to the found wider activation of many different areas, olfactory bulbs and tracts from the olfactory neu- including visual and cingulate areas (Table 4, Fig roepithelium and ciliated nerves that pierce the 4). Yousem et al ~8 found that there was accommo- cribriform plate. A decrease in central neurotrans- dation (diminution of brain activation) to pleasant mitters is a less plausible explanation for the quan- -mediated odors, but amplification titative findings because the predominant effect (an increase in brain activation) to repeated testing seen is at the bulb and tract level, not at the cortical with trigeminally mediated odors. level. Fulbright et a119 reported that pleasant odors lateralized to the left insula region whereas the FUNCTIONAL IMAGING (NORMAL) unpleasant odors were more left frontal. Functional magnetic resonance imaging (fMRI) In a study of the effects of age on fMRI, 2° 5 has been used in an attempt to localize regions of 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) At 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 , containing the olfactory neurons, and the olfactory bulb (the central target of 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 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 SMA 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 20-44 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 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 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 Allergic rhinitis is a common upper-airway con- olfactory deficits among patients with nasal and dition affecting about 30 million Americans with paranasal sinus disease is most likely caused by peak prevalence in the age group from 35 to 54 nasal airway obstruction. Recently, the influence of years. or is common with al- nasal obstruction on olfaction has been compre- lergic rhinitis, mainly caused by nasal obstruction hensively reviewed.22 Any cause of bilateral ob- by polyps or inflamed mucosa, which limit access struction can lead to decreased smell sensations by of inspired air to the roof of the nasal vault. The limiting airflow to the olfactory receptors. Besides diagnostic work-up begins with a careful history the obstructive effect, lesions that are located in the that attempts to identify offending allergens. Skin upper nasal vault and/or cribriform plate region testing of specific antigens is often used to confirm may also directly damage the olfactory epithelium the diagnosis. Medical imaging studies play a sup- and olfactory neurons. plementary role in the evaluation of sinonasal air- Paranasal sinusitis (Fig 7) is a relatively com- way status and differential diagnosis. CT and MRI mon disorder affecting approximately 30% of the are also important for detecting any complications population at some time in their lives. 23-26 One of such as sinusitis, mucoceles, and aggressive polyps the common symptoms of acute and chronic para- in patients with allergic rhinitis. Rounded excres- nasal sinusitis is decreased smell sensation, which cences and enlargement of ostia are seen in the is generally reversible. The prompt diagnosis and airway of patients with polyposis. treatment of sinusitis are important for restoring olfactory function. Though the exact cause of che- Trauma mosensory dysfunction secondary to sinusitis is The incidence of posttraumatic anosmia ranges elusive, alterations in nasal air flow and mucocili- from 24% to 30% for severe head injuries, 15% to ary clearance or obstruction from secretory prod- 19% for moderate head injuries, and 0% to 16% for ucts, polyps, or retention cysts may contribute to mild head injuries. 27 Blows to the frontal region or olfactory dysfunction. At present, high-resolution the occiput are commonly associated with post- computed tomography (CT) is the preferred imag- traumatic anosmia. Sumner2s found that a blow to ing technique to evaluate for sinusitis, preceded by the occiput has 5 times the chance of inducing nasal endoscopic examination. CT helps the func- anosmia than a blow to the forehead if posttrau- tional endoscopic sinus surgeons in planning effec- matic 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 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 or 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 YOUSEM, OGUZ, AND LI completely, 36% improved slightly, 45% had no believed that there may be fibrotic scarring that change, and 18% worsened. occurs at the cribriform plate that may prevent Retention of the sense of smell in