TITLE: Can You Smell That? Anatomy and Physiology of Smell
SOURCE: Grand Rounds Presentation, Department of Otolaryngology
The University of Texas Medical Branch (ut= mb Health)
DATE: January 30, 2012
RESIDENT PHYSICIAN: Benjamin Walton, MD
FACULTY PHYSICIAN: Patricia Maeso, MD
DISCUSSANT: Harold Pine, MD
SERIES EDITOR: Francis B. Quinn, Jr., MD
ARCHIVIST: Melinda Stoner Quinn, MSICS

"This material was prepared by resident phy= sicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head= and Neck Surgery and was not intended for clinical use in its present form. It = was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to= its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and sho= uld not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion."

Introduction

Olfaction is an often over-looked but vital sense to o= ur everyday living. As Otolaryngologists we are often at the forefront for diagnosis and treatment= of patients with olfactory disorders. The sense of smell is the most ancient of our distal senses and is f= ound in nearly all air-, water-, and land-dwelling creatures. OIfaction determines the flavor of foods and beverages. Also, olfaction plays a significan= t role in nutrition, safety, and maintenance of a person’s quality of life.<= span style=3D'mso-spacerun:yes'> There are 2.7 million adults (1.4%= ) in the U.S. alone with olfactory dysfunction.

There are multiple professions for which olfaction is depended on for making a living. These include cooks, firefighters, plumbers, wine merchants, perfume= rs, cosmetic retailers, and chemical plant workers. The sense of smell is often downpl= ayed but may be the first sign of other disorders which will be discussed in det= ail later.

Definitions

In order to better understand olfaction and olfactory disturbances, it is best to define the various disorders. Total anosmia refers to the inabil= ity to smell all odorants on both sides of the nose. Partial anosmia refers to the inab= ility to smell certain odorants, while specific anosmia refers to the lack of the ability to smell one or few odorants. Hyperosmia is described as an abnormally= acute smell function which is often interpreted as a hypersensitivity to odors. Dysosmia refers to a distorted or perverted smell perception. Parosmias or cacosmias are changes in the quality of an olfactory cue. Pha= ntosmia, which can be a very debilitating disorder, is a sense of odor, often foul, = in the absence of an olfactory stimulus. Olfactory agnosia is the inability to recognize odor sensations despite olfactory processing, language, and intellectual function being intact. Olfactory agnosia is often seen in certa= in stroke and post encephalitic patients.&nbs= p; Presbyosmia, which some believe is not a= true disorder, is smell loss due to aging.

Nasal Anatomy and Olfaction

Odor reception is the function of 4 cranial nerves. The olfactory nerve serves the gre= atest role in olfaction and will be emphasized in this talk. Also, the trigeminal nerve (CN V), glossopharyngeal nerve (CN IX), and vagus nerve= (CN X) play roles in olfactory input. Olfactory nerve stimulation requires odorant molecules to reach the olfactory mucosa at the top of the nasal cavity. In order for this to occur, a form= of nasal airflow must exist. The= re are two basic types of nasal airflow in relationship to olfaction. Orthonasal flow is the airflow toward the olfactory epithelium on inhalation or sniff. R= etronasal flow occurs during eating. Th= is flow is often what contributes greatly to the flavor of food. The physiologic airflow of the nas= al passages is directed most toward the middle meatus. Only approximately 15% of the total airflow of the nose passes through the olfactory region, and only 35% of to= tal airflow passes through the inferior meatus. This should come as no surprise th= at obstructive nasal disease, even minor, can cause major changes in olfactory sensing.

When presented with odors, it is our natural instinct = to sniff. However, there is no c= lear understanding why we sniff. S= tudies on the physiology of sniff have found no clear evidence that sniffing causes effects in the rapid change of flow velocity on the in vivo airflow pattern. Scherer and colleagu= es found percentages and velocity of airflow to the olfactory region to be sim= ilar for various steady-state rates in the normal physiologic range. There are some theories that sniff= ing may allow the trigeminal nerve to alert olfactory neurons that an odorants = will soon arrive. Finally, it appe= ars that a person’s natural sniff seems to optimal for their own nasal anatomy. One study analyzed patients’ sniff and various other sniff patterns but concluded that t= he natural sniff of the patient was optimal.

As olfactory molecules enter the nasal cavity, they mu= st pass through the tall but narrow nasal passages. Olfactory epithelium is wet with variable thickness and is aerodynamically “rough” in quality. This allows for turbulent flow to = occur which can lengthen the time air passes through the epithelium. Schneider and Wolf observed that olfactory ability is at its best when the epithelium is moderately congeste= d, wet, and red. These are all condition associated with a viral URI.&nbs= p; Also, studies have shown that olfaction seems to improve when the na= sal chambers are somewhat narrowed. The nasal cycle, however, does not have any effect on olfactory ability. Olfactory epithelium is found at t= he anterior skull base along the cribiform plate.<= span style=3D'mso-spacerun:yes'> Olfactory neu= roepithelium also exists along the superior turbinate and superior medial septum.

