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A Systematic Review of Imaging Studies in Olfactory Dysfunction Secondary to COVID-19

Published:August 29, 2021DOI:https://doi.org/10.1016/j.acra.2021.08.010

      Rationale and Objectives

      Hyposmia/anosmia is common among patients with coronavirus disease-2019 (COVID-19). Various imaging modalities have been used to assess olfactory dysfunction in COVID-19. In this systematic review, we sought to categorize and summarize the imaging data in COVID-19-induced anosmia.

      Material and Methods

      Eligible articles were included after a comprehensive review using online databases including Google scholar, Scopus, PubMed, Web of science and Elsevier. Duplicate results, conference abstracts, reviews, and studies in languages other than English were excluded.

      Results

      In total, 305 patients undergoing MRI/functional MRI (177), CT of paranasal sinuses (129), and PET/CT or PET/MRI scans (14) were included. Out of a total of 218 findings reported on MRI, 80 were reported on early (≤ 1 month) and 85 on late (>1 month) imaging in relation to the onset of anosmia. Overall, OB morphology and T2-weighted or FLAIR signal intensity were normal in 68/218 (31.2%), while partial or complete opacification of OC was observed in 60/218 (27.5%). T2 hyperintensity in OB was detected in 11/80 (13.75%) and 18/85 (21.17%) on early and late imaging, respectively. Moreover, OB atrophy was reported in 1/80 (1.25%) on early and in 9/85 (10.58%) on late imaging. Last, among a total of 129 CT scans included, paranasal sinuses were evalualted in 88 (68.21%), which were reported as normal in most cases (77/88, [87.5%]).

      Conclusion

      In this systematic review, normal morphology and T2/FLAIR signal intensity in OB and OC obstruction were the most common findings in COVID-19-induced anosmia, while paranasal sinuses were normal in most cases. OC obstruction is the likely mechanism for olfactory dysfunction in COVID-19. Abnormalities in OB signal intensity and OB atrophy suggest that central mechanisms may also play a role in late stage in COVID-19-induced anosmia.

      Key Words

      INTRODUCTION

      Hyposmia/anosmia is relatively common among patients with coronavirus disease-2019 (COVID-19), both as an isolated symptom or concomitant with other systemic or respiratory symptoms (
      • Mao L
      • Jin H
      • Wang M
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      ,
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ). Olfactory dysfunction may present as an alteration in the intensity of perceived odor or in odor quality. While hyposmia/anosmia is a frequent symptom associated with COVID-19, it is usually transient, and spontaneously resolves within a few weeks (
      • Mao L
      • Jin H
      • Wang M
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      ,
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ).
      The first step in the olfactory perception is activation by odorants of sensory neurons that are located in the olfactory epithelium. This sensory epithelium is located in the olfactory clefts (OC), which are two narrow passages at the upper part of the nasal cavities (
      • Strauss S
      • Lantos J
      • Heier L
      • et al.
      Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.
      ). The olfactory receptor neurons originating from the OC cross the cribriform plate to reach the olfactory bulb (OB) (
      • Strauss S
      • Lantos J
      • Heier L
      • et al.
      Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.
      ). The exact pathophysiology of COVID-19-induced anosmia is not fully understood (
      • Mao L
      • Jin H
      • Wang M
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      ,
      • Huang C
      • Wang Y
      • Li X
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      ,
      • Strauss S
      • Lantos J
      • Heier L
      • et al.
      Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.
      ). Various imaging modalities have been used to assess the olfactory dysfunction in COVID-19, mainly by imaging OB and OC, such as with magnetic resonance imaging (MRI) (
      • Politi LS
      • Salsano E
      • Grimaldi M.
      Magnetic resonance imaging alteration of the brain in a patient with coronavirus disease 2019 (COVID-19) and anosmia.
      ,
      • MdFVV Aragão
      • M Leal
      • Cartaxo Filho O
      • et al.
      Anosmia in COVID-19 associated with injury to the olfactory bulbs evident on MRI.
      ,
      • Chiu A
      • Fischbein N
      • Wintermark M
      • et al.
      COVID-19-induced anosmia associated with olfactory bulb atrophy.
      ,
      • Corrêa DG
      • da Cruz Jr LCH
      • Lopes FCR
      • et al.
      Magnetic resonance imaging features of COVID-19-related cranial nerve lesions.
      ,
      • Eliezer M
      • Hamel A-L
      • Houdart E
      • et al.
      Loss of smell in patients with COVID-19: MRI data reveal a transient edema of the olfactory clefts.
      ,
      • Hatipoglu N
      • Yazici ZM
      • Palabiyik F
      • et al.
      Olfactory bulb magnetic resonance imaging in SARS-CoV-2-induced anosmia in pediatric cases.
      ,
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ,
      • Schönegger CM
      • Gietl S
      • Heinzle B
      • et al.
      Smell and taste disorders in COVID-19 patients: objective testing and magnetic resonance imaging in five cases.
      ,
      • Strauss S
      • Lantos J
      • Heier L
      • et al.
      Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.
      ,
      • Wang E
      • Ulualp SO
      • Liu C
      • et al.
      Sudden anosmia and ageusia in a child: a COVID-19 case report.
      ,
      • Chetrit A
      • Lechien JR
      • Ammar A
      • et al.
      Magnetic resonance imaging of COVID-19 anosmic patients reveals abnormalities of the olfactory bulb: preliminary prospective study.
      ,
      • Yousefi-Koma A
      • Haseli S
      • Bakhshayeshkaram M
      • et al.
      Multimodality imaging with PET/CT and MRI reveals hypometabolism in tertiary olfactory cortex in parosmia of COVID-19.
      ,
      • Tsivgoulis G
      • Fragkou PC
      • Lachanis S
      • et al.
      Olfactory bulb and mucosa abnormalities in persistent COVID-19-induced anosmia: a magnetic resonance imaging study.
      ,
      • Li C-W
      • Syue L-S
      • Tsai Y-S
      • et al.
      Anosmia and olfactory tract neuropathy in a case of COVID-19.
      ,
      • Laurendon T
      • Radulesco T
      • Mugnier J
      • et al.
      Bilateral transient olfactory bulb edema during COVID-19–related anosmia.
      ,
      • Liang Y-C
      • Tsai Y-S
      • Syue L-S
      • et al.
      Olfactory bulb atrophy in a case of COVID-19 with hyposmia.
      ,
      • Theodorou DJ
      • Theodorou SJ
      • Tsaggou V
      • et al.
      Anosmia caused by ischaemic olfactory infarction: false alert for COVID-19 infection.
      ,
      • Melegari G
      • Rivi V
      • Zelent G
      • et al.
      Mild to severe neurological manifestations of COVID-19: cases reports.
      ,
      • Niesen M
      • Trotta N
      • Noel A
      • et al.
      Structural and metabolic brain abnormalities in COVID-19 patients with sudden loss of smell.
      ,
      • Eliezer M
      • Hautefort C
      • Hamel A-L
      • et al.
      Sudden and complete olfactory loss of function as a possible symptom of COVID-19.
      ,
      • Ismail II
      • Gad KA.
      Absent blood oxygen level–dependent functional magnetic resonance imaging activation of the orbitofrontal cortex in a patient with persistent cacosmia and cacogeusia after COVID-19 infection.
      ,
      • Galougahi MK
      • Ghorbani J
      • Bakhshayeshkaram M
      • et al.
      Olfactory bulb magnetic resonance imaging in SARS-CoV-2-induced anosmia: the first report.
      ,

      Politi LS, Grimaldi M, Balzarini L. MRI depicts olfactory bulbs and cortical involvement in COVID-19 patients with anosmia. MAGNETOM Flash; 2021;78(1)

      ,
      • Hajjij A
      • Benslima N
      • Aasfara J
      • et al.
      An MRI of the olfactory tract in a case of post-COVID-19 persistent anosmia.
      ,
      • MdFVV Aragao
      • MdC Leal
      • Andrade PHP
      • et al.
      Clinical and radiological profiles of COVID-19 patients with neurological symptomatology: a comparative study.
      ), computed tomography (CT) of paranasal sinuses (
      • Lechien JR
      • Michel J
      • Radulesco T
      • et al.
      Clinical and radiological evaluations of COVID-19 patients with anosmia: preliminary report.
      ,
      • Naeini AS
      • Karimi-Galougahi M
      • Raad N
      • et al.
      Paranasal sinuses computed tomography findings in anosmia of COVID-19.
      ,

      Yıldız E, Balcı A, Selendili O, Kuzu S. Covid 19 pandemic: paranasal diagnostic imaging in patients with olfactory loss. Research Square, 2020, doi: 10.21203/rs.3.rs-31774/v1.

