key: cord-0992968-rzommy5p authors: Thomas, Davis; Baddireddy, Sita Mahalakshmi; Kohli, Divya title: ANOSMIA - A REVIEW: IN THE CONTEXT OF COVID 19/OROFACIAL PAIN date: 2020-07-01 journal: J Am Dent Assoc DOI: 10.1016/j.adaj.2020.06.039 sha: 446bc886991c05199f6ae548a7833602bee4951e doc_id: 992968 cord_uid: rzommy5p ABSTRACT Background Anosmia/hyposmia is a relatively rare sensory disorder that could indicate an underlying more serious cause. In the context of the current COVID 19 pandemic, this could be one of the red flags for the dental practitioner in terms of screening potential COVID 19 patients. Methods The authors searched electronic databases with regards to anosmia/hyposmia and their relation to local and systemic causes. Results The authors found articles relating to the physiology and significance of normal olfaction, etiology, and pathophysiology of olfaction and disorders of the same. Also, we found the most recent literature of anosmia/hyposmia linked to early symptoms of this pandemic. Conclusions Anosmia/hyposmia is most likely indicative of a local or systemic pathology affecting the olfactory system. Recent evidence suggests the importance of this as related to the new global pandemic of COVID 19. Practical Implications The dental professional must be cognizant of the fact that anosmia/hyposmia could indicate a more serious underlying local or systemic issue. In the coming months of the new reality of COVID 19, dental practitioners have an additional role of potential early screening of these infections. Olfaction is the sense of smell. It is one of the chemical senses. It involves the detection of chemical stimuli and conversion of these stimuli into electrical energy for perception by the central nervous system. 1 Apart from playing a role in the determination of flavor of food and beverages, olfaction has a role in acting as an early warning system to detect hazards. Reduction of olfactory function has been shown to be associated with loss of appetite, consumption of bad food and in many people problems with cooking. 2 It has been hypothesized that olfaction aids in possible avoidance of food poisoning. 3 Olfaction also plays a significant role in the process of enjoyment of food. The majority of information regarding the flavor of food is thought to come from olfaction. 4 Lack of proper olfaction has also been associated with weight loss and weight gain. 5, 6 The sense of smell is reported in the literature as connected to emotions, either positive or negative. 7 The quality of life is significantly reduced in patients with olfactory disorders. 8 In recent literature, olfactory disorders have been prominent features which can be possible early signs of early neurodegenerative diseases. 9 Most recently, loss of this sensation has been attributed to be one of the first presenting symptom in corona virus infection . 10 This article is intended to highlight the basic principles underlying the physiology and pathophysiology of olfaction and its possible relationship with disease entities. We also look at the significance of olfaction as it related to dentistry and orofacial pain. Chemosensation of olfaction is mediated by the cranial nerves CN-I (olfactory) and CN-V (trigeminal nerve). 11 CN-I is responsible for olfaction while CN-V mediates general sensory innervation including chemosensation. The olfactory epithelium present in the superior part of the nostrils contains olfactory cells which are the receptor cells for olfaction. 12 An action potential (AP) is generated when the odorant molecule binds to the olfactory receptor. 13 The AP is carried by the axons of these primary afferent neurons to the olfactory bulb (OB), where the synapsing with second order neurons occurs. 14 Anatomically OB is positioned over the cribriform plate of the ethmoid bone. These second order neurons form the olfactory tract carrying these signals to the higher centers in the brain. 15 These centers include the primary and secondary olfactory cortices. 16 Figure 1 shows the gross structures involved in olfaction and olfactory pathways. Olfaction disorders may be classified as congenital or acquired. Being born with an olfactory disorder is rare. 8 Quantitatively, olfactory disorders can be divided into anosmia, hyposmia, and hyperosmia. Anosmia is the inability to perceive odors. It includes total anosmia which is an inability to perceive all odors, and partial anosmia, which is an inability to perceive some but not all odors. Reduced ability to smell is termed hyposmia. Enhanced ability to smell is termed hyperosmia, which is relatively rare. 17 Disorders of olfaction can be qualitatively categorized as paraosmia and phantosmia. 18 Distorted smell perception in the presence of odorant is dysosmia or paraosmia. 19 In particular, when this perception is fetid, it is referred to as cacosmia. 16 Phantosmia refers to the perception of an odorant in the absence of one. It is a form of olfactory hallucination. 20 Figure 2 shows the classification of olfactory disorders. Some recent literature has attempted to classify the degree of anosmia/ hyposmia as mild, moderate, severe (for hyposmia) and total anosmia amongst populations of patients who experienced hazardous events because of the smell disorder. 21 The risk for hazardous events increased proportionately with an increase in the degree of olfactory impairment. 22 Based on quantitative olfactory test, the overall prevalence of olfactory dysfunctions has been variedly reported as approximately 20-25% in earlier studies. 