Absorption

An important step in the detection of odorants is the absorption of molecules from the air into the mucus lining the epithelium.<= span style=3D'mso-spacerun:yes'> This helps in increasing the trave= l time through the nasal passageways. The absorption of odorants may have a profound influence on the spectrum of chemicals reaching the olfactory cleft.&nb= sp; Highly absorbable chemicals may have minimal or no odor as they never reach the olfactory cleft.

Olfactory mucus is produced by Bowman’s glands a= nd goblet cells of the adjacent respiratory epithelium. As mentioned, partitioning odorant molecules between the air phase and mucus phase is important in the odorants reaching the olfactory epithelium. Odorant molecules must be absorbable enough in the mucus but not too absorbable as to not interact with the receptors. Many medications can play a role i= n the properties of the overlying mucus. These include adrenergic, cholinergic, and pept= idergic agents. Just as important as absorbing molecules, clearing odorant appears to be another important role = in the olfactory mucus-epithelial system.&nbs= p; There is controversy about the role the olfactory mucus plays in dea= ctivating, removing, or desorbing odorants from the olfactory area.

Olfactory sensory neurons are protected in a 1-mm-wide crevice of the posterosuperior nose which covers roughly 1 cm² on each side. The neuroepithelium is a pseudostrat= ified columnar epithelium. The neur= ons are exposed to the outside world through their dendrites and cilia. These axons synapse at the base on= the brain in the olfactory bulb. = In the olfactory epithelium, there are at least six morphologically and biochemica= lly distinct cell types. Uniquely= , the olfactory neuroepithelium is a bipolar receptor= cell that projects from the nasal cavity into the brain without an intervening synapse. This can be a major = route of viral and xenobiotic invasion into the central nervous system. There have been case reports and r= ecent events in the news concerning deaths and cases of Naeg= leria infections caused by sinus rinse use due to infiltration through the cribiform plate.

The major cell in the olfactory n= euroepithelium is the olfactory receptor cell. Each receptor cell expresses a single odorant receptor gene. There are over one thousand differ= ent types of receptor cells present within the olfactory epithelium. The olfactory receptor gens accoun= t for approximately 1% of all expressed genes in the human genome. This makes it the largest known vertebrate gene family. It ap= pears that receptors are not randomly distributed along the mucosa but confined to one of several non-overlapping striplike zones.= Each cell appears to be responsive= to a wide, but circumscribed, range of stimuli.= Mouse models have shown that their olfactory epithelium is roughly divided into four zones. Stud= ies have shown groups of different olfactory receptor subtypes are confined wit= hin the designated zone. It also appears that most receptors are specific for certain odorants. Loss of specific odor receptor gen= es creates an inability to perceive particular odorants in mice.

The stimulatory guanine nucleotide-binding protein Golf links olfactory receptor proteins. The olfactory receptor cell is derived from the ectoderm and is a first-order neuron. It has the ability to regenerate after damage. Glial-type cells ensheathe the olfactory neurons and support axonal growth of both olfactory and nonolfactory neurons. These cells have ser= ved as special interest in the research of spinal cord injury and demyelinating diseases. The cilia of the olfactory receptor cells differ from respiratory epithelium. The cilia are generally longer and= lack dynein arms. Lacking dynein a= rms makes these cilia immotile. Overall, the surface area of the cilia exceeds 22 cm&sup= 2; in humans. In sharp contrast, the surface area of cilia in a German Shepard dog exceeds 100 cm².

Besides the olfactory receptor cell, there are 5 other cells identifiable. The supporting = or sustentacular cell contains microvilli and insulates = the bipolar receptor cells. It al= so helps to regulate composition of olfactory mucus. Microvillar cells are poorly understood cells located at the epithelial surface. A fourth cell type lines Bowman= 217;s glands and ducts. Horizontal = or dark and globose or light basal cells are locat= ed near the basement membrane. T= hese cells function to create the other cell types of the olfactory epithelium.<= o:p>

Olfactory Transduction

Once the odorant molecule has been absorbed properly in the mu= cus, olfactory binding proteins act to bind and solubilize the hydrophobic odora= nt molecules into the hydrophilic olfactory mucus. The ability of the odorant binding proteins to solublize the odorant particles inc= reases the concentration of the odorants into the surrounding environment by as mu= ch as 1,000 to 10,000 times more than their concentration in the ambient air.<= span style=3D'mso-spacerun:yes'> There is speculation that the bind= ing proteins also act to remove odorant molecules from the regions of the recep= tor cells. Once an odorant molecu= le links to the G protein receptor molecule, an enzyme cascade activates cAMP which then opens Ca,Na ion channels which depolarize the cell and start an action potential. cAMP a= nd IP3 appear to be the primary signaling pathways mediating olfactory transductio= n. Deficiencies of cAMP and stimulatory G_olf have been found in patients with Type 1a Pseudohypoparathyroidism. These patients often complain of olfactory loses.

