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A Comparative Olfactory MRI, DTI and fMRI Study of COVID-19 Related Anosmia and Post Viral Olfactory Dysfunction
Abstract
Objective
: To evaluate how COVID-19 anosmia imaging findings resembled and differed from post-infectious olfactory dysfunction (OD).
Material and Methods
: A total of 31 patients presenting with persistent COVID-19 related OD and 97 patients with post-infectious OD were included. Olfactory bulb MRI, DTI and olfactory fMRI findings in both groups were retrospectively assessed.
Results
: All COVID-19 related OD cases were anosmic, 18.6% of post-infectious OD patients were hyposmic and remaining 81.4% were anosmic. Mean interval between onset of OD and imaging was 1.5 months for COVID-19 related OD and 6 months for post-infectious OD.
Olfactory bulb volumes were significantly higher in COVID-19 related OD than post-infectious OD. Deformed bulb morphology and increased olfactory bulb signal intensity was seen in 58.1% and 51.6% with COVID-19 related OD; and 63.9% and 46.4% with post-infectious OD; without significant difference. Significantly higher rate of olfactory nerve clumping and higher QA values at orbitofrontal and entorhinal regions were observed in COVID-19 related OD than post-infectious OD.
Absence of orbitofrontal and entorhinal activity showed no statistically significant difference between COVID-19 related OD and post-infectious OD, however trigeminosensory activity was more robust in COVID-19 related OD cases.
Conclusion
: Olfactory bulb damage may play a central role in persistent COVID-19 related anosmia. Though there is decreased olfactory bulb volume and decreased white matter tract integrity of olfactory regions in COVID-19 related anosmia, this is not as pronounced as in other post-infectious OD. Trigeminosensory activity was more robust in COVID-19 related OD. These findings may reflect better preserved central olfactory system in COVID-19 related OD compared to COVID-19 related OD.
... Thirteen studies used sMRI to investigate brain changes in PCCs [26,36,38,40,[46][47][48][49][50][51][52][53][54]. The most consistent findings were the decreased GM volume (GMV) and CTh in various brain regions. ...
... The most notably affected areas included the frontal, temporal, and parietal lobes, as well as the cerebellum, hippocampus, amygdala, and basal ganglia. Fourteen studies employed diffusion-based MRI techniques with particular emphasis on biomarkers such as FA, MD, RD, and AD [20,26,38,40,47,50,[52][53][54][55][56][57][58][59]. These studies mainly reported MD and RD alterations in WMTs, notably in the corpus callosum, corona radiata, superior longitudinal fasciculus (SLF), and frontal occipital fasciculus (FOF). ...
... These studies mainly reported MD and RD alterations in WMTs, notably in the corpus callosum, corona radiata, superior longitudinal fasciculus (SLF), and frontal occipital fasciculus (FOF). fMRI was used in nine studies, focusing mainly on changes in FC, amplitude of low-frequency fluctuations (ALFF), and brain activation in different networks and regions [21,36,40,52,53,56,58,60,61]. The most prevalent finding was variation in FC, particularly in the networks involved in cognition and olfaction. ...
Post-COVID conditions (PCCs) cover a wide spectrum of lingering symptoms experienced by survivors of coronavirus disease 2019 (COVID-19). Neurological and neuropsychiatric sequelae are common in PCCs. Advanced magnetic resonance imaging (MRI) techniques can reveal subtle alterations in brain structure, function, and perfusion that underlie these sequelae. This systematic review aimed to synthesize findings from studies that used advanced MRI to characterize brain changes in individuals with PCCs. A detailed literature search was conducted in the PubMed and Scopus databases to identify relevant studies that used advanced MRI modalities, such as structural MRI (sMRI), diffusion tensor imaging (DTI), functional MRI (fMRI), and perfusion-weighted imaging (PWI), to evaluate brain changes in PCCs. Twenty-five studies met the inclusion criteria, comprising 1219 participants with PCCs. The most consistent findings from sMRI were reduced gray matter volume (GMV) and cortical thickness (CTh) in cortical and subcortical regions. DTI frequently reveals increased mean diffusivity (MD), radial diffusivity (RD), and decreased fractional anisotropy (FA) in white matter tracts (WMTs) such as the corpus callosum, corona radiata, and superior longitudinal fasciculus. fMRI demonstrated altered functional connectivity (FC) within the default mode, salience, frontoparietal, somatomotor, subcortical, and cerebellar networks. PWI showed decreased cerebral blood flow (CBF) in the frontotemporal area, thalamus, and basal ganglia. Advanced MRI shows changes in the brain networks and regions of the PCCs, which may cause neurological and neuropsychiatric problems. Multimodal neuroimaging may help understand brain-behavior relationships. Longitudinal studies are necessary to better understand the progression of these brain anomalies.
... ], a finding also reported in an earlier study [11]. Looking specifically at magnetic resonance imaging (MRI), studies have shown limited utility and cost-effectiveness of its use in evaluating patients with COVID-19 OD [12,13]. One of the studies comparing MRI of patients with postinfectious OD reported olfactory bulb volume to be higher in post-COVID-19 OD as compared to other postinfectious OD (right: 60.3AE12.7 vs. 48.6AE15.4 ...
... mm 3 ; left: 59.5AE16.4 vs. 48.9 AE15.6 mm 3 , P < 0.001 and P ¼ 0.002 respectively), though there was similar olfactory bulb morphology and signal intensity between the different etiologies [12]. Olfactory functional MRI also showed no difference in orbitofrontal activity and entorhinal activity between these two groups, despite some increased trigeminosensory activity in post-COVID-19 OD (35.7% vs. 10.6%, ...
... Olfactory functional MRI also showed no difference in orbitofrontal activity and entorhinal activity between these two groups, despite some increased trigeminosensory activity in post-COVID-19 OD (35.7% vs. 10.6%, P ¼ 0.005) [12]. In one study, patients who underwent MRI for persistent post-COVID-19 OD (>2 months) had no change in the diagnosis or management of their condition, with up to 82% of MRIs done for this purpose considered normal by radiologists on initial impression [13]. ...
Purpose of review: The purpose of this review is to summarize the recent literature relating to viral, fungal and bacterial infections and their interactions within the sinonasal tract in the past 18 months.
Recent findings: Coronavirus disease 2019 (COVID-19)-associated olfactory dysfunction (OD) is variant dependent. Magnetic resonance imaging studies have found greater olfactory cleft opacification and higher olfactory bulb volume in post-COVID-19 OD. Olfactory training remains the mainstay of treatment, while platelet-rich plasma injections and ultramicronized palmitoylethanolamide and luteolin combination oral supplementation have shown early promise.Consensus statements on paranasal sinus fungal balls and acute invasive fungal sinusitis have been released.Studies on the nasal microbiome have reported Staphylococcus and Corynebacterium as the most abundant genera, with higher levels of Staphylococcus and Corynebacterium being found in patients with chronic rhinosinusitis (CRS) and healthy individuals respectively. However, there is conflicting evidence on the significance of biodiversity of the nasal microbiome found in CRS versus healthy patients.
Summary: While the peak of the COVID-19 pandemic is behind us, its sequelae continue to pose treatment challenges. Further studies in OD have implications in managing the condition, beyond those afflicted post-COVID-19 infection. Similarly, more research is needed in studying the nasal microbiome and its implications in the development and treatment of CRS.
... Olfactory and gustatory deficits are two prominent and well-recognised symptoms of the coronavirus disease 2019 (Covid- 19) infection, yet smell seems to be more compromised than taste. 1 Approximately half of the affected Covid-19 individuals show evidence, suggested by a meta-analysis, of a conductive mechanism of olfactory dysfunction localised within the olfactory cleft. 2 It is now established that anosmia or hyposmia serve as typical symptoms beneficial for the diagnosis of Covid-19. Acute olfactory dysfunction is characterised by a diminished or altered sense of smell persisting for 14 days or fewer, in the absence of chronic rhinosinusitis, previous head trauma or neurotoxic drug use. ...
... 11 Test results were conveyed as a numerical value ranging from 0 to 24, indicative of olfactory function. 12 This scale measures: anosmia (scores of 0-9), severe microsmia (scores of 10-13), mild microsmia (scores of [14][15][16][17][18] and normosmia (scores of [19][20][21][22][23][24]. 13 These evaluations were carried out in a sufficiently ventilated space by a resident doctor in otolaryngology. ...
... 18 Yildirim et al. analysed the olfactory functional MRI results of 97 individuals experiencing post-infectious olfactory dysfunction, in addition to 31 patients exhibiting chronic Covid-19-associated olfactory dysfunction. 19 Their study concluded that the olfactory bulb volumes were noticeably larger in Covid-19-associated olfactory dysfunction cases than in post-infectious olfactory dysfunction cases. However, they found no statistically significant difference regarding the lack of activity in the orbitofrontal and entorhinal regions. ...
Objective: Evaluating the fMRI changes in the olfactory structures of COVID-19 patients experiencing olfactory dysfunction.
Methods: We included patients aged between 25 and 65 years old, who presented with a sudden loss of smell, confirmed COVID-19 infection, and persistent olfactory dysfunction for a minimum of 2 months without any treatment.
Results: Irrespective of the side of activation, the analysis of the cumulative maximum diameter of the activation zones revealed significantly lower activation in the upper frontal lobe (p-value=0.037), and basal ganglia (p-value=0.023) in olfactory dysfunction (OD) patients. Irrespective of the side of activation, the analysis of the number of activation points demonstrated significantly lower activation in the upper frontal lobe (p-value=0.036) and basal ganglia (p-value=0.009) in OD patients.
Conclusion: Patients with COVID-19-triggered OD exhibited lower activity in their basal ganglia and upper frontal lobe.
... Many disorders affecting smell and taste have been connected to the COVID-19 gene. A major contributor to this result is the presence of significant differences in OB volume [74,90,91,[132][133][134][135][136]. In the most severe form of COVID-19 illness, OBs decrease relative to their normal size. ...
... In the most severe form of COVID-19 illness, OBs decrease relative to their normal size. If performed early enough, an MRI may be able to detect these alterations in the early stages of the disease, which might lead to an earlier and more accurate diagnosis of severe COVID-19 consequences [17,41,111,132,134,[136][137][138]. Although Lin et al. [51] and Eliezer et al. [133] didn't find any significant changes in OB volume in COVID-19 patients, two investigations did discover a change in OB volume and signal intensity [136,139]. ...
... If performed early enough, an MRI may be able to detect these alterations in the early stages of the disease, which might lead to an earlier and more accurate diagnosis of severe COVID-19 consequences [17,41,111,132,134,[136][137][138]. Although Lin et al. [51] and Eliezer et al. [133] didn't find any significant changes in OB volume in COVID-19 patients, two investigations did discover a change in OB volume and signal intensity [136,139]. The need for more research into brain structure and function is evident. ...
Objective:
Magnetic resonance imaging (MRI) of the brain or spine examines the findings as well as the time interval between the onset of symptoms and other adverse effects in coronavirus disease that first appeared in 2019 (COVID-19) patients. The goal of this study is to look at studies that use neuroimaging to look at neurological and neuroradiological symptoms in COVID-19 patients.
Methods:
We try to put together all of the research on how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes neurological symptoms and cognitive-behavioral changes and give a full picture.
Results:
We have categorized neuroimaging findings into subtitles such as: headache and dizziness; cerebrovascular complications after stroke; Intracerebral Hemorrhage (ICH); Cerebral Microbleeds (CMBs); encephalopathy; meningitis; encephalitis and myelitis; altered mental status (AMS) and delirium; seizure; neuropsychiatric symptoms; Guillain-Barre Syndrome (GBS) and its variants; smell and taste disorders; peripheral neuropathy; Mild Cognitive Impairment (MCI); and myopathy and myositis.
Conclusion:
In this review study, we talked about some MRI findings that show how COVID-19 affects the nervous system based on what we found.
... It may involve disrupting the olfactory system at different levels, from the sensory epithelium located in the olfactory clefts to olfactory neurons in the olfactory bulb and olfactory cortices (Xydakis et al., 2021). Previous magnetic resonance imaging (MRI) studies revealed a variety of abnormalities of both peripheral and central olfactory areas, including olfactory cleft obstruction, abnormalities in olfactory bulb signal intensity and atrophy, and, notably, neurodegenerative changes in the limbic structures involved in the processing of olfactory stimuli and cognitive functions, also in patients with persistent OD (Kandemirli et al., 2021;Keshavarz et al., 2021;Yildirim et al., 2022;Douaud et al., 2022;Capelli et al., 2023). Taskbased olfactory functional MRI (fMRI) in COVID-19-related OD revealed absent activation of the orbitofrontal cortex and a more robust activation in the trigeminosensory activity (Yildirim et al., 2022;Ismail and Gad, 2021). ...
... Previous magnetic resonance imaging (MRI) studies revealed a variety of abnormalities of both peripheral and central olfactory areas, including olfactory cleft obstruction, abnormalities in olfactory bulb signal intensity and atrophy, and, notably, neurodegenerative changes in the limbic structures involved in the processing of olfactory stimuli and cognitive functions, also in patients with persistent OD (Kandemirli et al., 2021;Keshavarz et al., 2021;Yildirim et al., 2022;Douaud et al., 2022;Capelli et al., 2023). Taskbased olfactory functional MRI (fMRI) in COVID-19-related OD revealed absent activation of the orbitofrontal cortex and a more robust activation in the trigeminosensory activity (Yildirim et al., 2022;Ismail and Gad, 2021). Resting-state fMRI (rs-fMRI) represents an innovative, alternative technique to study the functional connectivity (FC) of the olfactory network, which may provide additional elements to task-based fMRI, as regions involved in olfactory tasks are not necessarily chemosensory in nature or activated by active sniffing (Lu et al., 2019;Tobia et al., 2016). ...