      ,
      • Jalessi M
      • Barati M
      • Rohani M
      • et al.
      Frequency and outcome of olfactory impairment and sinonasal involvement in hospitalized patients with COVID-19.
      ), or with functional modalities such as positron emission tomography (PET) of brain (
      • Yousefi-Koma A
      • Haseli S
      • Bakhshayeshkaram M
      • et al.
      Multimodality imaging with PET/CT and MRI reveals hypometabolism in tertiary olfactory cortex in parosmia of COVID-19.
      ,
      • Niesen M
      • Trotta N
      • Noel A
      • et al.
      Structural and metabolic brain abnormalities in COVID-19 patients with sudden loss of smell.
      ,
      • Karimi-Galougahi M
      • Yousefi-Koma A
      • Bakhshayeshkaram M
      • et al.
      18FDG PET/CT scan reveals hypoactive orbitofrontal cortex in anosmia of COVID-19.
      ). These studies have reported a variety of findings, which are at times divergent.
      In the present report, we sought to systematically review the imaging studies that have investigated COVID-19-induced olfactory dysfunction and to categorize the data from these studies, including based on the timing of the imaging in relation to the onset of olfactory dysfunction in the course of COVID-19.

      MATERIALS AND METHODS

      Study Selection and Eligibility Criteria

      We identified studies that have used imaging modalities such as brain CT, MRI, or PET in patients with COVID-19, confirmed with reverse transcription-polymerase chain reaction, and a clinical presentation with anosmia or olfactory dysfunction. Relevant studies were searched using MEDLINE (PubMed), Web of Science, Embase (Elsevier), Scopus, and Google Scholar databases (search was undertaken on May 26, 2021). The following medical subject headings and keywords were used: “Coronavirus,” “COVID-19,” “SARS-CoV-19,” “2019-CoV-19,” “radiolog*,” “radiograph*,” “Anosmia,” “Hyposmia,” “Olfactory Bulb,” “Tomography, X-ray Computed,” “CT,” “MRI,” and “PET.” The full list of the keywords that were used for search in the PubMed is provided in the Supplementary Appendix. Duplicates, conference abstracts, reviews, and studies in languages other than English were excluded.

      Data Collection and Analysis

      The following data from the eligible studies were collected by two independent investigators and were subsequently cross-checked. Disagreements between the investigators were resolved by a third investigator after discussions and reaching consensus. The following information were collected: first author's name, country where the study was conducted, study type, clinical characteristics of participants, clinical presentation of the olfactory dysfunction, findings on brain imaging, and clinical outcomes.

      RESULTS

      After excluding duplicate search results, titles and abstracts of 1490 studies were assessed, and 50 eligible studies were assessed by full-text review. Thirty-one studies, including seven cohort studies, six case series/reports, two case-control studies, one cross-sectional study, and 15 commentaries, letters to the editor, and short reports were included in the final analysis. The PRISMA flow diagram for study selection is shown in Figure 1.
      Figure 1
      Figure 1Flow diagram of the study selection process. (Color version of figure is available online.)

      Clinical Characteristics of the Study Participants

      Types of the studies and clinical characteristics of the patients are summarized in Table 1. In total, 305 patients were included in the studies. Of these participants, 161 (52.8%) were female, 137 (44.9%) male, and gender was not specified in 7 (2.3%). Age of the participants ranged between 13 and 84 years. Olfactory disorder was self-reported in 157 (51.5%) and by objective olfactory tests in 148 (48.5%). 259 (84.9%) patients had olfactory dysfunction (hyposmia/anosmia). Concomitant taste dysfunction was seen in 98 (32.1%) cases. The most common general symptoms were fever (141, 46.2%), cough (128, 41.9%), myalgia (120, 39.3%), headache (111, 36.3%), dyspnea (98, 32.1%), asthenia/fatigue (38, 12.4%), and gastrointestinal symptoms (21, 6.8%). Other clinical findings (rhinorrhea, coriza, nasal obstruction and facial pain) were less frequently reported.
      Table 1Design of the Imaging Studies and Ear, Nose, Throat and Neurological Symptoms in Patients with Olfactory Dysfunction Secondary to COVID-19
      First Author (Ref)CountryStudy DesignPariticipantsENT and Neurological Symptoms (n)Reporting ofAnosmia (n)Resolution of Symptoms
      Politi et al.(
      • Politi LS
      • Salsano E
      • Grimaldi M.
      Magnetic resonance imaging alteration of the brain in a patient with coronavirus disease 2019 (COVID-19) and anosmia.
      )
      ItalyCase report (n=1)Female (25 yo)Anosmia, dysgeusiaSelf- reportedFull recovery
      Aragao et al.(
      • MdFVV Aragão
      • M Leal
      • Cartaxo Filho O
      • et al.
      Anosmia in COVID-19 associated with injury to the olfactory bulbs evident on MRI.
      )
      BrazilCase series (n=5)Not reportedAnosmia, motor deficit (1)Self- reportedNot reported
      Chiu et al.(
      • Chiu A
      • Fischbein N
      • Wintermark M
      • et al.
      COVID-19-induced anosmia associated with olfactory bulb atrophy.
      )
      USACase report (n=1)Female (19 yo)AnosmiaSelf- reportedNot reported
      Correa et al.(
      • Corrêa DG
      • da Cruz Jr LCH
      • Lopes FCR
      • et al.
      Magnetic resonance imaging features of COVID-19-related cranial nerve lesions.
      )
      BrazilCase report (n=1)Female (41 yo)Anosmia, ageusiaSelf- reportedPersistent anosmia
      Eliezer et al.(
      • Eliezer M
      • Hamel A-L
      • Houdart E
      • et al.
      Loss of smell in patients with COVID-19: MRI data reveal a transient edema of the olfactory clefts.
      )
      FranceProspective case-control (n=20)10 males, 10 females (21-53 yo)Sudden-onset olfactory dysfunction (18),

      progressive olfactory dysfunction (2)
      Olfactory testFull recovery (4)

      Partial recovery (4)

      Not reported (12)
      Hatipoglu et al.(
      • Hatipoglu N
      • Yazici ZM
      • Palabiyik F
      • et al.
      Olfactory bulb magnetic resonance imaging in SARS-CoV-2-induced anosmia in pediatric cases.
      )
      TurkeyCase series (n=3)2 males (13 yo) 1 female (13 yo)AnosmiaSelf- reportedFull recovery (2)

      Persistent anosmia (1)
      Kandemirli et al.(
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      )
      TurkeyProspective non-controlled (n=23)9 males, 14 females

      (median age: 29 yo)
      Anosmia (23) (sudden-onset [4], progressive [19]), sinonasal symptoms (7)Olfactory testNot reported
      Lechien et al.(
      • Lechien JR
      • Michel J
      • Radulesco T
      • et al.
      Clinical and radiological evaluations of COVID-19 patients with anosmia: preliminary report.
      )
      BelgiumProspective non-controlled (n=16)8 males, 8 females (36±10.1 yo)Anosmia (16), nasal obstruction (6)Olfactory testNot reported
      Schonegger et al.(
      • Schönegger CM
      • Gietl S
      • Heinzle B
      • et al.
      Smell and taste disorders in COVID-19 patients: objective testing and magnetic resonance imaging in five cases.
      )
      AustriaCase series (n=5)5 females (41-57 yo)Anosmia (3), hyposmia (1), hypogeusia (2), ageusia (1)Olfactory testPersistent anosmia (2)

      Partial recovery (1)

      Full recovery (2)
      Strauss et al.(
      • Strauss S
      • Lantos J
      • Heier L
      • et al.
      Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.
      )
      USARetrospective case-control (n=24)9 males, 15 females (58 ± 15 yo)

      Anosmia (8), hyposmia (3)

      phantosmia (2), paresthesia (1),

      altered mental status (9), status epilepticus (1), ataxia and dysarthria(1)
      Self-reportedNot reported
      Wang et al.(
      • Wang E
      • Ulualp SO
      • Liu C
      • et al.
      Sudden anosmia and ageusia in a child: a COVID-19 case report.
      )
      USACase report (n=1)Male (17 yo)Anosmia, ageusia, epistaxisOlfactory testNot reported
      Zhang et al.(
      • Zhang Q
      • Shan KS
      • Abdollahi S
      • et al.
      Anosmia and ageusia as the only indicators of Coronavirus Disease 2019 (COVID-19).
      )
      USACase report (n=1)Female (60 yo)Anosmia, dysgeusiaSelf- reportedNot reported
      Safavi Naeinia et al.(
      • Naeini AS
      • Karimi-Galougahi M
      • Raad N
      • et al.
      Paranasal sinuses computed tomography findings in anosmia of COVID-19.
      )
      IranProspective non-controlled (n=49)27 males, 22 females (45 ± 12.2 yo)Anosmia/hyposmia (49), dysgeusia (37), nasal obstruction (16), sore throat (22,) rhinorrhea (9)Self- reportedNot reported
      Chetrit et al.(
      • Chetrit A
      • Lechien JR
      • Ammar A
      • et al.
      Magnetic resonance imaging of COVID-19 anosmic patients reveals abnormalities of the olfactory bulb: preliminary prospective study.
      )
      FranceCase series (n=23)9 males, 14 females (39 ± 17.1 yo)Anosmia (19), no anosmia (4, used as "controls")Olfactory testNot reported
      Yousefi-Koma et al.(
      • Yousefi-Koma A
      • Haseli S
      • Bakhshayeshkaram M
      • et al.
      Multimodality imaging with PET/CT and MRI reveals hypometabolism in tertiary olfactory cortex in parosmia of COVID-19.
      )
      IranCase report (n=1)Female (28 yo)Anosmia followed by persistent parosmiaSelf- reportedNot reported
      Tsivgoulis et al.(
      • Tsivgoulis G
      • Fragkou PC
      • Lachanis S
      • et al.
      Olfactory bulb and mucosa abnormalities in persistent COVID-19-induced anosmia: a magnetic resonance imaging study.
      )
      GreeceCase series (n=8)2 males, 6 females (19-53 yo)Anosmia (1), hyposmia (6), ageusia (7)