Vomeronasal Organ<= /h1>
In the human septum there is an identifiable pit or groove at = the anterioinferior part of the nasal septum. This area contains chemosensitive cells. There is debate about whether this correlates with a functioning chemosensit= ive organ in humans. In most anim= als, there is an identifiable nerve connecting these cells to the central nervous system. In humans, however, t= here is no identifiable connection from the vomeronasal organ (Jacobson’s organ) in humans to the CNS. Physiological studies have shown t= hat activation of the area produces negative action potentials without a subjec= tive response from the individual tested. Experts are unsure of the exact role the vomero= nasal organ plays but it may function as a neuroendocrine system. It should be remembered that this = area should be left undisturbed during nasal surgery unless necessary.

Olfactory Bulb

The olfactory neuroepithelium syna= pse together in bilateral structures at the frontal cortex base known as the olfactory bulbs. These bulbs = act as the first relay station in the olfactory pathway. First order neurons synapse with post-synaptic nerves which form dense aggregates called glomeruli. Studies have shown that a given re= gion of the bulb receives its most dense input from a particular region of the mucosa. Inputs to a particular region of the bulb are composed of many receptor cells distributed througho= ut a certain zone of the mucosa. W= ith intricate connections, excitatory and inhibitory influences narrow the neur= al stimulus from the olfactory mucosa.

Aging appears to have a profound effect on the olfactory bulb.= Younger persons have thousands of = the 50- to 200-µm glomeruli arranged in single or double layers. It appears that these glomeruli de= crease gradually in number with age. Often, these glomeruli area nearly absent in persons older than 80 y= ears of age.

Olfactory Connections

The central processing of the sense of smell is complex with connections to many different structures.&= nbsp; The olfactory system is connected with the olfactory tubercule, prepiriform cortex, amygda= loid nuclei, and the nucleus of the terminal stria.<= span style=3D'mso-spacerun:yes'> The vast amount of connections ties olfaction into many functions including:&n= bsp; food intake, temperature regulation, sleeping cycle, vision, memory, hearing, and taste. Smell app= ears to have intimate connections with our other senses. It helps to shape our memory and is often one of the strongest triggers for our memories.

Olfactory Cognition

As previously stated, our sense of smell is very important in = our everyday life. However, it ap= pears that our everyday lives have an equally important role in our cognition of smell. We appear to understand odors largely based on experience. Each person develops his or her own hedonic code within a culture restraint. Smell has a very s= trong association with memory. Stud= ies have shown that odor memory can last at least 1 year while visual memory may last only a few months. Interestingly, odor memory is best facilitated by bilateral nasal stimulation. Some studies have suggested that patients with one-sided nasal obstruction may form poorer od= or memories. Even at birth, odor cognition plays an important role. Macfarlane examined 30 women and their newborn babies. Women washed one of their breasts = prior to feeding and placed their newborns in a prone position over the midline chest. 22 out of the 30 newbo= rns selected the unwashed or odorous breast.

Pheromones

There is debate whether humans secrete or respond to pheromones. Pheromones are chemicals released by one member of a species and received by another member that results in a specific action or developmental process. There are multiple behavioral and anatomic studies that support the possibility of human communication through odorants. Russell and associa= tes placed underarm secretions and alcohol on 5 experimental subjects and alcoh= ol on 6 control subjects. They f= ound that over a period of 5 months, there was a statistically significant great= er tendency for menstrual synchrony.

Evaluation of Olfaction

Patients will often present to the clinic with complai= nts of lack of taste, but often these patients have a definable lack of olfactory sensation. An evaluation of 7= 50 patients with chemosensory dysfunction demonstrated that most patients pres= ented with both smell and taste loss. However, less than 5% had identifiable whole-mouth gustatory deficit. Taste is defined as true gustation= while flavor is the olfactory-derived sensation from food. Whole-mouth taste function is much= more resistant to injury than olfactory function due to its redundancy of innervation. Patients with to= tal loss of olfaction are left with only sweet, sour, salty, bitter and umami (MSG-like) sensation. It is important that the clinician be aware of the complaints of patients with relation to taste and flavor and differentiates an olfactory deficit versus= a gustatory deficit.

The evaluation of olfaction begins with a thorough cli= nical history. It is important to d= efine the nature and onset of the chemosensory problem. Discovering associated events such= as viral or bacterial infections, head trauma, exposure to toxic fumes, systemic diseases, or signs of dementia is very important in the work-up. Also, defining the scope of olfact= ory loss and distinguishing between anosmia and hyposmia is important. One should disc= uss with the patient whether there is total loss of odorants or a loss of a few odorants. The timetable of th= e loss is very important in the prognosis of the olfactory loss. The possibility of spontaneous rec= overy is related to the duration of the problem.= After approximately 6 months, spontaneous recovery is often minimal. The clinician should examine the patient’s taste. <= /span>Anosmic patients will still be able to differentiate = the saltiness, sourness, or sweetness of foods.

