Anatomy and Physiology

Olfaction

The olfactory receptor cells, which number around 6 million in the human, are located within a pseudostratified columnar neuroepithelium that also contains sustentacular or supporting cells, basal cells (the precursors of other cell types within the epithelium), and the poorly understood microvillar cells. This epithelium lines the cribriform plate and sectors of the superior septum, the middle turbinate, and the superior turbinate and is supported by a highly vascularized lamina propria that contains Bowman glands, the major source of the overlying mucus and enzymes that detoxify xenobiotic agents. It is into this mucus that each of the bipolar receptor cells projects 3 to 30 receptor-bearing cilia that interact with odorant molecules. These cells are unique, since they serve as both a receptor cell and a first-order neuron and can regenerate to some degree from basal cells after being damaged. Moreover, they exhibit the most diverse molecular phenotype of any neuron, expressing a wide range of receptor protein types and cell-surface antigens. A photomicrograph of the surface of the olfactory epithelium is shown in Fig. 17.1.

Fig. 17.1 Surface transition region between olfactory and respiratory epithelia. Bottom half displays olfactory epithelium; top half, respiratory epithelium. Arrows identify olfactory receptor cell dendritic endings with cilia. Bar = 5 µm.

(From Menco, B.Ph.M., Morrison, E.E., 2003. Morphology of the mammalian olfactory epithelium: form, fine structure, function, and pathology. In: Doty, R.L. (Ed.), Handbook of Olfaction and Gustation, second ed. Marcel Dekker, New York, pp. 32-97, with permission.)

In the human, each receptor cell expresses only one of about 380 functional types of receptor proteins. Although roughly 950 genes express such receptor proteins, most of these genes are pseudogenes. Odor receptor genes are found in approximately 100 locations on all chromosomes except 20 and Y. Remarkably, the olfactory subgenome spans 1% to 2% of the total genomic DNA. Most single-chemical odorants stimulate more than one type of receptor, and overlap typically exists among the sets of receptors stimulated by various chemicals, implying complex across-fiber sensory coding at the periphery.

After coalescing into bundles (fila) within the lamina propria, the olfactory receptor axons traverse the foramina of the cribriform plate. These axons then distribute themselves across the surface of the olfactory bulb, a distinctly layered ovid structure composed of afferent and efferent nerve fibers, multiple interneurons, microglia, astrocytes, and blood vessels. The receptor cell axons selectively enter the sphere-like olfactory glomeruli located within an outer layer of the bulb. Those receptor cells expressing the same odorant protein converge onto the same glomerulus. The glomeruli number in the thousands in younger persons and are a defining feature of the olfactory system. With age, however, their number and integrity greatly decrease, being nearly absent in the elderly.

The activity of the primary output neurons of the olfactory bulb, the mitral and tufted cells, is modulated by many factors. In addition to being influenced directly by olfactory receptor cell activation, their membrane potentials are altered by numerous local interneurons and by centrifugal fibers. The most numerous cells of the olfactory bulb, the γ-aminobutyric acid (GABA)-ergic granule cells, can inhibit mitral and tufted cell activity via their connections with mitral cell secondary dendrites. These cells make up much of the core of the bulb and receive numerous inputs from central brain regions.

Unlike nearly all other central nervous system (CNS) neurons, the granule cells, as well as the largely dopaminergic periglomerular cells, undergo replacement over time (Altman, 1969). Astrocyte-like stem cells within the anterior subventricular zone of the brain generate large numbers of neuroblasts, some of which undergo restricted chain migration along the rostral migratory stream (Rousselot et al., 1994). This migration largely terminates within the granule cell layer of the olfactory bulb, from which some differentiating neuroblasts migrate more peripherally, thereby repopulating periglomerular cells. The architecture of the olfactory bulb, including its main cell types, is presented schematically in Fig. 17.2.

Fig. 17.2 Schematic of olfactory bulb structures, neurons, and layers.

