-------------------------------------------------------------------------------- TITLE: OLFACTORY DISORDERS SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds DATE: November 17, 1993 RESIDENT PHYSICIAN: Kelly Sweeny, M.D. FACULTY: Karen H. Calhoun, M.D. DATABASE ADMINISTRATOR: Melinda McCracken, M.S. -------------------------------------------------------------------------------- "This material was prepared by resident physicians 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 should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion." Olfactory Disorders I. Introduction A. Importance of Olfaction: 1. First special sensory organ to develop embryologically. 2. By the time infants are seven days old, they show a preference for a pad from their own mother's breast. 3. It serves as an important early warning system for the detection of fire, dangerous fumes, leaking gas, and spoiled food. 4. It largely determines the flavor of the foods we eat and the beverages we drink. 5. It enhances socialization and interpersonal relationships by protecting against objectionable body odors. 6. It may be involved in human reproductivity via the presence of chemical pheromones (speculative). 7. Loss results in disability for persons employed in the perfume, firefighting, or gourmet food industry. B. Prevalence: Approximately two million American adults suffer from disorders of taste and smell. C. Odor Memories: 1. Established when a significant or memorable event occurs in the presence of a particular odor. 2. These associations require only one exposure but are notoriously difficult to erase from memory even though the incident which formed the memory is forgotten. 3. An odor aversion can be formed to good food after an episode of overindulgence. 4. Similarly, becoming ill for an unrelated reason while eating an otherwise innocuous food can produce the same effect. II. Anatomy A. Olfactory Epithelium: 1. Located in the superior aspect of each nostril. Folds down over the superior septal surface medially and over the superior turbinate and a small portion of the medial turbinate laterally. 2. Covers an area of approximately one square centimeter on each side of the nose. 3. Begins as a solid sheet. With aging, small islands of respiratory epithelium develop within the olfactory epithelium and enlarge over time. 4. Pseudostratified columnar epithelium. B. Cell Types: 1. Olfactory Receptor Cells: a. Only specialized sensory neuron with regenerative capabilities. b. Bipolar neuron: (1)Dendrite: extends to surface of the olfactory epithelium and forms a dilitation (olfactory vesicle) from which 15-20 sensory cilia project into the mucus layer and expand the interactive surface area. (2)Axon: central, thin, unmyelinated end of the neuron. Groups of 20 of these axons combine into bundles, fila olfactoria, and pass through foramina in the cribriform plate of the ethmoid bone to enter the olfactory bulb. Here they form glomeruli where 100-1000 primary afferent neurons converge on a single post synaptic cell. c. About 25 million olfactory receptor cells in each nasal cavity in young adults. 2. Microvillar Cells: a. Exact function unknown. b. Thought to be a second type of olfactory receptor. c. Has a central axon that extends into the lamina propria, but further connections are not known. 3. Basal Cells: a. Form the stem cell population- progenitor cell for the olfactory epithelium. b. Death of an olfactory receptor cell triggers basal cell division and differentiation into a new neuron. c. This self-replication is unique to the olfactory system (not seen in the visual or auditory systems). 4. Sustentacular Cells: a. Tall, bottle-shaped cells that join tightly with the surface of the receptor cells and microvillar cells. b. Traverse the entire width of the epithelium. c. Resemble glia and serve to electrically insulate neighboring receptor cells. d. These cells do not generate action potentials. e. Contribute mucus and may regulate extracellular potassium content. 5. Bowman's Glands: a. Found deep in the lamina propria. b. Secrete mucus to coat the olfactory epithelium. C. Olfactory Bulb: 1. Located on top of the cribriform plate at the base of frontal cortex in the anterior cranial fossa. 2. Receives thousands of primary axons from the olfactory receptors that converge onto a much smaller number of secondary neurons forming the olfactory tract. 3. Olfactory Tract: sends projections to multiple areas of the brain, including the frontal and temporal lobes, thalamus, and hypothalamus. Plays a role in food intake,temperature regulation, sleep, vision, taste, memory, and cognition. 