Clues into the cause of anosmia can be found in a thor= ough past medical and surgical history. Reviewing the patient’s past endocrinolog= ic state may reveal a history of delayed puberty that may point to Kallmann syndrome.&n= bsp; A history of allergies or a history= of nasal or sinus infection may point toward the cause of anosmia. One should ask about a history of radiation therapy and a current list of medications. Previous sinus or nasal surgeries = should be inquired. Although it is r= are, olfactory deficits can occur after nasal surgery.

Social history can offer clues into causes of anosmia.= It is important to examine the patient’s smoking history. Tobacco use can cause partial or total ansomia<= /span>. It has been found that olfactory a= bility decreases as a function of cumulative smoking dose. One should counsel patients on smo= king cessation. Cessation can resu= lt in improvement in olfactory function over time. While the underlying cause of the olfactory lose may not be directly attributed to tobacco use, cessation of smoking can improve the ability to a degree.

Physical Examination

The physical examination should include a full otolaryngologic examination with anterior rhinoscopy and nasal endoscopy. Studies have shown, however, that = nasal endoscopy is not overly sensitive. Often positive findings on endoscopy do not correlate with symptoms. During nasal endosc= opy, one should examine the nasal mucosa for color, surface texture, swelling, inflammation, exudates, ulceration, epithelia metaplasia, erosion or atrophy. Noting polypoid disease may further lead to clues. Even minor or minimal polypoid disease a= t the olfactory cleft can account for olfactory dysfunction. Performing a cranial nerve examina= tion can elicit potential central or peripheral neuropathies. It is also important to perform an= optic disc examination determine whether there is increased intracranial pressure. Foster Kennedy synd= rome is secondary to tumors of the olfactory groove or sphe= noidal ridge. The syndrome involves = ipsilateral ansomia or hyposmia, ipsilateral opt= ic atrophy, and central papilledema. Physical examination is an important part in differentiating the cau= ses of olfactory disturbances.

Olfactory Testing

Olfactory testing continues to develop. Currently olfactory testing is mos= tly subjective. Objective testing= of olfaction has limited applications currently. However, olfactory testing is esse= ntial for many factors. It is often essential in validating a patient’s complaint. It can characterize the specific n= ature of the problem. Testing can m= onitor changes in function over time. Importantly, objective testing can also detect malingering. Often, patients complaining of ano= smia or hyposmia have normal function relative to ag= e and gender. Also, some population= s have demonstrable smell loss and do not know it. 90% of patients with idiopathic Parkinson’s Disease have smell loss, yet less than 15% are aware of t= heir problem.

Developing olfactory testing has improved our diagnost= ic ability. Asking a patient to = sniff odors is like testing vision by shining a light in each eye and asking whet= her the patient can see the light. However, there is no current testing that can distinguish central and peripheral deficits. Unilater= al testing is often warranted and can be easily accomplished by sealing the co= ntralateral naris using Microfoam tape. Having the patient sniff naturally= and exhale through the mouth stops olfactory stimulation secondary to retronasal flow.

Anosmia has many indications in medical/legal matters.= Anosmia is common in head injuries= and is often the only residual neurologic impairment. Claims of accidental and iatrogenic smell disturbance often result in substantial financial awards. The Veterans Administration awards= a 10% whole-body disability for total ansomia. Also, many occupations rely heavil= y upon the sense of smell and should justly be taken into account in disability issues.

There are three main types of olfactory testing available. Psychophysical tes= ting is the most common and least expensive.&nb= sp; The most well-known olfactory test is the UPSIT (University of Pennsylvania Smell Identification Test or simply the Smell Identification Test. The test is made of 4 booklets of 10 odorants apiece. It can easily be administered in 10 to 15 minutes by most patients. The stimuli embedded into 10- to 5= 0-&mic= ro;m diameter microencapsulated crystals. The test is made of multiple choice questions with four response alternatives. The test is force-choice. This requires t= he participant to choose an answer even if none seems appropriate. Repeated testing has shown that ch= ance performance is 10 out of 40. = With this, lower scores can often represent avoidance. There are norms available based on= the cumulative data from administration to 4,000 people. Individuals are ranked relative to= age and gender. The test can clas= sify an individual’s function into 6 categories: normosmia, mild microsmia, moderate m= icrosmia, severe microsmia, anosmia, and probable malingering. The test has been proven very reliable with a test-retest Pearson r=3D 0.94. In medical/legal considerations, t= he UPSIT is sensitive to malingering. The theoretical probability of a true anosmic to score UPSIT 5 or less is 0.05%. The theoretical probability of true anosmic scoring a 0 on the UPSIT is 0.00001. The UPSIT has become a mainstay in olfactory testing and should be considered in patients with olfactory disturbances.

