key: cord-0880453-a2y3g5qd
authors: Beigi-khoozani, Atefeh; Merajikhah, Amirmohammad; Soleimani, Mahdieh
title: Magnetic Resonance Imaging Findings of Olfactory Bulb in Anosmic Patients with COVID-19: A Systematic Review
date: 2022-03-31
journal: Chinese Medical Sciences Journal
DOI: 10.24920/003982
sha: f54bba642beb6568aa758720154fd5728ab79aa6
doc_id: 880453
cord_uid: a2y3g5qd

Background Anosmia is one of the symptoms in individuals with SARS-CoV-2 infection. In anosmic patients, SARS-CoV-2 temporarily alters the signaling process in olfactory nerve cells and olfactory bulb (OB), which eventually damages the structure of the olfactory epithelium, leading to a permanent disorder in the olfactory pathway that this damaged structure is showed in MRI imaging Method Two investigators independently searched four databases consisting of PubMed, ProQuest, Scopus, and Web of Science for relevant records as of November 11, 2020 with no time, space, and language restrictions. Google Scholar was also searched for the related resources within the time limit of 2020. All the found articles were reviewed based on the PRISMA flow diagram. Qualitative studies, case reports, editorials, letters, and other non-original studies were excluded from this systematic analysis. Results Initial search yielded 434 records. After reviewing the titles and abstracts, we selected 74 articles; finally, 8 articles were depicted to be investigated and read in full text. The obtained results showed an increase in the width and volume of the olfactory cleft (OC), complete or partial destruction of OC, and complete occlusion of OC in COVID-19 patients. Deformation and degeneration as well as a subtle asymmetry were evident in the OBs. Computed tomography (CT), meganetic resonance imaging (MRI), and positron emission tomography (PET) were used to detect the outcomes of anosmia in these studies. Conclusions The changes in OC are greater than those in OB in patients with COVID-19, mainly due to the inflammatory and immune responses in OC. However, fewer changes in OB are due to neurological or vascular disorders. Topical steroid therapy and topical saline can be helpful.

SARS-CoV-2, the virus that causes the coronavirus disease 2019 (COVID- 19) , was first detected in Wuhan, China, and then worldwide [1] . On March 11, 2020 , the World Health Organization (WHO) declared COVID-19 a pandemic [2] . The typical clinical manifestations of COVID-19 include fever, muscle or joint pain, loss of smell (anosmia) and taste [3] , and respiratory symptoms [1] . An early report in the Republic of Korea showed that about two-thirds of COVID-19 patients experienced March 2022 Chinese Medical Sciences Journal 24 being exposed to SARS-CoV-2 or its variants [11] .

Generally, angiotensin-converting enzyme 2 (ACE2) is abundant in the epithelium of the oral and nasal mucosae [12, 13] . Covered by olfactory neuroepithelium, the olfactory cleft (OC) is located between the middle turbinate and the nasal septum [14] . ACE2 and transmembrane protease serine 2 (TMPRSS2) work in stem cells residing in the olfactory epithelium and in vascular cells in the nose and olfactory bulb (OB) [15] .

SARS-CoV-2 can enter the host body through respiratory mucosa or other mucosal surfaces [1] . Using its spike proteins (protein S), the virus enters human cells and binds to ACE2 in the target cells [16] . Therefore, due to the high concentrations of ACE2 and TMPRSS2 in OC and the tendency of SARS-COV-2 to bind to these receptors, the virus is transmitted through the nose to the brain [17] [18] [19] [20] [21] . Damage to the olfactory system can be the result of a local infection in the supporting cells that causes a temporary alteration in the signaling process in olfactory neurons and OBs, or the damage can hurt the entire structure of the olfactory epithelium and cause permanent disorder in the olfactory pathway [15] . These disorders impair the ability of patients to smell food and the environment and lower the quality of life associated with social interactions, eating, and well-being [22] . The extent to which the loss of smell and taste after SARS-CoV-2 infection is due to OC edema, structural deformation of the olfactory neuroepithelium, or direct invasion of the olfactory nerve pathways remains controversial [10, 23] .

Magnetic resonance imaging (MRI) of OB is useful for evaluating patients with anosmia/hyposmia [24] . In patients with severe COVID-19, MRI may reveal the damaged OB structure that leads to local inflammatory response [25] . Brain MRI performed on anosemic COVID-19 patients shows that the anosmia may be due to central olfactory system abnormalities [26] . Furthermore, in a study in which patients underwent neuroimaging, 7 out of 37 patients were found to have OB abnormalities [27] . In 

The full texts of the eligible articles were examined.

Two researchers extracted the data include magnetic resonance imaging results of OB separately.