4. Importance: the extensive interconnections between the primary olfactory center and many other areas of the brain suggests that the sense of smell plays a role in many biological functions. III. Physiology A. Olfactory Pathway: 1. Airflow: odorant must enter the nasal cavity either via the anterior nostrils during inhalation, or via the posterior choanae during exhalation. 15% of the inhaled air stream reaches the olfactory cleft. 2. Mucus Layer: odorant must be part hydrophilic in order to successfully diffuse through the mucus layer. 3. Transduction: a. Occurs once the odorant molecule reaches the receptor protein on the surface of the olfactory cilia. b. Involves activation of a G-protein specific for olfactory epithelium which causes an increase in cAMP (second messenger). c. This increase in cAMP activates an ion channel leading to depolarization of the cell and the generation of an action potential. d. This action potential results in perception of the odorant via CN I. e. Role of calcium unclear, but important. B. Odorant Binding Proteins: 1. Bind and solubilize hydrophobic odorant molecules. 2. Increase the concentration of odorant molecules in each receptor cell by as much as 10,000 times. 3. May aid in removal of the odorant molecules after transmission complete. C. Common Chemical Sense: 1. Consists of free nerve endings from CN V, IX, and X. 2. Provides added chemoreceptivity in the mucosa of the respiratory tract. 3. Responsible for the tingle perceived with ammonia and for the burn of a chili pepper. 4. Usually preserved in anosmic individuals. IV. Evaluation and Diagnosis of Olfactory Disorders A. General: 1. Over 200 medical conditions and many medications have been associated with olfactory changes and loss. 2. Multiple Chemosensory Centers were developed in the 1980's to evaluate and treat patients with chemosensory disorders and to integrate clinical investigations and treatment with basic science research. 3. Data from several of these centers support three major causes of olfactory dysfunction: a. Obstructive Nasal and Sinus Disease b. Upper Respiratory Viral Infection c. Head Trauma 4. In 22% of cases no cause is ever found (idiopathic). B. Patient Evaluation: 1. History: Most important aspect. Must determine: a. Degree of olfactory ability prior to the loss. b. Severity of the perceived olfactory loss. c. Time period over which the loss occurred. d. Decreased sensitivity vs. distorted perception. e. Prior therapy for nasal or sinus disease. f. History of nasal and allergic symptoms. g. Events occurring around the time of the loss (in particular head trauma, URI, toxic exposure). h. Taste vs. smell (80% of flavor is olfaction). i. Associated medical conditions. j. List of current and previous medications. k. Unilateral vs. bilateral involvement. l. Any associated psychological problems. 2. Physical Examination: a. Must be complete. b. Emphasis on the head and neck exam. c. Nasal endoscopy can be of diagnostic value. d. Neurological exam very important. 3. Laboratory Studies: a. Routine studies if indicated. b. Serum IgE may be helpful in supporting NSD as cause. c. Rhinomanometry may help illustrate nasal airflow. d. No specific recommendations. 4. Imaging studies a. Plain films +/- CXR. b. CT scan of nose and sinuses (coronal view with 3mm cuts- most sensitive). C. Chemosensory Testing: Many methods available. 1. Connecticut Chemosensory Clinical Research Center Test (CCCRC): Cain WS, 1983: a. Threshold component: 20 minutes (1)Quantifies the most dilute concentration of odorant the patient can detect. (2)Uses butanol as odorant (low toxicity, water soluble, standard odorant) up to a maximum concentration of 4%. (3)Start at the lowest concentration and work in an upward direction to prevent adaptation (loss of sensitivity from repeated stimulation). (4)Patient given two bottles to sample and must choose the one with butanol (forced-choice). (5)Correct answer-same concentration and a blank given again. Incorrect-next higher concentration given. (6)Testing ends when patient gives 4 correct answers in a row (threshold), or if patient displays no consistent detection (anosmic). b. Identification Component: 15 minutes (1)Uses 8 items (7 olfactory/1 CCS) presented in opaque jars with gauze covering to prevent visual cues. (2)Patient given list of 16 choices(the 8 actual items and 8 distractors). (3)Not forced-choice: may indicate "don't know". (4)Corrective feedback given after errors. (5)Missed items presented again with correct response cancelling wrong answer. c. Composite Score: derived from the performance average of the two components (0-7): anosmia 0.0-1.75 severe hyposmia 2.0-3.75 moderate hyposmia 4.0-4.75 mild hyposmia 5.0-5.75 normosmia 6.0-7.0 d. Applies equally to men and women across all decades except the elderly (> 65 years.) Scores relaxed by 1.0 point for these patients. e. Strengths: In routine ENT practice the CCCRC could be used to help establish initial severity of olfactory disorder and to chart course during and after medical therapy or surgery. Portable and relatively inexpensive. f. Weaknesses: Labor intensive and time consuming. 