      Olfactory testNot reported
      Karimi-Galougahi et al.(
      • Karimi-Galougahi M
      • Yousefi-Koma A
      • Bakhshayeshkaram M
      • et al.
      18FDG PET/CT scan reveals hypoactive orbitofrontal cortex in anosmia of COVID-19.
      )
      IranCase report (n=1)Female (27 yo)AnosmiaSelf- reportedNot reported
      Li et al.(
      • Li C-W
      • Syue L-S
      • Tsai Y-S
      • et al.
      Anosmia and olfactory tract neuropathy in a case of COVID-19.
      )
      TaiwanCase report (n=1)Male (21 yo)AnosmiaSelf- reportedPartial recovery
      Laurendon et al.(
      • Laurendon T
      • Radulesco T
      • Mugnier J
      • et al.
      Bilateral transient olfactory bulb edema during COVID-19–related anosmia.
      )
      FranceCase report (n=1)Male (27 yo)Anosmia, dysgeusiaSelf- reportedFull recovery
      Liang et al.(
      • Liang Y-C
      • Tsai Y-S
      • Syue L-S
      • et al.
      Olfactory bulb atrophy in a case of COVID-19 with hyposmia.
      )
      TaiwanCase report (n=1)Female (16 yo)Hyposmia, rhinorrheaSelf-reportedPersistent hyposmia
      Yildiz et al.(

      Yıldız E, Balcı A, Selendili O, Kuzu S. Covid 19 pandemic: paranasal diagnostic imaging in patients with olfactory loss. Research Square, 2020, doi: 10.21203/rs.3.rs-31774/v1.

      )
      TurkeyProspective non-controlled (n=40)20 males, 20 females (58±20.57 yo)Anosmia (5), mild hyposmia (13), moderate hyposmia (13), severe hyposmia (9)Olfactory testNot reported
      Theodorou et al.(
      • Theodorou DJ
      • Theodorou SJ
      • Tsaggou V
      • et al.
      Anosmia caused by ischaemic olfactory infarction: false alert for COVID-19 infection.
      )
      GreeceCase report (n=1)Female (68 yo)AnosmiaSelf-reportedNot reported
      Melegari et al.(
      • Melegari G
      • Rivi V
      • Zelent G
      • et al.
      Mild to severe neurological manifestations of COVID-19: cases reports.
      )
      ItalyCase report (n=1)Female (31 yo)Anosmia, ageusiaSelf-reportedPersistent anosmia
      Niesen et al.(
      • Niesen M
      • Trotta N
      • Noel A
      • et al.
      Structural and metabolic brain abnormalities in COVID-19 patients with sudden loss of smell.
      )
      BelgiumProspective non-controlled (n=12)2 males, 10 females (23-60 yo)Anosmia (7), hyposmia (5),

      dysgeusia (11)
      Olfactory test

      Full recovery (5)

      Persistent hyposmia (7)
      Jalessi et al.(
      • Jalessi M
      • Barati M
      • Rohani M
      • et al.
      Frequency and outcome of olfactory impairment and sinonasal involvement in hospitalized patients with COVID-19.
      )
      IranProspective non-controlled (n=22)13 males, 9 females (52 ± 11.7 yo)Anosmia/hyposmia (22), dysgeusia (15), sore throat (8), rhinorrhea (5)Self-reportedFull recovery (21)

      Partial recovery (1)
      Ismail et al.(
      • Ismail II
      • Gad KA.
      Absent blood oxygen level–dependent functional magnetic resonance imaging activation of the orbitofrontal cortex in a patient with persistent cacosmia and cacogeusia after COVID-19 infection.
      )
      KuwaitCase report (n=1)Female (25 yo)Anosmia, ageusiaSelf-reportedPartial recovery
      Eliezer et al.(
      • Eliezer M
      • Hautefort C
      • Hamel A-L
      • et al.
      Sudden and complete olfactory loss of function as a possible symptom of COVID-19.
      )
      FranceCase report (n=1)Female (40 yo)AnosmiaSelf-reportedNot reported
      Karimi-Galougahi et al.(
      • Galougahi MK
      • Ghorbani J
      • Bakhshayeshkaram M
      • et al.
      Olfactory bulb magnetic resonance imaging in SARS-CoV-2-induced anosmia: the first report.
      )
      IranCase report (n=1)Male (27 yo)AnosmiaSelf-reportedNot reported
      Letterio et al.(

      Politi LS, Grimaldi M, Balzarini L. MRI depicts olfactory bulbs and cortical involvement in COVID-19 patients with anosmia. MAGNETOM Flash; 2021;78(1)

      )
      ItalyCase series (n=4)2 females (25, 39 yo), sex/age not reported(2)Anosmia (4), dysgeusia (1)Self-reportedFull recovery
      Hajjij et al.(
      • Hajjij A
      • Benslima N
      • Aasfara J
      • et al.
      An MRI of the olfactory tract in a case of post-COVID-19 persistent anosmia.
      )
      MoroccoCase report (n=1)Male (21 yo)AnosmiaSelf-reportedPersistent anosmia
      Aragao et al.(
      • MdFVV Aragao
      • MdC Leal
      • Andrade PHP
      • et al.
      Clinical and radiological profiles of COVID-19 patients with neurological symptomatology: a comparative study.
      )
      BrazilRetrospective study (n=35)14 females, 21 males (25-84 yo)Anosmia (7)Self –reportedNot reported
      Total (n=305)Self-reported anosmia: 157, Anosmia based on olfactory tests: 148
      ENT, ear, nose, and throat; Ref, reference.
      In total, 14 studies (74 of 305 patients, 24.3%) reported the outcome of the olfactory symptoms. In 28 of 74 (37.8%) cases with reported outcomes, hyposmia/anosmia persisted at the time of reporting, while in 46 of 74 (62.2%) hyposmia/anosmia was partially or completely resolved.

      Imaging Modalities

      Findings using various imaging modalities are summarized in Table 2. In total, 305 patients undergoing a total of 320 imaging studies were included. Imaging modalities used to assess changes in the olfactory tract in COVID-19-induced anosmia included MRI/functional MRI (n=177), CT of the paranasal sinuses and brain (n=129), and PET/CT or PET/MRI scans (n=14).
      Table 2Findings on Various Imaging Modalities in Patients with Olfactory Dysfunction Secondary to COVID-19
      First Author (Ref)MRI (n)PNS CT (n)PET/CT, PET/MRI (n)
      Politi et al.(
      • Politi LS
      • Salsano E
      • Grimaldi M.
      Magnetic resonance imaging alteration of the brain in a patient with coronavirus disease 2019 (COVID-19) and anosmia.
      )
      OB and right Hyperintensity in the rectus gyrus cortex,

      subtle hyperintensity of OBs
      Aragao et al.(
      • MdFVV Aragão
      • M Leal
      • Cartaxo Filho O
      • et al.
      Anosmia in COVID-19 associated with injury to the olfactory bulbs evident on MRI.
      )
      Hypointensity in OB (1), enhancement in OB (4)
      Chiu et al.(
      • Chiu A
      • Fischbein N
      • Wintermark M
      • et al.
      COVID-19-induced anosmia associated with olfactory bulb atrophy.
      )
      Volume reduction in OB
      Correa et al.(
      • Corrêa DG
      • da Cruz Jr LCH
      • Lopes FCR
      • et al.
      Magnetic resonance imaging features of COVID-19-related cranial nerve lesions.
      )
      Bilateral enhancement of OB
      Eliezer et al.(
      • Eliezer M
      • Hamel A-L
      • Houdart E
      • et al.
      Loss of smell in patients with COVID-19: MRI data reveal a transient edema of the olfactory clefts.
      )
      Normal olfactory cleft (1), olfactory cleft obstruction (19) (bilateral: 17, right: 1, left: 1)
      Hatipoglu et al.(
      • Hatipoglu N
      • Yazici ZM
      • Palabiyik F
      • et al.
      Olfactory bulb magnetic resonance imaging in SARS-CoV-2-induced anosmia in pediatric cases.
      )
      Normal OB morphology and signal intensity (3)
      Kandemirli et al.(
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      )
      -Olfactory cleft opacification (17) (partial [16], total [1]) -OB morphology: normal (8), mild irregularity with preserved J shape (2), contour lobulations (5), rectangular shape (8) -OB signal intensity: normal (2), diffusely increased signal (9), hyperintense foci (16), hyperintense foci with halo (5), microhemorrhages (4) -Olfactory tract signal abnormality (7), olfactory cortex signal abnormality (5), olfactory nerve morphology: normal (13), evident clumping (8), thinning with scarcity (2)Olfactory cleft opacification: partial (16), total (1), normal olfactory cleft (6)