(From Alloway, K.D., Pritchard, T.C., 2007. Medical Neuroscience. Hayes Barton, Raleigh, North Carolina, with permission.)

Central brain structures that receive the output axons of the mitral and tufted cells via the lateral olfactory tract include the anterior olfactory nucleus, the piriform cortex, the anterior cortical nucleus of the amygdala, the periamygdaloid complex, and the rostral entorhinal cortex. These structures, collectively termed primary olfactory cortex, have reciprocal relations with one another and numerous other brain centers. For example, the entire length of the hippocampus receives fibers from the entorhinal cortex. Pyramidal cells from the anterior olfactory nucleus project to numerous ipsilateral and contralateral brain structures, the latter via the anterior commissure. While the olfactory system projects to cortical structures without initially synapsing in the thalamus, connections via the thalamus are present between primary (e.g., entorhinal) cortex and secondary (i.e., orbitofrontal) cortex.

The relative roles of central brain structures in odor perception are poorly understood. The piriform cortex appears to encode higher-order representations of odor quality, identity, and familiarity. This brain region also plays a role in odor learning and memory, as well as in coordinating information between olfaction, taste, and vision (Gottfried et al., 2002). The entorhinal cortex preprocesses information entering the hippocampus, whereas the amygdala seems to respond to the intensity of emotionally significant odors. The rostral regions of the orbitofrontal cortex are involved in odor memory, whereas the caudal regions are associated with odor detection. The processing of hedonic information about odors seems to occur within the orbitofrontal cortex, with pleasant odors activating the medial orbitofrontal cortex and unpleasant odors activating the lateral orbitofrontal cortex.

Gustation

Taste plays a critical role in identifying substances in foods and beverages, such as sugars and poisonous alkaloids, that promote or disrupt homeostasis. The taste receptor cells are found within the taste buds, small flask-like structures located on the surface of the oral epithelium (Fig. 17.3). These cells extend microvilli into the lumen of the bud near its apical opening, termed the taste pore. Like olfactory receptor cells, taste receptors die and become replaced at various intervals from basal cells within the bud.

Fig. 17.3 Idealized drawing of longitudinal section of mammalian taste bud. Cells of type I, II, and III are elongated and form the sensory epithelium of the bud. These cells have different types of microvilli within the taste pit and may reach the taste pore. Type IV are basal cells, and type V are marginal cells. Synapses are most apparent at the bases of type III cells. The connecting taste nerves have myelin sheaths.

(From Witt, M., Reutter, K., Miller I.J., Jr. [2003] Morphology of the peripheral taste system. In: Doty, R.L., (Ed), Handbook of Olfaction and Gustation. NY: Marcel Dekker, pp. 651-677. The figure is on p. 663).

Humans possess approximately 7500 taste buds, most of which are found on lingual protuberances called papillae (Fig. 17.4). Taste buds innervated by the chorda tympani division of the facial nerve (CN VII) are found on the fungiform papillae, which are most dense on the tip and lateral margins of the anterior tongue. The palatine branch of the greater superficial petrosal division of CN VII innervates the taste buds on the soft palate. Some taste buds found on the anterior foliate papillae, located on a sector of the tongue’s posterior lateral margins, may also be innervated by branches of the chorda tympani nerve. Most foliate buds, as well as the buds on the circumvallate papillae—six to eight large structures that resemble flattened hills across the “chevron” of the posterior tongue—are innervated by the glossopharyngeal nerve (CN IX). Taste buds within the oral pharynx are supplied by the vagus (CN X) nerve. The small and somewhat pointed filiform papillae, which cover the entire tongue, harbor no taste buds. Although not involved in taste perception as such, the trigeminal nerve (CN V) participates in the formation of flavor via free nerve endings in the oral mucosa signaling sensations of touch, pain, and temperature. Thus, the fizziness of carbonated soft drinks and the warmth of coffee are dependent upon the stimulation of this nerve.