2. University of Pennsylvania Smell Identification Test (UPSIT): Doty RL, 1984: a. First easy to administer, commercially available test of olfaction. b. Consists of 4 booklets of 10 odorants in micro- encapsulated crystals in scratch and sniff form. c. Self administered (can be mailed to physician), easily stored, with a multiple choice format. d. Specific UPSIT score determined on scale of 0-40: normal 36-40 Partial anosmia 20-35 total anosmia 8-15 (1/4 by chance) malingerers 0-5 e. Allows percentile ranking of results by age, sex, and against national norms. f. Correlated significantly with traditional odor detection thresholds. g. Clearly and reliable differentiates between patients with normal olfactory ability, those with olfactory dysfunction, and malingerers. h. The portability of the booklets and the fun of of taking the test contribute to the UPSIT's popularity. 3. Oderant Confusion Matrix (OCM): Wright HN, 1987: a. Ten chemical odorants representing common items and one blank presented in random order 10 times. b. Subjects given list of 10 choices and must chose one (forced-choice). c. Results represented as matrix- can target fatigue, anosmia, hyposmia. d. Some CCS items on test to determine CN I vs. CN V dysfunction. e. Cumbersome, time consuming, inconvenient, but popular at chemosensory centers. 4. Chemosensory Testing of Taste: a. No standard method. b. Patient asked to distinguish sweet, salty, sour and bitter. c. Helps to identify the rare patient with taste loss. d. Helps to demonstrate taste to patient and to illustrate preservation in a patient complaining of loss of taste. V. Classification of Olfactory Disorders A. Obstructive Nasal and Sinus Disease (NSD): 1. Incidence: Most common cause of olfactory dysfunction. 2. Possible causes: a. Chronic sinusitis b. Anatomic abnormalities c. Intranasal polyps d. Mucosal thickening and edema e. Septal deviation 3. Critical Area: Space between the nasal septum and the middle turbinate below and anterior to the cribriform plate is the critical nasal opening required for optimal olfaction. Obstruction in this area due to mucosal edema, polyps, or scarring can decrease olfactory ability even when the rest of the nasal cavity is normal. 4. Patient Profile: a. All age groups are represented. b. Females > Males. c. Patients typically report gradual and progressive olfactory loss. d. Hyposmia > Anosmia. e. Sudden deterioration with acute infection or allergen exposure common. f. Fluctuations common with temporary improvement in sensitivity with exercise or with showering. 5. Diagnosis: a. History: inhalant allergies, asthma, chronic sinusitis, prior nasal/sinus surgery, sneezing, rhinorrhea, nasal obstruction, post-nasal drip, sinus pressure or tenderness. b. Physical: Nasal endoscopy is diagnostic. (1) Patency of the nasal airways (2) Characteristics of mucosa (3) Color and consistency of the mucus (4) Presence or absence of polyps c. CT Scan: Coronal views with 3 mm windows: Most sensitive and usually necessary to fully evaluate the patency of the upper nasal cavity and to help distinguish between NSD and post-URI olfactory loss. 6. Jafek et al, 1987- Steroid Dependent Anosmia: a. Type of olfactory loss in patients with non- obstructive nasal inflammatory disease. b. Responds well to systemic steroids due to a decrease in the inflammation, but recurs shortly after stopping the drug. c. Inflammation thought to cause: (1) Impaired odorant binding to olfactory receptor cilia due to changes in mucus content. (2) Stretching of primary olfactory neurons due to edema which impedes transmission of synaptic impulses. (3) Destruction of olfactory receptors due to the products of inflammation. d. Controversy surrounding this treatment: risks of systemic steroids out-weigh benefits, but a 1-2 week course can serve as a diagnostic test for NSD as cause of the anosmia. 7. Treatment: a. Medical: (1) Antibiotics x 3 weeks (2) Decongestants (3) Topical Corticosteroids (4) Short course of po steroids (5) Chromolyn (6) Desensitization b. Surgical: (1) FESS (2) Polypectomy (3) Septoplasty B. Post Upper Respiratory Tract Infection: 1. Any respiratory virus causing intranasal edema and inflammation can theoretically cause temporary olfactory losses which should resolve after nasal symptoms subside. However, specific viruses have a propensity to damage the olfactory system and may cause sudden, permanent damage even after a mild URI (dogs- canine distemper virus causes anosmia). 