... Similarly to Douad et al., we did not find any difference in the volumes of the manually segmented olfactory bulb between patients and controls. Contrastingly, a few previous neuroimaging reports described olfactory bulb atrophy and signal abnormalities in patients with COVID-19-related OD (Keshavarz et al., 2021;Yildirim et al., 2022), findings consistent with those of an autoptic study showing axon injury and microvasculopathy in the olfactory tissue (Ho et al., 2022). These discrepancies among neuroimaging studies may be explained by the localization of the olfactory bulbs in a region above the sinuses prone to susceptibility distortions and difficulties in segmenting MRI data (Douaud et al., 2022). ...
Objectives:
To explore the neuropsychological profile and the integrity of the olfactory network in patients with COVID-19-related persistent olfactory dysfunction (OD).
Methods:
Patients with persistent COVID-19-related OD underwent olfactory assessment with Sniffin' Sticks and neuropsychological evaluation. Additionally, both patients and a control group underwent brain MRI, including T1-weighted and resting-state functional MRI (rs-fMRI) sequences on a 3 T scanner. Morphometrical properties were evaluated in olfaction-associated regions; the rs-fMRI data were analysed using graph theory at the whole-brain level and within a standard parcellation of the olfactory functional network. All the MR-derived quantities were compared between the two groups and their correlation with clinical scores in patients were explored.
Results:
We included 23 patients (mean age 37 ± 14 years, 12 females) with persistent (mean duration 11 ± 5 months, range 2-19 months) COVID-19-related OD (mean score 23.63 ± 5.32/48, hyposmia cut-off: 30.75) and 26 sex- and age-matched healthy controls. Applying population-derived cut-off values, the two cognitive domains mainly impaired were visuospatial memory and executive functions (17 % and 13 % of patients). Brain MRI did not show gross morphological abnormalities. The lateral orbital cortex, hippocampus, and amygdala volumes exhibited a reduction trend in patients, not significant after the correction for multiple comparisons. The olfactory bulb volumes did not differ between patients and controls. Graph analysis of the functional olfactory network showed altered global and local properties in the patients' group (n = 19, 4 excluded due to artifacts) compared to controls. Specifically, we detected a reduction in the global modularity coefficient, positively correlated with hyposmia severity, and an increase of the degree and strength of the right thalamus functional connections, negatively correlated with short-term verbal memory scores.
Discussion:
Patients with persistent COVID-19-related OD showed an altered olfactory network connectivity correlated with hyposmia severity and neuropsychological performance. No significant morphological alterations were found in patients compared with controls.
... Nonetheless, to our knowledge, MRI-based evaluations of olfactory system alterations associated with COVID-19 are still limited to small investigational studies, case series, and case reports [12][13][14][15][16][17][18]. Only a few studies performing systematic, quantitative olfactory system measurements have been published so far, but still on quite small populations [19][20][21][22][23][24][25]. The high prevalence of OD in COVID-19 patients, its impact on the quality of life, and its possible association with the CNS manifestations, make the investigation of this phenomenon of considerable importance. ...
... These findings are in line with previous studies showing OB volume loss occurring in response to upper respiratory tract infections [28][29][30] and correlating with olfactory function [11,28,[31][32][33]. Moreover, our findings are also in line with previous case reports [14,17] and quantitative studies [20][21][22], still limited to quite small populations, reporting OB atrophy in patients with COVID-19 related anosmia. ...
... We found no significant evidence of FLAIR signal alteration within the OT in the COVID-19 patient group, except for few outliers. This result seems in contrast with previous case reports showing FLAIR hyperintensities in the OB and/ or OT of COVID-19 patients [12,15,19], and with few COVID-19 studies finding FLAIR OB hyperintensity in 12 COVID-19 patients with neurological symptoms compared with age-matched controls with olfactory dysfunction [21], in 19 anosmic COVID-19 patients [22], and in other 19 COVID-19 patients with persistent olfactory dysfunction [22]. However, beyond the limited sample size of the previous studies, likely causing possible outliers to significantly bias the results, there are several methodological details that may explain this discrepancy. ...
Background and objectiveDespite olfactory disorders being among the most common neurological complications of coronavirus disease 2019 (COVID-19), their pathogenesis has not been fully elucidated yet. Brain MR imaging is a consolidated method for evaluating olfactory system’s morphological modification, but a few quantitative studies have been published so far. The aim of the study was to provide MRI evidence of olfactory system alterations in patients with COVID-19 and neurological symptoms, including olfactory dysfunction.Methods196 COVID-19 patients (median age: 53 years, 56% females) and 39 controls (median age 55 years, 49% females) were included in this cross-sectional observational study; 78 of the patients reported olfactory loss as the only neurological symptom. MRI processing was performed by ad-hoc semi-automatic processing procedures. Olfactory bulb (OB) volume was measured on T2-weighted MRI based on manual tracing and normalized to the brain volume. Olfactory tract (OT) median signal intensity was quantified on fluid attenuated inversion recovery (FLAIR) sequences, after preliminary intensity normalization.ResultsCOVID-19 patients showed significantly lower left, right and total OB volumes than controls (p < 0.05). Age-related OB atrophy was found in the control but not in the patient population. No significant difference was found between patients with olfactory disorders and other neurological symptoms. Several outliers with abnormally high OT FLAIR signal intensity were found in the patient group.Conclusions
Brain MRI findings demonstrated OB damage in COVID-19 patients with neurological complications. Future longitudinal studies are needed to clarify the transient or permanent nature of OB atrophy in COVID-19 pathology.Graphical abstract
... After discussing with a third reviewer, one of these studies was included [31], and the rest were excluded. Ten studies were included for the narrative synthesis of the current review [4,5,31,[33][34][35][36][37][38][39]. Two of the included studies were excluded from the quantitative analysis due to the low number of participants in the control group [31,38]. ...
... Also, the only variable measured in the study of Tsivgoulis et al. was only reported in one study, and thus, we were not able to include this study in the meta-analysis [36]. Therefore, seven studies with 491 participants (183 cases with COVID-19 and 308 controls without COVID-19) were included in the meta-analysis [4,[33][34][35][36][37]39]. ...
... The most frequently reported structural measurements were right OB volume and left OB volume with six studies [4, 33-35, 37, 39], right OS depth and left OS depth with five studies [4,33,34,37,39], and signal intensity of OB with three studies [31,38,39]. Quality assessment of the included studies by the NOS scale indicated a fair status for most of the articles, with the total score ranging from two to seven (Table 2). ...
Purpose
The neurotropism of SARS-CoV-2 and the consequential damage to the olfactory system have been proposed as one of the possible underlying causes of olfactory dysfunction in COVID-19. We aimed to aggregate the results of the studies which reported imaging of the olfactory system of patients with COVID-19 versus controls.
Methods
PubMed and EMBASE were searched to identify relevant literature reporting the structural imaging characteristics of the olfactory bulb (OB), olfactory cleft, olfactory sulcus (OS), or olfactory tract in COVID-19 patients. Hedge’s g and weighted mean difference were used as a measure of effect size. Quality assessment, subgroup analyses, meta-regression, and sensitivity analysis were also conducted.
Results
Ten studies were included in the qualitative synthesis, out of which seven studies with 183 cases with COVID-19 and 308 controls without COVID-19 were enrolled in the quantitative synthesis. No significant differences were detected in analyses of right OB volume and left OB volume. Likewise, right OS depth and left OS depth were also not significantly different in COVID-19 cases compared to non-COVID-19 controls. Also, we performed subgroup analysis, meta-regression, and sensitivity analysis to investigate the potential effect of confounding moderators.
Conclusion
The findings of this review did not confirm alterations in structural imaging of the olfactory system, including OB volume and OS depth by Covid-19 which is consistent with the results of recent histopathological evaluations.
... Previous studies have demonstrated impaired activation of olfactoryrelated brain regions in PD patients 7,8 . In the context of PV olfactory dysfunction, the application of fMRI has shown no significant differences in terms of olfactory brain activity between COVID-19 and other PV patients 9 . ...
... This contradiction may be rooted in the fact that many PD patients are unaware of their olfactory dysfunction, potentially due to the gradual onset of olfactory loss, with adaptation over time 38 . A previous olfactory fMRI study, comparing COVID-19 related olfactory dysfunction with other postinfectious olfactory dysfunction, did not yield any significant differences in orbitofrontal or entorhinal activity 9 . ...
Olfactory dysfunction is a common feature of both postviral upper respiratory tract infections (PV) and idiopathic Parkinson's disease (PD). Our aim was to investigate potential differences in the connectivity of the posterior piriform cortex, a major component of the olfactory cortex, between PV and PD patients. Fifteen healthy controls (median age 66 years, 9 men), 15 PV (median age 63 years, 7 men) and 14 PD patients (median age 70 years, 9 men) were examined with task-based olfactory fMRI, including two odors: peach and fish. fMRI data were analyzed with the co-activation pattern (CAP) toolbox, which allows a dynamic temporal assessment of posterior piriform cortex (PPC) connectivity. CAP analysis revealed 2 distinct brain networks interacting with the PPC. The first network included regions related to emotion recognition and attention, such as the anterior cingulate and the middle frontal gyri. The occurrences of this network were significantly fewer in PD patients compared to healthy controls (p = 0.023), with no significant differences among PV patients and the other groups. The second network revealed a dissociation between the olfactory cortex (piriform and entorhinal cortices), the anterior cingulate gyrus and the middle frontal gyri. This second network was significantly more active during the latter part of the stimulation, across all groups, possibly due to habituation. Our study shows how the PPC interacts with areas that regulate higher order processing and how this network is substantially affected in PD. Our findings also suggest that olfactory habituation is independent of disease.
... Generally, N-acetyl-aspartate (NAA), choline (Cho), creatine (Cr), and their ratios are the most common metabolites of the brain that are detected by MRS. 1 In the last years, 2019 novel coronavirus disease (COVID- 19) infection has been a common cause of olfactory dysfunction. ...
... A few radiological studies (e.g., MRI, Diffusion tensor imaging, and olfactory functional magnetic resonance imaging) have indicated that the main pathology in COVID-19-related olfactory dysfunction is better justified by CNS dysfunction.19 Contrary to our results, Ho et al. suggest that COVID-19 infection may not have a role in frontotemporal cortex function because of the relatively normal oxyhemoglobin area under the curve in COVID-19-related anosmic patients comparing the healthy control group.20 ...
Objectives
2019 novel coronavirus disease (COVID‐19) infection is commonly associated with olfactory dysfunctions, but the basic pathogenesis of these complications remains controversial. This study seeks to evaluate the value of magnetic resonance spectroscopy (MRS) in determining the molecular neurometabolite alterations within the main brain olfactory areas in patients with COVID‐19‐related anosmia.
Methods
In a cross‐sectional study, seven patients with persistent COVID‐19‐related anosmia (mean age: 29.57 years) and seven healthy volunteers (mean age: 27.28 years) underwent MRS in which N‐acetyl‐aspartate (NAA), choline (Cho), creatine (Cr), and their ratios were measured in the anterior cingulate cortex, dorsolateral prefrontal cortex, orbitofrontal cortex (OFC), insular cortex, and ventromedial prefrontal cortex. Data were analyzed using TARQUIN software (version 4.3.10), and the results were compared with an independent sample t‐test and nonparametric Mann–Whitney test based on the normality of the MRS data distribution.
Results
The mean duration of anosmia before imaging was 8.5 months in COVID‐19‐related anosmia group. MRS analysis elucidated a significant association between MRS findings within OFC and COVID‐19‐related anosmia (Pdisease < 0.01), and NAA was among the most important neurometabolites (Pinteraction = 0.006). Reduced levels of NAA (P < 0.001), Cr (P < 0.001) and NAA/Cho ratio (P = 0.007) within OFC characterize COVID‐19‐related anosmia.
Conclusions
This study emphasizes that MRS can be illuminating in COVID‐19‐related anosmia and indicates a possible association between central nervous system impairment and persistent COVID‐19‐related anosmia.
... Generally, N-acetyl-aspartate (NAA), choline (Cho), creatine (Cr), and their ratios are the most common metabolites of the brain that are detected by MRS. 1 In the last years, 2019 novel coronavirus disease (COVID- 19) infection has been a common cause of olfactory dysfunction. ...
... A few radiological studies (e.g., MRI, Diffusion tensor imaging, and olfactory functional magnetic resonance imaging) have indicated that the main pathology in COVID-19-related olfactory dysfunction is better justified by CNS dysfunction.19 Contrary to our results, Ho et al. suggest that COVID-19 infection may not have a role in frontotemporal cortex function because of the relatively normal oxyhemoglobin area under the curve in COVID-19-related anosmic patients comparing the healthy control group.20 ...
... A recent work used diffusion tensor imaging (DTI) data to study white matter (WM) integrity in post COVID-19 patients with persistent olfactory dysfunction compared to post-infectious olfactory loss related to other pathogens. 11 This work points toward damage in the olfactory bulb and shows higher quantitative anisotropy in the orbitofrontal and entorhinal cortices but does not elucidate if this damage is also present in COVID-19 patients who have recovered their sense of smell. In the same line, structural connectivity derived from diffusion MRI data was found to be higher in COVID-19 patients than in healthy control subjects with no history of COVID-19 infection in the medial orbitofrontal subdivision. ...
... Structural changes in some of these structures have been reported elsewhere. 7,11,13,21 Some of these findings were located in regions functionally connected with the piriform olfactory cortex and anterior olfactory nucleus compared to healthy subjects. 13 However, this later work did not include an objective measure of olfaction, which does not allow the study of the relationship between olfactory dysfunction and underlying structural brain damage. ...
Objective:
This research aims to study structural brain changes in patients with persistent olfactory dysfunctions after coronavirus disease 2019 (COVID-19).
Methods:
COVID-19 patients were evaluated using T1-weighted and diffusion tensor imaging (DTI) on a 3T MRI scanner, 9.94 ± 3.83 months after COVID-19 diagnosis. Gray matter (GM) voxel-based morphometry was performed using FSL-VBM. Voxelwise statistical analysis of the fractional anisotropy, mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity was carried out with the tract-based spatial statistics in the olfactory system. The smell identification test (UPSIT) was used to classify patients as normal olfaction or olfactory dysfunction groups. Intergroup comparisons between GM and DTI measures were computed, as well as correlations with the UPSIT scores.