      Normal ethmoid air cells and nasal cavity (no opacification) in all cases (23)
      Lechien et al.(
      • Lechien JR
      • Michel J
      • Radulesco T
      • et al.
      Clinical and radiological evaluations of COVID-19 patients with anosmia: preliminary report.
      )
      Olfactory cleft pacification (9) (total [3], partial [6]), Normal (7)
      Schonegger et al.(
      • Schönegger CM
      • Gietl S
      • Heinzle B
      • et al.
      Smell and taste disorders in COVID-19 patients: objective testing and magnetic resonance imaging in five cases.
      )
      Slight hyperintensity of the left caudate and parahippocampus (1), normal OB morphology and signal intensity (5)
      Strauss et al.(
      • Strauss S
      • Lantos J
      • Heier L
      • et al.
      Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.
      )
      Intraneural hyperintensity (4), normal olfactory recess (12), Normal OB morphology and signal intensity (12), hypersignal orbitofrontal and entorhinal cortex (1)
      Wang et al.(
      • Wang E
      • Ulualp SO
      • Liu C
      • et al.
      Sudden anosmia and ageusia in a child: a COVID-19 case report.
      )
      Normal morphology of OB and olfactory sulcus
      Zhang et al.(
      • Zhang Q
      • Shan KS
      • Abdollahi S
      • et al.
      Anosmia and ageusia as the only indicators of Coronavirus Disease 2019 (COVID-19).
      )
      Stable white matter changes
      Safavi Naeinia et al.(
      • Naeini AS
      • Karimi-Galougahi M
      • Raad N
      • et al.
      Paranasal sinuses computed tomography findings in anosmia of COVID-19.
      )
      Septal deviation (24), concha bullosa (27), no significant changes on PNS CT (49)
      Chetrit et al.(
      • Chetrit A
      • Lechien JR
      • Ammar A
      • et al.
      Magnetic resonance imaging of COVID-19 anosmic patients reveals abnormalities of the olfactory bulb: preliminary prospective study.
      )
      Normal OB morphology and signal intensity (14) (4 normosmic and 10 anosmic patients)

      Olfactory cleft obstruction (10) (1 normosmic and 9 anosmic patients)
      Yousefi-Koma et al.(
      • Yousefi-Koma A
      • Haseli S
      • Bakhshayeshkaram M
      • et al.
      Multimodality imaging with PET/CT and MRI reveals hypometabolism in tertiary olfactory cortex in parosmia of COVID-19.
      )
      Normal OB volume and signal intensityHypometabolism in left insula, inferior frontal gyrus, hippocampus, amygdal (1)
      Tsivgoulis et al.(
      • Tsivgoulis G
      • Fragkou PC
      • Lachanis S
      • et al.
      Olfactory bulb and mucosa abnormalities in persistent COVID-19-induced anosmia: a magnetic resonance imaging study.
      )
      Mild to moderate OB atrophy (7), Olfactory mucosal thickening (4), Olfactory mucosal enhancement (1)
      Karimi-Galougahi et al.(
      • Karimi-Galougahi M
      • Yousefi-Koma A
      • Bakhshayeshkaram M
      • et al.
      18FDG PET/CT scan reveals hypoactive orbitofrontal cortex in anosmia of COVID-19.
      )
      Hypometabolism in the left orbitofrontal cortex (1)
      Li et al.(
      • Li C-W
      • Syue L-S
      • Tsai Y-S
      • et al.
      Anosmia and olfactory tract neuropathy in a case of COVID-19.
      )
      Bilateral linear hyperintensities within

      olfactory nerves (suggestive of bilateral olfactory neuropathy), smaller OB on the right side
      Laurendon et al.(
      • Laurendon T
      • Radulesco T
      • Mugnier J
      • et al.
      Bilateral transient olfactory bulb edema during COVID-19–related anosmia.
      )
      Hyperintensity and significant enlargement of OB, mild edema in the olfactory cleft, normal olfactory pathway and cortical projection
      Liang et al.(
      • Liang Y-C
      • Tsai Y-S
      • Syue L-S
      • et al.
      Olfactory bulb atrophy in a case of COVID-19 with hyposmia.
      )
      Smaller OB on the right-side, olfactory tract hyperitensity
      Yildiz et al.(

      Yıldız E, Balcı A, Selendili O, Kuzu S. Covid 19 pandemic: paranasal diagnostic imaging in patients with olfactory loss. Research Square, 2020, doi: 10.21203/rs.3.rs-31774/v1.

      )
      Abnormal finding: drainage disorder or soft tissue thickening in olfactory region (13)
      Theodorou et al.(
      • Theodorou DJ
      • Theodorou SJ
      • Tsaggou V
      • et al.
      Anosmia caused by ischaemic olfactory infarction: false alert for COVID-19 infection.
      )
      Hyperintensity in olfactory sulci, high-signal intensity infarcts in olfactory tract
      Melegari et al.(
      • Melegari G
      • Rivi V
      • Zelent G
      • et al.
      Mild to severe neurological manifestations of COVID-19: cases reports.
      )
      Persistent hyperintensity of olfactory nucleus
      Niesen et al.(
      • Niesen M
      • Trotta N
      • Noel A
      • et al.
      Structural and metabolic brain abnormalities in COVID-19 patients with sudden loss of smell.
      )
      Complete olfactory cleft obstruction (6), partial olfactory cleft obstruction (2), normal olfactory cleft (4)Olfactory cleft obliteration (6), OB asymmetry (3). Glucose metabolism alteration in olfactory core and higher brain networks (12)
      Jalessi et al.(
      • Jalessi M
      • Barati M
      • Rohani M
      • et al.
      Frequency and outcome of olfactory impairment and sinonasal involvement in hospitalized patients with COVID-19.
      )
      Obstruction of olfactory cleft (kissing mucosal swelling) (1)
      Ismail et al.(
      • Ismail II
      • Gad KA.
      Absent blood oxygen level–dependent functional magnetic resonance imaging activation of the orbitofrontal cortex in a patient with persistent cacosmia and cacogeusia after COVID-19 infection.
      )
      Normal OB and sulci

      BOLD map: inactivation of orbitofrontal cortex with strong BOLD signal within right piriform cortex and uncus
      Eliezer et al.(
      • Eliezer M
      • Hautefort C
      • Hamel A-L
      • et al.
      Sudden and complete olfactory loss of function as a possible symptom of COVID-19.
      )
      Bilateral obstruction of the olfactory cleft, normal OB morphology and signal intensity
      Karimi-Galougahi et al.(
      • Galougahi MK
      • Ghorbani J
      • Bakhshayeshkaram M
      • et al.
      Olfactory bulb magnetic resonance imaging in SARS-CoV-2-induced anosmia: the first report.
      )
      Normal olfactory bulb and signal intensity
      Letterio et al.(

      Politi LS, Grimaldi M, Balzarini L. MRI depicts olfactory bulbs and cortical involvement in COVID-19 patients with anosmia. MAGNETOM Flash; 2021;78(1)

      )
      Bilateral hyperintensity in OB (1), similar but less obvious hyperintensity of OB (1), normal OB volume and signal intensity (2)
      Hajjij et al.(
      • Hajjij A
      • Benslima N
      • Aasfara J
      • et al.
      An MRI of the olfactory tract in a case of post-COVID-19 persistent anosmia.
      )
      Normal olfactory bulb and signal intensity
      Aragao et al.(
      • MdFVV Aragao
      • MdC Leal
      • Andrade PHP
      • et al.
      Clinical and radiological profiles of COVID-19 patients with neurological symptomatology: a comparative study.
      )
      "OB injury" (enhancement or microbleeding) (12)
      BOLD, Blood oxygen level dependent; CT, Computed tomography; MRI, Magnetic resonance imaging; NL, Normal, OB: Olfactory bulb; OC, Olfactory cleft; OM, Olfactory mucosa; PET/CT, Positron emission tomography/ Computed tomography; PNS CT, Paranasal sinus computed tomography.
      Olfactory bulb or cortical hyperintensity were reported on 2D or 3D fluid-attenuated inversion recovery or T2-weighted images. Enhancement was reported based on T1-weighted images following administration of gadolinium-based contrasts.