Fig. 17.4 Schematic representation of the tongue, demonstrating the relative distribution of the four main classes of taste papillae. Note that the fungiform papillae can vary considerably in size, and that they are more dense on the anterior and lateral regions of the tongue.

Individuals differ markedly in terms of the number and distribution of their taste buds. Although some physiology textbooks suggest that different regions of the tongue are responsible for the four basic taste qualities, this is an oversimplification of the facts. In general, the front of the tongue is more sensitive than other tongue regions to all taste qualities, although in the case of bitter, the back of the tongue is typically much more sensitive. The relative average sensitivity of tongue regions to the four prototypical taste qualities is shown in Fig. 17.5, although it must be emphasized that significant individual differences exist.

Fig. 17.5 Relative sensitivity of the edge of the tongue to the four classic taste qualities. Sensitivity reflects the reciprocal of the threshold value and is plotted as a ratio of maximal sensitivity = 1. Threshold data are from Hänig (1901). Note that all regions of the tongue that were evaluated were responsive to some degree to all stimuli, but that the anterior tongue was most sensitive to sweet, sour, and salty and least sensitive to bitter. The rear (base) of the tongue was relatively more sensitive to bitter.

(Adapted from Boring, E.G., 1942. Sensation and Perception in the History of Experimental Psychology. Appleton-Century Crofts, New York.)

The specific receptors involved in sensing taste stimuli have now been identified (Hoon et al., 1999). A small family of three G protein–coupled receptors (GPCRs)—T1R1, T1R2, and T1R3—encode sweet and umami (monosodium glutamate–like) sensations. Bitter sensations are mediated by the T2R receptors, a family of about 30 GPCRs that are expressed on cells different from those that express the sweet and umami receptors. The salty sensation of sodium chloride arises from the entrance of Na⁺ ions into the cells via specialized membrane channels such as the amiloride-sensitive Na⁺ channel. Although sour taste has been suggested to depend upon a range of receptors, PKD2L1 is likely the primary sour taste receptor.

The nerves innervating the taste buds converge centrally onto the nucleus of the solitary tract of the brainstem. Although species differences exist, the afferent taste nerve fibers can be classified electrophysiologically into categories based upon their relative responsiveness to sweet, sour, bitter, and salty-tasting stimuli. In the hamster, for example, sucrose-best, HCl-best, and NaCl-best fibers have been observed (Frank et al., 1988). Despite the fact that fibers are generally “tuned” for rather specific stimuli, they can nonetheless respond to other stimuli. For example, a few sucrose-best fibers also respond to NaCl and HCl. NaCl-best fibers and HCl-best fibers are less tightly tuned than sucrose-best fibers, with more fibers responding to multiple classes of stimuli.

Fibers from the nucleus of the solitary tract project to a taste center within the upper regions of the ventral posterior nuclei of the thalamus via the medial lemniscus, a pathway connecting the brainstem to the thalamus. From here, information is sent to the amygdala and several cortical regions including the primary somatosensory cortex and the anterior insular cortex. Neurons within these regions respond to taste, touch, and in some cases odors.

The “taste code” interpreted by the brain depends on the specific neurons that are activated and the patterns of firing that occur both within and between these nerves. As with odors, the brain must remember what a particular tastant tastes like (e.g., sweet), and a matching or comparison of information coming from the taste pathways must be made at some point with the remembered sensation to allow for its recognition or identification. Higher brain regions play a significant role in establishing taste contrasts (e.g., something tasting more sour after prior experience with a sweet stimulus), inducing sensory fatigue, integrating multiple taste sensations, influencing taste hedonics, and integrating information from other senses to establish the experience of flavor.

