The sense of smell determines the flavor and palatability of food and drink. Along with the trigeminal system, it serves as a monitor of inhaled chemicals, including dangerous substances such as natural gas and smoke, and odors common to everyday life. The loss of smell or a decreased ability to smell affects approximately 1% of people under age 60 and more than half of the population beyond this age.
Abnormalities of olfaction include the following: (1) anosmia (absence of the sense of smell); (2) hyposmia (diminished olfactory sensitivity); (3) dysosmia (distorted sense of smell); (4) phantosmia (perception of an odorant when none is present); and (5) agnosia (inability to classify, contrast, or identify odor sensations verbally, even though the ability to distinguish between odorants may be normal).
Disorders of the sense of smell are caused by conditions that interfere with the access of the odorant to the olfactory neuroepithelium (transport loss), injure the receptor region (sensory loss), or damage the central olfactory pathways (neural loss). Table 10–1 summarizes the most common causes of olfactory dysfunction.
Table 10–1. Causes of Olfactory Dysfunction. ||Download (.pdf)
Table 10–1. Causes of Olfactory Dysfunction.
- Transport Olfactory Losses
- Allergic rhinitis
- Bacterial rhinitis and sinusitis
- Congenital abnormality (encephalocele)
- Nasal neoplasms
- Nasal polyps
- Nasal septal deviation
- Nasal surgery
- Viral infections
- Sensory Olfactory Losses
- Radiation therapy
- Toxic chemical exposure
- Viral infections
- Neural Olfactory Losses
- Alzheimer disease
- Chemical toxins
- Cigarette smoke
- Diabetes mellitus
- Huntington's chorea
- Kallmann syndrome
- Korsakoff psychosis
- Parkinson disease
- Vitamin B12 deficiency
- Zinc deficiency
Transport olfactory loss can result from the following conditions: a swollen nasal mucous membrane in acute viral upper respiratory infections; bacterial rhinitis and sinusitis; allergic rhinitis; and structural changes in the nasal cavity (eg, deviations of the nasal septum, polyps, and neoplasms). It is also likely that abnormalities of mucus secretion, in which the olfactory cilia are immersed, could result in a loss of olfactory sensitivity.
Sensory olfactory loss results from damage to the olfactory neuroepithelium by any of the following causes: viral infections, neoplasms, the inhalation of toxic chemicals, drugs that affect cell turnover, and radiation therapy to the head.
Neural olfactory loss can occur in a number of ways: head trauma, with or without fracture of the base of the anterior cranial fossa or cribriform plate area; Parkinson disease; Alzheimer disease; Korsakoff psychosis; vitamin B12 deficiency; neoplasms of the anterior cranial fossa; neurosurgical procedures; administration of neurotoxic agents (eg, ethanol, amphetamines, topical cocaine, aminoglycosides, tetracycline, cigarette smoke); and in some congenital disorders such as Kallmann syndrome. Other endocrine disorders can affect smell perception, including Cushing syndrome, hypothyroidism, and diabetes mellitus.
Molecular aspects of olfaction are now becoming understood. In mammals, there are probably 300–1000 olfactory receptor genes belonging to 20 different families located on various chromosomes in clusters. The receptor genes are present at more than 25 different human chromosomal locations. Olfactory receptor proteins are G protein-coupled receptors characterized by the presence of seven alpha-helical transmembrane domains. Each olfactory neuron expresses only one or, at most, a few receptor genes, providing the molecular basis of odor distinction. The olfactory system is thus characterized by three important features: (1) the large family of receptor genes exhibits remarkable diversity allowing response to a variety of smells, (2) the receptor proteins exhibit exquisite specificity allowing for odor discrimination, and (3) odor associations are well kept in memory long after the incident that formed the association is forgotten.
Many patients experience olfactory dysfunction due to one or more of the following causes: obstructive nasal and sinus disease, post-upper respiratory infection, cranial trauma, and congenital causes. Aging, exposure to toxins, and idiopathic causes also account for the loss of smell.