Results:
Forty-eight COVID-19 patients were included in the study. Twenty-three were classified as olfactory dysfunction, and 25 as normal olfaction. The olfactory dysfunction group had lower GM volume in a cluster involving the left amygdala, insular cortex, parahippocampal gyrus, frontal superior and inferior orbital gyri, gyrus rectus, olfactory cortex, caudate, and putamen. This group also showed higher MD values in the genu of the corpus callosum, the orbitofrontal area, the anterior thalamic radiation, and the forceps minor; and higher RD values in the anterior corona radiata, the genu of the corpus callosum, and uncinate fasciculus compared with the normal olfaction group. The UPSIT scores for the whole sample were negatively associated with both MD and RD values (p-value ≤0.05 FWE-corrected).
Interpretation:
There is decreased GM volume and increased MD in olfactory-related regions explaining prolonged olfactory deficits in post-acute COVID-19 patients.
... Moreover, only a small number of studies have simultaneously assessed chronic neuropsychological symptoms and carried out neuroimaging. In particular, to date, few studies have investigated functional connectivity in patients in longterm following SARS-CoV-2 infection (>3 months postinfection), or only in the acute phase (Benedetti et al., 2021;Esposito et al., 2022;Fischer et al., 2022;Yildirim et al., 2022) and considering psychiatric (Benedetti et al., 2021) or olfactory symptoms (Esposito et al., 2022;Yildirim et al., 2022). Nevertheless, Fu et al. (2021) identified pattern of functional connectivity, associated with post-traumatic stress disorder symptoms, revealing modifications in the sensorimotor and visual networks. ...
... Moreover, only a small number of studies have simultaneously assessed chronic neuropsychological symptoms and carried out neuroimaging. In particular, to date, few studies have investigated functional connectivity in patients in longterm following SARS-CoV-2 infection (>3 months postinfection), or only in the acute phase (Benedetti et al., 2021;Esposito et al., 2022;Fischer et al., 2022;Yildirim et al., 2022) and considering psychiatric (Benedetti et al., 2021) or olfactory symptoms (Esposito et al., 2022;Yildirim et al., 2022). Nevertheless, Fu et al. (2021) identified pattern of functional connectivity, associated with post-traumatic stress disorder symptoms, revealing modifications in the sensorimotor and visual networks. ...
Neuropsychological deficits and brain damage following SARS-CoV-2 infection are not well understood. Then, 116 patients, with either severe, moderate, or mild disease in the acute phase underwent neuropsychological and olfactory tests, as well as completed psychiatric and respiratory questionnaires at 223 ± 42 days postinfection. Additionally, a subgroup of 50 patients underwent functional magnetic resonance imaging. Patients in the severe group displayed poorer verbal episodic memory performances, and moderate patients had reduced mental flexibility. Neuroimaging revealed patterns of hypofunctional and hyperfunctional connectivities in severe patients, while only hyperconnectivity patterns were observed for moderate. The default mode, somatosensory, dorsal attention, subcortical, and cerebellar networks were implicated. Partial least squares correlations analysis confirmed specific association between memory, executive functions performances and brain functional connectivity. The severity of the infection in the acute phase is a predictor of neuropsychological performance 6-9 months following SARS-CoV-2 infection. SARS-CoV-2 infection causes long-term memory and executive dysfunctions, related to large-scale functional brain connectivity alterations.
... Dysregulations in resting state functional connectivity (rsFC) within and between major neural networks have been identified among COVID-19 survivors two weeks to six months after infection. These alternations were associated with cognitive deficits, fatigue, depression, psychological distress, and posttraumatic stress disorder (PTSD) symptoms (Benedetti et al., 2021;Esposito et al., 2022;Fu et al., 2021;Hafiz et al., 2022;Silva et al., 2021;Tu et al., 2021;Yildirim et al., 2022). ...
... Alterations in the olfactory brain network are associated with COVID-19 related hyposmia (Chung et al., 2021;Douaud et al., 2021;Esposito et al., 2022;Yildirim et al., 2022;Zhang et al., 2022). Although the pathogenesis of the post-COVID-19 condition is not yet determined, it was suggested that possible mechanisms include direct brain invasion of the virus, dysregulated immunologic responses, thrombotic disease, mitochondrial dysfunction and vascular injury with secondary tissue hypoxia (Silva Andrade et al., 2021;Yong and Liu, 2021). ...
Introduction:
Post-COVID-19 condition refers to a range of persisting physical, neurocognitive, and neuropsychological symptoms after SARS-CoV-2 infection. Abnormalities in brain connectivity were found in recovered patients compared to non-infected controls. This study aims to evaluate the effect of hyperbaric oxygen therapy (HBOT) on brain connectivity in post-COVID-19 patients.
Methods:
In this randomized, sham-controlled, double-blind trial, 73 patients were randomized to receive 40 daily sessions of HBOT (n = 37) or sham treatment (n = 36). We examined pre- and post-treatment resting-state brain functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) scans to evaluate functional and structural connectivity changes, which were correlated to cognitive and psychological distress measures.
Results:
The ROI-to-ROI analysis revealed decreased internetwork connectivity in the HBOT group which was negatively correlated to improvements in attention and executive function scores (p < 0.001). Significant group-by-time interactions were demonstrated in the right hippocampal resting state function connectivity (rsFC) in the medial prefrontal cortex (PFWE = 0.002). Seed-to-voxel analysis also revealed a negative correlation in the brief symptom inventory (BSI-18) score and in the rsFC between the amygdala seed, the angular gyrus, and the primary sensory motor area (PFWE = 0.012, 0.002). Positive correlations were found between the BSI-18 score and the left insular cortex seed and FPN (angular gyrus) (PFWE < 0.0001). Tractography based structural connectivity analysis showed a significant group-by-time interaction in the fractional anisotropy (FA) of left amygdala tracts (F = 7.81, P = 0.007). The efficacy measure had significant group-by-time interactions (F = 5.98, p = 0.017) in the amygdala circuit.
Conclusions:
This study indicates that HBOT improves disruptions in white matter tracts and alters the functional connectivity organization of neural pathways attributed to cognitive and emotional recovery in post-COVID-19 patients. This study also highlights the potential of structural and functional connectivity analysis as a promising treatment response monitoring tool.
... Regarding treatment, a pilot study in a small sample of patients included in Table II of this review using the Sniffin' sticks test reported that a 10-day treatment of oral corticosteroids associated with olfactory training led to significant improvement of the olfactory score compared to olfactory training alone 50 . In these radiological studies, abnormalities such as higher olfactory cleft width and volume 71,74 and decreased white matter tract integrity of olfactory regions were detected in COVID-19 patients 75 . In contrast, a post-mortem study on 85 COVID-19 deceased patients demonstrated that sustentacular cells are the main target in the olfactory mucosa, while olfactory sensory neurons and parenchyma of the olfactory bulb are not affected 91 . ...
... The debate concerning the pathogenesis of SARS-CoV-2 chemosensory dysfunction is still open and some studies have postulated that the viral-associated damage might be extended not only to the olfactory epithelium, but also to the olfactory bulb and the central nervous system 8 . Five studies[71][72][73][74][75] included inTable IIIused imaging techniques (i.e., computed tomography-CT scan, magnetic resonance imaging-MRI) to investigate chemosensory dysfunction in COVID-19 patients and contributed to the understanding of the mechanisms underlying smell and taste impairment. ...
Risultati dei test psicofisici olfattivi e gustativi durante l’infezione COVID-19: revisione della letteratura.
Riassunto: La maggioranza degli studi ha valutato la capacità olfattiva e gustativa nei pazienti COVID-19 con questionari e autovalutazione. Data l’eterogeneità della letteratura pubblicata, lo scopo di questa ‘review’ è stato quello di analizzare gli articoli sull’argomento, focalizzando l’attenzione sui test psicofisici. È stata eseguita una ricerca su PubMed e Web of Science da dicembre 2019 a novembre 2021. I principali criteri di inclusione sono stati articoli in lingua inglese, che studiavano le caratteristiche cliniche dell’olfatto e del gusto nei pazienti COVID-19 utilizzando test soggettivi, psicofisici e ‘imaging’ radiologico. In totale sono stati identificati 638 articoli e di questi ne sono stati inclusi 66. In 31 studi è stata eseguita una valutazione soggettiva, mentre in 30 sono stati utilizzati test psicofisici e in 5 tecniche di ‘imaging’ radiologico. La prevalenza della disfunzione chemosensoriale è stata l’argomento più studiato, seguita dal tempo di recupero. Per quanto riguarda la valutazione psicofisica, gli Sniffin’ Sticks sono stati utilizzati in 11 articoli e il test del Connecticut Chemosensory Clinical Research Center in altri 11. La performance della soglia olfattiva è stata la più intaccata rispetto alle capacità di discriminazione e identificazione in linea con l’ipotesi di un tropismo del virus COVID-19 per la mucosa olfattoria. La tempistica ha influenzato significativamente i risultati del test psicofisico con solo il 20% dei pazienti affetti da disfunzione olfattiva dopo un mese dall’infezione.
... 15 A large-scale study by Douaud et al. 16 investigated the morphological changes in the brain post-COVID and observed reduced thickness of grey matter in the orbitofrontal cortex and parahippocampal areas. A multi-sequence MRI study by Yildirim et al. 17 highlighted microstructural changes represented by higher anisotropy in the orbitofrontal and entorhinal cortices in COVID survivors using diffusion tensor imaging (DTI). The limbic regions and basal ganglia exhibited increased grey matter volumes and also showed significant correlations with fatigue in COVID-recovered subjects. ...
Delirium, memory loss, attention deficit and fatigue are frequently reported by COVID survivors, yet the neurological pathways underlying these symptoms are not well understood. To study the possible mechanisms for these long-term sequelae after COVID-19 recovery, we investigated the microstructural properties of white matter in Indian cohorts of COVID-recovered patients and healthy controls. For the cross-sectional study presented here, we recruited 44 COVID-recovered patients and 29 healthy controls in New Delhi, India. Using deterministic whole-brain tractography on the acquired diffusion MRI scans, we traced 20 white matter tracts and compared fractional anisotropy, axial, mean and radial diffusivity between the cohorts. Our results revealed statistically significant differences (PFWE < 0.01) in the uncinate fasciculus, cingulum cingulate, cingulum hippocampus and arcuate fasciculus in COVID survivors, suggesting the presence of microstructural abnormalities. Additionally, in a subsequent subgroup analysis based on infection severity (healthy control, non-hospitalized patients and hospitalized patients), we observed a correlation between tract diffusion measures and COVID-19 infection severity. Although there were significant differences between healthy controls and infected groups, we found no significant differences between hospitalized and non-hospitalized COVID patients. Notably, the identified tracts are part of the limbic system and orbitofrontal cortex, indicating microstructural differences in neural circuits associated with memory and emotion. The observed white matter alterations in the limbic system resonate strongly with the functional deficits reported in Long COVID. Overall, our study provides additional evidence that damage to the limbic system could be a neuroimaging signature of Long COVID. The findings identify targets for follow-up studies investigating the long-term physiological and psychological impact of COVID-19.
... by BBB impairment (24) and is accepted as a marker of subtle BBB impairment at the capillary level before there is gadolinium enhancement on standard MRI sequences (25). Both cortical grey and white matter injury have been a consistent feature of PASC (11,26,27), even in those with mild acute COVID-19. However, these studies have shown variable outcomes in DWI metrics with some showing increased FA and decreased MD (16) and others the opposite (7,14). ...
Objective
To investigate the association between blood–brain barrier permeability, brain metabolites, microstructural integrity of the white matter, and cognitive impairment (CI) in post-acute sequelae of SARS-COV-2 infection (PASC).
Methods
In this multimodal longitudinal MRI study 14 PASC participants with CI and 10 healthy controls were enrolled. All completed investigations at 3 months following acute infection (3 months ± 2 weeks SD), and 10 PASC participants completed at 12 months ± 2.22 SD weeks. The assessments included a standard neurological assessment, a cognitive screen using the brief CogState battery and multi-modal MRI derived metrics from Dynamic contrast enhanced (DCE) perfusion Imaging, Diffusion Tensor Imaging (DTI), and single voxel proton Magnetic Resonance Spectroscopy. These measures were compared between patients and controls and correlated with cognitive scores.
Results
At baseline, and relative to controls, PASC participants had higher K-Trans and Myo-inositol, and lower levels of Glutamate/Glutamine in the frontal white matter (FWM) (p < 0.01) as well as in brain stem (p < 0.05), and higher FA and lower MD in the FWM (p < 0.05). In PASC participants, FA and MD decreased in the FWM at 12 months compared to baseline (p < 0.05). K-Trans and metabolite concentrations did not change significantly over time. Neurocognitive scores did not correlation with the increased permeability (K trans).
Interpretation
PASC with CI is associated with BBB impairment, loss of WM integrity, and inflammation at 3 months which significantly but not uniformly improved at 12 months. The loss of WM integrity is possibly mediated by BBB impairment and associated glutamatergic excitotoxicity.
... This can provide valuable data for the study of PCS, offering a deeper understanding of the neurological implications of the disease. Rs-fMRI metrics such as ALFF and fALFF, as well as FC are some of the metrics that can be used to detect abnormalities and changes in intrinsic connectivity [23,47,[51][52][53][54][55][56][57][58] . ...
Long-term or post-COVID-19 syndrome (PCS) is a condition that affects people infected with severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus that causes coronavirus disease 2019 (COVID-19). PCS is characterized by a wide range of persistent or new symptoms that last months after the initial infection, such as fatigue, shortness of breath, cognitive dysfunction, and pain. Advanced magnetic resonance (MR) neuroimaging techniques can provide valuable information on the structural and functional changes in the brain associated with PCS as well as potential biomarkers for diagnosis and prognosis. In this review, we discuss the feasibility and applications of various advanced MR neuroimaging techniques in PCS, including perfusion-weighted imaging (PWI), diffusion-weighted imaging (DWI), susceptibility-weighted imaging (SWI), functional MR imaging (fMRI), diffusion tensor imaging (DTI), and tractography. We summarize the current evidence on neuroimaging findings in PCS, the challenges and limitations of these techniques, and the future directions for research and clinical practice. Although still uncertain, advanced MRI techniques show promise for gaining insight into the pathophysiology and guiding the management of COVID-19 syndrome, pending larger validation studies.