Electrophysiologic testing= is available. It offers objective testing but its application is largely experimental. Two procedures are currently avail= able. Odor Event-Related Potentials (OER= Ps) and Electro-olfactogram (EOG) are the two electrophysiologic testing. Odor Event-Related Potentials (OER= Ps) involves discerning synchronized brain EEG activity recorded on the scalp f= rom overall EEG activity following presentations of odorants. The stimuli are presented in a pre= cise manner using equipment that produces stimuli embedded in a warm, humidified= air stream. The problem is that t= est reliability is poor, and necessary trials cannot be performed to establish = normative data. The data cannot make any inference in regarding the location of a lesion or deficit. OERPs can be usefully in detecting malingering. Electro-olfactograms measure electrodes placed on the surface= of the olfactory epithelium. How= ever, few patients are amenable to recordings as the electrodes must be placed un= der endoscopic guidance without local anesthesia. This can be quite unpleasant and c= ause sneezing or mucous discharge. In many subjects, it cannot be reliably recorded. Also, the presence of a robust EOG= does not always represent olfactory functioning. Anosmic patients with Kallmann syndrome and hyposmic patients with schizophrenia have large EOG responses. These tests have s= ome limited application at this time.

Due to a strong association between Alzheimer’s = and Parkinson’s disease and olfactory dysfunction, n= europsychologic testing can be very helpful. = In certain situations, patients complaining of ansomia warrant a brief neuropsychologic testing to det= ermine the presence of dementia. The Mini-Mental Status Examination is a quick screening tool for dementia and c= an be administered in a few minutes. More specific testing should be left to a qualified Neurologist.

Neuroimaging

In cases where olfactory dysfunction has no known caus= e, imaging is warranted. Often in idiopathic cases, high-resolution CT is the most useful and cost-effective screening tool. MRI is useful= in evaluating the olfactory bulbs, olfactory tract, and intracranial structures. MRI can detect decrements of anosmia associated with patients with schizophrenia.

Olfactory Biopsy

If tissue is needed in diagnosis or treatment, a small amount of superior septal tissue can be removed= . This is often best accomplished by= an experienced rhinologist as there is an increase= d risk of CSF leak. It is recommende= d to take multiple biopsies as to get sufficient olfactory = neuroepithelium. Especially in older persons where = much of the olfactory neuroepithelium is replaced wi= th respiratory epithelium, it is very important to take more biopsies.

Disorders of Olfaction

As discussed earlier, anosmia and olfactory disturbance affects over 2 million Americans. There are more than 200 conditions associated with changes in chemosensory ability and olfactory deficiency. While there are so many categories, breaking them down into broader categories will make it easier to form a differential diagnosis during the work-up.=

Obstructive Nasal and Sinus Disease

Obstructive nasal disease is the most common form of olfactory dysfunction and ansomia making up 20-= 33% of all olfactory loss. The anosm= ia is generally produced by nasal polyps, mucosal swelling and/or nostril occlusi= on which generally resolves when the obstruction is released. The opening to the olfactory cleft= is medial and anterior to the lower part of the middle turbinate. Scarring from surgery between the = middle turbinate and nasal septum can effectively close off the olfactory cleft to airflow and cause anosmia. Any anatomical changes to this area can result in anosmia. One of the most practical ways to diagnosis obstructive causes is a 1- or 2-week course of steroids. The anosmia will generally resolve= after the steroid therapy. It is ra= re that an external nasal deformity can cause anosmia from obstruction. Chronic rhino= sinusitis causes edema and polyps which then obstruct the olfactory cleft. Kern studies the affects of rhinosinusitis on olfactory mucosa. He found inflammatory changes in olfactory epithelium. This ap= peared to be an inflammation-driven, primary neuron dysfunction. This observation may explain why c= hronic rhinosinusitis can contribute to olfactory dysfunction without signs of obstruction and why some patients do not impro= ve with steroids. Kern found evi= dence of active apoptosis of olfactory receptor neurons. Correcting obstructive cause= s and treating with anti-inflammatory medications can improve or cure obstructive forms of anosmia.

Upper Respiratory Infection

Upper respiratory infections cause roughly 10-15% of a= ll olfactory dysfunction. Patien= ts often complain of olfactory loss during a URI.&n= bsp; This is most often secondary to obstruction and resolves within 1 to= 3 days. However, there is a sma= ll percentage of patients who suffer total loss after a URI. This occurs more commonly in patie= nts in their fourth, fifth, or sixth decade of life. There is also a larger (70-80%) disparity toward women. Often= in these patients, biopsy results reveal decreased numbers of olfactory receptors. Total olfactory lo= ss after an upper respiratory infection is generally poor.

Head Trauma

The incidence of olfactory loss in adult patients with= head trauma is 5 to 10%. In genera= l, the severity of the trauma is associated directly with the loss. Frontal blows are the most frequent cause of olfactory loss; however, occipital blows carry a 5 times higher ri= sk of total anosmia. Onset of an= osmia is generally immediate and the rate of recovery is less than 10%. The quality of olfactory ability t= hat is generally recovered is poor. Unfortunately, the exact injury from head trauma is not totally understood. Most believe that= it is secondary to the shearing of the olfactory nerves on the cribiform plate or contusions to the olfactory bulbs.