one is regenerating axons from connecting to the second- uncommon (< 11% of patients) in posttraumatic ary neurons of the olfactory bulb. 33 patients evaluated for chemosensory abnormalities. To evaluate the sites of injury in patients with In patients who have partial or incomplete loss of posttraumatic olfactory deficits, Yousem et a134 olfactory function, the deficit may go completely studied 25 patients with posttraumatic smell dys- unnoticed. function by using olfactory testing and MR. Quan- Recovery of olfactory function after head titative and qualitative gradings for olfactory bulb, trauma is variable. Return of olfactory function can tract, subfrontal region, , and tempo- occur in 14% to 39% of patients initially anos- ral lobe damage were correlated with olfactory test mic 2am'3z especially if the interval of posttrau- results. Twelve patients were anosmic, 8 had se- matic amnesia is less than 24 hours. Although 74% vere impairment, and 5 were mildly impaired. of patients recovering olfactory function do so Olfactory bulb and tract (88% of patients), sub- within 12 weeks, 1 study reported that an addi- frontal (60%), and temporal lobe (32%) injuries tional 22% will regain function by the second year were found (Fig 8), but did not correlate well with after the injury. 28 Despite the fact that reports of the UPSIT scores. Odor discrimination deficits return of olfactory function as long as 7 years after correlated best with frontal injury and odor mem- injury have been published, few studies have used ory correlated best with temporal lobe damage. quantitative tests of olfactory function. Olfactory These relationships did not achieve statistical sig- neurons have the capacity for allow- nificance. The finding that the OBT volumes in ing new receptor growth, so it is surmised that the patients with posttraumatic anosmia are smaller late return of function may be related to a periph- than those of patients with residual smell function eral (olfactory nerves-bulbs-tracts) mechanism or control subjects suggests that the source of the rather than a more central one. In it is 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 465 level or even more proximally in the olfactory patients with congenital anosmia and/or Kall- neurons. Shearing of nerves at the cribriform plate mann's syndrome is still being debated. Thus, 2 is the most plausible explanation. camps have developed; those that believe that Kallmann's syndrome patients have no epithelium CONGENITAL and those that believe that the olfactory axons Congenital anosmia is said to exist when a simply fail to reach the prosencephalon and hence patient has no recall of smell sensation dating to do not connect intracranially. The hypogonadism early childhood. Some patients report a reduced of Kallmann's syndrome is thought to be caused by sense of smell since birth (congenital hyposmia) either a lack of cells that can express luteinizing and still others who claim to have no sense of smell hormone releasing hormone (LHRH) or by abnor- may show some residual or normal function on mal migration of the LHRH neurons from the laboratory testing. Although the etiology of early olfactory placode in the nose to the hypothala- anosmia or hyposmia may include such entities as mus. 37 Truwit et al4° support the neuronal migra- viral infections, posttraumatic injury to the ol- tional anomaly theory. They believe that soft tissue factory epithelium, choanal atresia, holoprosen- seen by MR in the region below the expected cephaly, septo-optic dysplasia, meningoencephalo- location of the olfactory bulbs represents arrested celes that affect the frontoethmoidal region, or neurons. Kallmann's syndrome (anosmia with hypogo- In a study of 24 individuals with congenital nadotropic hypogonadism), 35 studies conducted by anosmia, Yousem et a141'42 showed absence of the Jafek et a136 and Leopold et a137 suggest that olfactory bulbs and tracts in 16 patients, hypoplasia congenital anosmia usually does not occur in as- of bulbs and tracts in 4 patients, and absent bulbs sociation with other anomalies. but hypoplastic tracts in 4 patients (Fig 9). Three Kallmann's syndrome was extensively de- individuals could smell, though with severe deficits scribed in 194435 and has been the focus of a (UPSITS 18-24 of a possible 40), and 2 of the 3 number of clinical, genetic, and pathologic studies. had intact small bulbs and tracts. 