      MRI

      A summary of the findings on MRI in anosmia of COVID-19 is provided in Tables 2 and 3. In total, 218 MRI findings were reported. Abnormalities on MRI can be divided into the following categories: changes in the morphology and signal intensity in OB, OC, or cortex, and abnormalities on functional MRI. With regard to the timing of imaging in relation to the onset of olfactory symptoms, the studies can be categorized to early imaging (≤1 month since the onset of olfactory dysfunction) and late imaging (> 1 month). Of the total of 218 MRI findings, 80 were detected in the early and 85 in the late phase, while the timing was not specified in the remainder (n=53) (Table 4).
      Table 3Findings on MRI in Patients with Olfactory Dysfunction Secondary to COVID-19
      RefNLOBOB EnhancementHypersignal OB/TractHyposignal OB/MicrobleedOBAtrophyNLOCOC OblitertaionOM EnhancementHypersignal Cortex
      4--1-1---1
      5-4-1-----
      6----1----
      7-1-------
      8-1---119--
      93--------
      1023-174--17-5
      115-------1
      1212-4-----1
      131--------
      1414-----10--
      151--------
      16----7-41-
      17--1------
      18--1---1--
      19--1-1----
      20--1------
      21--1------
      223----48--
      231-----1--
      241--------
      251--------
      262-2-----2
      271--------
      28-12-12-----
      Total

      n=218
      68

      31.2%
      18

      8.25%
      29

      13.3%
      17

      7.8%
      10

      4.6%
      5

      2.3%
      60

      27.5%
      1

      0.45%
      10

      4.6%
      NL, Normal; NR, not reported; OB, Olfactory bulb; OC, Olfactory cleft; OM, Olfactory mucosa.
      Olfactory bulb or cortical hyperintensity were reported on 2D or 3D fluid-attenuated inversion recovery or T2-weighted images. Enhancement was reported based on T1-weighted images following administration of gadolinium-based contrasts.
      Table 4Findings on MRI of Olfactory Tract and Central Pathways in Anosmia Secondary to COVID-19 Based on the Timing of Imaging
      MRI ≤ 1 Month From Onset of Anosmia; (n, %)(Total n=80)MRI > 1 Month After Onset of Anosmia;(n, %) (Total n=85)Timing Not Reported; (n, %)(Total n=53)
      OC obliteration28 (35%)Normal OB26 (30.58%)OB enhancement16 (30.18%)
      Normal OB28 (35%)OC obliteration22 (25.9%)Normal OB14 (26.4%)
      Hypersignal OB/tract11 (13.75%)Hypersignal OB/tract18 (21.17%)Hyposignal (microbleed) OB13 (24.52%)
      Normal OC5 (6.25%)OB atrophy9 (10.58%)OC obliteration10 (18.9%)
      Hypersignal cortex5 (6.25%)Hypersignal cortex5 (5.9%)Hypersignal OB/tract0 (0%)
      OB enhancement2 (2.5%)Hyposignal (microbleed) OB4 (4.70%)Normal OC0 (0%)
      OB atrophy1 (1.25%)OM enhancement1 (1.17%)Hypersignal cortex0 (0%)
      Hyposignal (microbleed) OB0 (0%)Normal OC0 (0.0%)OB atrophy0 (0%)
      OM enhancement0 (0%)OB enhancement0 (0.0%)OM enhancement0 (0%)
      OB, Olfactory bulb; OC, Olfactory cleft; OM, Olfactory mucosa.
      Findings are listed in the order of their frequencies.

      Morphology and Signal Intensity of OB

      Of the total of 218 findings on MRI, both morphology and signal intensity of OB were normal in 68/218 (31.2%) (Fig 2), which were the most common overall MRI finding (
      • Hatipoglu N
      • Yazici ZM
      • Palabiyik F
      • et al.
      Olfactory bulb magnetic resonance imaging in SARS-CoV-2-induced anosmia in pediatric cases.
      ,
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ,
      • Schönegger CM
      • Gietl S
      • Heinzle B
      • et al.
      Smell and taste disorders in COVID-19 patients: objective testing and magnetic resonance imaging in five cases.
      ,
      • Strauss S
      • Lantos J
      • Heier L
      • et al.
      Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.
      ,
      • Wang E
      • Ulualp SO
      • Liu C
      • et al.
      Sudden anosmia and ageusia in a child: a COVID-19 case report.
      ,
      • Chetrit A
      • Lechien JR
      • Ammar A
      • et al.
      Magnetic resonance imaging of COVID-19 anosmic patients reveals abnormalities of the olfactory bulb: preliminary prospective study.
      ,
      • Yousefi-Koma A
      • Haseli S
      • Bakhshayeshkaram M
      • et al.
      Multimodality imaging with PET/CT and MRI reveals hypometabolism in tertiary olfactory cortex in parosmia of COVID-19.
      ,
      • Niesen M
      • Trotta N
      • Noel A
      • et al.
      Structural and metabolic brain abnormalities in COVID-19 patients with sudden loss of smell.
      ,
      • Eliezer M
      • Hautefort C
      • Hamel A-L
      • et al.
      Sudden and complete olfactory loss of function as a possible symptom of COVID-19.
      ,
      • Ismail II
      • Gad KA.
      Absent blood oxygen level–dependent functional magnetic resonance imaging activation of the orbitofrontal cortex in a patient with persistent cacosmia and cacogeusia after COVID-19 infection.
      ,
      • Galougahi MK
      • Ghorbani J
      • Bakhshayeshkaram M
      • et al.
      Olfactory bulb magnetic resonance imaging in SARS-CoV-2-induced anosmia: the first report.
      ,

      Politi LS, Grimaldi M, Balzarini L. MRI depicts olfactory bulbs and cortical involvement in COVID-19 patients with anosmia. MAGNETOM Flash; 2021;78(1)

      ,
      • Hajjij A
      • Benslima N
      • Aasfara J
      • et al.
      An MRI of the olfactory tract in a case of post-COVID-19 persistent anosmia.
      ). OB morphology and signal was normal in 28/80 (35%) in the early and in 26/85 (30.6%) on late imaging, similarly constituting the most common findings on both early and late imaging.
      Figure 2
      Figure 2A. Coronal T2-weighted magnetic resonance imaging (MRI) of olfactory bulb in a patient with COVID-19-induced anosmia shows rectangular shape of both olfactory bulbs (arrow). Adapted from Kandemirli et al (
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ) with permission. B. Coronal nonenhanced T2-weighted MRI of a young man with sudden-onset anosmia shows normal olfactory bulb morphology and signal intensity (arrow). Olfactory cleft is also shown (*) with no evidence of mucosal thickening or obliteration. Adapted from Galougahi et al (
      • Galougahi MK
      • Ghorbani J
      • Bakhshayeshkaram M
      • et al.
      Olfactory bulb magnetic resonance imaging in SARS-CoV-2-induced anosmia: the first report.
      ) with permission.
      Other findings on MRI included OB enhancement following gadolinium injection in 18/218 (8.25%) (
      • MdFVV Aragão
      • M Leal
      • Cartaxo Filho O
      • et al.
      Anosmia in COVID-19 associated with injury to the olfactory bulbs evident on MRI.
      ,
      • Corrêa DG
      • da Cruz Jr LCH
      • Lopes FCR
      • et al.
      Magnetic resonance imaging features of COVID-19-related cranial nerve lesions.
      ,
      • Eliezer M
      • Hamel A-L
      • Houdart E
      • et al.
      Loss of smell in patients with COVID-19: MRI data reveal a transient edema of the olfactory clefts.
      ,
      • MdFVV Aragao
      • MdC Leal
      • Andrade PHP
      • et al.
      Clinical and radiological profiles of COVID-19 patients with neurological symptomatology: a comparative study.
      ) and T2 hyperintensity in the OB/tract in 29/218 (13.30%) (
      • Politi LS
      • Salsano E
      • Grimaldi M.
      Magnetic resonance imaging alteration of the brain in a patient with coronavirus disease 2019 (COVID-19) and anosmia.
      ,
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ,
      • Strauss S
      • Lantos J
      • Heier L
      • et al.
      Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.
      ,
      • Li C-W
      • Syue L-S
      • Tsai Y-S
      • et al.
      Anosmia and olfactory tract neuropathy in a case of COVID-19.
      ,
      • Laurendon T
      • Radulesco T
      • Mugnier J
      • et al.
      Bilateral transient olfactory bulb edema during COVID-19–related anosmia.
      ,
      • Liang Y-C
      • Tsai Y-S
      • Syue L-S
      • et al.
      Olfactory bulb atrophy in a case of COVID-19 with hyposmia.
      ,
      • Theodorou DJ
      • Theodorou SJ
      • Tsaggou V
      • et al.
      Anosmia caused by ischaemic olfactory infarction: false alert for COVID-19 infection.
      ,
      • Melegari G
      • Rivi V
      • Zelent G
      • et al.
      Mild to severe neurological manifestations of COVID-19: cases reports.
      ,

      Politi LS, Grimaldi M, Balzarini L. MRI depicts olfactory bulbs and cortical involvement in COVID-19 patients with anosmia. MAGNETOM Flash; 2021;78(1)