Chemosensory Testing

Three general classes of sensory tests are available for quantifying human chemosensory function: psychophysical, electrophysiological, and psychophysiological (Doty, 2007). Psychophysical tests include tests where subjects make a conscious response, such as in tests of odor adaptation, detection, recognition, identification, discrimination, memory, hedonics, and suprathreshold scaling of various sensory dimensions. Electrophysiological tests measure minute stimulus-induced electrical changes from sensory receptors or the brain in the absence of verbal or other consciously overt subject responses. Included are summated electrical potentials from the surface of the olfactory epithelium (termed the electro-olfactogram), tongue, or scalp (changes in the electroencephalogram, such as event-related potentials or summated total power). Clinically, psychophysical tests have been most widely employed, in part due to reliability, practicality, and cost.

The most widely used psychophysical tests are those of identification and detection (Doty, 2007). In identification tests, a subject is typically asked to identify, usually from a list of alternatives, the quality of the sensation experienced when sniffing or tasting a stimulus. A response is required even if no sensation is perceived, a procedure called forced-choice responding. For example, in the most popular odor identification test, the University of Pennsylvania Smell Identification Test (UPSIT), the subject is provided with a series of 40 microencapsulated (scratch and sniff) odors and in each case asked to choose the name of the odor from four response alternatives (Doty et al., 1984b) (Fig. 17.6). The number of correct answers determines the degree of deficit and allows for both overall classification of function (i.e., normosmia, mild microsmia, moderate microsmia, severe microsmia, anosmia) and a relative percentile classification based upon age- and sex-related norms. Malingering can be discerned by improbable responses in the forced-choice situation, such as not correctly identifying any odors or otherwise identifying odors at a rate significantly below the expected chance performance of 25%. In an odor detection threshold test, a subject is typically presented with an odor and one or more blanks in random fashion and asked to identify which stimulus is stronger or otherwise discernable from the other stimuli. A common procedure is to present stronger stimuli when a miss occurs and weaker stimuli when a hit occurs, following a defined algorithm. This is termed a staircase procedure, and the threshold is defined as a set number of reversals of the staircase. With the exception of tests of hedonics and suprathreshold scaling, scores on tests of odor identification and detection, as well as discrimination and memory, are highly correlated, with the size of the correlations being dependent upon the less reliable of the intercorrelated tests (Doty et al., 1994). It is for this reason that a rather complete characterization of smell function can be obtained by simply using a reliable odor identification test.

Fig. 17.6 Booklets of the University of Pennsylvania Smell Identification Test (UPSIT). The test comprises 4 booklets, each containing 10 microencapsulated scratch-and-sniff odorants that are released by a pencil tip. Associated with each odorant is a multiple-choice question about which of four possibilities is correct. Forced-choice answers are recorded on the last page of each booklet and assessed with a simple scoring key.

Although very brief tests can be useful in screening, they have significant limitations. Short tests do not allow for the detection of malingering and are generally less sensitive than longer tests. As a general rule, the more trials contained in a test, the higher its reliability and sensitivity (Doty et al., 1995). Despite the fact that some very brief tests are reliable, their reliability is associated with less sensitivity and specificity, as brief tests can only clump patients into very broad dysfunction categories. This is analogous to the ability of a flashlight to determine blindness in a patient. While this may allow for accurate detection of absolute blindness, it does not allow for assessing varying degrees of less than total blindness.

Disorders of Olfaction

Olfactory loss can be total (anosmia) or less than total (hyposmia or microsmia). Strange and distorted smells, sometimes described as “chemical” or “garbage-like,” can occur either in the absence of a stimulus (phantosmia, also called olfactory hallucinations) or when an odorant or warm air is smelled (dysosmia or parosmia). When a fecal-like character is present, this is often termed cacosmia. Most cases of dysosmia or phantosmia are due to neurological causes such as altered firing of the receptor cells during degeneration or regeneration, although in some instances, bacterial infections within the nose or sinuses can produce foul smells that result in this condition. Olfactory agnosia, the inability to recognize odors by an otherwise intact olfactory system, may occur secondary to some brain lesions, although distinguishing this problem from other forms of dysfunction is challenging. Hypersensitivity to odorants (hyperosmia) has been reported, but many persons claiming hypersensitivity are experiencing dysosmias and show decrements in function upon testing. As with the other senses, olfactory dysfunction can be bilateral or unilateral.

