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 | Neurology | JAMA Neurology | JAMA Network
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January 22, 2021

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

Author Affiliations
  • 1Department of Neurology, Ibn Sina Hospital, Sabah Health Region, Kuwait
  • 2Department of Radiology, Ibn Sina Hospital, Sabah Health Region, Kuwait
  • 3Diagnostic Radiology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
JAMA Neurol. 2021;78(5):609-610. doi:10.1001/jamaneurol.2021.0009

A 25-year-old woman with no relevant medical history developed fever, generalized body pain, dry cough, anosmia, and ageusia in April 2020. She was diagnosed with coronavirus disease 2019 (COVID-19) by positive findings on polymerase chain reaction assay and positive findings on computed tomography of the chest. Her clinical course was uncomplicated, and she was treated conservatively. Anosmia and ageusia started to improve during the following month. However, during the recovery phase, she started to experience offensive odor (cacosmia) and taste (cacogeusia) with stimulation of these sensations. Ear, nose, and throat evaluation showed normal clinical and endoscopic nasal examination findings. Computed tomography findings of the paranasal sinuses were unremarkable. She was given oral and intranasal corticosteroids, in addition to multivitamins, zinc, and olfactory training. However, her symptoms persisted for 3 months, and she was referred to our neurology clinic for further evaluation. Findings of her neurological examination were normal.

Magnetic resonance imaging (MRI) of the brain revealed normal findings, including the olfactory bulbs and sulci, which showed no structural or signal abnormality (Figure 1A). A task-based functional MRI (fMRI) study was designed as alternating blocks of smell activation by a pleasant scent intervened with periods of rest. Blood oxygen level–dependent (BOLD) activation maps were generated and fused to T1-weighted multiplanar images. There was absent activation in the region of the orbitofrontal cortex (OFC), while the right uncus/piriform cortex demonstrated strong BOLD signal (Figure 1B and Figure 2).

Figure 1.  Functional Magnetic Resonance Imaging (MRI) of the Brain 3 Months After Coronavirus Disease 2019 Infection in a 25-Year-Old Woman
Functional Magnetic Resonance Imaging (MRI) of the Brain 3 Months After Coronavirus Disease 2019 Infection in a 25-Year-Old Woman

A, Axial T2-weighted image of the brain at the level of medial temporal lobes, gyrus rectus, and orbitofrontal gyrus showing no structural or signal abnormalities. B, Fused blood oxygen level–dependent (BOLD) map on coronal T1-weighted image showing no activation in the region of the orbitofrontal cortex.

Figure 2.  Functional Magnetic Resonance Imaging (MRI) of the Brain 3 Months After Coronavirus Disease 2019 Infection in a 25-Year-Old Woman
Functional Magnetic Resonance Imaging (MRI) of the Brain 3 Months After Coronavirus Disease 2019 Infection in a 25-Year-Old Woman

A, Fused blood oxygen level–dependent (BOLD) map on coronal T1-weighted image showing activation of the right uncus at the region of piriform cortex and at the anterior cingulate. B, Fused BOLD map on axial T1-weighted image showing 2 sites of activation of the right uncus at the region of piriform cortex. T map threshold approximately 40% to 50% (P < .05).

Discussion

The association of COVID-19 with olfactory and gustatory dysfunction is evident and recognized among its cardinal symptoms, although smell seems to be more affected than taste. In a 2020 meta-analysis,1 alteration in smell (dysosmia, hyposmia, and anosmia) and taste (dysgeusia, hypogeusia, and ageusia) was estimated to affect 52.7% and 43.9%, respectively, of patients recovered from COVID-19 infection. While olfactory dysfunction in association with viral infection can be secondary to peripheral causes (eg, nasal congestion and rhinitis), COVID-19 is less commonly associated with these symptoms, and a central cause of olfactory processing is thought to be the underlying etiology, based on the potential neurotropic features of severe acute respiratory syndrome coronavirus 2.1