      ) (Fig 3a), while hypointense focus, consistent with microhemorrhage/methemoglobin deposition (Fig 3b), was identified in 17/218 (7.8%) (
      • MdFVV Aragão
      • M Leal
      • Cartaxo Filho O
      • et al.
      Anosmia in COVID-19 associated with injury to the olfactory bulbs evident on MRI.
      ,
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ,
      • MdFVV Aragao
      • MdC Leal
      • Andrade PHP
      • et al.
      Clinical and radiological profiles of COVID-19 patients with neurological symptomatology: a comparative study.
      ). T2 hyperintensity in OB was detected in 11/80 (13.75%) and 18/85 (21.17%) during the early and late imaging, respectively. Moreover, a reduction in the OB volume was detected in 10/218 (4.6%) (
      • Politi LS
      • Salsano E
      • Grimaldi M.
      Magnetic resonance imaging alteration of the brain in a patient with coronavirus disease 2019 (COVID-19) and anosmia.
      ,
      • Chiu A
      • Fischbein N
      • Wintermark M
      • et al.
      COVID-19-induced anosmia associated with olfactory bulb atrophy.
      ,
      • Tsivgoulis G
      • Fragkou PC
      • Lachanis S
      • et al.
      Olfactory bulb and mucosa abnormalities in persistent COVID-19-induced anosmia: a magnetic resonance imaging study.
      ,
      • Liang Y-C
      • Tsai Y-S
      • Syue L-S
      • et al.
      Olfactory bulb atrophy in a case of COVID-19 with hyposmia.
      ). OB atrophy was reported in one case (1/80 [1.25%]) on early imaging and in none on late imaging (9/85 [10.58%]) (Table 4).
      Figure 3
      Figure 3(a) Hyperintense foci are noted within both olfactory bulbs of a patient with COVID-19-induced anosmia (arrows). (b) Coronal T2-weighted image at the level of olfactory bulbs revealed bilateral scattered foci of hypointensity (arrows). Both images are adapted from Kandemirli et al (
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ) with permission.

      Morphology and Signal Intensity of OC

      Partial or complete obliteration of OC was the second most common finding on MRI, and was observed in 60/218 (27.5%) (
      • Eliezer M
      • Hamel A-L
      • Houdart E
      • et al.
      Loss of smell in patients with COVID-19: MRI data reveal a transient edema of the olfactory clefts.
      ,
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ,
      • Chetrit A
      • Lechien JR
      • Ammar A
      • et al.
      Magnetic resonance imaging of COVID-19 anosmic patients reveals abnormalities of the olfactory bulb: preliminary prospective study.
      ,
      • Tsivgoulis G
      • Fragkou PC
      • Lachanis S
      • et al.
      Olfactory bulb and mucosa abnormalities in persistent COVID-19-induced anosmia: a magnetic resonance imaging study.
      ,
      • Laurendon T
      • Radulesco T
      • Mugnier J
      • et al.
      Bilateral transient olfactory bulb edema during COVID-19–related anosmia.
      ,
      • Niesen M
      • Trotta N
      • Noel A
      • et al.
      Structural and metabolic brain abnormalities in COVID-19 patients with sudden loss of smell.
      ,
      • Eliezer M
      • Hautefort C
      • Hamel A-L
      • et al.
      Sudden and complete olfactory loss of function as a possible symptom of COVID-19.
      ). OC was normal in 5/218 (2.3%) (
      • Eliezer M
      • Hamel A-L
      • Houdart E
      • et al.
      Loss of smell in patients with COVID-19: MRI data reveal a transient edema of the olfactory clefts.
      ,
      • Niesen M
      • Trotta N
      • Noel A
      • et al.
      Structural and metabolic brain abnormalities in COVID-19 patients with sudden loss of smell.
      ). OC obliteration was detected in 28/80 (35%) on early imaging and in 22/85 (25.9%) on late imaging. No enhancement in the mucosal lining of OC was detected on early imaging, while this change was only detected in one case (1/85 [1.17%]) in the late phase (
      • Tsivgoulis G
      • Fragkou PC
      • Lachanis S
      • et al.
      Olfactory bulb and mucosa abnormalities in persistent COVID-19-induced anosmia: a magnetic resonance imaging study.
      ).

      Morphology and Signal Intensity of Cortex

      Studies assessing central olfactory centers were scarce, with signal alteration in the olfactory cortices reported in 10/218 [4.6%]) (
      • Politi LS
      • Salsano E
      • Grimaldi M.
      Magnetic resonance imaging alteration of the brain in a patient with coronavirus disease 2019 (COVID-19) and anosmia.
      ,
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ,
      • Schönegger CM
      • Gietl S
      • Heinzle B
      • et al.
      Smell and taste disorders in COVID-19 patients: objective testing and magnetic resonance imaging in five cases.
      ,
      • Strauss S
      • Lantos J
      • Heier L
      • et al.
      Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.
      ,

      Politi LS, Grimaldi M, Balzarini L. MRI depicts olfactory bulbs and cortical involvement in COVID-19 patients with anosmia. MAGNETOM Flash; 2021;78(1)

      ). Hyperintensity in the orbitofrontal and entorhinal cortices (
      • Strauss S
      • Lantos J
      • Heier L
      • et al.
      Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.
      ), in the right rectus gyrus (
      • Politi LS
      • Salsano E
      • Grimaldi M.
      Magnetic resonance imaging alteration of the brain in a patient with coronavirus disease 2019 (COVID-19) and anosmia.
      ) and in the left caudate and parahippocampus (
      • Schönegger CM
      • Gietl S
      • Heinzle B
      • et al.
      Smell and taste disorders in COVID-19 patients: objective testing and magnetic resonance imaging in five cases.
      ) have been reported. T2 hyperintensity in cortex both on early and late imaging were reported in 6.3% and 5.9% cases, respectively. Bilateral inferior frontal lobe hypodensity involving the straight gyrus was reported in one patient (
      • Theodorou DJ
      • Theodorou SJ
      • Tsaggou V
      • et al.
      Anosmia caused by ischaemic olfactory infarction: false alert for COVID-19 infection.
      ).

      Changes on Functional MRI

      Only one report on the use of functional MRI in anosmia secondary to COVID-19 has been published, where strong blood oxygen level-dependent signal within the piriform and right uncal cortices was detected (
      • Ismail II
      • Gad KA.
      Absent blood oxygen level–dependent functional magnetic resonance imaging activation of the orbitofrontal cortex in a patient with persistent cacosmia and cacogeusia after COVID-19 infection.
      ).

      CT of Paranasal Sinuses

      Findings on CT of paranasal sinuses can be categorized into two main groups: changes in the paranasal sinuses (opacification of the sinuses) or in OC (partial or complete opacification). Among a total of 129 CT scans included in the present review, paranasal sinuses were evaluated and reported in 88 of 129 (68.21%) (
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ,
      • Lechien JR
      • Michel J
      • Radulesco T
      • et al.
      Clinical and radiological evaluations of COVID-19 patients with anosmia: preliminary report.
      ,
      • Naeini AS
      • Karimi-Galougahi M
      • Raad N
      • et al.
      Paranasal sinuses computed tomography findings in anosmia of COVID-19.
      ). In the majority of these scans (77/88 [87.5%]), paranasal sinuses were normal (
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ,
      • Naeini AS
      • Karimi-Galougahi M
      • Raad N
      • et al.
      Paranasal sinuses computed tomography findings in anosmia of COVID-19.
      ), with opacification of the paranasal sinuses only observed in 11/88 [12.5%]) (
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ,
      • Naeini AS
      • Karimi-Galougahi M
      • Raad N
      • et al.
      Paranasal sinuses computed tomography findings in anosmia of COVID-19.
      ). Moreover, out of the total 129 CT scans, OC was normal in 100/129 (77.5%), while in 29/129 (22.5%) complete or partial opacification of OC was reported (
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ,
      • Lechien JR
      • Michel J
      • Radulesco T
      • et al.
      Clinical and radiological evaluations of COVID-19 patients with anosmia: preliminary report.
      ,
      • Naeini AS
      • Karimi-Galougahi M
      • Raad N
      • et al.
      Paranasal sinuses computed tomography findings in anosmia of COVID-19.
      ,

      Yıldız E, Balcı A, Selendili O, Kuzu S. Covid 19 pandemic: paranasal diagnostic imaging in patients with olfactory loss. Research Square, 2020, doi: 10.21203/rs.3.rs-31774/v1.

      ,
      • Jalessi M
      • Barati M
      • Rohani M
      • et al.
      Frequency and outcome of olfactory impairment and sinonasal involvement in hospitalized patients with COVID-19.
      ).