41"42 Vogl et a143 The disorder appears to be found most commonly also documented the ability of MR to show abnor- as an x-linked disorder, but can be inherited malities of the olfactory pathway in patients with through autosomal transmission as well. 38 Patients congenital anosmia. Eighteen patients diagnosed are eunuchoid and may have coexistent renal with Kallmann's syndrome and 10 patients with anomalies, cleft lips or palates, infertility, spastic idiopathic hypogonadatrophic hypogonadism were paraplegia, cerebellar dysfunction, nystagmus, or included in this study, which used a head coil. loss. 38 Although most initial reports noted Seventeen of the 18 patients with Kallmann's syn- the absence of olfactory bulbs and tracts in Kall- drome showed absence of the olfactory bulbs and mann's syndrome macroscopically, 35'39 the pres- tracts and 8 of these individuals had normal olfac- ence or absence of olfactory neuroepithelium in tory sulci adjacent to the gyms rectus. Olfactory

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. 466 YOUSEM, OGUZ, AND LI

bulbs and tracts were present in all 10 patients who an important role. Generally speaking, MRI is had idiopathic hypogonadotropic hypogonadism, more accurate than CT in showing the tumor's though 3 showed some degree of hypoplasia. In intracranial extent. MRI is also exquisitely useful 3 other studies of patients with Kallmann's syn- for differentiating neoplasm from postobstructive drome, complete absence or hypoplasia of the secretions because of the difference in the signal olfactory bulbs and tracts was the predominant intensity (secretions are bright on T2, tumor inter- finding. 38'4°'44'45 The olfactory sulci may be vari- mediate) and gadolinium enhancement. Unfortu- ably aplastic, hypoplastic, or normal. nately, signal intensity characteristics of various sinonasal tract tumors overlap each other, so MRI TUMORS OF THE NASAL CAVITY AND cannot usually predict specific tumor histology. PARANASAL SINUSES However, a recently described imaging finding Neoplasms of the sinonasal tract are uncommon. characteristic of olfactory neuroblastomas is the Malignant tumors of the nasal cavity and paranasal presence of peripheral peritumoral cysts along the sinuses account for only 0.2% to 0.8% of all intracranial portion of the tumor. If stippled calci- human malignancies. 46-49 Early symptoms of si- fications are also seen on CT, the diagnosis is nonasal tract tumors, nasal discharge, unilateral relatively assured. 5°'51 nasal obstruction, and minor intermittent epistaxis may simulate low-grade chronic infection. Almost INVERTED PAPILLOMA all sinonasal tract tumors and tumor-like condi- The inverted papilloma is a relatively rare and tions that grow to a large size may cause a decline locally aggressive sinonasal tumor. It constitutes in olfactory acuity by interfering with patency of 0.5% to 4% of primary nasal tumors and occurs in the nasal airway or directly destroying the olfac- all age groups and in men more than women. The tory receptors. The most common malignancies of most common presenting symptoms are nasal ob- the sinonasal system are squamous cell carcinoma struction, epistaxis, and hyposmia. Subsequent si- and adenocarcinoma, but lymphoma, melanoma, nusitis and tumor extension into the sinuses and adenoid cystic carcinoma, and chondrosarcomas orbits can cause purulent nasal discharge, , and also populate the nasal cavity. Two examples of . Radiographic findings of inverted papil- intrinsic sinonasal tract tumors relatively unique to loma can vary from a small nasal polypoid nodule the sinuses (the olfactory neuroblastoma and the to an expansile large mass, which may remodel the inverted papilloma, both of which often cause nasal vault and extend into the sinuses, orbits, or hyposmia or anosmia) may serve as prototypes for even the anterior skull base. CT and MRI are very masses in this region. useful in defining the location and extension of the tumor. 