Effectiveness Of Clinical Testing Of Olfaction - Case Study Example

Effectiveness Of Clinical Testing Of Olfaction Abstract The sense of olfaction is considered to be the most basic of all sensory perceptions. The interpretation of olfactory stimuli occupies a very large portion of the brains of lower animals. In humans, this portion of the brain has been superseded by the extensive development of the prefrontal cortex; however, the sensory stimuli associated with olfaction continue to comprise an essential component of the perceptive capacities of the human brain. Unfortunately, this important sensory apparatus has received little attention, and its importance to health is frequently underestimated. Among the common tests of olfaction are measurements of odor detection, odor identification, the discernment of odor variations, odor memory, suprathreshold intensity and the qualitative assessment of odor quality. Given the importance of disorders of olfaction as primary disorders and as secondary complications to many important human diseases, effective tools to evaluate olfaction are critical clinical assessment tools. This paper provides a survey of the major diagnostic tests for olfaction and an evaluation of their overall validity and reliability. Introduction The earliest studies of olfaction began with the work of Valentin in 1848 and were developed further by Toulouse and Vaschide, and Zwaardemaker in the late 1800s and by Proetz in the early part of the 20th century (1).These early studies of olfactory anatomy and physiology incorporated tests to measure both qualitatively and quantitatively the sensory parameters of olfaction. Over the years, these tests were developed further to include assessments of olfactory sensitivity by means of odor detection and the recognition of specific odors, thresholds of identification and discrimination of different odors, odor memory, assessments of odor intensity scales, and discriminations of sensory pleasure associated with specific scents (2). Anatomy and physiology of olfaction The most distinctive feature of nasal anatomy is the dominance of the turbine bones (3, 4 and 5). Very little inspired air reaches the tissues of the nasal epithelium due to the blocking effect of the turbines. The olfactory epithelium is located at the apex of the nasal passages, and is the primary interface at which the tissue exchange of inspired gases, primarily oxygen and carbon dioxide, occurs (5). The olfactory epithelium is covered by a layer of mucous that is produced by Bowman’s gland (5). During this process the air reaches body temperature and becomes saturated with water vapor (5). The dust particles and other materials adhere to the nasal mucosa and then are swept by the hair-like cilia that line the mucosa to the pharynx (5). Some of this particulate material becomes trapped in the mucous produced by the mucosal tissue. The tissue components of the olfactory epithelium include receptor cells, basal cells and sustentacular cells (5). The receptor cells are sensory cells that share structural and functional similarity to the bipolar receptor cells of the retina (5). The exterior of these cells is encased with rigid cilia that are believed to function as the primary receptor of sensory input (5). The neural connections of the sensory receptor tissue of the cilia extend by means of axons through a structure called the cribiform plate to synapse with the olfactory bulb of the brain (5). The nasal passages are innervated by the trigeminal nerve which synapses with the trigeminal nucleus of the pons. The role of the sustentacular cells is to provide a structural framework for the receptor cells (5). Thousands of axons from the sensory receptor cells synapse with mitral and periglomerular cells in the glomerulus (6). The axons of the mitral cells comprise the lateral olfactory tract that carries sensory impulses to the brain where they interconnect with granular cells, which in turn synapse with centrifugal neurons (6). These synapse with the granule cells in the ipsilateral anterior olfactory nucleus and band of Broca of the contralateral olfactory bulb by way of the anterior commisure, ultimately synapsing with the periglomerular cells (5). The axons of the periglomerular cells conserve to interconnect separate glomeruli (5). In the brain, the olfactory cortex is the site of convergence of the olfactory neural extensions of the lateral olfactory tract (6). Neural fibers from the anterior olfactory connect with the medial forebrain bundle which extends further to the hypothalamus (6). Prepyriform cortical fibers connect the amygdale, the hypothalamus and the hippocampus. More recently identified connections extend to the orbitofrontal cortex from the amygdale and the prepyriform cortex (6). The sensory perception of odors is dependent on the duration of the odor, the volume of inspired odorant molecules and the speed of sniffing (7). The olfactory receptor is a primary bipolar neuron; there are approximately 100 million receptor neurons in the nasal passages (8). These receptors are re-generated every 30-60 days throughout one’s lifetime by the underlying basal cells. The olfactory receptors are found in the rigid cilia and are G-protein coupled receptors (GPCRs) that act as signal transduction messengers involved in the conversion of chemical odorant sensations to neural stimuli (7). There are approximately 300-400 different types of olfactory receptors with different sensory capacities (7). The chemical composition associated with specific odors activates a specific set of receptors which further results in the activation of the glomeruli in the olfactory bulbs (9). Each