xRead - Olfactory Disorders (September 2023)

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symptoms, 295 one study utilizing psychophysical testing found a higher prevalence of OD 30 days after infection in patients with mild or moderate disease when compared with those with severe COVID-19. 296 It has been hypoth esized that the damage to the olfactory pathway may be protective in preventing viral entry to the CNS. 297 There is some support from animal models for this theory; destruc tion of the OE before inoculation has been shown to pro tect against intracranial invasion in murine studies. 278 Sim ilarly, ablation of the OB can prevent CNS infection after nasal inoculation with a neurotropic coronavirus. 298 It is possible that post-COVID OD may be caused by disruption at many levels of the olfactory pathway; however, current evidence supports viral-mediated injury to the sustentacular cells, resulting in indirect injury to the OSNs or downregulation of receptors as the most likely mechanism in COVID-19–related anosmia. While recovery may occur quickly in most patients, ongoing disruption of the OE or persistent inflammation may account for more long-lasting loss. There is less evidence to support a neu rotropic pathway as playing a major role. The mechanism underlying parosmia, a prevalent symptom developing in the months after SARS-CoV-2 infection, is likely intimately related to the underlying mechanism of olfactory loss and is an area where further research is needed. C Head Trauma Olfactory impairment associated with traumatic injury (head trauma or brain injury) can be attributed to several mechanisms: (1) injury to the nasal cavity resulting in a conductive loss (blockage of airflow to the ORs); (2) injury to the olfactory nerves preventing olfactory signals from reaching cortical regions for odor processing (discrimina tion, identification); and (3) brain injuries including corti cal contusion and hemorrhage resulting from coup or con trecoup injuries or displacement of the brain within the cranial vault. In moderate to severe head injuries, severing of the olfactory nerves at the level of the cribriform plate may result in a total loss of smell function (complete anos mia). Head injury is one of the most common causes of post traumatic olfactory loss. In a US national study of 1281 adults, OF was found to be impaired in patients aged ≥ 40 years in 10.1% who reported loss of consciousness caused by head injury (n = 178) and 10.0% of those reporting seri ous injury to the face or skull (n = 203). 122 In a study of 114 children with head injuries, olfactory impairment was present in 12% of the cases. 299 Multiple studies have exam ined the overall occurrence of olfactory impairment fol lowing head injury, with reports ranging between 7% and 22%. 69,122,300–303

supported a route of viral entry through the OB with rapid invasion of the CNS. 281 A series of 37 MRI scans performed in hospitalized patients with COVID-19 reported signal abnormalities of the OB in 19% of cases. 282 Several case reports documented hyperintensity in the OB, which resolved on repeat imag ing 1 month later with subsequent loss of OBV 283–285 ; however, it was unclear whether this reflected transient initial edema or subsequent atrophy. Patients with PVOL have previously been found to have reduced volume in the OB and olfactory cortex. 254 One patient with persis tent COVID-19–induced OD had MRI performed before COVID-19 infection, which provided baseline volumes of her OB and confirmed significant atrophy of the OB in images performed 2 months after onset. 286 Positron emis sion tomography imaging found hypometabolism in the gyrus rectus in two patients with persistent COVID-19 OD. 287 While these studies have reported evidence of neu rotropism, atrophy, and hypometabolism, this may be an indirect consequence of loss of function at the level of the OE, and they do not provide direct proof of retrograde transport of SARS-CoV-2 into the OB. One of the first postmortem studies in a patient with severe respiratory COVID-19 disease and anosmia found extensive tissue damage within the olfactory nerve and intracytoplasmic viral inclusion bodies in the OB. 288 A larger postmortem series in preprint demonstrated that three of 32 OB samples were positive for SARS-CoV-2 RNA. 289 In contrast, a series of four postmortem stud ies failed to demonstrate injury to either the OE or OB, although it was not reported whether these patients reported olfactory deficits. 290 We are slowly gaining better understanding of how SARS-CoV-2 gains entry into the OSNs and the OB in the absence of ACE2 expression. SARS-CoV-2 may utilize basigin (CD147) and neuropilin-1 as docking receptors on intracerebral vascular endothelial cells in order to cross the blood-brain barrier, while a range of proteases including TMPRSS11A/B, cathepsin B and L, and furin have been shown to facilitate viral cell entry and replication. 291 Alter natively, the virus may gain entry through cerebrospinal fluid (CSF)–filled spaces in perineural nerve sheaths and then into the ventricular system. 292 Anosmia as a protective mechanism? The destruction of the OE is thought to be an unwanted consequence of direct infection of epithelial cells and injury caused by associated inflammation. The prevalence of olfactory loss appears to be higher in patients reporting a milder course of COVID-19 infection. 293,294 Although this may simply reflect recall bias in patients with more severe