Many factors influence the ability to smell: age, sex, smoking behavior, reproductive state, nutrition, toxic exposures, head trauma, and numerous diseases (Table 17.1). Men generally perform less well than women on olfactory tests. Age is a major correlate of smell dysfunction, with significant decrements occurring in over 50% of those between 65 and 80 years of age and in 75% of those 80 years of age and older (Doty et al., 1984a) (Fig. 17.7). Such losses help explain why many elderly find food distasteful and succumb to nutritional deficiencies and, in rare instances, natural gas poisoning.

Table 17.1 Disorders and Conditions Associated with Compromised Olfactory Function, as Measured by Olfactory Testing

AD, Alzheimer disease; AIDS, acquired immunodeficiency syndrome; ALS, amyotrophic lateral sclerosis; COPD, chronic obstructive pulmonary disease; FTLD, frontotemporal lobar degeneration; HD, Huntington disease; HIV, human immunodeficiency virus; MS, multiple sclerosis; OCD, obsessive compulsive disorder; PD, Parkinson disease; PTSD, posttraumatic stress disorder; REM, rapid eye movement.

Fig. 17.7 Scores on the University of Pennsylvania Smell Identification Test (UPSIT) as a function of subject age and sex. Numbers by each data point indicate sample sizes. Note that women identify odorants better than men at all ages.

(From Doty, R.L., Shaman, P., Applebaum, S.L., et al., 1984a. Smell identification ability: changes with age. Science 226, 1441-1443.

The three most common causes of long-lasting or permanent smell loss of patients who present to smell and taste centers are, in order of frequency, upper respiratory infections, head trauma, and chronic rhinosinusitis (Deems et al., 1991a). Congenital, iatrogenic, and toxic chemical exposures are the next most common causes. These etiologies can result in permanent damage to the olfactory neuroepithelium, decreased number of receptor cells, and replacement of sensory epithelium with other types of epithelia. Susceptibility to such damage likely increases from reduction or inhibition of mucociliary transport by a range of factors including diet, drugs, disease, genetics, and age-related changes in nasal function and normal defense mechanisms.

Symptoms of the common cold and influenza are readily apparent to the patient, but it is important to remember that most viral infections are either entirely asymptomatic or so mild that they go unrecognized. Thus, during seasonal epidemics, the number of serologically documented influenza or arboviral encephalitis infections exceeds the number of acute cases by several hundred-fold (Stroop, 1995). For these and other reasons, many idiopathic cases of smell dysfunction likely reflect unrecognized viral infections. Smell dysfunction has been reported in rare instances following influenza vaccine inoculations (Fiser and Borotski, 1979). This may reflect a subtle but defining influence on an already compromised olfactory epithelium, although coincidental viral infection cannot be excluded from consideration. Under certain circumstances, some viruses can enter the brain after incorporation into the olfactory receptor cells, possibly catalyzing neurodegenerative disease (Doty, 2008). Such viruses as herpes simplex types 1 and 2, polio, the Indiana strain of wild-type vesicular stomatitis, rabies, mouse hepatitis, Borna disease, and canine distemper viruses are neurotropic for peripheral olfactory structures.

Loss of smell function from head trauma usually reflects coup-contrecoup movement of the brain that shears off the olfactory fila at the level of the cribriform plate (Doty et al., 1997). In most cases, scar tissue forms, precluding reconnection of axons from regenerating receptor cells. Fractures of the cribriform plate or other elements of the skull are rare in such cases and are not a prerequisite for the smell loss. In general, the more severe the head trauma, the higher the likelihood that smell loss is present.