Olfactory perception is a complex and sophisticated process that involves different parts of the brain. In normal individuals, several fMRI studies have shown an almost consistent pattern of BOLD activation of primary (eg, piriform cortex, amygdala, and entorhinal cortex) as well as secondary (eg, OFC, hypothalamus, and insula) olfactory areas. OFC contains the secondary and tertiary olfactory and gustatory cortex areas, where processing of this information occurs.2

There is accumulating evidence of implication of OFC in patients with COVID-19 with olfactory dysfunction. A recent study reported hypometabolism of OFC using fluorodeoxyglucose positron emission tomography, while another report documented right OFC hyperintensity on brain MRI with frontal electroencephalography abnormalities in such patients.3 Moreover, Politi et al4 described transient cortical fluid-attenuated inversion recovery hyperintensity in the right gyrus rectus, suggesting that severe acute respiratory syndrome coronavirus 2 might invade the brain through the olfactory pathway and cause an olfactory dysfunction of sensorineural origin.

The utility of fMRI in patients with COVID-19 is not well established, and to our knowledge, this is the first published report using fMRI in a patient with persistent cacosmia and cacogeusia after COVID-19 infection. Given these findings, we could suggest central olfactory pathway impairment, mainly involving OFC, may be involved in the underlying etiology of persistence of olfactory and gustatory symptoms in patients after COVID-19 infection.

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Article Information

Corresponding Author: Khaled A. Gad, MD, Department of Radiology, Ibn Sina Hospital, Gamal Abdel Nasser St, Sabah Health Region, Kuwait (khaledgad611@gmail.com).

Published Online: January 22, 2021. doi:10.1001/jamaneurol.2021.0009

Conflict of Interest Disclosures: None reported.

Additional Contributions: We thank the patient for granting permission to publish this information.