2. Pathophysiology: unknown. The presumed mechanism of loss of smell in these cases is neuropathic damage to the olfactory epithelium, olfactory bulbs, or to the olfactory tract. 3. Requirements for Diagnosis: a. Temporal association of the loss with a URI b. Absence of other possible causes 4. Jafek et al, 1987: Performed biopsies on 17 patients with post-URI olfactory loss and found damaged olfactory neurons, which were decreased in number and sometimes completely replaced by respiratory epithelium, with the degree of damage paralleling the degree of the olfactory loss. 5. Patient Profile: a. Generally healthy before the URI b. Typically older (> 65) c. Female > Male (80%) d. Normal examination and CT scan e. Hyposmia > Anosmia f. Associated phantosmias and parosmias common 6. Treatment: None effective. a. Zinc recommended in the past but a double blind crossover study showed that it was no more effective than placebo (Henkin et al, 1976). b. Similar results with Vitamins A, E, and B. 7. Prognosis: varies. If the olfactory loss is due to damage of the peripheral olfactory neurons, then spontaneous recovery is possible, but the prognosis is usually poor. C. Head Trauma: 1. Incidence: Loss of olfactory ability occurs in 5% of adults and 1% of children after head trauma. 2. Degree of Loss: Generally related to the severity of the trauma, but anosmia has been reported to occur even after minor head injuries. 3. Site of Trauma: Frontal blows more frequently cause olfactory loss, but total anosmia is 5 times more likely to occur after an occipital blow. 4. Patient Profile: a. Younger (20 - 50) b. Male > Female c. Onset typically immediate, but delays of up to 4 months have been reported. d. Anosmia >> Hyposmia e. +/- Parosmias 5. Mechanism of Injury: The most common type of head injury associated with olfactory dysfunction is a deceleration injury following a blow to the head. This results in displacement of the relatively mobile brain within the rigid confines of the skull and can lead to: a. Shearing of the fila olfactoria as they pass through the cribriform foramina, severing their connections with neurons in the olfactory bulb. b. Fractures of the cribriform plate. c. Contusion of the olfactory bulb or cerebrum leading to impairment in olfaction. 6. Biopsies: taken from patients who sustained trauma with resultant olfactory loss show: a. Distorted olfactory neurons, less compact with large, bloated cells and nuclei dispersion. b. Multiple axonal tangles present in the lamina propria, extending to the mucosal surface. c. Bald olfactory vesicles with little or no cilia. d. These results suggest that the olfactory epithelium regenerated after the head trauma and the receptor cells attempted to send axons centrally, but were blocked by scar formation and were unable to make contact with the olfactory bulb neurons resulting in axonal tangles. 7. Treatment: No known effective therapy. 8. Prognosis: Varies. a. 8-39% recover function. b. Amnesia > 24 hours associated with permanent loss in > 90% of cases. c. Timing of recovery varies but 75% of patients who recover do so within 3 months. D. Aging: 1. The total number of fibers in the olfactory bulb decreases at a rate of 1% per year. 2. The level of the deficit is not well defined, but older people have a gradual loss of olfactory sensitivity. 3. Skip et al, 1993: Examined the influence of age, gender, medical treatment and medications on smell identification in a group of generally healthy individuals between the ages of 19 and 95 (UPSIT). a. Older subjects had lower UPSIT scores and were more likely to be anosmic than younger subjects. b. Females scored higher than males at all ages. c. Patients being treated for medical problems and taking prescription medication had lower UPSIT scores and more smell complaints. d. Age related decline in olfaction occurs as a part of the normal physiologic aging process. 4. Olfactory dysfunction seen early in the course of Alzheimer's Disease. E. Toxins: 1. The inhalation of a number of environmental and industrial chemicals can lead to olfactory disturbances. 2. The degree of olfactory damage seems to be related to the timing and length of exposure, concentration of the agent, and the toxicity of the agent. 3. Anosmia and hyposmia have been reported after a single exposure to sulfuric acid, hydrogen cyanide, phosphorous oxychloride, and other agents, but these cases are rare and usually associated with extremely high concentrations of the agent. 4. More typically are the large number of reports of olfactory dysfunction following chronic exposure to low levels of benzene, butyl acetate, formaldehyde, paint solvent, and other agents. 5. Many dusts produced in industry can cause hyposmia. Examples: grain, silicone, spices, cotton, paper, cement, lead, coal, chromium, and nickel. 