A major development in neurology is the discovery that a number of neurodegenerative diseases are associated with smell loss early in their course, most notably AD and PD. In most cases, the smell loss precedes the presentation of the classic clinical phenotype by several years. Interestingly, a number of disorders often confused with these two diseases are unaccompanied by meaningful olfactory dysfunction, making smell testing potentially useful as an aid in differential diagnosis. For AD, major affective disorder is an example (McCaffrey et al., 2000). For PD, such examples include progressive supranuclear palsy (PSP) (Doty et al., 1993), essential tremor (Busenbark et al., 1992), MPTP-induced parkinsonism (Doty et al., 1992), and vascular parkinsonism (Katzenschlager et al., 2004). The relative severity of olfactory dysfunction in a range of neurodegenerative diseases and in schizophrenia is shown in Table 17.2.

Table 17.2 Relative Degree of Olfactory Dysfunction in Various Neurological Diseases on an Arbitrary Scale

Key: ++++ marked damage; + mild damage; 0 normal. Note that most of the values are based on relatively small patient numbers except for idiopathic PD.

AD, Alzheimer disease; DLB, dementia with lewy bodies; FTD, frontotemporal dementia; HD, Huntington disease; PD, Parkinson disease; PSP, progressive supranuclear palsy; SCA, spinocerebellar atrophy.

Modified and updated from Hawkes, C.H., Doty, R.L., 2009. The Neurology of Olfaction. Cambridge University Press, Cambridge, with permission.

It is noteworthy that the olfactory loss is present in idiopathic rapid eye movement sleep behavior disorder (iRBD) as well as in PD, since individuals with iRBD frequently develop PD. The fact that rapid eye movement(REM) behavior disorder is seen not only in its idiopathic form but in association with narcolepsy led has led to findings that narcolepsy—independent of REM behavior disorder—is associated with a significant impairment in olfactory function (Buskova et al., 2010; Stiasny-Kolster et al., 2007). Orexin A, also called hypocretin-1, is significantly decreased or undetectable in the cerebrospinal fluid of patients with narcolepsy and cataplexy. The orexin-containing hypothalamic neurons project throughout the entire olfactory system (from the olfactory epithelium to the olfactory cortex) (Caillol et al., 2003). Thus, damage to these projections may potentially impair olfactory performance in narcoleptic patients. The intranasal administration of orexin A (hypocretin-1) to narcoleptic patients with cataplexy has been found to improve their olfactory function, implying that mild olfactory impairment is not only a primary feature of this disorder but that CNS orexin deficiency could be a possible mechanism for this loss (Baier et al., 2008).

Disorders of Taste

As noted in the beginning of the chapter, most patients with complaints of taste loss have olfactory dysfunction, not taste dysfunction. This reflects the greater fragility of the olfactory system and the dependence of flavor sensations upon retronasal stimulation of this system. Impairment of whole-mouth gustatory function is rare outside of generalized metabolic disturbances, such as from diabetes, chronic renal failure, end-stage liver disease, thyroid disease, hypothyroidism, medications, and vitamin and mineral deficiencies. Nonetheless, taste perception can be altered by (1) viral invasion of one or more taste nerves, (2) the release of foul-tasting materials from the nasal and oral cavities secondary to medical conditions and oral appliances (e.g., rhinosinusitis, gingivitis, purulent sialadenitis), (3) transport problems of tastants to the taste buds (e.g., scaring of the lingual surface, mucosal drying, inflammatory conditions, infections), (4) damage to the taste buds (e.g., invasive carcinomas, local trauma), (5) damage to the taste nerves (e.g., chorda tympani damage from Bell palsy, middle ear infections or operations), and (6) damage to taste-related CNS structures from disorders such as multiple sclerosis, tumors, epilepsy, and stroke. Lesions caudal to the pons produce ipsilateral deficits, whereas lesions within the pons proper can produce ipsilateral, contralateral, or bilateral deficits. Both ipsilateral and contralateral taste deficits have been noted in patients with lesions of the insular cortex, reflecting the bilateral representation of taste function at this level (Pritchard et al., 1999). Unlike CN VII, CN IX is relatively protected along its path, although iatrogenic interventions can result in CN IX injury (e.g., from tonsillectomy, bronchoscopy, laryngoscopy, radiation therapy), and this nerve is not immune to damage from tumors, vascular lesions, and infection. On rare occasion, epilepsy or migraine is associated with a gustatory prodrome or aura, and some tastes may actually trigger seizures or migraine attacks.