23, 24 More recent studies place the overall prevalence at an average of 20% and prevalence in older persons at an average of 40%. 25 Based on the etiology, these disorders can be categorized as local or systemic. Olfactory disturbances most commonly occur due to local nasal diseases. These can prevent odorant from reaching the nasal epithelium due to conductive and inflammatory issues. This includes polyposis, seasonal rhinitis, allergic rhinitis, sinusitis, trauma or malignancy of the nose, paranasal sinuses, or nasopharynx. [26] [27] [28] [29] [30] [31] Numerous systemic factors are known to be associated with disorders of olfaction. Many infections such as bacterial, viral, and fungal have been known to be associated with smell disorders. [32] [33] [34] Trauma involving the head has been associated with olfactory dysfunctions. 35, 36 Abnormalities of olfaction are involved in several neurologic conditions. Olfactory dysfunctions including aura have been documented with epilepsy. [37] [38] [39] Literature has shown the presence of olfactory dysfunctions with migraine episodes. 40 The association of osmophobia with migraine is well documented in the literature. Some odors have been reported to be triggers for migraines. 41, 42 To a lesser extent migraine can also be associated with phantosmia and cacosmia. 43 Olfactory disorders are seen in patients with multiple sclerosis. 44 As the disease progresses, olfactory function impairment increases. 45 Neurodegenerative (ND) diseases including Parkinson's and Alzheimer have been associated with olfactory dysfunctions. Studies have suggested that olfactory disorders could be an early indicator of these ND diseases. 46, 47 Several endocrinological disease entities have been documented to have an association with olfaction disorders. Diabetes, Addison's disease, Cushing syndrome, and hypothyroidism are some of the endocrine diseases associated with smell dysfunctions. [48] [49] [50] [51] Chronic renal disorders and their relation to dysfunctions of olfaction including hyposmia and anosmia have been documented in the literature. 52, 53 Olfactory functions are altered in liver diseases as well. 54 Certain drugs such as antibiotics and antidepressants have been known to cause olfactory dysfunction. [55] [56] [57] [58] [59] Table 1 shows the etiology of olfactory disorders. The sensory innervation to oral, perioral, nasal structures comes predominantly from the trigeminal nerve. 60 The trigeminal and olfactory systems are distinct yet interrelated entities in the nasal cavity. 61 Most chemosensory stimulants on entering the nasal cavity produce olfactory and trigeminal sensations. 62 The stimulation of the trigeminal nerve by such stimulants can produce different sensations like burning, prickling, stinging, etc. 62 There is ample evidence that the trigeminal nerve works concurrently with the olfactory nerve to bring about perception of smell. 63 Variations in trigeminal nerve sensitivity have also been reported to coexist in patients with olfactory disorders. 64 Relation to taste: Taste, smell, and touch contribute to providing the flavor of food/beverages. 65 Olfaction plays a major role in the perception of flavors. A neurological connection between smell and taste sensations is well documented in the literature. 66 Olfaction via particular retronasal passages are involved in the perception of taste/flavor. 2, 67 In the process of mastication, volatile molecules from the food travel to the nasal cavity through the posterior part of the oral cavity. This is responsible for the phenomenon of retro nasal olfaction. 68 Dysgeusia is an altered perception of taste in response to a tastant stimulus. Phantogeusia is unpleasant taste due to a gustatory hallucination (in the absence of any stimulus). 69 Olfactory dysfunctions have been known to affect gustatory function. 70 Often patients presenting with taste disorders have olfactory disorders rather than gustatory dysfunction. 71, 72 Patients may not be completely aware of the presence and/or severity of anosmia/hyposmia. 73 Patients tend to consult the dentist if they perceive a disordered taste sensation. Dental practitioners must be aware of this fact. Protective nature of olfaction Compared to other mammals and lower animals evolutionarily humans have lost a good percentage of our strength of olfactory senses. 74 It is conceivable that humans use olfaction to detect the relative quality of the food that is about to be consumed. We use the sense of smell to become "sense of protection" to check if the food is suitable for ingestion. Literature suggests approximately 50% of the patients with olfactory dysfunctions may eat rotten food while approximately 30% could eat burnt food, possibly causing food poisoning. 3 This points to a possible protective nature of olfaction as related to sustenance of life. It has to be taken into consideration that olfaction alone might not serve this protective function fully but in conjunction with other senses such as gustation. Anosmia/ hyposmia has been known to induce potentially deleterious habits of consumption, such as excessive eating of sweet and fat food. Burning mouth syndrome (BMS) is a pain condition classically described as coexisting with taste alterations. Taste disturbances are present in approximately 70 % of BMS patients. 