unique chemical structure associated with a specific odorant activates a specific pattern of excitation by utilizing distinct sets of receptors within the glomeruli to generate a unique signal pattern that is conducted to the brain via the neural tissue (9). Axons from the glomeruli travel to the olfactory cortex. There are 5 component parts of this structure, including the anterior olfactory nucleus that connects the two olfactory bulbs via the anterior commisure, the olfactory tubercle, the pyriform cortex, which is the primary site of odor interpretation, the cortical nucleus of the amygdala, and the entorhinal area that extends to the hippocampus (8). These latter regions appear to play a role in the affective components of odors (9). The process of olfaction begins with the inspiration of chemicals carried by the airflow into the nasal passages. Stimulus intensity is determined by the concentration of chemicals of any given type in the gas phase of the air molecules that reach olfactory epithelium the nasal passages (10). Sensory adaptation usually occurs when repeated inspirations of a particular odor or similar odors occur that results in reduced sensitivity of odor perception (10). There are many theories that have been proposed to explain the process of olfaction. Amoore 31 Beets 32 The stereo-chemical theory proposed by Amore and Beets states that specific shapes on olfactory receptor sites bind to complementary shapes of chemical structures that comprise odor molecules (11, 12). They further proposed that specific shapes correspond to primary odors that form the basis of the repertoire of sensations of smell detected by olfaction. Little direct evidence to support this theory has been experimentally validated (13). Another theory to explain olfaction suggested that odor molecules produce olfaction by penetrating the membrane of the receptor cell to induce depolarization (14). The efficiency of membrane depolarization by different chemical entities of odor molecules is the basis of differential odor sensations, according to this theory (14). Another theory to explain the process of olfaction , called the molecular vibration theory (15). This model of olfaction proposed that the vibrational frequency of odorant molecules is responsible for the sensation of different odors (14). In addition, the theory proposed that the intensity of odor is determined by the solubility properties of the molecule. Yet another model of olfaction, called the spatio-temporal model of olfaction, states that the pattern of molecular attachment to the receptors in the nasal epithelia are responsible for different sensations of odor quality (16). Etiology of olfactory dysfunction Disorders of olfaction may represent primary conditions or may occur secondarily to other pathological conditions in the body (17). Approximately three million people in the United States have been diagnosed with disorders of olfaction; however, this may represent a considerable underestimation given the difficulty in achieving a definitive diagnosis (18). This difficulty is attributed to the lack of reliable objective screening tools of olfactory function and a fundamental lack of understanding of the sensory process of olfaction (17). The inability to detect odor is called anosmia (18). This represents the most severe category of olfactory dysfunction. Less severe disorders of this sensory function include hyposmia, which refers to the deceased sensation of odor and dysosmia, which involves a distortion of responses to common odors (18). Several variant forms of dysosmia may occur, including parosmia involving an altered perception of foul smelling odors, phantosmia, a perception of odor where none is present (absence of a stimulus) and agnosia involving the inability to discriminate or distinguish between different odors (18). Ageusia is inability to taste (18). The primary disorders of olfaction may involve neural impairments that affect the sensorineural components of olfaction or conductive impairments that impede the flow of odorant molecules to the olfactory neuroepithelium (19). The most common causes of primary disorders of olfaction are sinus infections and diseases, upper respiratory infections (URIs) and physical trauma to the head that affects the nasal anatomy. Chronic inflammation of the nasal cavity is a major cause of conductive defects (19). Other causes of conductive defects include nasal polyps, inverting papilloma, and malignancies in this region. Rarely, developmental abnormalities may produce conductive deficits (20). These include encephaloceles, and dermoid cysts that obstruct the nasal passages. Surgical procedures such as laryngiectomies and tracheotomies may reduce the airflow to the nasal cavity (19). The primary causes of sensorineural defects are infections and chronic inflammation that affect the transmission of neural impulses from the olfactory bulb to the central nervous system (20). These infections may produce damage to the neuroepithelium which is proximal cause of this type of sensory deficit. Viral infections, sarcoidosis, Wegener granulomatosis and multiple sclerosis have all been associated with this type of sensorineural defect (20). Additionally, congenital defects may produce transmission defects (21). Kallman syndrome results from the developmental failure of ontogenesis of olfactory system (21). Disturbances of endocrine function, such as diabetes mellitus, hypothyroidism and hypoadrenalism may also contribute to sensori-neural defects (20). Physical damage resulting from head trauma due to injury, brain surgery of subarachnoid hemorrhages may affect sensori-neural function (20). The use