paring the healthy control group20. In our opinion, normal oxyhemoglobin AUS based on
the functional near-infrared spectroscopy (fNIRS) study could not rule
out biochemical changes in neuronal damage 20.
Overall, the findings of this study suggest that olfactory dysfunction
in patients with COVID-19 related anosmia is significantly associated
with central nervous system impairment. Since the NAA originates from
mitochondria, it can reflect neuronal integrity and viability; the
significant decrease of NAA andNAA/Cho in the OFC in COVID-19 related
anosmia strongly suggests regional neuronal OFC impairment in the
context of persistent COVID-19 anosmia. The second significant
alteration in our patients was a reduction of Cr levels within OFC. Cr
works as an indirect intermediator of cellular energy and previous
studies have shown its reduction following nerve injuries1. Although this cellular dysfunction emphasized the
hypothesis that impairment of OFC function is significantly associated
with permanent anosmia, these results could not answer a controversy
about the cause-and-effect relationship between brain neurometabolite
dysfunction and COVID-19 related anosmia.
Finally, it should be noted that the results of recent clinical trials
that did not achieve significant improvement from
intranasal
corticosteroids raise the property of central nervous system mechanisms
for COVID-19 related anosmia 21-23.
4.2 Limitations and comments of the
study
The small number of patients is certainly a major limitation of our
study, but this is a well-designed preliminary study. Another limitation
of our study was the nature of our scanner. More powerful scanners and
multivoxel spectroscopy can detect extra metabolites such as
Myo-inositol, glutamate, glutamine, glutathione, gamma-aminobutyric
acid, and lactate.
Despite the limitations of this study, we believe that the MRS is a
valuable advanced neuroimaging technique and could provide very
important landmarks in the diagnosis, treatment and follow-up of
patients with anosmia.
Interestingly, as MRS provides valuable, quantifiable data, it would be
possible to build a predictive score based on future longitudinal
studies and neural network to predict the outcomes of patients with
acquired anosmia.
According to a suggestive origin of injury in patients with COVID-19
related anosmia, pharmacologic or nonpharmacologic therapies in order to
increase NAA levels using electroconvulsive therapy, cognitive
behavioral therapy, and physical exercise or short-course
pharmacological therapies with lithium, valproate, or antipsychotics
could be tried in these patients as they can lead to a widespread
increase in brain NAA levels 24,25.
Conclusions
MRS is an exciting and novel approach to evaluating prolonged olfactory
dysfunction after COVID-19 related anosmia. However, it is still not
entirely clear that abnormalities in the CNS are the cause or the result
of olfactory loss due to COVID-19. We believe further neuroimaging
studies and clinical trials could answer some controversies about the
cause-and-effect relationship between the neurometabolic alterations
within OFC in COVID-19 anosmia.
References
1. Haghani Dogahe M, Feizkhah A, Seddighi S, Kiani P, Shafaei F.
Application of Magnetic Resonance Spectroscopy in Neurocognitive
Assessment After Head Injury: A Systematic Review. Caspian Journal of
Neurological Sciences. 2021;7(2):116-129.
2. Lechien JR, Michel J, Radulesco T, et al. Clinical and Radiological
Evaluations of COVID-19 Patients With Anosmia: Preliminary Report.
Laryngoscope. 2020;130(11):2526-2531.
3. Taziki Balajelini MH, Rajabi A, Mohammadi M, et al. Virus load and
incidence of olfactory, gustatory, respiratory, gastrointestinal
disorders in COVID-19 patients: A retrospective cohort study. Clinical
otolaryngology : official journal of ENT-UK ; official journal of
Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery.
2021;46(6):1331-1338.
4. Noh H, Choi B, Jeong H, Moon WJ, Kim JK. Diagnosis of isolated
congenital anosmia using simultaneous functional magnetic resonance
imaging and olfactory event-related potentials: Our experience in six
patients. Clinical otolaryngology : official journal of ENT-UK ;
official journal of Netherlands Society for Oto-Rhino-Laryngology &
Cervico-Facial Surgery. 2021;46(4):906-910.
5. Naeini AS, Karimi-Galougahi M, Raad N, et al. Paranasal sinuses
computed tomography findings in anosmia of COVID-19. Am J Otolaryngol.
2020;41(6):102636.
6. Zhou G, Lane G, Cooper SL, Kahnt T, Zelano C. Characterizing
functional pathways of the human olfactory system. Elife. 2019;8.
7. Hutson K, Kumaresan K, Johnstone L, Philpott C. The use of MRI in a
tertiary smell and taste clinic: Lessons learned based on a
retrospective analysis. Clinical otolaryngology : official journal of
ENT-UK ; official journal of Netherlands Society for
Oto-Rhino-Laryngology & Cervico-Facial Surgery. 2022;47(6):656-663.
8. Gottfried JA, Smith AP, Rugg MD, Dolan RJ. Remembrance of odors past:
human olfactory cortex in cross-modal recognition memory. Neuron.