      PET/CT

      Few studies using PET/CT for assessment of olfactory dysfunction in COVID-19 have been performed. Reduction in fluorodeoxyglucose uptake in the left insula, left inferior frontal gyrus, left hippocampus and left amigdala compared with the contralateral side were identified in one patient (
      • Yousefi-Koma A
      • Haseli S
      • Bakhshayeshkaram M
      • et al.
      Multimodality imaging with PET/CT and MRI reveals hypometabolism in tertiary olfactory cortex in parosmia of COVID-19.
      ). Additionally, hypometabolic activity of the left orbitofrontal cortex was detected in a patient who underwent PET/CT for evaluation of COVID-19-induced olfactory dysfunction (
      • Karimi-Galougahi M
      • Yousefi-Koma A
      • Bakhshayeshkaram M
      • et al.
      18FDG PET/CT scan reveals hypoactive orbitofrontal cortex in anosmia of COVID-19.
      ). Alterantions in glucose metabolism in the olfactory tract and higher brain networks have also been reported in 12 patients with anosmia secondary to COVID-19 (
      • Niesen M
      • Trotta N
      • Noel A
      • et al.
      Structural and metabolic brain abnormalities in COVID-19 patients with sudden loss of smell.
      ).

      Imaging Data in Case-Control Studies

      There was heterogeneity in what has been defined as “control” in the three case-control studies included in the current review. Some studies included normosmic individuals without COVID-19 as the control group (
      • Eliezer M
      • Hamel A-L
      • Houdart E
      • et al.
      Loss of smell in patients with COVID-19: MRI data reveal a transient edema of the olfactory clefts.
      ), whereas others included normosmic patients with COVID-19 as controls (
      • Chetrit A
      • Lechien JR
      • Ammar A
      • et al.
      Magnetic resonance imaging of COVID-19 anosmic patients reveals abnormalities of the olfactory bulb: preliminary prospective study.
      ). In one study, patients with olfactory dysfunction but without COVID-19 were included as controls for imaging evaluation of neurological manifestations of COVID-19 (
      • Strauss S
      • Lantos J
      • Heier L
      • et al.
      Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.
      ).
      Elezier et al. (
      • Eliezer M
      • Hamel A-L
      • Houdart E
      • et al.
      Loss of smell in patients with COVID-19: MRI data reveal a transient edema of the olfactory clefts.
      ) prospectively compared 20 anosmic patients with COVID-19 with 20 age- and sex-matched normosmic individuals without COVID-19 on MRI, which was performed at baseline and 1 month later. There was OC opacification in 19 of 20 cases and in none of the controls at baseline (p<0.001). On repeat MRI, OC opacification was resolved in 12 of 19 and persisted in seven of 12 patients, with the resolution of OC opacification correlating with improved olfaction as assessed by olfactory tests. There was no difference in the OB volume between cases and controls at baseline (p=0.33), and no significant changes in the OB volume were noted in the cases on follow-up MRI (p=0.53). Chetrit et al. (
      • Chetrit A
      • Lechien JR
      • Ammar A
      • et al.
      Magnetic resonance imaging of COVID-19 anosmic patients reveals abnormalities of the olfactory bulb: preliminary prospective study.
      ) prospectively compared 19 patients with COVID-19 and olfactory dysfunction with four patients with COVID-19 and no olfactory dysfunction as controls. There was OC opacification in nine of 19 cases and one of four controls (p value not reported). The OC opacification in one control patient with COVID-19 but without olfactory dysfunction was attributed to initial inflammatory reaction of the nasal mucosa to mild-to-moderate COVID-19. There was higher T2-weighted fluid attenuated inversion recovery (T2 FLAIR) signal intensity in the OB in the cases compared with controls (p<0.001). Last, Strauss et al. (
      • Strauss S
      • Lantos J
      • Heier L
      • et al.
      Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.
      ) retrospectively compared 12 patients with COVID-19 and neurological symptoms with 12 age-matched controls without COVID-19 who had undergone MRI for evaluation of olfactory dysfunction. T2 FLAIR signal intensity in OB was higher in patients with COVID-19 compared to patients with olfactory dysfunction without COVID-19 (p=0.003). Four of 12 patients with COVID-19 demonstrated T2 signal hyperintensity on 3D T2 FLAIR compared to none of the 12 controls with olfactory dysfunction without COVID-19 (p=0.028). OB volume was similar between the two groups (p value not reported).

      DISCUSSION

      In this systematic review, opacification of OC together with normal OB morphology and signal intensity were the most common imaging findings in patients with olfactory dysfunction secondary to COVID-19, while paranasal sinuses were normal in most cases. OC opacification was detected in most anosmic patients with COVID-19 compared to the normal OC in normosmic controls, with resolution of OC opacification correlating with improved olfaction. Taken together, these data suggest obstruction of OC, which likely results in mixed conductive and peripheral sensory-neural anosmia, as the most likely mechanism for olfactory dysfunction in COVID-19. An increase in the frequency of abnormalities in signal intensity and morphology of OB on late versus early imaging suggests that central mechanisms for anosmia may also play a role, especially in the late phase - a postulate that is supported by functional abnormalities detected on PET and functional MRI studies.
      The exact pathogenesis of the olfactory dysfunction in COVID-19 is not fully elucidated. Possible mechanisms include neurotropism and invasion of the OB by the virus, inflammatory changes, and impairment of the olfactory epithelium via angiotensin converting enzyme two receptors that are expressed by the non-neural olfactory supporting cells (
      • Bilinska K
      • Butowt R.
      Anosmia in COVID-19: a bumpy road to establishing a cellular mechanism.
      ). Persistent olfactory dysfunction after sinonasal symptoms resolve suggests possible injury to the olfactory stem cells and impairment of the supporting cells (
      • Cooper KW
      • Brann DH
      • Farruggia MC
      • et al.
      COVID-19 and the chemical senses: supporting players take center stage.
      ).
      Post-viral ansomia due to upper respiratory tract infections can occur in up to 40% of cases, which is often secondary to diffuse sinonasal mucosal thickening. Nevertheles, sudden, transient olfactory dysfunction is common in COVID-19 (
      • Mao L
      • Jin H
      • Wang M
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      ,
      • Politi LS
      • Salsano E
      • Grimaldi M.
      Magnetic resonance imaging alteration of the brain in a patient with coronavirus disease 2019 (COVID-19) and anosmia.
      ,
      • Eliezer M
      • Hamel A-L
      • Houdart E
      • et al.
      Loss of smell in patients with COVID-19: MRI data reveal a transient edema of the olfactory clefts.
      ,
      • Strauss S
      • Lantos J
      • Heier L
      • et al.
      Olfactory bulb signal abnormality in patients with COVID-19 who present with neurologic symptoms.
      ,
      • Eliezer M
      • Hautefort C
      • Hamel A-L
      • et al.
      Sudden and complete olfactory loss of function as a possible symptom of COVID-19.
      ,
      • Ismail II
      • Gad KA.
      Absent blood oxygen level–dependent functional magnetic resonance imaging activation of the orbitofrontal cortex in a patient with persistent cacosmia and cacogeusia after COVID-19 infection.
      ,

      Politi LS, Grimaldi M, Balzarini L. MRI depicts olfactory bulbs and cortical involvement in COVID-19 patients with anosmia. MAGNETOM Flash; 2021;78(1)

      ,
      • Lechien JR
      • Michel J
      • Radulesco T
      • et al.
      Clinical and radiological evaluations of COVID-19 patients with anosmia: preliminary report.
      ,
      • Han AY
      • Mukdad L
      • Long JL
      • et al.
      Anosmia in COVID-19: mechanisms and significance.
      ). Lack of concomitant sinonasal symptoms (i.e., nasal obstruction and mucosal congestion) in majority of the cases (
      • Butowt R
      • von Bartheld CS.
      covid19 Anosmia in COVID-19: underlying mechanisms and assessment of an olfactory route to brain infection.
      ) indicates that diffuse sinonasal mucosal thickening may not be a contributing mechanism in most cases of COVID-19-induced anosmia. Consistent with this, CT of paranasal sinuses was normal in most patients with COVID-19-induced anosmia, with no mucosal thickening or obstruction detected (
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ,
      • Lechien JR
      • Michel J
      • Radulesco T
      • et al.
      Clinical and radiological evaluations of COVID-19 patients with anosmia: preliminary report.
      ,
      • Naeini AS
      • Karimi-Galougahi M
      • Raad N
      • et al.
      Paranasal sinuses computed tomography findings in anosmia of COVID-19.
      ,

      Yıldız E, Balcı A, Selendili O, Kuzu S. Covid 19 pandemic: paranasal diagnostic imaging in patients with olfactory loss. Research Square, 2020, doi: 10.21203/rs.3.rs-31774/v1.