References
1.
Tong  JY, Wong  A, Zhu  D, Fastenberg  JH, Tham  T.  The prevalence of olfactory and gustatory dysfunction in COVID-19 patients: a systematic review and meta-analysis.   Otolaryngol Head Neck Surg. 2020;163(1):3-11. doi:10.1177/0194599820926473PubMedGoogle ScholarCrossref
2.
Weismann  M, Yousry  I, Heuberger  E,  et al.  Functional magnetic resonance imaging of human olfaction.   Neuroimaging Clin N Am. 2001;11(2):237-250, viii.PubMedGoogle Scholar
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Le Guennec  L, Devianne  J, Jalin  L,  et al.  Orbitofrontal involvement in a neuroCOVID-19 patient.   Epilepsia. 2020;61(8):e90-e94. doi:10.1111/epi.16612PubMedGoogle ScholarCrossref
4.
Politi  LS, Salsano  E, Grimaldi  M.  Magnetic resonance imaging alteration of the brain in a patient with coronavirus disease 2019 (COVID-19) and anosmia.   JAMA Neurol. 2020;77(8):1028-1029. doi:10.1001/jamaneurol.2020.2125PubMedGoogle ScholarCrossref
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    2 Comments for this article
    EXPAND ALL
    Neurotropism of SARS-CoV-2
    Ana cintra wittlin, Pós Graduação(Neurologia) |
    It has already been seen that there is no neurotropism of the virus that causes COVID-19 in the same way that HIV is not a neurotropic virus but that gets involved in the region through the lymphatic system.
    In the case of Coronavirus, the possible existence of the findings reported above must have their cause in vascularization, considering that the virus develops a series of embolic and thromboembolic reactions.
    In order to affirm that there is tropism of Coronavirus by the cerebral parenchyma and / or its structures, it would be almost mandatory the presence of the virus, or the marking of it or its residues in brain cells, which has not been found so far.
    There would have to be the same number of patients, or a very close number of patients, with cerebral and pulmonary involvement.
    I suggest that:
    1)If you have an anatomopathological examination of the cerebral parenchyma of all patients who died by Covid-19
    2)Make a careful assessment of the Pituitary, not only in living patients but also in those who have died.
    3)Look for a correlation of primary and secondary olfactory areas in normal patients and with Covid-19, and if both sides of the brain always correspond to BOLD activation (if there is no dominance or only one side is absolutely functional, for example), as well as cerebral angiography, with a good window for the middle cerebral artery, the anterior cerebral artery, and for the pituitary artery. Perhaps we would have some interesting answers.
    4)Evaluate the length of stay, the severity of the cases and the use of invasive procedures such as intubation, and others.
    All these data will help to correlate the presence of olfactory and gustatory changes that present themselves in a significant number of patients, to the point that it cannot be said that it is a fluke, with the persistent conditions in convalescence.
    A review of all cases, including the case above, would be of great value, especially because its transitory character speaks in favor of a vascular alteration that has occurred and to which the brain has achieved the necessary plasticity for recovery, quite different from the parenchymal alterations seen in different viruses.
    There are a few more possible correlations, but at the moment the most important would be these and a past pathological history, a social history (housing locations, sanitary conditions, products of daily use, most common zoonoses in the regions, etc.) and a history of places already visited and / or people with whom he lived from any region of the planet.
    CONFLICT OF INTEREST: None Reported
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    Cortical dysfunction might remain at cortical level in the smell and taste pathways after SARS-CoV-2 infection
    Calixto Machado, MD, PhD | Institute of Neurology and Neurosurgery, Havana, Cuba
    I read with interest the paper by Ismail and Gad. These authors demonstrated in a COVID-19 patient who developed during the recovery phase, offensive odor (cacosmia) and taste (cacogeusia). What is interesting in this case is that Magnetic resonance imaging (MRI) of the brain revealed normal findings, including the olfactory bulbs and sulci, showing no structural or signal abnormality. Nonetheless, by a task-based functional MRI (fMRI) study, these authors found that there was no activation in the region of the orbitofrontal cortex (OFC), while the right uncus/piriform cortex showed sturdy BOLD signal. (1)
    Anosmia and ageusia have been frequently reported
    in C0VID-19 patients, although smell seems to be more affected than taste. In fact, sense of smell functions and pathways are intricately related. SARS-CoV-2 is believed to enter the nasal and mouth tissues through the angiotensin converting enzyme 2 (ACE2), where this receptor is abundantly present. (2,3)
    The olfactory nerve connects the nasal cavity directly with the CNS and is a fast shortcut for SARS-CoV-2 into the CNS. The synapse between the first and second neurons of the olfactory pathway occur at the olfactory bulb. Axons of the second-order neurons follow a central route into the olfactory tract. The primary central projections of the olfactory bulb are the olfactory nucleus, olfactory tubercle, piriform cortex, amygdala, peri-amygdaloid cortex, insula, and the anterior part of the parahippocampal gyrus frontal gyrus. The corticomedial amygdala is connected to the anterior preoptic and ventromedial nucleus of the hypothalamus. The primary olfactory cortex sends information to the frontal lobe. (2,3) Casez et al. reported MRI findings which showed virus spread to cortical regions connected though neural pathways to the olfactory system.(4)
    Hence, the importance of the Ismail and Gad findings (1) indicate that cortical dysfunction might remain at cortical level in the smell and taste pathways, explaining the appearance of cacosmia and cacogeusia in their patient.
    References
    1. 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. . JAMA Neurol. 2021.
    2. Machado C, Machado Y, Chinchlla M, Sániová D. Anosmia and ageusia as initial symptoms after COVID-19 (Review Article). . Russian Journal of Anesthesiology and Reanimatology 2020;6(2):13-19.
    3. Machado C. Reader response: SARS-CoV-2 related encephalitis: MRI pattern of the olfactory tract involvement. Neurology. 2021
    4. Casez O, Willaume G, Grand S, et al. SARS-CoV-2 Related Encephalitis: MRI Pattern of the Olfactory Tract Involvement. Neurology. Nov 2020; 10.1212/WNL.0000000000011150; DOI: 10.1212/WNL.0000000000011150
    CONFLICT OF INTEREST: None Reported
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