75 Literature suggests patients with BMS can exhibit varied taste disturbances such as dysgeusia and ageusia, which can occur as alteration on taste perception or persistently altered taste or both. 76, 77 However there are relatively recent reports of concomitant alterations in olfaction as well. Studies have shown the olfactory threshold to be higher in BMS patients compared to controls. 78, 79 BMS patients are proposed to have reduced capability of identifying odors compared to control. 80 Odors have been shown to induce changes in perception of taste. 81 The interaction between trigeminal, olfactory, and gustatory systems has also been proposed in the literature with regards to the pathophysiology of BMS. 79 It has been well documented in the literature that olfactory dysfunctions coexist with abnormalities in thresholds for pain, tactile sensation, temperature perception and gustation. 79 The brain center responsible for convergence of impulses from the olfactory and gustatory pathways is the orbitofrontal cortex. 82, 83 Pain syndromes such as BMS and dysfunctions of olfaction have similarities in that, both these entities are affected/modulated by same/similar centers in the brain. Complex interactions exist among the immune system and the olfactory system. Changes in the immune system can affect olfaction. 84 Sjogren's syndrome (SS) is an autoimmune disease affecting multiple organ systems including salivary and lacrimal glands. Impaired smell and taste are common symptoms reported by SS patients. 80, 85 In patients with SS there is a reduction in olfactory acuity. By and large, this is related to generalized hyposmia in these patients. There is no definitive inability to recognize or detect any specific odor in these patients. 86 Mechanisms involved in olfactory changes of SS include decreased mucin (an odorant carrier), recurrent rhinosinusitis, septal ulcerations, crustings, and immunological mechanisms. 80, 84 Pathogens like bacteria and viruses are known to cause olfactory disturbances. 87, 88 The most common causes are local nasal infections and upper respiratory diseases. Chronic sinusitis patients complain of pain, and persistent smell loss even after medical or surgical treatment. 28 Viral infections are hypothesized to cause damage to the olfactory epithelium. 89, 90 Olfactory dysfunctions like anosmia/hyposmia are common during severe upper respiratory infections and persist long after the other symptoms have resolved. 91 Detection of the virus in patients with post-viral infections could indicate the role of the virus in olfactory dysfunction. 92 The mechanism underlying olfactory dysfunction in infections is controversial. It could be the result of a conductive problem (preventing air from reaching the olfactory neuroepithelium), or it could be nasal inflammation (inhibiting function). 16 There is some evidence that post-viral anosmia may be centrally mediated where there is a decreased metabolism of certain regions of the brain where olfactory information is perceived. 93 This post-viral anosmia is also poorly responsive to treatment although anti-inflammatory medications or steroids are beneficial in some cases. 91 The current Coronavirus 2019 (COVID 19) pandemic has prompted researchers to look into the association of this new infection to anosmia. It is caused by a new Severe Acute Respiratory Syndrome SARS-CoV-2 coronavirus strain. 94 In addition to the common clinical features such as dry cough, fever, sore throat, shortness of breath, and headache, there are several recent reports of anosmia/hyposmia associated with this condition. [95] [96] [97] [98] Very much like viral infections discussed above, recent studies from 2020 showed the presence of olfactory dysfunctions in COVID patients. 97 The earliest reports of anosmia occurring in COVID 19 patients came in February 2020. 99, 100 Since these reports, there have been others describing new-onset anosmia that occurs concomitantly with COVID 19. It is the belief of the scientific community that olfactory dysfunction is potentially an early symptom of COVID infection. 101 The "new loss of smell" was added by the Centers for Disease Control and Prevention (CDC) to the symptom list (the symptoms starting within 2-14 days of COVID 19 exposure). 102 The prevalence of olfactory dysfunction is reported to be an average of 50 % in COVID 19 infected patients. 103 Anosmia is being considered as a marker for COVID 19 infection by reputed international medical entities such as the British Association for otorhinolaryngology. 104 In addition, there is also a suggestion that patients with new-onset anosmia, even though they are asymptomatic, quarantine themselves in anticipation of the possible onset of COVID 19. This might help in reducing the further communal spread of the infection. 105 It has been hypothesized that the two possible routes of entry of COVID 19 virus into the central nervous system is either through the circulation or across the cribriform plate of ethmoid bone (the site of olfactory nerve entry). 106 Two medications used in orofacial pain management, ibuprofen (for inflammatory pain) and renin-angiotensin system (RAS) blockers (Angiotensin Converting Enzyme, ACE inhibitors for prophylactic treatment of migraine), have come into the very recent literature with the hypothesis that they facilitate or worsen the effects of COVID 19 infection. 107 However other recent articles have questioned this, and disputed any such role these drugs play. 108 Redeployment/ reassignment of practicing pain physicians in the backdrop of the pandemic has further put significant constraints on access to care for chronic pain patients. 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