2004;42(4):687-695.
9. Niesen M, Trotta N, Noel A, et al. Structural and metabolic brain
abnormalities in COVID-19 patients with sudden loss of smell. Eur J Nucl
Med Mol Imaging. 2021;48(6):1890-1901.
10. Kollndorfer K, Jakab A, Mueller CA, Trattnig S, Schöpf V. Effects of
chronic peripheral olfactory loss on functional brain networks.
Neuroscience. 2015;310:589-599.
11. Felix C, Chahine LM, Hengenius J, et al. Diffusion Tensor Imaging of
the Olfactory System in Older Adults With and Without Hyposmia. Front
Aging Neurosci. 2021;13:648598.
12. Tabari A, Golpayegani G, Tabari A, et al. Olfactory Dysfunction is
Associated with More Severe Clinical Course in COVID-19. Indian journal
of otolaryngology and head and neck surgery : official publication of
the Association of Otolaryngologists of India. 2021:1-6.
13. Taherkhani S, Moztarzadeh F, Mehdizadeh Seraj J, et al. Iran Smell
Identification Test (Iran-SIT): a Modified Version of the University of
Pennsylvania Smell Identification Test (UPSIT) for Iranian Population.
Chemosensory Perception. 2015;8(4):183-191.
14. Wilson M, Reynolds G, Kauppinen RA, Arvanitis TN, Peet AC. A
constrained least-squares approach to the automated quantitation of in
vivo ¹H magnetic resonance spectroscopy data. Magnetic resonance in
medicine. 2011;65(1):1-12.
15. Bitter T, Gudziol H, Burmeister HP, Mentzel HJ, Guntinas-Lichius O,
Gaser C. Anosmia leads to a loss of gray matter in cortical brain areas.
Chem Senses. 2010;35(5):407-415.
16. Dade LA, Zatorre RJ, Jones-Gotman M. Olfactory learning: convergent
findings from lesion and brain imaging studies in humans. Brain.
2002;125(Pt 1):86-101.
17. Levy LM, Henkin RI. Brain gamma-aminobutyric acid levels are
decreased in patients with phantageusia and phantosmia demonstrated by
magnetic resonance spectroscopy. J Comput Assist Tomogr.
2004;28(6):721-727.
18. Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and
gustatory dysfunctions as a clinical presentation of mild-to-moderate
forms of the coronavirus disease (COVID-19): a multicenter European
study. European archives of oto-rhino-laryngology : official journal of
the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) :
affiliated with the German Society for Oto-Rhino-Laryngology - Head and
Neck Surgery. 2020;277(8):2251-2261.
19. Yildirim D, Kandemirli SG, Tekcan Sanli DE, Akinci O, Altundag A. A
Comparative Olfactory MRI, DTI and fMRI Study of COVID-19 Related
Anosmia and Post Viral Olfactory Dysfunction. Acad Radiol. 2021.
20. Ho RC, Sharma VK, Tan BYQ, et al. Comparison of Brain Activation
Patterns during Olfactory Stimuli between Recovered COVID-19 Patients
and Healthy Controls: A Functional Near-Infrared Spectroscopy (fNIRS)
Study. Brain Sci. 2021;11(8).
21. Tragoonrungsea J, Tangbumrungtham N, Nitivanichsakul T,
Roongpuvapaht B, Tanjararak K. Corticosteroid Nasal Irrigation as Early
Treatment of Olfactory Dysfunction in COVID-19: A prospective randomized
controlled trial. Clinical otolaryngology : official journal of ENT-UK ;
official journal of Netherlands Society for Oto-Rhino-Laryngology &
Cervico-Facial Surgery. 2022.
22. Hosseinpoor M, Kabiri M, Rajati Haghi M, et al. Intranasal
Corticosteroid Treatment on Recovery of Long-Term Olfactory Dysfunction
Due to COVID-19. The Laryngoscope. 2022;132(11):2209-2216.
23. Kim DH, Kim SW, Kang M, Hwang SH. Efficacy of topical steroids for
the treatment of olfactory disorders caused by COVID-19: A systematic
review and meta-analysis. Clinical otolaryngology : official journal of
ENT-UK ; official journal of Netherlands Society for
Oto-Rhino-Laryngology & Cervico-Facial Surgery. 2022;47(4):509-515.
24. Vecera CM, Chong AC, Ruiz AC, et al. Chapter 6 - Magnetic Resonance
Spectroscopy in Bipolar Disorder. In: Machado-Vieira R, Soares JC, eds.
Biomarkers in Bipolar Disorders. Academic Press; 2022:95-113.
25. Khormali M, Heidari S, Ahmadi S, Arab Bafrani M, Baigi V,
Sharif-Alhoseini M. N-methyl-D-aspartate receptor antagonists in
improving cognitive deficits following traumatic brain injury: a
systematic review. Brain injury. 2022;36(9):1071-1088.