... Changes in the volume of OB may trigger persistent OD in COVID- 19 and there have been multiple observations of decreased OB volume in COVID-19 patients with OD [130][131][132]. The virus invades the CNS by penetrating the interface of neural-mucosal within olfactory mucosa, and then passes through the designated neuroanatomical locations [127]. ...
At present Coronavirus disease-2019 (COVID-19) is one of the leading contributing factor to mortality and the impact of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection on the sinonasal tract has become more prominent, particularly with the rising awareness of olfactory dysfunction (OD). We extracted data from published papers available in electronic databases (Wiley online library, PubMed, and Nature). We used the following search terms alone or with combinations - Olfactory dysfunction, SARS-CoV-2, mechanism and treatments. We found worldwide up to 98% of patients confirmed OD due to COVID-19. Current studies have implied that regardless of the high self-reported recovery rate, 25–40% of patients after 1 or 2 months and approximately 15%–28% of patients at six months struggle to fully restore their sense of smell. Moreover, female sex, younger and older age, active smoking, and chronic lung disease are reported as the associated risk factors of OD. Although the pathophysiological mechanism of action(s) of the OD is yet to be explored in depth, central nervous system (CNS) entrance, olfactory bulb (OB) and sustentacular cell damage, neural routes inflammation, non-neuronal cells damage, decreased OB volume and deregulation of olfactory receptor genes are among the commonly reported mechanisms for the development of OD.
... Another 1.5-month follow-up study found that olfactory bulb volume and white matter integrity of olfactory regions decreased in COVID-19 patients with anosmia. The results indicated that olfactory bulb injury might be the critical COVID-19-related olfactory dysfunction [17]. Yang et al. [18] demonstrated that 3-month follow-up recovered COVID-19 patients presented widespread white matter damage and abnormal white matter structure network in superior occipital gyrus. ...
Background
Although most patients can recover from SARS-CoV-2 infection during the short-term, the long-term effects of COVID-19 on the brain remain explored. Functional MRI (fMRI) could potentially elucidate or otherwise contribute to the investigation of the long COVID syndrome. A lower fMRI response would be translated into decreased brain activity or delayed signal transferring reflecting decreased connectivity. This research aimed to investigate the long-term alterations in the local (regional) brain activity and remote (interregional) functional connection in recovered COVID-19.
Methods
Thirty-five previously hospitalized COVID-19 patients underwent 3D T1weighed imaging and resting-state fMRI at 6-month follow-up, and 36 demographic-matched healthy controls (HCs) were recruited accordingly. The amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) was used to assess the regional intrinsic brain activity and the influence of regional disturbances on FC with other brain regions. Spearman correlation analyses were performed to evaluate the association between brain function changes and clinical variables.
Results
The incidence of neurosymptoms (6/35, 17.14%) decreased significantly at 6-month follow-up, compared with COVID-19 hospitalization stage (21/35, 60%). Compared with HCs, recovered COVID-19 exhibited higher ALFF in right precuneus, middle temporal gyrus, middle and inferior occipital gyrus, lower ALFF in right middle frontal gyrus and bilateral inferior temporal gyrus. Furthermore, setting seven abnormal activity regions as seeds, we found increased FC between right middle occipital gyrus and left inferior occipital gyrus, and reduced FC between right inferior occipital gyrus and right inferior temporal gyrus/bilateral fusiform gyrus, and between right middle frontal gyrus and right middle frontal gyrus/ supplementary motor cortex/ precuneus. Additionally, abnormal ALFF and FC were associated with clinical variables.
Conclusions
COVID-19 related neurological symptoms can self heal over time. Recovered COVID-19 presented functional alterations in right frontal, temporal and occipital lobe at 6-month follow-up. Most regional disturbances in ALFF were related to the weakening of short-range regional interactions in the same brain function.
... The orbitofrontal cortex, as the secondary olfactory cortex, plays an important role in the olfactory pathway [47]. COVID-19 might affect olfactory perception through the orbitofrontal cortex [16,48,49]. As this brain region is the core of the olfaction-emotion neural circuit, abnormal activation could lead to cacosmia and might further cause anxiety and depression in patients with COVID-19 [50,51]. ...
Background
Previous studies have found a correlation between coronavirus disease 2019 (COVID-19) and changes in brain structure and cognitive function, but it remains unclear whether COVID-19 causes brain structural changes and which specific brain regions are affected. Herein, we conducted a Mendelian randomization (MR) study to investigate this causal relationship and to identify specific brain regions vulnerable to COVID-19.
Methods
Genome-wide association study (GWAS) data for COVID-19 phenotypes (28,900 COVID-19 cases and 3,251,161 controls) were selected as exposures, and GWAS data for brain structural traits (cortical thickness and surface area from 51,665 participants and volume of subcortical structures from 30,717 participants) were selected as outcomes. Inverse-variance weighted method was used as the main estimate method. The weighted median, MR-Egger, MR-PRESSO global test, and Cochran’s Q statistic were used to detect heterogeneity and pleiotropy.
Results
The genetically predicted COVID-19 infection phenotype was nominally associated with reduced cortical thickness in the caudal middle frontal gyrus (β = − 0.0044, p = 0.0412). The hospitalized COVID-19 phenotype was nominally associated with reduced cortical thickness in the lateral orbitofrontal gyrus (β = − 0.0049, p = 0.0328) and rostral middle frontal gyrus (β = − 0.0022, p = 0.0032) as well as with reduced cortical surface area of the middle temporal gyrus (β = − 10.8855, p = 0.0266). These causal relationships were also identified in the severe COVID-19 phenotype. Additionally, the severe COVID-19 phenotype was nominally associated with reduced cortical thickness in the cuneus (β = − 0.0024, p = 0.0168); reduced cortical surface area of the pericalcarine (β = − 2.6628, p = 0.0492), superior parietal gyrus (β = − 5.6310, p = 0.0408), and parahippocampal gyrus (β = − 0.1473, p = 0.0297); and reduced volume in the hippocampus (β = − 15.9130, p = 0.0024).
Conclusions
Our study indicates a suggestively significant association between genetic predisposition to COVID-19 and atrophy in specific functional regions of the human brain. Patients with COVID-19 and cognitive impairment should be actively managed to alleviate neurocognitive symptoms and minimize long-term effects.
... Infection with SARS-CoV-2 could affect the olfactory bulb and other olfaction-related brain regions. The average volume of the olfactory bulb and tract was significantly reduced in COVID-19 patients compared with the control (Altunisik et al., 2021;Yildirim et al., 2022). Douaud et al. (2022) found that the gray matter thickness of the OFC and the parahippocampal gyrus decreased among COVID-19 cases, which echoes the histological findings that ischemic injury was observed through the hippocampal CA1 region and the surrounding parahippocampal region (Fabbri et al., 2021). ...
Olfactory dysfunction and neuropsychiatric symptoms are commonly reported by patients of coronavirus disease 2019 (COVID-19), a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence from recent research suggests linkages between altered or loss of smell and neuropsychiatric symptoms after infection with the coronavirus. Systemic inflammation and ischemic injury are believed to be the major cause of COVID-19-related CNS manifestation. Yet, some evidence suggest a neurotropic property of SARS-CoV-2. This mini-review article summarizes the neural correlates of olfaction and discusses the potential of trans-neuronal transmission of SARS-CoV-2 or its particles within the olfactory connections in the brain. The impact of the dysfunction in the olfactory network on the neuropsychiatric symptoms associated with COVID-19 will also be discussed.
... Researchers have been studying the phenomenon, including its pathogeny, symptoms, duration, and recovery. Evidence implies characteristics unique from the obstructive etiology of the olfactory impairment in other viral upper respiratory tract infections, since there is a decreased incidence of sinonasal symptoms in COVID-19 associated olfactory impairment, while the pathogenesis of COVID-19 anosmia is still under question [7,8]. Olfactory recess obstruction/inflammation and/or olfactory bulb injury are suggested causes of COVID-19 anosmia [9]. ...
Background:
Olfactory impairment is a major symptom of COVID-19. Is it necessary for COVID-19 patients to perform the detection of olfactory function, even how to select the olfactory psychophysical assessment tool.
Methods:
Patients infected with SARS-CoV-2 Delta variant were firstly taken into three categories (mild, moderate, and severe) according to the clinical classification. The Odor Stick Identification Test for the Japanese (OSIT-J) and the Simple Olfactory Test were used to assess olfactory function. Moreover, these patients were divided into three groups based on the results of the olfactory degree (euosmia, hyposmia, and dysosmia), too. The statistical analysis of the correlations between olfaction and clinical characteristics of patients were performed.
Results:
Our study demonstrated that the elderly men of Han were more susceptible to infected SARS-CoV-2, the clinical symptoms of the COVID-19 patients showed a clear correspondence with the disease type and the degree of olfactory disturbance. Whether or not to vaccinate and whether to complete the whole course of vaccination was closely related to the patient's condition. OSIT-J Test and Simple Test were consistent in our work, indicating that olfactory grading would worsen with the aggravation of symptoms. Furthermore, the OSIT-J method maybe better than Simple Olfactory Test.
Conclusion:
The vaccination has an important protective effect on the general population, and vaccination should be vigorously promoted. Moreover, it is necessary for COVID-19 patients to perform the detection of olfactory function, and the easier, faster and less expensive method for determination of olfactory function should be utilized to COVID-19 patients as the vital physical examination.
... During the COVID-19 pandemic, centers for smell and taste disorders have also started focusing on novel testing methods and smell tests when evaluating anosmia and parosmia. While not all are used in current clinical practices, methods such as surveys, evaluation forms, neurocognitive tests, parosmia-specific odor identification tests, fMRI, MRI, PET/ CT, and gas chromatography have all helped smell and taste specialists investigate the chemical basis of smell even more in-depth [38,[45][46][47][48][49][50][51]. The previously mentioned parosmiaspecific surveys and tests make it easier for clinicians to keep track of patient progress, and for patients to stay on top of their treatment process. ...
Purpose of Review
The purpose of this review was to summarize the current knowledge on parosmia and phantosmia and introduce support and treatment algorithms for the two qualitative olfactory disorders.
Recent Findings
Recent literature regarding parosmia has revealed that patients with the disorder are mainly triggered by certain substances, including thiols and pyrazines. In 2015, the existing “olfactory training” regimen was improved to more effectively treat post-infectious olfactory loss and was named “modified olfactory training” (MOT). It was also found in 2022 that MOT is also effective against COVID-19-induced parosmia.
Summary
Parosmia, the distortion of smells, is a symptom in qualitative olfactory disorders that severely affects patients’ mental well-being and enjoyment of their everyday lives. The condition was first documented in 1895 and can affect up to 5% of the general population. Etiologies of parosmia include sinonasal diseases, viruses, surgeries, traumatic brain injury, neurological and psychiatric conditions, toxic chemicals, and medications. Parosmia has seen a surge in cases since the onset of the COVID-19 pandemic and is linked to changes in brain structure following an infection. The evaluation of the symptom is done using surveys, smell identification tests, fMRI, MRI, PET/CT, and gas chromatography. Treatment for parosmia can vary in duration, which makes it essential to focus not only on helping the patients regain normosmia, but also on supporting the patient through the recovery journey. Parosmia should not be confused with phantosmia, in which the distortion of smells occurs in the absence of olfactory stimuli. The etiology of phantosmia can vary from infections and traumatic brain injury to psychiatric disorders like schizophrenia. Unlike parosmia, the treatment of phantosmia is less straightforward, with an emphasis on determining the etiology and providing symptomatic relief.
... Когда нейроны обонятельных рецепторов умирают, для их замены требуется от 8 до 10 дней [42,43], а также около [31,44]. Таким образом, функциональное восстановление после аносмии происходит быстрее, чем время, необходимое для замены нейронов, созревания ресничек и роста новых аксонов из обонятельного эпителия через решетчатую пластинку для формирования синапсов в обонятельной луковице [27,29]. ...
... Significant reductions were also present in the olfactory tract lengths and sulcus depths. Nevertheless, one study found the decrement in olfactory bulb size of 31 COVID-19 patients evaluated over 1 month since illness onset was less pronounced than that seen in 97 non-COVID-19 PVOD cases [110]. ...
Decreased smell function is related to brain health, future mortality, and quality of life. Most people inflicted with the SARS-CoV-2 virus evidence some measurable smell dysfunction during its acute phase, although many are unaware of the loss. Long-term deficits occur in up to 30% of COVID-19 cases, although total anosmia is relatively rare. This review explores what is presently known about the nature and pathophysiology of olfactory dysfunction due to the SARS-CoV-2 virus, including reversible inflammation within the olfactory cleft, downregulation of olfactory receptor proteins, and long-lasting peripheral and central damage to olfactory structures. It also addresses the question as to whether long-term smell loss might increase the likelihood of future development of cognitive and neurological deficits.
... However, fMRI tractography brought into discussion the fact that the structural changes take time and that the imaging studies are performed with priority in COVID-19 cases compared with past cases with anosmia induced by other viruses. Also, there was no significant difference in orbitofrontal and entorhinal activity between COVID-19-related anosmia and post-infectious anosmia, whereas trigeminosensory activity was more robust in COVID-19-related anosmia (8) . ...
After contracting COVID-19, a substantial number of individuals develop a Post-COVID-Condition, marked by neurologic symptoms such as cognitive deficits, olfactory dysfunction, and fatigue. Despite this, biomarkers and pathophysiological understandings of this condition remain limited. Employing magnetic resonance imaging, we conduct a comparative analysis of cerebral microstructure among patients with Post-COVID-Condition, healthy controls, and individuals that contracted COVID-19 without long-term symptoms. We reveal widespread alterations in cerebral microstructure, attributed to a shift in volume from neuronal compartments to free fluid, associated with the severity of the initial infection. Correlating these alterations with cognition, olfaction, and fatigue unveils distinct affected networks, which are in close anatomical-functional relationship with the respective symptoms.