of nasal x sprays containing zinc has also resulted in anosmia and has resulted in their removal from the consumer market (22). In addition, hyposmia may result due to degeneration of the CNS as normally occurs during the aging process or as a result of degenerative disease such as Parkinson’s Disease and Alzheimer’s Disease (22). Interestingly, the early onset of Alzheimer’s Disease may be presaged by a loss of the sense of smell (22). Given the importance of disorders of olfaction as primary disorders and as secondary complications to many important human diseases, effective tools to evaluate olfaction are critical clinical assessment tools. This paper provides a survey of the major diagnostic tests for olfaction and an evaluation of their overall validity and reliability. Results: survey of diagnostic tests for olfactory function One the most important and popular standardized tests of olfaction is the University of Pennsylvania Smell Identification Test (UPSIT) (23). The test involves the identification of 40 odorants presented to a subject as a multiple choice, four option format for each odor assessed. The test is assessed by the number of correct choices indicated by the study subject. This test is widely used due to its simplicity and the fact that comparative assessments with many other tests of olfaction indicate that the results have greater validity and reliability than most other diagnostic tests of olfaction (24). Another widely used forced-choice test is the modular smell identification test (MSIT), or the Cross-Cultural Smell Identification Test. (CC-SIT) (25). This test is essentially a shortened version of the UPSIT includes 12 questions and requires only 5 minutes for administration. The method of evaluation is also the same as for the UPSIT. The shortness of the test has been shown to affect both its reliability and validity in comparison with the UPSIT (24). The single ascending series of butanol odor detection threshold test consists of a series of dilute solutions of butanol which comprise the testing material (26). The forced-choice test provides for 2 choice alternatives for subject responses. The threshold measurement involves a determination of the lowest concentration odorant that is detectable by the subject correctly in 5 repetitive trials. Cain et al. (1988) and Stevens et al. (1988), (see Cain and Rabin, 1989). This is a useful test for hyposmia (27). The phenyl ethyl alcohol single staircase odor detection threshold test utilizes a chemical called phenyl ethyl alcohol, an odorant that smells similar to roses, for measurement of olfaction (28). A series of stepwise increments of odorant concentration of a dilution series ranging from -10log concentration to -2log concentration is administered to a study subject. The lowest concentration at which correct odorant identification is made in 5 consecutive trials is recorded by the experimenter. The mean of the responses is recorded as the threshold measure. Although more quantitative than the most commonly used test, the calculations are cumbersome and time-consuming. (29). Another type of olfaction test is the odor recognition memory test. This is a 12-trial test that assesses the ability of a subject to identify an odor based on four different choices that include the odor inspired by the subject prior to the test (30). The timing between the initial presentation of the target odor and the memory test is varied between 10, 30 and 60 second intervals. The number of trials within each time frame in which the target odor is correctly identified by the subject is the primary dependent measure of this test. The odor discrimination test involves 16 sets of odorants presented as microcapsules. In each set, two of the odorants are the same and one is different, all are screened to be of similar intensity. The different odor within each group must be identified by the subject. The number of correct identifications comprises the primary dependent measure. This test is useful for older patients, particularly those with degenerative diseases (31). 1 The Yes-No odor identification test involves 20 different odorants that are each presented twice to the subject (30,32). In one of the tests the odor corresponds to its descriptor; in the alternate presentation, it does not. The subject must correctly determine whether a given odorant matches its descriptor. The percentage of correct identifications is recorded. In addition, two single detection measures are recorded; the ‘d’ and ‘Cl’ . ‘d’ is a measure of signal sensitivity and ‘Cl’ measures the response bias (32). Suprathreshold Amyl Acetate Odor Intensity and Odor Pleasantness Rating Tests are used to determine subject responses to odor intensity and pleasantness (33). Sniff bottles containing different concentrations amyl acetate raincluding-1, -2, and -3 -4 log vol/vol increments are presented to the subject 5 times each in opposite order. The subject is asked to rank the intensity and pleasantness of each vial. The test uses a nine point category scale to record subject responses. The intensity measurements are 1-10 for no smell to extremely strong smell. The pleasantness scale also records categories 1-10, with 1 corresponding to extremely unpleasant to 10 which is extremely pleasant. Odor intensity measurements are calculated as the slope of the concentration/log transformation of intensity rank. The mean of the pleasantness scale was used as the dependent measure. The nominal scales used in this test may be subject to subject bias and variation (34). The “Sniffin Sticks’ test was named after the pen-like container that discharges the odorant chemicals for subject assessment (35). This olfaction test was designed to evaluate three components of olfaction: odor threshold, identification and discrimination. The odorant utilized in the threshold test is n-butanol which is presented to the subject in incremental concentration differences presented in 16 test pairs involving forced-choice responses. The odor-identification component utilizes 16 common odorant chemicals for subject identification and the odor discrimination component has the subject assess paired odorants. Each of these parameters involves forced-choice responses. The simplicity of this test makes it easy for clinicians to administer (34). The olfactory-evoked response is carried out to evaluate the physical responses of the patient by means of an electro-oculogram, which measures electrical potentials produced by olfactory responses (36). Standardization of responses is achieved by including visual tracking measurements to ensure constant levels of alertness and the administration of white noise to override auditory sensations. The olfaction test involves the administration of either carbon dioxide which acts as a trigeminal stimulant even though it has no perceptible odor or hydrogen sulfide using an olfactometer which ensures the constant rate of delivery of the odorant stimulus. Two major peak responses are assessed, N1 and P2. N1 corresponds to the first negative signal peak that is recorded and P2 is the second positive signal depression. Latencies are determined by these two values. This is the only major test of olfaction that directly measures sensory responses in the brain which provides a quantitative basis for response evaluation (36). Discussion The most commonly utilized test of olfaction in North America is the UPSIT and its modified version, the CC-SIT (37). This test was developed in 1984 and is one of the few olfaction tests whose reliability and validity have reviewed extensively. A rigorous comparative assessment of the UPSIT and the Connecticut Chemosensory Clinical Research Center Test (CCCRC) in 50 patients with olfactory dysfunction showed a correlation coefficient of 0.92 indicating significant agreement between the two tests of olfaction in regard to odor identification assessments in this group of patients (37). The data from the threshold component assessment components of these two tests did not correlate as well. When the stringency of assessment of threshold parameters of olfaction was increased, the correlation between the results of these two tests was significantly increased to 0.96. Other comparative assessments of the UPSIT and the CCCRC have produced similar results (38). Further evidence supporting the validity and the reliability of the UPSIT was provided in a comparative study with the quantitative physiological measurements provided by the Olfactory-Evoked Response Test (39). In comparison with the UPSIT, the Olfactory-Evoked Response Test less frequently indicated the presence of olfactory abnormalities in patients with diagnosed neurologic diseases affecting olfaction than the UPSIT. In the absence of research tools permitting the objective assessment of olfactory sensory function, clinicians must rely on the application of subjective patient responses to semi-qualitative measures of olfactory function. This impediment limits the effectiveness of diagnosis and clinical assessment of problems of hyposmia and anosmia (40). Although threshold tests and odor identification tests are routinely used in the assessment of patients with disorders of olfaction, their objective validation has been difficult to achieve and, therefore, is the subject of considerable controversy. Perception of odor intensity is often mathematically represented by the log function of odorant concentration (40). The slope is determined by the solubility of the odorant in water vapor. Measurements of stimulus intensity have been confounded by differences in individual perception and variability in the applications of quantitative measuring tools (40). Despite the prevalence of clinical assessment tools of olfactory function, clinicians report that in practice, few of these tests are used on a regular basis in patient diagnosis and assessment (34). Numerous reasons have been suggested for the underutilization of these olfactory diagnostic tests; among the most compelling are the lack of consistency of results, poor reliability and the absence of comparative normative data (31). Each of these reasons has limited the implementation of tests of olfaction in the clinic, with the result that diagnostic criteria to assess olfactory dysfunction have been seriously compromised (40). The reliability of clinical standardized measurements of olfaction has been questioned by many researchers as there are few quantification tools to address the validity and consistency of analytic measurements of olfaction (23). In these types of psychometric studies, it is essential to establish parameters of reliability in order to assess the validity of data measurements. References 1. Shepherd, GM. Olfactory bulb. In: Shepherd GM, editor. The Synaptic Organization of the Brain: Oxford Univ. Press, Oxford-New York. 1979:152-183. 2. Lohman AM, Lammers HJ. On the structure and fiber connections of the olfactory centres in mammals. In: Zotterman Y, editor. Progress in Brain Research: Sensory Mechanisms, Vol 23. New York: Elsevier 1967: 65-82. 3. Benignust VA, Prah JD. Olfaction: Anatomy, Physiology and Behavior Environmental Health Perspectives 1982; 44:15-21. 4. Schneider, R. A. Newer insights into the role and modifications of olfaction in man through clinical studies. Ann. N. Y. 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