52 Yousem et al52 have shown that this OLFACTORY NEUROBLASTOMA tumor can be separated from obstructed secretions Olfactory neuroblastoma, or esthesioneuroblas- based on lower T2-weighted (T2W) signal inten- toma, is a rare nasal tumor originating from the sity and solid enhancement in inverted papillomas. olfactory neuroepithelium lining the roof of the However squamous cell carcinoma and inverted nasal vault and in close proximity to the cribriform papillomas look alike (Fig 10), which is important plate. There have been less than 300 reported cases because coincidental carcinomas occur in up to in literature worldwide. Olfactory neuroblastomas 15% of patients with inverted papillomas. occur in all age groups with a peak incidence in the Other benign neoplasms to affect the sinonasal 11 to 20 and 51 to 60 years age groups. There is a cavity include osteomas, enchondromas, schwan- slight preponderance of the tumor in women. The nomas, and juvenile angiofibromas. incidence of olfactory neuroblastoma has been es- timated to range from 2% to 3% of all malignant Malignant Neoplasms intranasal neoplasms. The most common symp- Squamous cell carcinomas account for 80% of toms are unilateral nasal obstruction and recurrent the malignancies that affect the paranasal sinuses epistaxis. Hyposmia and rhinorrhea are not un- and 80% occur in the maxillary sinus. The hall- usual. Extension into the orbit, paranasal sinuses, mark of malignancies of the sinonasal cavity is or may cause vision distur- bony destruction, which is seen in approximately bances and headache. In the detection and staging 80% of CT scans of sinonasal squamous cells of olfactory neuroblastoma, CT and/or MRI play carcinoma at initial presentation. The lesion is IMAGING OF THE OLFACTORY SYSTEM 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, Fig 10. Inverted papilloma. Separating the low-intensity inverted papilloma (*) from the high-intensity secretions (S) is multiplicity of lesions becomes a problem when easy on the T2-weighted in this patient. dealing with melanomas. Neither CT nor MRI is particularly helpful in identifying the microscopic field cancerization of melanoma. When melanoma confined to the maxillary antrum in only 25% of contains melanin there is paramagnetism that cases at presentation. 49 In most series, the lesion is causes T1 and T2 shortening (Fig 11), accounting characterized by a low-signal intensity on T2W for high-signal intensity on TlW scans and low- scans. This is why differentiation with obstructed signal intensity on T2W scans. 55 However, an secretions that are typically bright in signal inten- amelanotic melanoma may have bright signal in- sity on T2W scans is so easy on MRI. tensity on T2W scans. The presence of hemorrhage Minor salivary gland tumors and melanoma are associated with the melanoma, a common occur- the next most common malignancies to affect the rence because of the coincidence of epistaxis, may sinonasal cavity after squamous cell carcinoma. 49 further obfuscate the signal intensity pattern. The minor salivary gland tumors represent a wide Lymphoma does occur in the paranasal sinuses variety of histologic types including adenocarci- and may have variable signal intensity as well. It is noma, adenoid cystic carcinoma, mucoepidermoid characterized by homogeneous signal intensity carcinoma, and sinonasal undifferentiated carci- without necrosis and is associated with cervical noma. Of all minor salivary gland tumors, adenoid lymphadenopathy. cystic carcinoma is the most common variety. Its Metastatic disease to the paranasal sinuses is signal intensity may be high or low on T2W scans, extremely rare. Of the primary causes of metasta- possibly related to the degree of tubular or cribri- ses to the sinuses, renal cell carcinoma is probably form histologic pattern as well as cystic spaces, the most common. This is a tumor that also has a necrosis, and tumor cell density. 53 Tissue specific- propensity for hemorrhage and that may also have ity is not readily achievable with MRI or CT. a variable signal intensity depending on the stage Gadolinium is of particular use with adenoid cystic of hemorrhage. carcinomas, which have propensity for perineural spread. 54 Enhancing may be present. MISCELLANEOUS PERIPHERAL CAUSES With sinonasal cavity malignancies one should It is estimated that 30 million Americans have always attempt to trace back the branches of the used cocaine and 5 million use it regularly. 56 fifth cranial nerve via the pterygopalatine fossa, Intranasal use of cocaine and heroin has reached foramen rotundum, foramen ovale, and orbital fis- epidemic proportions in the United States. Al- sures to identify perineural neoplastic spread. though hyposmia or anosmia has been suggested to Adenocarcinomas of the paranasal sinuses have occur often in cocaine abusers, few studies that a predilection for the ethmoid sinuses and appear used quantitative measures of olfactory function more commonly in woodworkers. This tumor also have confirmed such reports. A recent study re- tends to have low-signal intensity on T2W MRI ported that, of t 1 cocaine abusers who underwent images, but may have high-signal intensity in a detailed olfactory testing, only 1 was found to be small percentage of patients. anosmic and another had mild olfactory discrimi- 468 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. nation dysfunction.57 These investigators note that system (CNS) effects.59 One report of anosmia as most cocaine abusers do not develop permanent a sequela of hydrogen sulfide (H2S) olfactory dysfunction. If, in fact, olfactory distur- suggested the loss to be caused by central brain bance occurs as a result of heavy cocaine use, it damage. 