Nasal Obstruction and Upper Respiratory Infection
Air flows through the medial and anterior to the lower part of the middle turbinate to reach the olfactory cleft. Nasal obstruction at this area or above it caused by severe mucosal swelling, tumors, nasal polyps, or bony deformities can result in hyposmia or anosmia. In addition, patients often report a loss of sense of smell during an upper respiratory infection; generally, this loss is due to airway obstruction secondary to mucosal swelling. Olfactory ability should improve or return altogether with relief of the obstruction.
Approximately 5–10% of adult patients with head trauma report olfactory loss to be in the anosmic range. The degree of olfactory loss is generally associated with two things: the severity of the trauma and the site of cranial trauma. Total anosmia is more likely to occur with occipital traumas; however, frontal blows most frequently cause olfactory loss.
Perhaps the most well-known type of congenital anosmia is Kallmann syndrome, an X-linked disorder. Caused by mutation in the KAL gene, Kallmann syndrome is characterized by hypogonadotropic hypogonadism, which results when olfactory receptor neurons and neurons synthesizing gonadotropin-releasing hormone fail to migrate from the olfactory placode.
Aging and dementia-related diseases can result in olfactory loss. Olfactory sensitivity tends to drop sharply in the sixth and seventh decades of life. Anatomically, cellular elements associated with olfaction decrease with age, as does olfactory bulb volume (found at the base of the frontal cortex). Alzheimer disease and Parkinson disease may be associated with olfactory dysfunction. In these patients, the most likely mechanism is damage to the olfactory bulb or central olfactory cortex, which results in the loss of olfactory detection and recognition ability.
Olfactory loss from toxins may occur over a period of days or years. Formalin exposure is an example of a toxicity that accumulates over a period of years. Most agents that cause olfactory loss are either gases or aerosols that enter the nose with the respiratory air stream.
Patients with depression and schizophrenia may have olfactory losses as part of their illnesses. Although depressed patients do have some altered gustatory ability, the ability to identify odorants is usually normal; when it is not, the olfactory complaints most likely stem from a problem in the central nervous system. It may be that the same chemicals that cause symptoms of depression affect the neural connections between the limbic system and the hypothalamus.
Knowing the onset and development of an olfactory disorder may be of paramount importance in making an etiologic diagnosis. Unilateral anosmia is rarely a complaint; it can be recognized only by separately testing smell in each nasal cavity. Bilateral anosmia, on the other hand, does bring patients to medical attention. Anosmic patients usually complain of loss of the sense of taste, even though their taste thresholds may be within normal limits. In actuality, they are complaining of a loss of flavor detection, which is mainly an olfactory function.
The physical examination should include a complete examination of the ears, upper respiratory tract, head, and neck. Pathology of each area of the head and neck can result in olfactory dysfunction. The presence of serous otitis media suggests the presence of a nasopharyngeal mass or inflammation. A careful nasal examination for nasal mass, clot, polyps, and nasal membrane inflammation is critical. When available, anterior rhinoscopy should be supplemented with endoscopic examination of the nasal cavity and nasopharynx. The presence of telecanthus on the ocular exam may suggest a sinus mass or inflammation. Nasopharyngeal masses protruding into the oral cavity or purulent drainage within the oropharynx may be seen during the oral examination. The neck should be palpated for masses or thyroid enlargement. A neurologic examination emphasizing the cranial nerves and cerebellar and sensorimotor function is essential. The patient's general mood should be assessed and signs of depression should be noted.
Techniques have been developed to biopsy the olfactory neuroepithelium. However, because of the widespread degeneration of the olfactory neuroepithelium and intercalation of respiratory epithelium in the olfactory area of adults with no apparent olfactory dysfunction, biopsy material must be interpreted cautiously.
A computed tomography (CT) scan or magnetic resonance imaging (MRI) of the head is required to rule out neoplasms of the anterior cranial fossa, unsuspected fractures of the anterior cranial fossa, paranasal sinusitis, and neoplasms of the nasal cavity and paranasal sinuses. Bone abnormalities are best seen with CT, whereas MRI is useful in evaluating olfactory bulbs, ventricles, and other soft tissues of the brain. Coronal CT is optimal for assessing the cribriform plate, anterior cranial fossa, and sinus anatomy and disease.
The sensory evaluation of olfactory function is necessary to (1) corroborate the patient's complaint, (2) evaluate the efficacy of treatment, and (3) determine the degree of permanent impairment.