      ,
      • Jalessi M
      • Barati M
      • Rohani M
      • et al.
      Frequency and outcome of olfactory impairment and sinonasal involvement in hospitalized patients with COVID-19.
      ).
      Similarly, On MRI, OB and OC were normal in most cases with COVID-19-induced anosmia. Nevertheless, infection of the olfactory epithelial support cells (Bowman and sustentacular cells) plays a key role in ansomia of COVID-19 (
      • Zheng J
      • Wong LY
      • Li K
      • et al.
      COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice.
      ). SARS-CoV-2 utilizes angiotensin converting enzyme 2 and transmembrane serine protease 2 to enter the respiratory epithelial cells, which act as a viral reservoir for COVID-19 (
      • Bilinska K
      • Butowt R.
      Anosmia in COVID-19: a bumpy road to establishing a cellular mechanism.
      ). The localized respiratory epithelial involvement and inflammation in the OC may appear as hyperintense mucosal thickening and obstruction, which indeed was the second most common abnormality on MRI in the present review. It is postulated that patients with obstruction in the OC may develop more severe olfactory dysfunction compared with patients with normal OC (
      • Lechien JR
      • Michel J
      • Radulesco T
      • et al.
      Clinical and radiological evaluations of COVID-19 patients with anosmia: preliminary report.
      ).
      Inflammation of the OB with blood brain barrier breakdown can result in edema in OB, which appears as hypersignal intensity on T2-weighted images. Prolonged inflammation of the olfactory tract can be detected as thickening and clumped appearance of the olfactory nerve filia on MRI (
      • MdFVV Aragão
      • M Leal
      • Cartaxo Filho O
      • et al.
      Anosmia in COVID-19 associated with injury to the olfactory bulbs evident on MRI.
      ,
      • Corrêa DG
      • da Cruz Jr LCH
      • Lopes FCR
      • et al.
      Magnetic resonance imaging features of COVID-19-related cranial nerve lesions.
      ,
      • Eliezer M
      • Hamel A-L
      • Houdart E
      • et al.
      Loss of smell in patients with COVID-19: MRI data reveal a transient edema of the olfactory clefts.
      ). Additionally, microbleeding secondary to microvascular injury and microthrombosis by SARS-Cov-2 may appear as foci of hyposignal intensity within the OB (
      • MdFVV Aragão
      • M Leal
      • Cartaxo Filho O
      • et al.
      Anosmia in COVID-19 associated with injury to the olfactory bulbs evident on MRI.
      ,
      • Kandemirli SG
      • Altundag A
      • Yildirim D
      • et al.
      Olfactory bulb MRI and paranasal sinus CT findings in persistent COVID-19 anosmia.
      ,
      • MdFVV Aragao
      • MdC Leal
      • Andrade PHP
      • et al.
      Clinical and radiological profiles of COVID-19 patients with neurological symptomatology: a comparative study.
      ).
      Overall, timing of the imaging studies during the course of COVID-19-induced olfactory dysfunction appears to be important in detection of abnormalities on imaging. While imaging of OB in most cases is normal within the early days after the onset of olfactory dysucntion, a decrease in the OB volume, detected as thinning or loss of normal oval shape and asymmetry compared with the contralateral OB (
      • Liang Y-C
      • Tsai Y-S
      • Syue L-S
      • et al.
      Olfactory bulb atrophy in a case of COVID-19 with hyposmia.
      ), is more frequently detected at later stages. Additionally, it is plausible that persistently low activity in the afferent olfactory neurons may result in further reduction in the OB volume. Indeed, it takes several weeks for structural changes in the OB to appear in the course of COVID-19-induced anosmia. This observation might suggest impairment in the olfactory stem cells in addition to damage to the epithelial support cells (
      • Cooper KW
      • Brann DH
      • Farruggia MC
      • et al.
      COVID-19 and the chemical senses: supporting players take center stage.
      ), which in combination may lead to olfactory dysfunction and atrophy of OB.
      Finally, decreased metabolic activity of the orbitofrontal cortex on PET-CT (
      • Karimi-Galougahi M
      • Yousefi-Koma A
      • Bakhshayeshkaram M
      • et al.
      18FDG PET/CT scan reveals hypoactive orbitofrontal cortex in anosmia of COVID-19.
      ) may be a result of direct viral neurotropism through the olfactory pathways (
      • Butowt R
      • von Bartheld CS.
      covid19 Anosmia in COVID-19: underlying mechanisms and assessment of an olfactory route to brain infection.
      ) as suggested by cortical hyperintensity on FLAIR sequence on MRI (
      • Schönegger CM
      • Gietl S
      • Heinzle B
      • et al.
      Smell and taste disorders in COVID-19 patients: objective testing and magnetic resonance imaging in five cases.
      ,
      • Theodorou DJ
      • Theodorou SJ
      • Tsaggou V
      • et al.
      Anosmia caused by ischaemic olfactory infarction: false alert for COVID-19 infection.
      ). Additionally, deafferentation process and functional reorganization secondary to absent sensory stimulation of the olfactory pathways (
      • Niesen M
      • Trotta N
      • Noel A
      • et al.
      Structural and metabolic brain abnormalities in COVID-19 patients with sudden loss of smell.
      ,
      • Han AY
      • Mukdad L
      • Long JL
      • et al.
      Anosmia in COVID-19: mechanisms and significance.
      ) may also contribute to the observed hypometabolism on PET-CT.
      Limitations: there was significant heterogeneity in the reported studies, which included case reports, case series, retrospective studies as well as prospective controlled and non-controlled studies. Due to the paucity of well-designed prospective studies, case reports and case series reporting the imaging findings in anosmia of COVID-19 constitute a significant proportion of the available data and were therefore included in the present review. Other limitations include incomplete reporting of demographics and timing of the imaging studies in relation to the onset of olfactory dysfunction and a lack of systemic follow-up in some studies.

      CONCLUSION

      This systematic review suggests that focal mucosal thickening and obstruction of OC plays a dominant mechanistic role in COVID-19-induced olfactory dysfunction. Hyperintensity in the OB, OB atrophy, cortical hyperintensity, and hypometabolic cortical activity indicate a central mechanism at later stages, likely due to the direct neurotropism of SARS-CoV-2. Further studies are needed to elucidate the exact pathogenesis and the full spectrum of imaging manifestations during the evolution of olfactory dysfunction secondary to COVID-19.

      Author Contributions

      Study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of the final version of the submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, P.K., F.Y., S.H.; and manuscript editing, all authors.

      Appendix B. Supplementary materials

      Appendix. Search Strategy

      PubMed Keywords

      ("coronavirus 2" [Title/Abstract] OR "coronavirus 2"[Mesh] OR "coronavirus infections"[Title/Abstract] OR "coronavirus infections"[Mesh] OR "COVID-19"[Title/Abstract] OR "COVID-19"[Mesh] OR "coronavirus"[Title/Abstract] OR "coronavirus"[Mesh] OR "2019-nCoV"[Title/Abstract] OR "COVID-2019"[Title/Abstract] OR "COVID19"[Title/Abstract] OR "nCoV"[Title/Abstract] OR "coronavirus disease 2019"[Title/Abstract] OR "2019 novel coronavirus"[Title/Abstract] OR "severe acute respiratory syndrome"[Title/Abstract] OR "SARS-CoV-19"[Title/Abstract] OR "SARS-CoV-2"[Title/Abstract] OR "2019-CoV-19"[Title/Abstract] OR "SARS-CoV"[Title/Abstract] OR "2019nCoV"[Title/Abstract] OR "coronavirinae"[Title/Abstract] OR "2019 Novel Coronavirus Infection"[Title/Abstract] OR "2019 nCoV Infection"[Title/Abstract] OR "Bat coronavirus"[Title/Abstract] OR "betacoronavirus*"[Title/Abstract] OR "coronavirus Infection Disease 2019"[Title/Abstract] OR "covid*"[Title/Abstract] OR "Novel Coronavirus Pneumonia"[Title/Abstract] OR "Wuhan virus"[Title/Abstract]) AND (Radiology[Mesh] OR Radiology[Title/Abstract] OR "Tomography, X-ray Computed"[Mesh] OR "computed assisted tomography"[Title/Abstract] OR CT[Title/Abstract] OR (computed[Title/Abstract] AND tomograph[Title/Abstract]) OR (x-ray[Title/Abstract] AND computed[Title/Abstract]) OR (imaging[Title/Abstract] AND display[Title/Abstract]) OR "Diagnostic Imaging"[Title/Abstract] OR image*[Title/Abstract] OR imaging[Title/Abstract] OR radiography[Title/Abstract] OR radiolog*[Title/Abstract] OR radiograph*[Title/Abstract] OR MRI[Title/Abstract] OR "Magnetic Resonance Imaging"[Title/Abstract] OR PET[Title/Abstract] OR MRI-PET[Title/Abstract] OR PET/CT[Title/Abstract] OR PET/MR[Title/Abstract] OR PET-CT[Title/Abstract] OR "Positron Emission Tomograph*"[Title/Abstract] OR "FDG PET"[Title/Abstract] OR FDG-PET[Title/Abstract] OR "FDG PET/CT"[Title/Abstract]) AND (Anosmia[Mesh] OR Anosmia[Title/Abstract] OR Olfactory[Title/Abstract] OR "Olfactory Dysfunction"[Title/Abstract] OR "Olfactory Bulb"[Mesh] OR "Olfactory Bulb"[Title/Abstract] OR "Olfactory cortex"[Mesh] OR "Olfactory cortex"[Title/Abstract] OR "Olfactory tract"[Title/Abstract] OR Hyposmia[Title/Abstract] OR Parosmia[Title/Abstract] OR Phantosmia[Title/Abstract] OR "Loss of smell"[Title/Abstract])
      Time: 2019 – 2021

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