6° could be caused by associated conductive disor- ders, nasal airway obstruction, alteration in sinona- DISEASE STATES (CENTRAL) sal aerodynamics, damage to the olfactory epithe- Neurodegenerative Disorders lium, damage to the central olfactory system, or osteolysis of the cribriform plate. 5s of the Alzheimer' s type. From a clin- Within the differential diagnosis for nasal sep- ical perspective, one of the earliest manifestations turn cartilaginous destruction, one should include of dementia of the Alzheimer's type (DAT) is a Wegener's granulomatosis, syphilis, leprosy, lym- loss of odor perception. 61-63 This is accounted for phoma, rhinoscleroma (a klebsiella infection), and pathologically by the presence of neurofibrillary fungal invasion. tangles, neuritic plaques, and cholinergic neuronal Hyposmia or anosmia induced by occupational loss in olfactory eloquent regions of the brain: the or accidental exposure to toxins has been tradition- entorhinal cortex, the olfactory bulbs, the hip- ally thought to be caused by damage to the periph- pocampi, the olfactory nuclei, and the piriform eral pathways. However, one study has suggested cortex (Fig 12). It appears that the olfactory system that olfactory deficits caused by occupational ex- is damaged early in DAT, with spread of neurofi- posure to toxins (acrylates or methylacrylates) brillary tangles from the entorhinal cortex to the have both peripheral toxic and central nervous limbic system, then to neocortical areas. Primary IMAGING OF THE OLFACTORY SYSTEM 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 Fig 12. Alzheimer's disease. The dilatation of the temporal ~sF-dopa in the caudate nuclei and , a horns (arrows) and the atrophy of the temporal lobes {T), as well as dilation of parahippocampal fissures, would sug- reduction of striatal storage, and reduced gest the diagnosis of Alzheimer's disease in a demented activity in . However, the olfactory individual. deficit is unrelated to the severity of motor or cognitive symptoms, and is not improved by L- dopa therapy. Olfaction in parkinsonism-dementia olfactory cortices are involved in more advanced complex (PDC) of Guam is similarly affected, but stages of the disease. 64 A theory espousing the in patients with progressive supranuclear palsy and possibility that DAT is a transmissible disease patients with 1-methyl-4-phenyl-l,2,3,6-tetrahy- spread through the nasal passages has emphasized dropyridine (MPTP)-induced parkinsonism, olfac- the early involvement of the olfactory system with tory function is normal. This may be a differential DAT. 65"66 The investigators note that (1) neurofi- point. brillary tangles are seen in olfactory eloquent areas Acquired immune deficiency syndrome. Olfac- including the bulbs, (2) olfactory dysfunction is tory deficits of patients with human immunodefi- invariably seen in patients with DAT, (3) olfactory ciency virus (HIV) infection have been recently deficits are present early in the disease, predating reported. 73 Patients with acquired immune defi- cognitive decline, (4) patients may be unaware of ciency syndrome (AIDS) dementia score lower on deficits, (5) the olfactory deficits appear to be UPSIT tests than those who have clinical disease unrelated to cognitive deficits both anatomically without dementia who, in turn, score worse than and functionally, (6) the olfactory dysfunction those who are seropositive without disease who mimics that in Parkinson's disease and Hunting- still perform worse than normal controls. Everall et ton's disease, and (7) DAT progression can be a174-77 have found that the neuronal numeric den- followed through olfactory testing. 