Step 1: Determining Qualitative Sensations
The first step in the sensory evaluation is to determine the degree to which qualitative sensations are present. Several methods are available for olfaction evaluation.
The Odor stix test uses a commercially available magic marker-like pen that produces odor. It is held approximately 3–6 inches from the patient's nose to check for gross perception of the odorant.
The Twelve-Inch Alcohol Test
Another test that assesses gross perception of an odorant, the twelve-inch alcohol test, uses a freshly opened isopropyl alcohol packet held approximately 12 inches from the patient's nose.
A scratch-and-sniff card that contains three odors to test gross olfaction is commercially available.
The University of Pennsylvania Smell Identification Test (UPSIT)
A far superior test to other assessments is the University of Pennsylvania Smell Identification Test (UPSIT); it is highly recommended for the evaluation of a patient with smell disorder. This test utilizes 40 forced-choice items that feature microencapsulated scratch-and-sniff odors. For example, one of the items reads, “This odor smells most like (a) chocolate, (b) banana, (c) onion, or (d) fruit punch.” The patient is instructed to answer one of the alternatives. The test is highly reliable (short-term test-retest reliability r = 0.95) and is sensitive to age and gender differences. It is an accurate quantitative determination of the relative degree of olfactory deficit. Individuals with a total loss of olfactory function score in the range of 7–19 out of 40. The average score for total anosmics is slightly higher than that expected on the basis of chance alone because of the inclusion of some odorants that act by trigeminal stimulation.
Step 2: Determining the Detection Threshold
After the physician determines the degree to which qualitative sensations are present, the second step in the sensory evaluation is to establish a detection threshold for the odorant phenylethyl alcohol. This threshold is established using a graduated stimulus. Sensitivity for each side of the nose is determined with a detection threshold for phenyl-ethyl methyl ethyl carbinol. Nasal resistance can also be measured with anterior rhinomanometry for each side of the nose.
At the present time, there are no psychophysical methods to differentiate sensory from neural olfactory loss. Fortunately, the history of olfactory loss provides important clues to the cause. The leading causes of olfactory disorders are head trauma and viral infections. Head trauma is a more common cause of anosmia in children and young adults, and viral infections are more common causes of anosmia in older adults.
Viral infections destroy the olfactory neuroepithelium; it is replaced by the respiratory epithelium. Parainfluenza virus type 3 appears to be especially detrimental to human olfaction. Human immunodeficiency virus (HIV) infection is associated with a subjective distortion of taste and smell that may become more severe as the disease progresses. Moreover, the loss of taste and smell may play an important role in the development and progression of HIV-associated wasting.
Cranial trauma is followed by a unilateral or bilateral impairment of smell in up to 15% of cases; anosmia is more common than hyposmia. Olfactory dysfunction is more common when associated with loss of consciousness, more severe head injuries (grades II–V), and skull fracture. Frontal injuries and fractures disrupt the cribriform plate and olfactory axons that perforate it. Sometimes an associated cerebrospinal fluid rhinorrhea results from a tearing of the dura overlying the cribriform plate and paranasal sinuses. Anosmia also may follow blows to the occiput. Once traumatic anosmia develops, it is usually permanent; only an estimated 10% of patients ever improve or recover. The perversion of the sense of smell may occur as a phase in the recovery process. Zinc sulfate therapy may enhance improvement in olfaction following trauma.
Congenital anosmias are rare but important. Kallmann syndrome is a neuronal migration defect for which the X-linked gene (KAL) has been cloned. It is characterized by congenital anosmia and hypogonadotropic hypogonadism. Anosmia also can occur in persons with albinism. The receptor cells are present but are hypoplastic, lack cilia, and do not project above the surrounding supporting cells.
Meningioma, Adenoma, and Aneurysm
Meningioma of the inferior frontal region is the most common neoplastic cause of anosmia; rarely, anosmia can occur with glioma of the frontal lobe. Occasionally, pituitary adenomas, craniopharyngiomas, suprasellar meningiomas, and aneurysms of the anterior part of the circle of Willis extend forward and damage olfactory structures. These tumors and hamartomas also may induce seizures with olfactory hallucinations, indicating involvement of the uncus of the temporal lobe.