The influence of medications on taste function is well established. Over 250 medications have been implicated in taste dysfunction, including antineoplastic agents, antirheumatic drugs, antibiotics, and blood pressure medications (Doty et al., 2008). Terbinafine, a popular antifungal, can produce long-lasting loss of sweet, sour, bitter, and salty taste perception (Doty and Haxel, 2005). A recent double-blind study found that eszopiclone, a widely used sleep medication, induces a bitter dysgeusia in approximately two-thirds of individuals tested (Doty et al., 2009). This sensation was related to the time since drug administration, was stronger for women than for men, and correlated with both saliva and blood levels of the drug.

Clinical Evaluation of Taste and Smell

Etiology can usually be established from a clinical history that explores symptom nature, onset, duration, pattern of fluctuations, and potential precipitating events, such as upper respiratory infections that occurred prior to symptom onset. Information regarding head trauma, smoking habits, drug and alcohol abuse (e.g., intranasal cocaine, chronic alcoholism in the context of Wernicke and Korsakoff syndromes), exposures to pesticides and other toxic agents, and medical interventions are informative. The possibility of multiple or cumulative effects cannot be discounted. A determination of all the medications that the patient was taking before and at the time of symptom onset is important, as are comorbid medical conditions potentially associated with taste and smell impairment, such as renal failure, liver disease, hypothyroidism, diabetes, and dementia. Delayed puberty in association with anosmia (with or without midline craniofacial abnormalities, deafness, and renal anomalies) suggests the possibility of Kallmann syndrome. Recollection of epistaxis, discharge (clear, purulent, bloody), nasal obstruction, allergies, and somatic symptoms including headache or irritation have potential localizing value. Questions related to memory, parkinsonian signs, and seizure activity (e.g., automatisms, occurrence of black-outs, auras, déjà vu) should be posed. The possibility of malingering should be considered, particularly if litigation is involved. Intermittent smell loss usually implies an obstructive disorder, such as from rhinosinusitis or other inflammatory problem. Sudden smell loss alerts the practitioner to head trauma, ischemia, infection, or a psychiatric condition. Gradual smell loss can be a marker for the development of a progressive obstructive lesion, cumulative drug effects, or simply presbyosmia or presbygeusia. While losses secondary to head trauma are most commonly abrupt, in some cases the loss appears over time or only becomes apparent to the patient after a long interval.

In addition to quantitative sensory evaluation, which is key in defining the dysfunction, neurological and otorhinolaryngological (ORL) examinations, along with appropriate brain and nasosinus imaging, aid in evaluating patients with olfactory or gustatory complaints. In the case of olfaction, the neural evaluation should pay particular attention to possible skull base and intracranial lesions. The ORL examination should thoroughly assess the intranasal architecture and mucosal surfaces. Polyps, masses, and adhesions of the turbinates to the septum may compromise the flow of air to the olfactory receptors, since less than a fifth of the inspired air traverses the olfactory cleft in the unobstructed state. Blood serum tests may be helpful to identify such conditions as diabetes, infection, heavy metal exposure, nutritional deficiency (e.g., vitamin B₆, B₁₂), allergy, and thyroid, liver, and kidney disease.