67 Nonetheless, sity in the frontal cortex is significantly lower in the volumes of the OBTs in DAT have not been the HIV group than in a control group, with a loss shown to be reduced in a preliminary study com- of about 38% of neurons in the superior frontal paring OBT volume and age-matched controls gyms. This may account for the olfactory deficits (D.M. Yousem, unpublished data, 1991). Clearly, in these patients. Patients with AIDS also develop however, temporal lobe volume loss is apparent in sinusitis more frequently. DAT. A number of other neurodegenerative disorders Multiple sclerosis. Multiple sclerosis (MS) af- including Huntington's disease, Korsakoff's psycho- fects millions of Americans in the prime of their sis, and multisystem atrophy show significant olfac- lives. Though the influence of MS on the sense of tory function loss during the course of the diseases. smell has long been controversial, recent MRI Schizophrenia. Impaired olfactory function studies have showed that the olfactory function in has been reported in schizophrenic patients, espe- patients with MS has closely correlated with the cially men. 78-86 These olfactory deficits, which are load of demyelinating plaques within central olfac- not of the same magnitude as those seen in patients tory processing areas of the brain. 68-v° In 1997, with AD and PD, are perhaps not unexpected, Doty et al68 found a strong negative relationship given the occurrence of olfactory as (Spearman r = -.94 ) between the UPSIT scores symptoms in a number of patients with schizophre- 470 YOUSEM, OGUZ, AND LI

nia, and the evidence linking both to temporal lobe MRI study. The results showed that the volume of dysfunction. Kopala et als5 studied olfactory iden- temporal lobe gray matter was 20% smaller in the tification ability in pre- and postmenopausal pa- patients than in the control subjects and lateral ven- tients with schizophrenia as well as control sub- tricular volume was 67% larger in the schizophrenia jects. Olfactory deficits were present in all group than in the control group. Schizophrenic pa- schizophrenic patients, but at a more pronounced tients tend to have smaller hippocampi than matched level in postmenopausal ones. The investigators controls. In a recent volumetric MRI study by stated that estrogen deficiency aggravates the con- Turetsky et al,79 patients with schizophrenia exhib- dition originating from schizophrenia. ited 23% smaller olfactory bulb volumes bilaterally Neuropathologic studies in schizophrenic pa- than comparison subjects. tients have reported neuronal loss in the entorhinal Epilepsy. Kohler et als9 studied patients with region and , gliosis in the basal schizophrenia and right and left mesial temporal lobe limbic structures of the , and atrophy in epilepsy (TLE). Patients with schizophrenia and temporolimbic structures. Neurophysiologic stud- right-sided TLE exhibited significant impairment on ies (including regional cerebral blood flow, brain olfactory tests, whereas patients with left-sided TLE electrical activity mapping, and regional metabolic and controls performed comparably. This study cor- activity in the brain) in patients with schizophrenia roborates the right-sided dominance of olfaction, s9 have shown prefrontal cortex and temporal lobe Unpleasant olfactory auras associated with dysfunction, s7 Functional imaging, such as pos- are not tmcommon, and epilepsy without schizophre- itron emission tomography (PET) or single photon nia has been associated with hyposmia. 9° Patients emission computed tomography (SPECT), has pro- with mesial TLE and sclerosis often have impaired vided some evidence that certain schizophrenic odor discrimination and identification 9t and patients have decreased blood flow and metabo- will correctly lateralize a focus in 74% of lism in the frontal lobes (hypofrontality). patients. After treatment of epilepsy with partial tem- Anatomic imaging findings have basically paral- poral lobe resections, even greater olfactory loss may leled the neuropathologic changes in the of be detectable. 9° patients with schizophrenia. The most consistent finding (on both CT and MRI) is an increase in the CONCLUSION size of the cerebral ventricular system, especially in The imaging evaluation of a patient with olfac- the frontal and temporal horns, and corresponding tory dysfunction may span a wide variety of dis- decreases in cerebral tissue, especially in the prefron- eases in the sinonasal cavity and brain. They may tal cortex and in medial temporolimbic structures, s7 be classified as peripheral or central or on the basis Suddath et a188 evaluated the volume of the temporal of pathology: inflammatory, neoplastic, traumatic, lobes in patients with schizophrenia by a quantitative congenital, and neurodegenerative.

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