Dysosmia, a subjective distortion of olfactory perception, may occur with intranasal disease that partially impairs smell or may represent a phase in the recovery from a neurogenic anosmia. Most dysosmic disorders consist of disagreeable or foul odors, and they may be accompanied by distortions of taste. Dysosmia is associated with depression.
Therapy for patients with transport olfactory losses due to allergic rhinitis, bacterial rhinitis and sinusitis, polyps, neoplasms, and structural abnormalities of the nasal cavities can be undertaken rationally and with a high likelihood of improvement. The following treatments are frequently effective in restoring the sense of smell: (1) allergy management; (2) antibiotic therapy; (3) topical and systemic glucocorticoid therapy; and (4) operations for nasal polyps, deviation of the nasal septum, and chronic hyperplastic sinusitis.
Sensorineural Olfactory Loss
There is no treatment with demonstrated efficacy for sensorineural olfactory losses. Fortunately, spontaneous recovery often occurs. Some clinicians advocate zinc and vitamin therapy. Profound zinc deficiency undoubtedly can result in loss and distortion of the sense of smell, but it is not a clinical problem except in very limited geographic areas. Vitamin therapy has been predominantly in the form of vitamin A. The epithelial degeneration associated with vitamin A deficiency can cause anosmia, but vitamin A deficiency is not a common clinical problem in Western societies. Exposure to cigarette smoke and other airborne toxic chemicals can cause metaplasia of the olfactory epithelium. Spontaneous recovery can occur if the insult is discontinued; therefore, patient counseling is helpful in these cases.
Aging-Related Olfactory Loss (Presbyosmia)
As previously mentioned, more than half of people older than age 60 suffer from olfactory dysfunction. No effective treatment exists for presbyosmia, but it is important to discuss the problem with elderly patients. It can be reassuring to patients when a physician recognizes and discusses that smell disorders are common. In addition, direct benefits can be gained by identifying the problem early; the incidence of natural gas–related accidents is disproportionately high in the elderly, perhaps in part because of the gradual loss of smell. Mercaptan, the pungent odor in natural gas, is an olfactory and not a trigeminal stimulant. Many older patients with olfactory dysfunction experience a decrease in flavor sensation and find it necessary to hyperflavor food. The most common method is by increasing the amount of salt in their diet. Careful counseling can help these patients develop healthy strategies to deal with their decreased sense of smell.
The outcome of olfactory dysfunction is largely dependent on its cause. Olfactory dysfunction due to an obstruction caused by polyps, neoplasms, mucosal swelling, or septal deviation is reversible. When the obstruction is released, olfactory ability should return. Most patients who lose their sense of smell during an upper respiratory infection completely recover olfactory ability; however, a small number of patients never recover after the other symptoms of the upper respiratory infection resolve. For unclear reasons, these patients are mostly women in their fourth, fifth, and sixth decades of life. The prognosis for recovery is generally poor. Olfactory identification ability and thresholds progressively decline with age. Head trauma to the frontal region most frequently causes olfactory loss, although total anosmia is five times more likely with an occipital blow. Recovery of olfactory function following traumatic cranial injury is only 10%, and the quality of the olfactory ability after recovery is usually poor. Exposure to toxins such as cigarette smoke can cause metaplasia of the olfactory epithelium. Recovery can occur with removal of the offending agent.
Doty RL. The olfactory system and its disorders. Semin Neurol
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Lane AP, Turner J, May L, Reed R. A genetic model of chronic rhinosinusitis-associated olfactory inflammation reveals reversible functional impairment and dramatic neuroepithelial reorganization. J Neurosci
. (In this mouse model of rhinosinusitis, the investigators showed that direct effect of inflammation on the olfactory epithelium structure and function are important mechanisms of olfactory dysfunction.)
Zou Z, Buck LB. Combinatorial effects of odorant mixes in olfactory cortex. Science
. (Cortical neurons that respond to combination of two odorants do not respond to a single odorant, thus explaining why odorant mixtures lead to novel precepts in humans.)
We would like to acknowledge Derek D. Mafong for his contribution to this chapter in the previous editions of CDT.