Aging

Aging contributes greatly to olfactory loss and most w= ill suffer with olfactory loss as one age.&nbs= p; Olfactory identification sharply decreases in the sixth and seventh decade of life. Olfactory loss plays an understated role in the elderly patient. It causes a decrease in magnitude matching of smells, changes in the perception of pleasantness, decrease nutritional status due to loss of flavor, and a decrease in the ability to discriminate flavors in everyday foods.&nb= sp; This olfactory loss can have a profound effect on the quality of many older individuals.

Dementia-related Diseases

The two main dementia-related diseases associated with anosmia are Parkinson’s Disease and Alzheimer’s Disease. Alzheimer’s Disease is characterized by the presence of neurofibrillary tangles and neuritis plaqu= es found in the central olfactory pathways.&n= bsp; Interestingly, there a= re similar pathologic changes and testing abnormalities in patients with Down’s syndrome which may suggest a possible genetic link related to olfactory losses. Also, it is interesting to note that Alzheimer’s affects the olfactory system dis= proportionately to the other areas of the brain. Pearson et al examined cadaveric brains and showed marked involvemen= t of the olfactory system contrasting with minimal abnormality in other areas of= the brain. The authors concluded = there may be an environmental agent that could cause Alzheimer’s Disease.

Parkinson’s Disease encompasses a number of nonmotor defects including depression and cognitive loss. The olfactory losses are independent of the cognitive and motor symptoms. The duration of the disease is str= ongly correlated with the neuronal losses in the olfactory bulb. In any patient diagnosed with Alzheimer’s Disease or Parkinson’s Disease who does not exhibit olfactory loss, one must be suspicious for alternative diseases.

Congenital Dysfunction

&= nbsp; Most patients with congenital olfactory loss are unaware of their loss until ear= ly adolescence when others point out the losses. The most well-known of these conge= nital disorders is Kallmann Syndrome. Kallmann syndrome is hypogonadotropic hypogonadism. Most commonly, it is a defect in t= he X chromosome KAL1 gene which encodes anosmin-1. Patients have agenesis of the olfa= ctory bulbs and stalks. They also h= ave incomplete development of the hypothalamus. Some authors believe that that exi= stence of Kallmann syndrome shows a strong association between sexual development and olfaction.

Toxic Exposure

&= nbsp; Many laborers can be exposed to toxins in the work place which can put their olfactory ability at risk. Th= ere are many toxins that have been shown to cause olfactory loss. Most of these toxins are aerosolized. It is important = to consider the concentration and duration of the exposure. Some toxins can cause loss immedia= tely and others will not present until much later. Also, some over-the-counter medica= tions can lead to toxic damage. One= of the most well-known is the over-the-counter allergy spray, Zicam. Lim et al studies the effects of <= span class=3DSpellE>Zicam, also known as zinc glucon= ate, and compared these effects to other common nasal sprays. They showed near absent responses = on EOG on Zicam-treated mice. Most interestingly, they found nas= al mucosa of Zicam-treated mice to be irreversibly destroyed.

Neoplasms

&nbs= p; Both intranasal and intracranial tumors can affect the sense of smell. Intranasal tumors can include inve= rted papillomas, adenomas, squamous cell carcinomas, and <= span class=3DSpellE>esthesioneuroblastomas. Intracranial tumors can include meningiomas, pituitary tumors, and gliomas. Approximately 25% of temporal lobe tumors can have olfactory disturbances.

HIV

There is a correlation among patients with HIV and olf= actory disturbance that is poorly understood.&nbs= p; The loss of olfactory ability is often variable. Also, the olfactory losses are ind= ependent of most HIV markers including CD4 count.&n= bsp; Also, the losses do not correlate with body weight, body composition, management, or diet.

Psychiatric Disease

Olfactory complaints are common in patients with depre= ssion, schizophrenia, and hallucinations. Studies have shown that olfactory identification deficits are only f= ound in schizophrenia. Patients wi= th intrinsic olfactory hallucinations believe a smell emanates from their own body. Extrinsic olfactory hallucinations cause the patient to believe the odor emanates from a source other than the patient’s own body.&n= bsp; In olfactory reference syndrome, patients exhibit an obsessive conce= rn over minor or absent odors. T= hese patients often bathe frequently and wear excessive perfumes or colognes. “Marcel Proust” syndro= me describes psychiatric disorder where certain smells trigger such a strong m= emory as to disrupt daily routines. This can be very debilitating for these patients and psychotherapy is often help= ful.

Medications

There are many medications that can cause anosmia and = the list continues to grow. It is beneficial to look over the list of common medications that can cause anosm= ia and be aware of which ones one uses. Often, avoiding certain medications in more susceptible patients can help avoid further disturbance.