Olfactory dysfunction (OD) is one of the most common symptoms in COVID-19 patients and can impact patients’ lives significantly. The aim of this review was to investigate the multifaceted impact of COVID-19 on the olfactory system and to provide an overview of magnetic resonance (MRI) findings and neurocognitive disorders in patients with COVID-19-related OD. Extensive searches were conducted across PubMed, Scopus, and Google Scholar until 5 December 2023. The included articles were 12 observational studies and 1 case report that assess structural changes in olfactory structures, highlighted through MRI, and 10 studies correlating the loss of smell with neurocognitive disorders or mood disorders in COVID-19 patients. MRI findings consistently indicate volumetric abnormalities, altered signal intensity of olfactory bulbs (OBs), and anomalies in the olfactory cortex among COVID-19 patients with persistent OD. The correlation between OD and neurocognitive deficits reveals associations with cognitive impairment, memory deficits, and persistent depressive symptoms. Treatment approaches, including olfactory training and pharmacological interventions, are discussed, emphasizing the need for sustained therapeutic interventions. This review points out several limitations in the current literature while exploring the intricate effects of COVID-19 on OD and its connection to cognitive deficits and mood disorders. The lack of objective olfactory measurements in some studies and potential validity issues in self-reports emphasize the need for cautious interpretation. Our research highlights the critical need for extensive studies with larger samples, proper controls, and objective measurements to deepen our understanding of COVID-19’s long-term effects on neurological and olfactory dysfunctions.
Introduction. The most common clinical symptoms of coronavirus disease 2019 include cough, high body temperature, malaise, weakness, headache, and diarrhea. When the pandemic slowed down, more and more patients reported symptoms atypical for the infection, such as hearing loss, tinnitus, and vertigo. The aim of this study was to assess current knowledge and data on the existence and prevalence of otorhinolaryngology sings and symptoms of coronavirus disease 2019. Material and Methods. The literature was reviewed from May to December 2022 and included articles published in 2020 or later. The main criterion was confirmed severe acute respiratory syndrome coronavirus 2 infection by means of the polymerase chain reaction test. Results. Sensorineural hearing loss presents as acute, chronic and subclinical. Tinnitus is associated with direct viral invasion and social factors. Vertigo is also associated with direct viral invasion and prolonged bed rest. Olfactory and gustatory disorders are known symptoms of viral infections. Olfactory dysfunction occurs as a consequence of the existence of angiotensin-converting enzyme 2 receptors in the nasal mucosa, which is the primary site for viral binding, and which explains the absence of nasal congestion. It has been shown that the pediatric population presents with different clinical symptoms of the infection. In children, rhinorrhea and pharyngitis are the most common symptoms, while in adults they are generally absent. Conclusion. The available literature data showed that otorhinolaryngology symptomatology of coronavirus disease 2019 is present, but the data are still very limited. The literature showed vast discrepancies in the prevalence and risk factors associated with coronavirus disease 2019. It is imperative that more research is done on the topic now that the pandemic is subsiding, and more attention should be paid to non-life-threatening symptoms.
Objectives
The aims of the study are to explore the morphological changes of olfactory bulb (OB) and olfactory sulcus in COVID-19 patients with associated olfactory dysfunction (OD) by measuring the OB volume (OBV) and olfactory sulcus depth (OSD) and to compare the measurement values with those of healthy individuals.
Methods
Between March 2020 and January 2022, 31 consecutive hospitalized patients with a diagnosis of COVID-19 with anosmia and hyposmia who underwent brain magnetic resonance imaging and 35 normosmic control individuals were retrospectively included in the study. Bilateral OBV and OSD were measured and shape of the OB was determined based on the consensus by a neuroradiologist and an otorrhynolaryngologist.
Results
The mean measurements for the right and the left sides for OBV (38 ± 8.5 and 37.1 ± 8.4, respectively) and OSD (7.4 ± 0.1 and 7.4 ± 1.0 mm, respectively) were significantly lower in COVID-19 patients with OD than those in control group (for the right and the left sides mean OBV 56.3 ± 17.1 and 49.1 ± 13.5, respectively, and mean OSD 9.6 ± 0.8 and 9.4 ± 0.8 mm, respectively). Abnormally shaped OB (lobulated, rectangular, or atrophic) were higher in patient group than those of controls.
For the optimal cutoff values, OBV showed sensitivity and specificity values of 90.32% and, 57.14%, for the right, and 87.1% and 62.86% for the left side, respectively (area under the curve, 0.819 and 0.780). Olfactory sulcus depth showed sensitivity and specificity values of 90.32% and 94.29%, for the right, and 96.77% and 85.71%, for the left side, respectively (area under the curve, 0.960 and 0.944).
Conclusions
Decrease in OBV and OSD measurements in COVID-19 patients with OD at the early chronic stage of the disease supports direct damage to olfactory neuronal pathways and may be used to monitor olfactory nerve renewal while returning back to normal function.
Olfaction is one of the five basic human senses, and it is known to be one of the most primitive senses. The sense of olfaction may have been critical for human survival in prehistoric society, and although many believe its importance has diminished over time, its impact on human interaction, bonding, and propagation of the species remains. Even if we are unaware of it, the sense of smell greatly affects our lives. Sense of smell is closely related to overall quality of life and health. However, olfaction has been neglected from a scientific perspective compared to other senses. Olfaction has recently received substantial attention since the loss of smell and taste has been noted as a key symptom of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Studies investigating olfaction loss in association with coronavirus disease 2019 (COVID-19) have revealed that olfactory dysfunction can be both conductive and sensorineural, possibly causing structural changes in the brain. Olfactory training is one of the effective treatments for olfactory dysfunction, suggesting the reorganization of neural associations. Reduced ability to smell may also alert suspicion for neurodegenerative or psychiatric disorders. Here, we summarize the basic knowledge that we, as otorhinolaryngologists, should have about the sense of smell and the peripheral and central olfactory pathway for managing and helping patients with olfactory dysfunction.
Respiratory tract viruses are the second leading cause of olfactory dysfunction. Between 2019 to 2022, the world has been plagued by the problem of olfaction caused by the COVID-19. As we learn more about the impact of severe acute respiratory syndrome coronavirus 2（SARS-CoV-2）, with the recognition that olfactory dysfunction is a key symptom of this disease process, there is a greater need than ever for evidence-based management of postinfectious olfactory dysfunction（PIOD）. The Clinical Olfactory Working Group has proposed theconsensus on the roles of PIOD. This paper is the detailed interpretation of the consensus.
Objectives: COVID-19 infection is commonly associated with olfactory dysfunctions, but the basic pathogenesis of these complications remains controversial. This study seeks to evaluate the value of magnetic resonance spectroscopy (MRS) in determining the molecular neurometabolite alterations within the main brain olfactory areas in patients with COVID-19 related anosmia. Methods: In a cross-sectional study, seven patients with persistent COVID19 related anosmia (mean age: 29.57 years) and seven healthy volunteers (mean age: 27.28 years) underwent MRS in which N-acetyl-aspartate (NAA), choline (Cho), creatine (Cr) and their ratios were measured in the anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), insular cortex (IC) and ventromedial prefrontal cortex (VMPFC). Data were analyzed using TARQUIN software (version 4.3.10), and the results were compared with an independent sample T test and non-parametric Mann-Whitney test based on the normality of the MRS data distribution. Results: The mean duration of anosmia before imaging was 8.5 months. MRS analysis elucidated a significant association between MRS findings within OFC and COVID-19 related anosmia (Pdisease<0.01), and NAA was among the most important neurometabolites (Pinteraction=0.006). Reduced levels of NAA (P<0.001), Cr (P<0.001) and NAA/Cho ratio (p=0.007) within OFC characterize COVID-19 related anosmia. Conclusions: This study emphasizes that MRS can be illuminating in COVID-19 related anosmia and indicates a possible association between central nervous system impairment and persistent COVID-19 related anosmia.
Objetivo: Discutir a anosmia após um quadro infeccioso por Covid-19 e suas principais características e implicações na saúde humana. Revisão Bibliográfica: Como principais fatores de risco levantados pela presente revisão, tem-se a idade e o sexo, sendo a anosmia mais frequente em pacientes com idade de 40 a 50 anos e pacientes do sexo feminino. Além da perda do olfato, fica evidente a possibilidade de surgirem outras comorbidades, como modificações morfofuncionais do Sistema Nervoso Central (SNC). Apesar dos mecanismos por trás da anosmia pós Covid-19 ainda serem incertos, tem-se como causas mais prováveis aquelas relacionadas ao comprometimento de estruturas do neuroepitélio olfatório. O exposto demonstra também não haver comprovação de tratamento farmacológico isolado eficaz para a anosmia, contudo, dependendo da gravidade e persistência de cada caso, é possível utilizar terapias não farmacológicas na tentativa de reestimular o olfato, tendo estas eficácia comprovada. Considerações Finais: Apesar de uma variedade considerável de informações sobre o tema, é evidente a necessidade de mais estudos sobre o assunto em face de algumas lacunas a serem preenchidas. Contudo, o artigo conseguiu trazer uma discussão abrangente e complexa, contemplando os vários objetivos esperados.
Background:
Acute neurological sequela in patients with COVID-19 infection include acute thromboembolic infarcts related to cytokine storm and post infectious immune activation resulting in a prothrombotic state. Radiologic imaging studies of the sinonasal tract and mastoid cavity in patients with COVID-19 infection are sparse and limited to case series. In this report, we investigate the radiologic involvement of nasal cavity, nasopharynx, paranasal sinuses, and mastoid cavity in patients with SARS-CoV-2 infection who presented with acute neurological symptoms.
Methods:
Retrospective review of medical records and neuroradiologic imaging in patients diagnosed with acute COVID-19 infection who presented with acute neurological symptoms to assess radiologic prevalence of sinus and mastoid disease and its correlation to upper respiratory tract symptoms.
Results:
Of the 55 patients, 23 (42%) had partial sinus opacification, with no evidence for complete sinus opacification. The ethmoid sinus was the most commonly affected (16/55 or 29%). An air fluid level was noted in 6/55 (11%) patients, most commonly in the maxillary sinus. Olfactory recess and mastoid opacification were uncommon. There was no evidence of bony destruction in any of the studies, Cough, nasal congestion, rhinorrhea, and sore throat were not significantly associated with any radiological findings.
Conclusion:
In patients who present with acute neurological symptoms, COVID-19 infection is characterized by limited and mild mucosal disease within the sinuses, nasopharynx and mastoid cavity.
Level of evidence:
4.
The complete features of the neurological complications of coronavirus disease 2019 (COVID-19) still need to be elucidated, including associated cranial nerve involvement. In the present study we describe cranial nerve lesions seen in magnetic resonance imaging (MRI) of six cases of confirmed COVID-19, involving the olfactory bulb, optic nerve, abducens nerve, and facial nerve. Cranial nerve involvement was associated with COVID-19, but whether by direct viral invasion or autoimmunity needs to be clarified. The development of neurological symptoms after initial respiratory symptoms and the absence of the virus in the cerebrospinal fluid (CSF) suggest the possibility of autoimmunity.
Objectives
Sudden loss of smell is a very common symptom of coronavirus disease 19 (COVID-19). This study characterizes the structural and metabolic cerebral correlates of dysosmia in patients with COVID-19.
Methods
Structural brain magnetic resonance imaging (MRI) and positron emission tomography with [18F]-fluorodeoxyglucose (FDG-PET) were prospectively acquired simultaneously on a hybrid PET-MR in 12 patients (2 males, 10 females, mean age: 42.6 years, age range: 23–60 years) with sudden dysosmia and positive detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on nasopharyngeal swab specimens. FDG-PET data were analyzed using a voxel-based approach and compared with that of a group of healthy subjects.
Results
Bilateral blocking of the olfactory cleft was observed in six patients, while subtle olfactory bulb asymmetry was found in three patients. No MRI signal abnormality downstream of the olfactory tract was observed. Decrease or increase in glucose metabolism abnormalities was observed (p < .001 uncorrected, k ≥ 50 voxels) in core olfactory and high-order neocortical areas. A modulation of regional cerebral glucose metabolism by the severity and the duration of COVID-19-related dysosmia was disclosed using correlation analyses.
Conclusions
This PET-MR study suggests that sudden loss of smell in COVID-19 is not related to central involvement due to SARS-CoV-2 neuroinvasiveness. Loss of smell is associated with subtle cerebral metabolic changes in core olfactory and high-order cortical areas likely related to combined processes of deafferentation and active functional reorganization secondary to the lack of olfactory stimulation.
Objective: This study aimed to define the clinical course of anosmia in relation to other clinical symptoms.
Methods: 135 patients with COVID-19 were reached by phone and subsequently included in the study. Olfactory functions were evaluated using a questionnaire for assessment of self-reported olfactory function. Patients were divided into four subgroups according to the presence of olfactory symptoms and temporal relationship with the other symptoms: group1 had only olfactory complaints (isolated, sudden-onset loss of smell); group2 had sudden-onset loss of smell, followed by COVID-19 related complaints; group3 initially had COVID-19 related complaints, then gradually developed olfactory complaints; and group4 had no olfactory complaints.
Results: In total, 59.3% of the patients interviewed had olfactory complaints during the disease course. The olfactory dysfunction severity during COVID-19 infection was significantly higher in group1 compared to groups 2 and 3. In groups1-3, the odor scores after recovery from COVID-19 disease were significantly lower compared to the status prior to disease onset. The residual olfactory dysfunction was similar between groups1 and 2, but was more evident than group3. Mean duration for loss of smell was 7.8 ± 3.1 (2-15) days. Duration of loss of smell was longer in groups1 and 2 than in group3. Odor scores completely returned back to the pre-disease values in 41 (51.2%) patients with olfactory dysfunction. Rate of complete olfactory dysfunction recovery was higher in group3 compared to groups1 and 2.
