xRead - Olfactory Disorders (September 2023)

20426984, 2022, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/alr.22929, Wiley Online Library on [04/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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with rhinosinusitis. 1056,1657 MRI is useful to diagnose OD caused by skull base disease. 1658 MRI is also useful to eval uate olfactory sulcus depth, OBV, and bulb and nerve mor phologies, which may provide diagnostic information on different causes of OD. 1053 However, it is sometimes diffi cult to exclude the possibility of OD because of airflow lim itation related to mild rhinosinusitis, previous mild head trauma, otherwise asymptomatic viral infection, and early neurodegenerative diseases, from the “idiopathic” olfac tory loss category—even using these modalities. It has been reported that a short course of oral steroid administration is useful to differentiate conductive olfactory loss; however, we know this may help with sensorineural loss as well. 137 Future improvement in testing methods using new technologies such as radioiso tope transport, 1067 biochemical analysis of olfactory mucus, ,183,1659 and technologies currently in development, may contribute to the establishment of improved classifi cation of OD based on more accurate pathophysiology. While the variety of insults causing OD are well cat egorized, different individual responses remain poorly understood. 1660 Among the most common causes of OD are rhinosinusitis, head trauma, presbyosmia, and postvi ral olfactory disorder. If nasal obstruction is excluded, mechanisms may be considered to be sensorineural, but causes can vary widely. For instance, there is evidence for “wear-and-tear” changes or patches of respiratory metaplasia occurring in the OE in presbyosmia, 162,1661 but related pathology in the OB or cortex may be contributory. 1662 Also, mechanisms underlying respira tory metaplasia are not clear: is this caused by failed epithelial reconstitution, or neurogenic exhaustion, and is it permanent? Analogous questions occur with postviral loss, which is associated with a large number of viruses, impacting different cell populations or triggering varying immune responses. SARS-CoV-2 poses additional ques tions, as sustentacular cells are the target, 268 and the clin ical picture ranges from no symptoms to fatal disease, with many patients exhibiting brief anosmia and others remaining hyposmic or parosmic longer term. The range of pathogens or injuries, coupled with the specific cellular targets and varying host immune responses pose a chal lenge for understanding the degree and duration of sensory dysfunction, and for developing the appropriate therapeu tic approaches. Research into these various mechanisms by which individuals become hyposmic will better delineate why some appear to be more susceptible than others to the same insult. 2 Relative susceptibility and underlying mechanisms

Knowledge gaps We need better animal models and understanding of what happens on a cellular level and olfactory system level in nonsinonasal inflammation–related causes of OD. Rodent models have provided a wealth of knowledge regarding olfaction, yet gaps remain. Disorders thought to result from direct damage to the OE have been mod eled in rodents using intranasal chemicals or systemic drugs. 273,1663 Following chemical damage, olfactory epithe lial reconstitution and axon projection to the OBs may be assessed. Olfactory bulbectomy may model central injuries marked by olfactory neuron degeneration, and weight drop or blast-injury models have also been useful for post head trauma olfactory modeling. 1664 Genetic models to test cell type–specific gene knockout, to target toxins to spe cific cell types, or to induce ciliopathy may test gene func tion or model certain diseases. For instance, anosmia is a hallmark of ciliopathy disorders, since ORs are expressed on the cilia membrane of olfactory neurons. Ciliopathy mice have permitted the successful testing of a viral gene therapy for a loss-of-function mutation in a cilia trans port gene. 1665 Nonetheless, better models for other disor ders are needed to understand the causes and to test thera pies. Recent rodent viral infection models may improve the understanding of classical postviral olfactory disorder, and models directing expression of specific viral entry genes on cell populations of interest will help us understand aspects of hyposmia associated with the novel coronavirus. 248 How culture and literacy affect some psychophysical test results a. Developing more clinically accessible, truly objective, quantitative tests As noted in above, there are hundreds of different psy chophysical olfactory tests. While these tests have been invaluable in gaining quantitative measures to compare against patients’ subjective complaints, there are some assumptions that are necessarily made when this type of testing occurs. Some smell tests have been adapted to different countries and cultures, so that the odors pre sented are familiar to patients, whereas some others have not. 1666–1669,804 Above and beyond this is that when a test is given to a patient to self-administer, as many of these tests are in a busy clinical practice, an assumption of literacy has been made. While it is likely that the majority of patients in first-world countries may be literate, shame and embar rassment will often prevent that important minority of patients from telling their providers about their illiteracy, B Clinical Assessment 1