In the initial search, a total of 434 articles were found In the articles included in the study, the MRI reveale increased width and volume of OC, complete bilateral or partial destruction of OC, complete obstruction of OC, as well as subtle deformation, degeneration, and asymmetry in OB. Aragão MFVV, et al [32] Retrospec- Brookes N, et al [33] Case series 4

University of Pennsylvania Smell Identification Test (UPSIT)

In two cases, MRI showed normal OB and cribriform plates, along with minimal mucosal thickening in the ethmoid sinuses.

Coolen T, et al [34] Prospective, showed deformation and degeneration of OB and emphasized that the high rate of OB degeneration was due to direct/indirect damage to the pathway of olfactory neurons. It is also particularly one of the reasons that can be attributed to patients with prolonged anosmia [31] . In general, the causes of anosmia can be classified into two groups: a) loss of conductive or sensorineural olfactory, which is a conduction disorder associated with the destruction of the airway in the nose; and b) damage of the sensorineural pathway, which is related to olfactory epithelium with longer lasting effects until it heals [42] .

In another study, OB enlargement was shown in the second stage of MRI, although there was no change in OB during the one-month follow-up. Eventually, the OB change was considered to be due to the invasion of SARS-COV-2 into the brain by the cribriform plate, which is close to OB and the olfactory epithelium [29] . Based on the available evidence, the virus mainly affects the cerebral cortex and hypothalamus [43] .

On the other hand, there were studies that did not show significant changes in OB. Niesen et al. (2020) found only three out of 12 COVID-19 patients showed subtle asymmetry in OB, so they considered that the development of severe anosmia in these patients was not due to the changes in OB and OB disorder was not involved in olfactory loss [30] . OB changes on MRI can be attributed to infection of vascular pericytes in OB, as ACE2 is expressed there [15] . On the other hand, Cao et al. (2019) showed that the receptor of ACE2 gene polymorphism in Asian and European populations can cause disease in patients with different periods [44] . In addition, in this regard, a study showed that there was no significant difference in OB volume in patients with COVID-19 [28] . However, studies conducted so far have shown that OB volume decreased due to damage to olfactory receptor in post-viral anosmia [45, 46] . Laurendon et al. revealed the increase in OB volume was associated with COVID-19. It was also shown that the volume and the intensity of the MRI signal returned to normal on the 24th day of the disease. Notably, there was no significant change in OB and signal in COVID-19-related anosmia [47] . According to the existing hypotheses, disruption in signaling to OB in the early days can be attributed to infection of sustentacular cells, which leads to disruption in signaling from olfactory sensory neurons to OB, and the sustentacular cells support the olfactory sensory neurons by maintaining ion balance.

Thus, when these cells are destroyed by infection, CILIA of the olfactory sensory neurons is destroyed and signal transmission is disrupted [48] .

The most common treatments for OD include: a)

Olfactory training: it includes frequent and intentional inhalation of a set of smells (usually lemon, rose, clove, and eucalyptus) for 20 seconds each time, at least twice a day for at least 3 months (or more if possible) [49] . b) Nasal lavage with saline [50] : medications that have shown to be effective in treating post-infectious OD also consist of intranasal vitamin A, which may enhance olfactory neurogenesis, intranasal sodium citrate, which seems to moderate olfactory receptor transduction cascades, and systemic Omega-3, which may function as anti-inflammatory or neurodegenerative [49] . c) Nasal or oral corticosteroids [50] : a recent study showed that oral prednisolone consumption after the course of the disease, when the PCR test is negative, can be effective in improving anosmia [51] .

Oral steroids are commonly used to treat anosmia. However, these drugs may impair the immune system and thus their use needs to be individualized [52] . As the exact cause of anosmia in COVID-19 patients is still unknown, there is no concesus on its definitive treatment [51] . In some studies, corticosteroids are not recommended for people with post-infection OD. However, for patients who have been taking intravenous or intranasal steroids before COVID-19, such therapies should be continued [49] . Plasma therapy is not effective in treating anosmia [48] .

A major limitation of our current study was that documented evidence in case reports was ruled out in this systematic review.

To sum up, as shown by MRI of the olfactory system in patients with COVID-19, the changes that happened in the OC due to COVID-19 are greater than those in the OB and can be attributed to inflammatory responses, immune responses, or the abundance of the olfactory epithelium in the OC structure, whereas small changes or no change in OB due to anosmia in these patients can be attributed to neurological or vascular disorders.

The authors disclosed no conflicting interest.

AB is the author of the letter structure and the second resource researcher; AM is the scientific author and owner of the idea letter; MS is the resource researcher.

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