Conclusion: In isolated anosmia cases, anosmia is more severe, and complete recovery rates are lower compared to the patients who have other clinical symptoms.
Introduction: To evaluate the recovery rate of loss of smell (LOS) with objective olfactory testing in COVID-19 patients.
Methods: Adults with confirmed COVID-19 and self-reported sudden LOS were prospectively recruited through a public call from the University of Mons (Belgium). Epidemiological and clinical data were collected using online patient-reported outcome questionnaires. Patients benefited from objective olfactory evaluation (Sniffin-Sticks-test) and were invited to attend for repeated evaluation until scores returned to normal levels.
Results: From March 22 to May 22, 2020, 88 patients with sudden-onset LOS completed the evaluations. LOS developed after general symptoms in 44.6% of cases. Regarding objective evaluation, 22 patients (25.0%) recovered olfaction within 14 days following the onset of LOS. The smell function recovered between the 16th and the 70th day post-LOS in 48 patients (54.5%). At the time of final assessment at 2 months, 20.5% of patients (N = 18) had not achieved normal levels of olfactory function. Higher baseline severity of olfactory loss measured using Sniffin-Sticks was strongly predictive of persistent loss (p < 0.001).
Conclusion: In the first 2 months, 79.5% of patients may expect to have complete recovery of their olfactory function. The severity of olfactory loss, as detected at the first Sniffin-Sticks-test, may predict the lack of mid-term recovery.
Background and purpose
There is limited literature consisting of case reports or series on olfactory bulb imaging in COVID-19 olfactory dysfunction. An imaging study with objective clinical correlation is needed in COVID-19 anosmia in order to better understand underlying pathogenesis.
Material and methods
We evaluated 23 patients with persistent COVID-19 olfactory dysfunction. Patients included in this study had a minimum 1-month duration between onset of olfactory dysfunction and evaluation. Olfactory functions were evaluated with Sniffin’ Sticks Test. Paranasal sinus CTs and MRI dedicated to olfactory nerves were acquired. On MRI, quantitative measurements of olfactory bulb volumes and olfactory sulcus depth and qualitative assessment of olfactory bulb morphology, signal intensity and olfactory nerve filia architecture were performed.
Results
All patients were anosmic at the time of imaging based on olfactory test results. On CT, Olfactory cleft opacification was seen in 73.9% of cases with a mid and posterior segment dominance. 43.5% of cases had below normal olfactory bulb volumes and 60.9% of cases had shallow olfactory sulci. 54.2% of cases had changes in normal inverted J shape of the bulb. 91.3% of cases had abnormality in olfactory bulb signal intensity in the forms of diffusely increased signal intensity, scattered hyperintense foci or microhemorrhages. Evident clumping of olfactory filia was seen in 34.8% of cases and thinning with scarcity of filia in 17.4%. Primary olfactory cortical signal abnormality was seen in 21.7% of cases.
Conclusion
Our findings indicate olfactory cleft and olfactory bulb abnormalities are seen in COVID-19 anosmia. There was a relatively high percentage of olfactory bulb degeneration. Further longitudinal imaging studies could shed light on the mechanism of olfactory neuronal pathway injury in COVID-19 anosmia.
Introduction: To evaluate the recovery rate of loss of smell (LOS) with objective olfactory testing in COVID-19 patients.
Methods: Adults with confirmed COVID-19 and self-reported sudden LOS were prospectively recruited through a public call from the University of Mons (Belgium). Epidemiological and clinical data were collected using online patient-reported outcome questionnaires. Patients benefited from objective olfactory evaluation (Sniffin-Sticks-test) and were invited to attend for repeated evaluation until scores returned to normal levels.
Results: From March 22 to May 22, 2020, 88 patients with sudden-onset LOS completed the evaluations. LOS developed after general symptoms in 44.6% of cases. Regarding objective evaluation, 22 patients (25.0%) recovered olfaction within 14 days following the onset of LOS. The smell function recovered between the 16th and the 70th day post-LOS in 48 patients (54.5%). At the time of final assessment at 2 months, 20.5% of patients ( N = 18) had not achieved normal levels of olfactory function. Higher baseline severity of olfactory loss measured using Sniffin-Sticks was strongly predictive of persistent loss ( p < 0.001).
Conclusion: In the first 2 months, 79.5% of patients may expect to have complete recovery of their olfactory function. The severity of olfactory loss, as detected at the first Sniffin-Sticks-test, may predict the lack of mid-term recovery.
Purpose:
Impaired olfactory function is one of the main features of Parkinson's disease. However, how peripheral olfactory structures are involved remains unclear. Using diffusion tensor imaging fiber tracking, we investigated for MRI microstructural changes in the parkinsonian peripheral olfactory system and particularly the olfactory tract, in order to seek a better understanding of the structural alternations underlying hyposmia in Parkinson's disease.
Methods:
All patients were assessed utilizing by the Italian Olfactory Identification Test for olfactory function and the Unified Parkinson's Disease Rating Scale-III part as well as Hoehn and Yahr rating scale for motor disability. Imaging was performed on a 3 T Clinical MR scanner. MRI data pre-processing was carried out by DTIPrep, diffusion tensor imaging reconstruction, and fiber tracking using Diffusion Toolkit and tractography analysis by TrackVis. The following parameters were used for groupwise comparison: fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, and tract volume.
Results:
Overall 23 patients with Parkinson's disease (mean age 63.6 ± 9.3 years, UPDRS-III 24.5 ± 12.3, H&Y 1.9 ± 0.5) and 18 controls (mean age 56.3 ± 13.7 years) were recruited. All patients had been diagnosed hyposmic. Diffusion tensor imaging analysis of the olfactory tract showed significant fractional anisotropy, and tract volume decreases for the Parkinson's disease group compared with controls (P < 0.05). Fractional anisotropy and age, in the control group, were significant for multiple correlations (r = - 0.36, P < 0.05, Spearman's rank correlation).
Conclusions:
Fiber tracking diffusion tensor imaging analysis of olfactory tract was feasible, and it could be helpful for characterizing hyposmia in Parkinson's disease.
Background. The long-term recovery rate of chemosensitive functions in coronavirus disease 2019 patients has not yet been determined.
Method. A multicentre prospective study on 138 coronavirus disease 2019 patients was conducted. Olfactory and gustatory functions were prospectively evaluated for 60 days.
Results. Within the first 4 days of coronavirus disease 2019, 84.8 per cent of patients had chemosensitive dysfunction that gradually improved over the observation period. The most significant increase in chemosensitive scores occurred in the first 10 days for taste and between 10 and 20 days for smell. At the end of the observation period (60 days after symptom onset), 7.2 per cent of the patients still had severe dysfunctions. The risk of developing a long-lasting disorder becomes significant at 10 days for taste (odds ratio = 40.2, 95 per cent confidence interval = 2.204–733.2, p = 0.013) and 20 days for smell (odds ratio = 58.5, 95 per cent confidence interval = 3.278–1043.5, p = 0.005).
Conclusion. Chemosensitive disturbances persisted in 7.2 per cent of patients 60 days after clinical onset. Specific therapies should be initiated in patients with severe olfactory and gustatory disturbances 20 days after disease onset.
Background
Considerable evidence suggests that smell dysfunction is common in Coronavirus Disease 2019 (COVID‐19). Unfortunately, extant data on prevalence and reversibility over time are highly variable, coming mainly from self‐report surveys prone to multiple biases. Thus, validated psychophysical olfactory testing is sorely needed to establish such parameters.
Methods
One hundred SARS‐CoV‐2 positive cases were administered the 40‐item University of Pennsylvania Smell Identification Test (UPSIT) in the hospital near the end of the acute phase of the disease. Eighty‐two were retested 1 or 4 weeks later at home. The data were analyzed using analysis of variance and mixed‐effect regression models.
Results
Initial UPSIT scores were indicative of severe microsmia, with 96% exhibiting measurable dysfunction; 18% were anosmic. The scores improved upon retest [initial and retest means (95%CIs) = 21.97 (20.84,23.09) & 31.13 (30.16,32.10; p<0.0001)]; no patient remained anosmic. After five weeks from COVID‐19 symptom onset, the test scores of 63% of the retested patients were normal. However, the mean UPSIT score at that time continued to remain below that of age‐ and sex‐matched healthy controls (p<0.001). Such scores were related to time since symptom onset, sex, and age.
Conclusion
Smell loss was extremely common in the acute phase of a cohort of 100 COVID‐19 patients when objectively measured. About one‐third of cases continued to exhibit dysfunction after five post‐symptom onset weeks. These findings have direct implications for the use of olfactory testing in identifying SARS‐CoV‐2 virus carriers and for counseling such patients in regards to their smell dysfunction and its reversibility.
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Altered olfactory function is a common symptom of COVID-19, but its etiology is unknown. A key question is whether SARS-CoV-2 (CoV-2) – the causal agent in COVID-19 – affects olfaction directly, by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, through perturbation of supporting cells. Here we identify cell types in the olfactory epithelium and olfactory bulb that express SARS-CoV-2 cell entry molecules. Bulk sequencing demonstrated that mouse, non-human primate and human olfactory mucosa expresses two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, single cell sequencing revealed that ACE2 is expressed in support cells, stem cells, and perivascular cells, rather than in neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally-located olfactory epithelial sustentacular cells and olfactory bulb pericytes in the mouse. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients.
Patients with coronavirus disease 2019 (COVID-19) may have symptoms of anosmia or partial loss of the sense of smell, often accompanied by changes in taste. We report 5 cases (3 with anosmia) of adult patients with COVID-19 in whom injury to the olfactory bulbs was interpreted as microbleeding or abnormal enhancement on MR imaging. The patients had persistent headache (n = 4) or motor deficits (n = 1). This olfactory bulb injury may be the mechanism by which the Severe Acute Respiratory Syndrome coronavirus 2 causes olfactory dysfunction.
An asymptomatic 27-year-old physician is diagnosed SARS-CoV-2 by occupational medicine after contagion (RT-PCR).
Patients with anosmia exhibit structural and functional brain abnormalities. The present study explored changes in brain white matter (WM) in non-neurodegenerative anosmia using diffusion-tensor-based network analysis. Twenty patients with anosmia and sixteen healthy controls were recruited in the cross-sectional, case–control study. Participants underwent olfactory tests (orthonasal and retronasal), neuropsychological assessment (cognitive function and depressive symptoms) and diffusion tensor imaging measurement. Tract-Based Spatial Statistics, graph theoretical analysis and Network-Based Statistics were used to explore the white matter. There was no significant difference in fractional anisotropy (FA) between patients and controls. In global network topological properties comparisons, patients exhibited higher γ and λ levels than controls, and both groups satisfied the criteria of small-world (σ > 1). In local network topological properties, patients had reduced betweenness, degree and efficiency (global and local), as well as increased shortest path length and cluster coefficient in olfactory-related brain areas (anterior cingulum, lenticular nucleus, putamen, hippocampus, amygdala, caudate nucleus, orbito-frontal gyrus). Olfactory threshold scores and the retronasal score were negatively correlated with γ and λ, and the retronasal score was positively correlated with FA values in certain WM tracts, i.e. middle cerebellar peduncle, right inferior cerebellar peduncle, left inferior cerebellar peduncle, right cerebral peduncle, left cerebral peduncle, left cingulum (cingulate gyrus), right cingulum (hippocampus), superior fronto-occipital fasciculus, and, left tapetum. Patients with anosmia demonstrated relevant WM network dysfunction though their structural integrity remained intact. Their retronasal olfaction deficits revealed to be more strongly associated with WM alterations compared with orthonasal olfactory scores.
Since the initial reports of the novel coronavirus disease (COVID-19) in December 2019 in Wuhan, China, and the declaration by the World Health Organization of the disease as a pandemic, increasing numbers of patients are diagnosed with COVID-19 globally on a daily basis. While initially fever, cough and dyspnea were thought to be the dominant symptoms, other unusual presentations of COVID-19 such as altered olfactory function have been increasingly recognized. Recently, isolated anosmia/hyposmia is reported as a marker of COVID-19. The onset of anosmia was sudden in majority of the cases and most had a concomitant decrease in taste sensation
Olfactory dysfunctions affect a larger portion of population (up to 15% with partial olfactory loss, and 5% with complete olfactory loss) as compared to other sensory dysfunctions (e.g. auditory or visual) and have a negative impact on the life quality. The impairment of olfactory functions may happen at each stage of the olfactory system, from epithelium to cortex. Non-invasive neuroimaging techniques such as the magnetic resonance imaging (MRI) have advanced the understanding of the advent and progress of olfactory dysfunctions in humans. The current review summarizes recent MRI studies on human olfactory dysfunction to present an updated and comprehensive picture of the structural and functional alterations in the central olfactory system as a consequence of olfactory loss and regain. Furthermore, the review also highlights recent progress on optimizing the olfactory functional MRI as well as new approaches for data processing that are promising for future clinical practice.
Background and purpose:
While posttraumatic anosmia is not uncommon, the olfactory function evaluation has strongly relied on subjective responses given by patients. We aimed to examine the utility of fMRI as an objective tool for diagnosing traumatic anosmia.
Materials and methods:
Sixteen patients (11 men and 5 women; mean age, 42.2 ± 10.4 years) with clinically diagnosed traumatic anosmia and 19 healthy control subjects (11 men and 8 women; mean age, 29.3 ± 8.5 years) underwent fMRI during olfactory stimulation with citral (a pleasant odor) or β-mercaptoethanol (an unpleasant odor). All patients were subjected to a clinical olfactory functional assessment and nasal endoscopic exploration. Two-sample t tests were conducted with age as a covariate to examine group differences in brain activation responses to olfactory stimulation (false discovery rate-corrected P < .05).
Results:
Compared with healthy control subjects, patients with traumatic anosmia had reduced activation in the bilateral primary and secondary olfactory cortices and the limbic system in response to β-mercaptoethanol stimulation, whereas reduced activation was observed only in the left frontal subgyral region in response to citral stimulation.