Surgery

Surgical procedures can cause loss of smell. There are reports of olfactory loss after rhinoplasty. Champion et al reviewed 100 consec= utive rhinoplasty patients. He found that 20% of patients complained of olfactory loss 6-18 mont= hs after surgery. Fortunately ov= er 95% of the losses were temporary. With the advancement of endoscopic skull base and sinus surgery, there is now mo= re accurate surgery and less olfactory damage. Patients with total laryngectomies have decreased olfactory ability due to shunting of air away from the nasal cavity. Patients can perform = certain exercises to induce airflow into the olfactory clef. *Studies have shown olfactory rece= ptors in these patients to function many years after the lar= yngectomy. Cranial and skull base surgeries c= an lead to total and permanent loss of olfactory ability.

Treatment and Management

In determining the treatment options for patients, it = is important to differentiate the conductive and receptive losses. As discussed, conductive losses of= smell are responsive to treatments of nasal disease. There are many treatments availabl= e for the opening of the nasal passageways including, intranasal steroids, antibiotics, allergy therapy, addressing ethmoid sinusitis via ethmoidectomy or treating intrana= sal tumors.

In receptive loss treatment, options are very limited = and without much benefit. Some advocate t= he use of Vitamin A. Vitamin A is necessary in the repair of epithelium.&nbs= p; Studies have shown that white rats become anosm= ic on a Vitamin A deficient diet. Also, mammalian olfactory epithelium contains a considerable amount = of Vitamin A. Duncan and Briggs studied Vitamin A supplementation on patients with anosmia and found succes= sful restoration of at least partial olfactory ability in 50 out of the 56 patie= nts. However, many other authors have b= een unable to reproduce the same benefits from Vitamin A supplementation.

Zinc has also been implicated in the treatment of rece= ptive olfactory loss. Zinc-deficient adult mice have been found to be anosmic. Zinc deficiency is rare and diffic= ult to substantiate. There are been occasional reports of improvement in anosmia with the treatment of zinc. Also, some authors advocate for th= e use of Aminophylline as cAMP has a strong role in t= he transduction of the olfactory signal. Again, few studies have shown marked improvement with Aminophylline.

Management

One of the most important steps in the management of olfactory loss is reassurance. Explaining the prognosis can be helpful and explaining that other patients suffer with the same losses can be comforting. The physician should discuss with = the patient improving the seasoning of the diet for the remaining sensory modalities. Emphasizing taste, color, texture, viscosity, and the feel of the foods can improve the qualit= y of life. With anosmia, smoke and= fire detectors are mandatory. Pati= ents with olfactory disturbance should elicit the confidential advice of others = in matters of odor. A patient wi= th anosmia should also be counseled on switching appliances from natural gas to electric or non-explosive heating.

Finally, patients with complaints of phantosmia can be challenging to treat. = Phantosmia is the perception of odor in the absence o= f a true odor. This is, most ofte= n, unpleasant. An effective ther= apy has been instilling four nasal saline drops in the affected nostril the with head positioned forward and down. Some have tried applications of topical cocaine hydrochloride to the olfactory mucosa. There is a = lack of good results with this treatment and a risk of total anosmia. In patients refractory to conserva= tive treatment, surgical options are available including neurosurgical resection= of the olfactory bulbs through a craniotomy.&= nbsp; Endoscopically, olfactory epithelium can= be removed from the underside of the cribiform plate. This approach requires= the repair of CSF leak. Good outc= omes have been demonstrated with surgical treatment of phan= tosmia but have inherent risks.

Conclusions

The sense of smell remains of the most primitive but important senses in our daily lives. It plays an integral role in our general well-being and quality of life. There is a strong corre= lation of our sense of smell with many of our other senses, our memories, and our quality of life in general. The Otolaryngologist needs to be aware of these disorders which cause anosmia especially as it can be a presenting symptom of many diseases. Unfortunately, current diagnostic = tools and treatment options remain limited. Further study and advancement are needed to help understand and corr= ect disorders that affect over 2 million Americans.

DISCUSSTION January 30= , 2012

Dr. Harold Pine

Has anybody used the Zycam to treat these fantasmias? Seems like it would be a great tre= atment for someone who has this horrible smell. It would be like squirting G= entamicin in the middle ear for someone who was a vestibular cripple. And then another question: you briefly mentioned that each of= the little cells is designed for its own particular odorant and you mentioned t= hat there seems to be some cultural or difference among different populations.<= span style=3D'mso-spacerun:yes'> I remember very distinctly that I = was on a trek somewhere in New Zealand when the guide pulled me off to the side of= the road and said "Here, smell this flower." And it was something like anise wh= ich is like a licorice flavor and he said very specifically, "We have certain populations of people that come here that can't smell this particular smell " which I thought was really weird.&n= bsp; There was a certain kind of Asian population that was coming through= and they couldn't smell it. =

Finally, is there something we can do or someone that wants to go into one of these jobs where the sense of smell is really important . Is it trainable? They sell these wi= ne appreciation kits with the different individual odorants that apparently if= you practice enough you can get better at identifying certain smells. I used to take high doses of vitam= ins A, C, E and selenium back in college during the anti-oxidant craze and I wonde= r if that has something to do because I felt like God had turned up my sense of smell ten-fold and I remember the day when my sense of smell became awesome= and it's continued like that and I tell people on rounds that I'm really good at smelling a couple things, like, you know, women's perfume, and pus.