Treatment and Management

Management of chemosensory disorders is condition specific. Optimism for prognosis is warranted for most patients with obstructive or inflammatory disorders (e.g., allergic rhinitis, glossitis, polyposis, intranasal or intraoral neoplasms) for which medical or surgical interventions are available. In cases of rhinosinusitis, for example, an oral taper of prednisone can initially be used to quell general inflammation, followed by topical administration of the nasal spray or drops in the inverted head position, such as the Moffett position (Canciani and Mastella, 1988), increasing the likelihood of the material reaching the olfactory epithelium. Candidiasis or other oral infections can be quelled with topical antifungal and antibiotic treatments. Some salty or bitter dysgeusias respond to chlorhexidine mouthwash, possibly as a result of its strong positive charge (Wang et al., 2009). Patients with excessive oral dryness, including dryness due to medications, often benefit from the use of mints, lozenges, or sugarless gum, as well as from oral pilocarpine or artificial saliva.

Medications that induce distortions of smell or taste can often be discontinued and other types of medications or modes of therapy substituted. Unfortunately, little empirical data are available for most drugs, and some drug-related effects on the taste system appear to be long lasting and not reversed by short-term drug discontinuance (Doty et al., 2008). There is suggestion that some antioxidants such as α-lipoic acid may be effectual in some cases of hyposmia, hypogeusia, dysosmia, dysgeusia, and burning mouth syndrome (Hummel et al., 2002), although strong scientific evidence for its efficacy is lacking. Despite being widely mentioned in the medical literature, zinc and vitamin A therapies offer unlikely benefit for olfactory disturbances except when frank deficiencies are present, although both of these agents may improve taste dysfunction secondary to hepatic deficiencies (Deems et al., 1991b). A recent report that theophylline improved smell function was not double blinded and lacked a control group, failing to take into account that some meaningful improvement occurs without treatment (Henkin et al., 2009). Indeed, the percentage of patients reported to be responsive to the treatment was about the same as that noted by others to show spontaneous improvement over a similar time period. Similar issues are inherent in a recent claims of efficacy for acupuncture and transcranial magnetic stimulation. There are claims that some antiepileptics and antidepressants (e.g., amitriptyline) may be of value in treating some chemosensory disturbances, particularly following head trauma. However, in the case of amitriptyline, there is clear evidence that it can distort taste function, possibly from its anticholinergic effects (Schiffman et al., 1999). A recent study suggests that donepezil (acetylcholinesterase inhibitor) improved odor identification scores in patients with AD, and that such scores correlated with overall clinician-based impressions of change scales (CIBIC-plus), leading the authors to suggest that tests of smell identification function may be useful in assessing treatment responses to this medication (Velayudhan and Lovestone, 2009).

It is of interest that repeated exposure to odorants may in fact increase sensitivity to them in both animals and humans, providing a rationale for therapies in which multiple odors are smelled before and after going to bed (Hummel et al., 2009). However, double-blind studies with appropriate controls are needed to confirm the effectiveness of this approach. Importantly, spontaneous recovery over time occurs in some instances, providing hope to at least some patients. In a longitudinal study of 542 patients presenting to our center with smell loss from a variety of causes, modest improvement occurred over an average time period of 4 years in about half of the participants (London et al., 2008). Nonetheless, normal age-related function returned in only 11% of the anosmic and 23% of the hyposmic patients. The amount of dysfunction present at the time of presentation, not etiology, was the best predictor of prognosis. Other predictors were patient age and the time between dysfunction onset and initial testing.

An important but overlooked element of therapy comes from chemosensory testing itself. Confirmation or lack of conformation of loss is beneficial to patients, particularly ones who come to believe they may be “crazy” as a result of unsupportive medical providers or family members. Quantitative testing places the patient’s problem into overall perspective, and if considerable function is present, patients can be informed of a more positive prognosis. It is extremely therapeutic for an older person to become aware that, while his or her smell function is not what it used to be, it still falls above the average of his or her peer group, a situation that happens, by definition, 50% of the time. It is unfortunate that many such patients are simply told by their physician they are getting old and nothing can be done for them, often exacerbating or leading to depression and decreased self-esteem.