Conclusions:
Brain activation was decreased in the bilateral primary and secondary olfactory cortices as well as the limbic system in response to olfactory stimulation in patients with traumatic anosmia compared with healthy control subjects. These preliminary results may shed light on the potential of fMRI for the diagnosis of traumatic anosmia.
Upper respiratory tract infection (URI) is one of the most common etiology of olfactory loss. Previous studies demonstrated that both olfactory bulb (OB) volume and sulcus (OS) depth decreased in patients with post-infectious olfactory loss (PIOL) compared to normal controls. The aim of our study was to observe alterations of central olfactory pathways in patients with PIOL. T1 weighted magnetic resonance images were acquired in 19 PIOL patients and 19 age- and sex-matched control subjects on a 3 T scanner. Voxel-based morphometry (VBM) was performed using VBM8 toolbox and SPM8 in a Matlab environment. We also analyzed OB volume in coronal T2-weighted images. Whole-brain analysis revealed a significant gray matter volume loss in the right orbitofrontal cortex (OFC) in patients group. Further analysis with region of interest exhibited a significant negative correlation between gray matter volume in right OFC as well as OB volume and the duration of olfactory loss in these patients (r = -0.566 and r = -0.535 both P < 0.05, respectively). In conclusion, the morphological alterations in the right OFC and OB might contribute to the pathogenic mechanism of olfactory dysfunction after upper respiratory tract infection.
PurposeThe olfactory nerve (OlfN) is a small neural structure with inconsistent visualization on neuroimages. The aim of this study was to delineate the intracranial course of the OlfN using constructive interference in steady state magnetic resonance (MR) imaging. MethodsA total of 168 patients were enrolled in this study. Following initial examinations with conventional MR sequences, constructive interference in steady-state sequence (CISS) was performed in coronal and axial sections. ResultsOn coronal sections, the OlfN was entirely visualized in 90 % of patients on the right and 92 % on the left, coursing along the olfactory sulcus. Complete visualization of the OlfN occurred in 100 % of patients on serial axial images. The OlfN was classified into four portions based on the topographical differences and surrounding structures. The olfactory fossa exhibited considerable variability at the midlevel of the olfactory bulb on coronal images. Characteristic appearance of the OlfN with respect to age range or gender was not observed. Conclusions
The OlfN follows a highly consistent course along the olfactory sulcus. Thin-sliced, CISS sequences are useful for consistent visualization of the OlfN.
Alzheimer's disease (AD) is accompanied by smell dysfunction, as measured by psychophysical tests. Currently, it is unknown whether AD-related alterations in central olfactory system neural activity, as measured by functional magnetic resonance imaging (fMRI), are detectable beyond those observed in healthy elderly. Moreover, it is not known whether such changes are correlated with indices of odor perception and dementia. To investigate these issues, 12 early stage AD patients and 13 nondemented controls underwent fMRI while being exposed to each of three concentrations of lavender oil odorant. All participants were administered the University of Pennsylvania Smell Identification Test (UPSIT), the Mini-Mental State Examination (MMSE), the Mattis Dementia Rating Scale-2 (DRS-2), and the Clinical Dementia Rating Scale (CDR). The blood oxygen level-dependent (BOLD) signal at primary olfactory cortex (POC) was weaker in AD than in HC subjects. At the lowest odorant concentration, the BOLD signals within POC, hippocampus, and insula were significantly correlated with UPSIT, MMSE, DRS-2, and CDR scores. The BOLD signal intensity and activation volume within the POC increased significantly as a function of odorant concentration in the AD group, but not in the control group. These findings demonstrate that olfactory fMRI is sensitive to the AD-related olfactory and cognitive functional decline.
The detection of time-related maturational changes of the olfactory bulb (OB) on MR imaging may help early identification of patients with abnormal OB development and anatomic-based odor-cueing anomalies.
Two separate reviewers retrospectively analyzed coronal T2-weighted spin-echo MR images of the frontobasal region in 121 patients. There were 22 patients who underwent MR imaging examinations several times, accounting for a total of 156 studies. Age range was 1 day to 19.6 years. OBs were bilaterally identified in all cases and categorized according to their shape and signal intensity.
Three different anatomic patterns were identified. In pattern 1 (median age, 15 days; age range, 1-168 days), the OBs were round to oval with a continuous external T2-hypointense rim and a prominent T2-hyperintense central area. In pattern 2 (median age, 287 days; age range, 4 days-22 months), the OBs were U shaped, with thinning and concave deformation of the superior layer. A hyperintense central area on T2-weighted images was still visible. In pattern 3 (median age, 5.2 years; age range, 107 days-19.6 years), the OBs were small, round, or J shaped with a more prominent lateral part. No difference in signal intensity between the central area and the peripheral layer was identified anymore.
The OBs show time-related maturational changes on MR imaging. There is a progressive reorganization of the peripheral neuronal layers and signal intensity changes of the central area, which are completed at the end of the second year, paralleling cerebral maturational changes.
Background
Smell disorders persist in about half of the patients with other symptoms of COVID-19 disease, but the exact duration of the symptoms is yet unknown. Especially, only a few studies used validated olfactory tests for this.
Aims/Objectives
The aim of this study was to investigate how many patients with olfactory function impairment, which was detected in a validated olfactory test 3 months after COVID-19 disease, showed improvement in olfactory function after 6 months.
Methods
About 26 patients with a PCR-confirmed, former COVID-19 disease, with an impaired olfactory function after three months, were included in the study. The olfactory function was evaluated with the sniffing sticks test, the taste function with taste sprays.
Results
Smelling function improved in all but one patient (96%). All measured subitems, i.e. olfactory threshold, identification and discrimination of odours significantly improved. In the whole mouth taste test all patients showed normal taste function.
Conclusions and significance
6 months after COVID-19 disease, olfactory function improves in just about all patients. Long-term measurements must investigate whether complete regeneration of the olfactory function will occur in all patients.
In this paper, we report three cases of pediatric patients with COVID-19 infection who presented with different symptoms and also anosmia and/or ageusia. The common feature of these 3 patients is that the smell and / or taste disorder developed without nasal symptoms such as nasal congestion, nasal obstruction or rhinorrhea. Although 40% of anosmies contains viral etiologies, COVID- 19 differs from other viral anosmies by the lack of nasal congestion and runny nose. Coronaviruses could invade the brain via the cribriform plate close to the olfactory bulb and the olfactory epithelium. We may expect some structural changes in the olfactory bulb so we evaluated our patient with cranial imaging.
Purpose: This study assesses the diagnostic utility of olfactory nerve and bulb morphologies in addition to volumetric analysis in classification of different olfactory dysfunction etiologies.
Methods: 106 patients presenting with olfactory loss and 17 control subjects were included. Based on detailed anamnesis, smell test and ear-nose-throat examination; patients were categorized into four groups as post-viral, post-traumatic, idiopathic, and obstructive olfactory dysfunction. Olfactory region was imaged with paranasal sinus CT and MRI dedicated to olfactory nerve. Olfactory bulb volume and olfactory sulcus depths were calculated on MRI. The olfactory bulb was assessed for morphology, contour lobulations and T2-signal intensity; and olfactory nerve for uniformity and clumping.
Results: Volumetric analysis showed decreased olfactory bulb volume in idiopathic and obstructive group compared to control subjects. Olfactory sulci were shallower in post-viral, post-traumatic, idiopathic, and obstructive group compared to the control group. In post-viral group; olfactory bulbs had lobulated contour and focal T2-hyperintense regions in 67 % of cases, and olfactory nerves had a clumped and thickened appearance in 66 % of cases. In idiopathic group, olfactory bulbs were rectangular shaped with minimally deformed contours, and olfactory nerves were thin and hard to delineate. No specific olfactory bulb or nerve pattern was identified in obstructive and post-traumatic groups, however closed olfactory cleft and siderotic frontobasal changes were helpful clues in obstructive and post-traumatic groups, respectively.
Conclusion: In addition to olfactory cleft patency, olfactory sulcus depth and olfactory bulb volume; bulb and nerve morphologies may provide diagnostic information on different etiologies of olfactory dysfunction.
Background and purpose:
Unique among the acute neurologic manifestations of Severe Acute Respiratory Syndrome coronavirus 2, the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, is chemosensory dysfunction (anosmia or dysgeusia), which can be seen in patients who are otherwise oligosymptomatic or even asymptomatic. The purpose of this study was to determine if there is imaging evidence of olfactory apparatus pathology in patients with COVID-19 and neurologic symptoms.
Materials and methods:
A retrospective case-control study compared the olfactory bulb and olfactory tract signal intensity on thin-section T2WI and postcontrast 3D T2 FLAIR images in patients with COVID-19 and neurologic symptoms, and age-matched controls imaged for olfactory dysfunction.
Results:
There was a significant difference in normalized olfactory bulb T2 FLAIR signal intensity between the patients with COVID-19 and the controls with anosmia (P = .003). Four of 12 patients with COVID-19 demonstrated intraneural T2 signal hyperintensity on postcontrast 3D T2 FLAIR compared with none of the 12 patients among the controls with anosmia (P = .028).
Conclusions:
Olfactory bulb 3D T2 FLAIR signal intensity was greater in the patients with COVID-19 and neurologic symptoms compared with an age-matched control group with olfactory dysfunction, and this was qualitatively apparent in 4 of 12 patients with COVID-19. Analysis of these preliminary finding suggests that olfactory apparatus vulnerability to COVID-19 might be supported on conventional neuroimaging and may serve as a noninvasive biomarker of infection.
Background
Olfactory dysfunction has shown to accompany COVID-19. There are varying data regarding the exact frequency in the various study population. The outcome of the olfactory impairment is also not clearly defined.Objective
To find the frequency of olfactory impairment and its outcome in hospitalized patients with positive swab test for COVID-19.Methods
This is a prospective descriptive study of 100 hospitalized COVID-19 patients, randomly sampled, from February to March 2020. Demographics, comorbidities, and laboratory findings were analyzed according to the olfactory loss or sinonasal symptoms. The olfactory impairment and sinonasal symptoms were evaluated by 9 Likert scale questions asked from the patients.ResultsNinety-two patients completed the follow-up (means 20.1 (± 7.42) days). Twenty-two (23.91%) patients complained of olfactory loss and in 6 (6.52%) patients olfactory loss was the first symptom of the disease. The olfactory loss was reported to be completely resolved in all but one patient. Thirty-nine (42.39%) patients had notable sinonasal symptoms while rhinorrhea was the first symptom in 3 (3.26%). Fifteen patients (16.3%) had a taste impairment. Patients with sinonasal symptoms had a lower age (p = 0.01). There was no significant relation between olfactory loss and sinonasal symptoms (p = 0.07).Conclusions
Sudden olfactory dysfunction and sinonasal symptoms have a considerable prevalence in patients with COVID-19. No significant association was noted between the sinonasal symptoms and the olfactory loss, which may suggest that other mechanisms beyond upper respiratory tract involvement are responsible for the olfactory loss.
The main neurological manifestation of COVID-19 is loss of smell or taste. The high incidence of smell loss without significant rhinorrhea or nasal congestion suggests that SARS-CoV-2 targets the chemical senses through mechanisms distinct from those used by endemic coronaviruses or other common cold-causing agents. Here we review recently developed hypotheses about how SARS-CoV-2 might alter the cells and circuits involved in chemosensory processing and thereby change perception. Given our limited understanding of SARS-CoV-2 pathogenesis, we propose future experiments to elucidate disease mechanisms and highlight the relevance of this ongoing work to understanding how the virus might alter brain function more broadly.
The global pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 remains a challenge for prevention due to asymptomatic or paucisymptomatic patients. Anecdotal and preliminary evidence from multiple institutions shows that these patients present with a sudden onset of anosmia without rhinitis. We aim to review the pathophysiology of anosmia related to viral upper respiratory infections and the prognostic implications. Current evidence suggests that SARS-CoV-2-related anosmia may be a new viral syndrome specific to COVID-19 and can be mediated by intranasal inoculation of SARS-CoV-2 into the olfactory neural circuitry. The clinical course of neuroinvasion of SARS-CoV-2 is yet unclear, however an extended follow up of these patients to assess for neurological sequelae including encephalitis, cerebrovascular accidents and long-term neurodegenerative risk may be indicated.
The neurotropism of human coronaviruses has already been demonstrated in small animals, and in autoptic studies the severe acute respiratory syndrome coronavirus (SARS-CoV), which was responsible for the SARS outbreak during 2002 to 2003, was found in the brains of patients with infection. It has been proposed that the neuroinvasive potential of the novel SARS-CoV-2, responsible for coronavirus disease 2019 (COVID-19), may be at least partially responsible for the respiratory failure of patients with COVID-19.2 In this article, we share the magnetic resonance imaging (MRI) evidence of in vivo brain alteration presumably due to SARS-CoV-2 and demonstrate that anosmia can represent the predominant symptom in COVID-19.
Background and purpose:
Although the olfactory bulb volume as assessed with MR imaging is known to reflect olfactory function, it is not always measured during olfactory pathway assessments in clinical settings. We aimed to evaluate the utility of visual olfactory bulb atrophy and neuropathy analyses using MR imaging in patients with olfactory dysfunction.
Materials and methods:
Thirty-four patients who presented with subjective olfactory loss between March 2016 and February 2017 were included. Patients underwent a nasal endoscopic examination, olfactory testing with the Korean Version of the Sniffin' Sticks test, and MR imaging. All patients completed the Sino-Nasal Outcome Test and Questionnaire of Olfactory Disorders. Olfactory bulb atrophy and neuropathy were evaluated on MR images by 2 head and neck radiologists.
Results:
The etiology of olfactory loss was chronic rhinosinusitis with/without nasal polyps in 15 (44.1%) patients, respiratory viral infection in 7 (20.6%), trauma in 2 (5.9%), and idiopathic in 10 (29.4%) patients. Although 10 (29.4%) of the 34 patients were normosmic according to the Sniffin' Sticks test, their scores on the other tests were like those of patients who were hyposmic/anosmic according to the Sniffin' Sticks test. However, the detection rate of olfactory bulb atrophy was significantly higher in patients with hyposmia/anosmia than it was in patients with normosmia (P = .002). No difference in olfactory bulb neuropathy was identified among patients with normosmia and hyposmia/anosmia (P = .395).