6. Effects of cigarette smoking: a. Frey et al, 1990: Administered the UPSIT to 638 subjects with known smoking histories and non-smoking controls of similar age and sex. (1) Smoking causes long term, but reversible adverse effect on olfactory ability and odor identification. (2) In previous smokers, the eventual return of olfaction to non-smoker levels requires the same amount of years as years spent smoking. (3) Smokers are twice as likely to have an olfactory deficit. b. Biological basis: (theories) (1) Adverse influence of cigarette toxins on olfactory receptors. (2) Adverse effect of toxins on mucus content. (3) Nasal airway constriction. c. Animal Studies: relatively brief exposure to cigarette smoke (twice a day for a week) can cause anatomical changes within the olfactory epithelium, including decrease in size and number of olfactory vesicles and cilia. 7. Treatment: Prevention is the key. F. Congenital Anosmia: 1. Commonly an isolated finding. 2. These patients do not understand the concept of an odor and are not concerned with the disability. 3. Can be associated with other abnormalities such as cryptorchidism, midline craniofacial defects, deafness, and renal agenesis. 4. Important to rule out other causes of anosmia which may have occurred in infancy and childhood. 5. Kallman's Syndrome: Hypogonadotrophic Hypogonadism: a. Most common form of congenital anosmia. b. Incidence: 1/10,000 males, 1/50,000 females. c. Agenesis of the olfactory bulbs associated with incomplete development of the hypothalamus, with decreased production of GRH. d. Autosomal dominant with variable expression. G. Medications: 1. Numerous drugs can cause olfactory disturbances as a side effect. 2. Injections of morphine and dilaudid are known to depress human smell function. 3. Hyposmia and anosmia have been associated with tetracycline, streptomycin, lincomycin, ZnSO4, D-penicillamine, and griseofulvin. 4. Olfactory ability will usually return to normal after stopping the offending medication, but cases of permanent loss have been documented. 5. Important to discuss these possible side effects when prescribing these medications. H. Tumors: 1. Intranasal: a. Inverting papilloma b. Adenoma c. Squamous cell carcinoma d. Esthesioneuroblastoma: RARE (1) Arises directly from olfactory epithelial cells (neural crest origin). (2) Cribriform plate involved early and intracranial extension is early and rapid. (3) Tend to be vascular and cause epistaxis. 2. Intracranial: a. Meningioma in the olfactory groove or cribriform plate b. Pituitary tumor with suprasellar extension c. Frontal lobe tumors d. Temporal lobe tumors (25% of these cause an olfactory disturbance- usually parosmias) 3. Treatment: Surgery, Chemotherapy, XRT. Olfactory function generally returns if the epithelium is intact and not destroyed by local invasion. I. Psychiatric Disorders: 1. Schizophrenia: 15-30% of these patients will have olfactory hallucinations. 2. Temporal lobe epilepsy: usually perceive unpleasant extrinsic phantosmia prior to the seizure activity. 3. Major Depression: may experience olfactory hallucinations. Olfactory reference syndrome- patient feels that he stinks and that every one can smell his foul body odors. He reacts by excessive bathing and withdrawal from society. J. Iatrogenic: 1. Anterior Craniotomy 2. Radiation Therapy 3. Arteriography 4. Influenza Vaccine 5. Hemodialysis 6. Complete Nasal Reconstruction (95% temporary) 7. Total Laryngectomy VI. Conclusions A. The sense of smell is extremely important to man for protection, nutrition, and socialization. B. A number of different diseases, conditions, and medications can lead to olfactory disturbances. C. The most common causes of olfactory dysfunction are: 1. Obstructive Nasal and Sinus Disease 2. Post Upper Respiratory Viral Illness 3. Head Trauma 4. Iatrogenic D. Treatment is not usually successful with the exception of olfactory loss secondary to NSD. E. Patients with olfactory problems due to neural loss as seen with head trauma, URI, aging, or congenital disorders currently cannot be treated. F. For patients who are untreatable, counseling is important. These patients need to understand that their disorder is not unique. Support groups are helpful. G. Patients with olfactory disorders need to take special precautions: 1. Install multiple smoke alarms in the home. 2. Change from natural gas appliances to electric. 3. Clearly mark expiration dates on food. 4. Enlist the help of friends and family in issues of social concern. H. Further research on this fascinating topic will hopefully lead to the development of treatment protocols to help the numerous patients who are currently untreatable. -------------------------------END---------------------------------------------