Dr. Bruce Liepzig:=

How useful is the University of Pennsylva= nia smell identification test?

Dr. Patton:

What I've shown here that if you do have anosmia, your chances are still to be ten out of forty so if you have somebody with true anosmia with this smell test I don't think it's enough if you want to have an actual distinct diagnosis of total anosmia because somebody with a partial anosmia can still score kind of low. The important thing about that tes= t is that if you score less than ten the chance probability is that you have tot= al anosmia. It's probably very u= seful in malingering and in setting them up whether you have sense of smell or ta= ste problems. <= /p>

Dr. Pine:

Just one more comment from a medicolegal standpoint, Most of you know that I was involved in= a medicolegal case in which it came out after the fact = was what I had done to her had ruined her sense of smell. That was her chief complaint and t= he prosecution's argument that w= e had caused her anosmia. What's so interesting about it was that we had gone to the patient and given her one = of these smell tests suggesting that we hadn't and then months and months later there was very little that there was very little motivation on the part of = our team to get her objectively tested so that there's still among the general population and among lawyers that a loss of the sense of smell is a very subjective complaint so just by the fact that she was moaning about it that carried weight even though objectively I suspect that she had very little r= eal loss in her sense of smell. <= o:p>

Bibliography

Doty RL, Bromley SM, Pangani= ban WD. Chapter 21. Olfactory Function and Dysfunction.” In: Bailey BJ, Johnson JT and Newlands SD, eds. Head & Neck Surgery – Otolaryngology, Philadelphia: Lippincott Williams & Wilkins; 2006.

Leopold DA, Holbrook EH. Chapter 41. Physiology of Olfaction. In: Flint PW, Haughey<= /span> BH, Lund VJ, Niparko JK, Richardson MA, Ro= bbins KT, Thomas JR, eds. F= lint: Cummings Otolaryngology: Head & Neck Surgery,. 5^th ed. Philadelphia: Mobsy; 2010.

Doty RL, ed.&nbs= p; Handbook of Olfaction and Gustation. 2^nd ed. New York: Marcel Dekker; 2003.

Brescia AL, Seiden AM. “The Anatomy and Physiology of Olfaction and Gustation.” Rhinology and Facial Plast= ic Surgery. Stucker et al, 2009; Springer.

O’Brien EK, Leopold DA; “Olfaction and Gustatio= n: Implications of Viral, Toxic Exposure, Head Injury, Aging, and Drugs.” Stucker et al, 2009; Springer.

Lim JH, Davis GE, Wang Z, Li V, Yuping W, Rue TC, Storm DR. = 220;Zicam-Induced Damage to Mouse and Human Nasal Tissue.” PloS One. 2009; 4: 1-10.

Doty RL, Bromley SM. Chapter 29. Disorders of Sme= ll and Taste. In: Longo DL, Fauci AS, Kasper = DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2= 012. http://www.accessmedicine.com/content.aspx?aID=3D9096908. Accessed Jan= uary 29, 2012.
Barrett KE, Barman SM, Boita= no S, Brooks H. Chapter 14. Smell & Taste. In: Barrett KE, Barman SM,= Boitano S, Brooks H, eds. <= i>Ganong's Review of Medical Physiology. 23rd ed. New York: McGraw-Hill; 2010. http://www.accessmedicine.com/content.aspx?aID=3D5240638. Accessed Jan= uary 29, 2012.
“Smell Identification Test.” http://sensonics.com/smell-products/= smell-identification-test-international-versions-available.html. Retrieved on 1/29/2012.
Som PM, Brandwein MS. Chapter 6. Tumors and Tumor-like Conditions. In: Som PM, Curtin HD. Head and Neck Imaging.= 4^th ed. St. Louis: Mosby; 2003
Schneider RA, Wolf S: Relatio= n of olfactory activity to nasal membrane function. J Appl Physiol&nbs= p; 1960; 15:914.
Macfarlane A: Olfaction in the developm= ent of social preferences in the human neonate. Ciba Found <= span class=3DSpellE>Symp 1975; 33:103.
Russell MJ, Switz<= /span> GM, Thompson K: Olfactory influences on the human menstrual cycle. Pharmacol Biochem Behav<= /i> 1980; 13:737.

Kern RC: Chronic sinusitis and anosmia: pathologic changes in the olfactory mucosa.  Laryngoscope=   2000; 110:1071.

Champion R: Anosmia associated with corrective rhinoplasty.  Br J= Plast Surg = 1966; 19:182.

Duncan RB, Briggs M: Treatmen= t of uncomplicated anosmia by vitamin A.  Arch Otolaryngol  1962; 75:116.