Conclusions:
MR imaging evaluations of olfactory bulb atrophy can be used to objectively diagnose olfactory dysfunction in patients with subjective olfactory loss.
Introduction:
Anosmia is a possible complication of Traumatic Brain Injury (TBI). Psychometric and electrophysiological methods of olfaction measure and Magnetic Resonance Imaging (MRI) are the tools to evaluate the post-traumatic olfactory loss. Diffusion Tensor Imaging (DTI) provides useful data for a better understanding of etiopathogenesis TBI-related anosmia, in particular the loss of neural connections and their eventual recovery over time.
Materials and methods:
This study describes a case of TBI-related anosmia. The olfactory function was evaluated by Sniffin' Sticks Test (SST), Olfactory Event-Related Potentials (OERPs), MRI and DTI at baseline (T0) and after one year (T1).
Results:
At baseline, SST highlighted a functional anosmia. The OERPs showed the presence of a small N1-P2 complex. MRI confirmed the presence of a scarring involved in the right orbitofrontal cortex (OFC). DTI detected a reduction in the average length and the number of neuronal fibre pathways of right OFC. At T1, a recovery of olfactory function was confirmed by SST and OERPs.
Conclusion:
While MRI images are unchanged from T0, DTI showed an increase in average length and number of fibre tracts in the right OFC. DTI could be a valid tool to display a post-traumatic loss of neural connections and to better understand TBI-recovery mechanisms.
Impaired olfaction is associated with a volume decrease in the olfactory bulb as well es in the grey matter of cortical olfactory areas. On the other hand, restitution of an impaired olfaction results in a regain of volume in these regions. Studies investigating similar changes in the cerebral white matter are virtually not existent. The aim of this prospective study therefore was to investigate cerebral white matter using magnetic resonance diffusion tensor imaging (DTI). 31 patients (54±13 years) with olfactory impairment (chronic rhinosinusitis) and planned functional endoscopic sinus surgery (FESS) were included. Magnetic resonance imaging (MRI) data sets were acquired pre-operatively and 3 months after surgery. Pre- and postoperative olfactory testing was performed to assess the olfactory threshold, discrimination, and identification (TDI) score. A significant postoperative TDI improvement by 9.06±8.81 points was observed. Two groups were subsequently formed – one with relevant postoperative olfactory gain (ΔTDI ≥10 points, 12 patients) and one without gain (ΔTDI <10 points, 19 patients). DTI parameter showed a significant correlation with the TDI score in the left anterior cingulate cortex and the right amygdala. In the group with relevant olfactory improvement higher values of fractional anisotropy and apparent diffusion coefficient were found in the right parahippocampal area and in the white matter below the left inferior temporal sulcus. Tract specific diffusion property analysis revealed significant group differences in the cingulate cortex in spatial relationship to the perisplenial cortex. Overall, this prospective study indicates structural changes in white matter after postoperative restoration of olfaction.
Objectives/hypothesis:
Postinfectious olfactory loss is among the most common causes of olfactory impairment and has substantial negative impact on patients' quality of life. Recovery rates have been shown to spontaneously improve in most of patients, usually within 2 to 3 years. However, existing studies are limited by small sample sizes and short follow-up. We aimed to assess the prognostic factors for recovery in a large sample of 791 patients with postinfectious olfactory disorders.
Study design:
Retrospective cohort.
Methods:
We performed a retrospective analysis of 791 patients with postinfectious olfactory loss. Olfactory functions were assessed using the Sniffin' Sticks test at the first and final visits (mean follow-up = 1.94 years).
Results:
Smell test scores improved over time. In particular, patient's age and the odor threshold (T), odor discrimination (D), and odor identification (I) (TDI) score at first visit were significant predictors of the extent of change. The percentage of anosmic and hyposmic patients exhibiting clinically significant improvement was 46% and 35%, respectively.
Conclusions:
This study provides new evidence within the postinfectious olfactory loss literature, shedding light on the prognostic factors and showing that recovery of olfactory function is very frequent, even many years after the infection.
Level of evidence:
4 Laryngoscope, 2017.
It has been shown that olfactory epithelium can be safely biopsied from the living, intact human being. Observations of the ultrastructure of this epithelium shows changes that can then be correlated with the etiology and degree of olfactory loss, allowing a greater understanding of both normal transduction and of the pathology of dysfunction. Examples of the common forms of olfactory dysfunction are presented and discussed. Additionally, the technique will allow additional immunohistochemical and molecular study of the tissue, will increase the understanding of both normal and pathological function and should translate to new therapeutic regimens.
Any dysfunction in olfaction requires a radiological exploration comprising the nasal cavity, the anterior base of the skull, in particular the frontal and temporal lobes. MRI is the reference examination, due to the frontal plane and the T1, T2 volume maps. In the child, aplasia of the olfactory bulbs falls within a polymalformation (CHARGE) or endocrine (Kallman) context. In the adult, rhino sinus disease and meningiomas are the most common etiologies. Frontal or temporal impairment: tumoral or vascular and neurodegenerative disorders (Parkinson's disease) may accompany a loss of olfaction.
Magnetic resonance diffusion tensor imaging with fiber tracking is used for 3-dimensional visualization of the nervous system. Peripheral nerves and all cranial nerves, except for the olfactory tract, have previously been visualized. The olfactory tracts are difficult to depict with diffusion-weighted imaging due to the high sensitivity to susceptibility artifacts at the base of the skull. Here we report an optimized single-shot diffusion-weighted echo planar imaging sequence that can visualize the olfactory tracts with fiber tracking. Five healthy individuals were examined, and the olfactory tracts could be fiber tracked with the diffusion-weighted sequence. For comparison and as a negative control, an anosmic patient was examined. No olfactory tracts were visualized on T2-weighted nor diffusion-weighted fiber tracking images. Measuring diffusion in the olfactory tracts promise to facilitate the identification of different hyposmic and anosmic conditions.
The olfactory bulb collects the sensory afferents of the olfactory receptor cells located in the olfactory neuroepithelium. The olfactory bulb ends with the olfactory tract and is closely related to the olfactory sulcus of the frontal lobe. Many studies demonstrated that olfactory bulb volume assessed with magnetic resonance imaging is related to the olfactory function both in normal and pathological conditions. It has been shown that olfactory bulb volume changes with the degree of olfactory dysfunction, that it decreases with the duration of the olfactory loss and that patients with qualitative disorder such as parosmia have smaller olfactory bulbs than patients without parosmia. In this review, we will discuss the actual knowledge regarding olfactory bulb function, practical ways to measure olfactory bulb volume and olfactory sulcus depth, and report systematic observations regarding these measurements related to various causes of olfactory dysfunction, e.g. infection of the upper respiratory tract, head trauma, or neurodegenerative disease. Measurement of olfactory bulb volume may provide valuable information for patients with olfactory dysfunction.
"Sniffin' Sticks" is a new test of nasal chemosensory performance based on pen-like odour-dispensing devices. This portable test is suited for repetitive, inexpensive screening of odour identification. The test includes a forced odour-identification task for seven odours performed by means of a list of four items (multiple-choice). In 146 subjects the basic screening test was compared to a down-scaled version of the UPSIT (CC-SIT). Sniffin' Sticks exhibited a relatively higher coefficient of correlation with the subjects' age; they also demonstrated the women's superior olfactory sensitivity more pronounced when compared to men. In addition, the coefficient of correlation between age and olfactory performance was slightly higher when the sticks were used. Preliminary investigations in nine patients with impaired olfactory function (i.e., anosmic or hyposmic patients) revealed significantly lower scores in patients compared to healthy controls matched for age and sex (p < 0.001). It is concluded that Sniffin' Sticks may be useful in the routine clinical assessment of olfactory performance where both time and costs matter.
To determine the locations and extent of activation in areas of the brain at functional magnetic resonance (MR) imaging with olfactory stimulation and to determine whether accommodation or amplification of brain activation occurs with sequential olfactory stimulation.
Five adult men with normal senses of smell underwent multisection, gradient-echo, echo-planar imaging according to a blood-oxygen-level-dependent experimental paradigm. Odorants that nearly exclusively stimulate the olfactory system and odorants that stimulate the olfactory and trigeminal nerves were compared by using repetitive imaging procedures.
Activation with olfactory nerve-mediated odorants was demonstrated in the orbitofrontal cortex (Brodmann area 11) with a right-sided predominance. Mild cerebellar stimulation was also observed. With repeated testing, overall activation with olfactory nerve-mediated odorants declined. Odorants that also stimulated the trigeminal nerve produced additional cingulate, temporal, cerebellar, and occipital activation. Activation with combined trigeminal and olfactory system odors increased more than sixfold with repeated testing.
Olfactory nerve-mediated and combined olfactory and trigeminal nerve-mediated odorants activate different regions of the brain. Orbitofrontal stimulation spreads to all parts of the brain when a trigeminal component is added. Habituation (deactivation) occurs with repeated testing of olfactory nerve-mediated odorants, while, paradoxically, activation increases with repeated exposure to odors that also stimulate the trigeminal nerve.
Objectives/hypothesis:
Two of the most common causes of olfactory loss include upper respiratory infection (URI) and nasal or sinus disease. The etiology of most URI-related losses is thought to be viral and, as yet, there is no available treatment. In contrast, nasal or sinus disease produces an obstructive or conductive loss that often responds dramatically to appropriate therapy. Therefore, the distinction is important but in many cases may be difficult because such patients often present with no other nasal symptoms, and routine physical findings may be nonspecific. The purpose of this report is to characterize those aspects of the history and physical examination that will help to substantiate the diagnosis of a conductive olfactory loss.
Study design:
A retrospective, nonrandomized study of consecutive patients presenting with a primary complaint of olfactory loss.
Methods:
This study reviewed 428 patients seen at a university-based taste and smell clinic from July 1987 through December 1998. Of this total, 60 patients were determined to have a conductive olfactory loss. All patients were referred specifically because of a primary chemosensory complaint. The University of Pennsylvania Smell Identification Test (UPSIT; Sensonics, Inc., Haddon Heights, NJ) was administered in all cases.
Results:
The most commonly diagnosed etiologies of olfactory loss were head injury (18%), upper respiratory infection (18%), and nasal or sinus disease (14%). Of the 60 patients with a conductive loss, only 30% complained of nasal obstruction, whereas 58% described a history of chronic sinusitis. Only 45% reported that their olfactory loss at times seemed to fluctuate in severity. Anterior rhinoscopy failed to diagnose pathology in 51% of cases, whereas nasal endoscopy missed the diagnosis in 9%. Systemic steroids elicited a temporary reversal of conductive olfactory loss in 83% of patients who received them, offering a useful diagnostic maneuver, whereas topical steroids did so in only 25%.
Conclusions:
The etiology for olfactory loss can in many cases be difficult to determine, but it is important to establish prognosis and to predict response to therapy. Diagnosis requires a thorough history, appropriate chemosensory testing, and a physical examination that should include nasal endoscopy. A trial of systemic steroids may serve to verify that the loss is indeed conductive.
This study investigated human BOLD responses in primary and higher order olfactory cortices following presentation of short- and long-duration odorant stimuli using a 3-T MR scanner. The goal was to identify temporal differences in the course of the response that might underlie habituation. A short-duration stimulus (9 s) consistently activated the primary olfactory cortex (POC). After a long stimulus (60 s), the temporal form of the response differed in different parts of the olfactory network: (1) The POC (piriform, entorhinal cortex, amygdala) and, interestingly, the hippocampus and, to a certain degree, the anterior insula show a short, phasic increase in the signal, followed by a prolonged decrease below baseline. (2) In the orbitofrontal cortex a sustained increase in activation was seen. This increase lasted approximately as long as the duration of odorant presentation ( approximately 60 s). (3) The mediodorsal nucleus of the thalamus and the caudate nucleus responded with an increase in signal which returned to baseline after approximately 15 to 30 s. The correlated biphasic hemodynamic response in the POC, hippocampus, and anterior insula during prolonged olfactory stimulation suggests that these three areas may interact closely with each other in the control of habituation. These results extend recent data which showed habituation of the rat piriform cortex and dissociation between the POC and the orbitofrontal cortex.
The olfactory system consists of the primary olfactory nerves in the nasal cavity, the olfactory bulbs and tracts, and numerous intracranial connections and pathways. Diseases affecting the sense of smell can be located both extracranially and intracranially. Many sinonasal inflammatory and neoplastic processes may affect olfaction. Intracranially congenital, traumatic, and neurodegenerative disorders are usually to blame for olfactory dysfunction. The breadth of diseases that affect the sense of smell is astounding, yet the imaging ramifications have barely been explored.
An anatomical parcellation of the spatially normalized single-subject high-resolution T1 volume provided by the Montreal Neurological Institute (MNI) (D. L. Collins et al., 1998, Trans. Med. Imag. 17, 463-468) was performed. The MNI single-subject main sulci were first delineated and further used as landmarks for the 3D definition of 45 anatomical volumes of interest (AVOI) in each hemisphere. This procedure was performed using a dedicated software which allowed a 3D following of the sulci course on the edited brain. Regions of interest were then drawn manually with the same software every 2 mm on the axial slices of the high-resolution MNI single subject. The 90 AVOI were reconstructed and assigned a label. Using this parcellation method, three procedures to perform the automated anatomical labeling of functional studies are proposed: (1) labeling of an extremum defined by a set of coordinates, (2) percentage of voxels belonging to each of the AVOI intersected by a sphere centered by a set of coordinates, and (3) percentage of voxels belonging to each of the AVOI intersected by an activated cluster. An interface with the Statistical Parametric Mapping package (SPM, J. Ashburner and K. J. Friston, 1999, Hum. Brain Mapp. 7, 254-266) is provided as a freeware to researchers of the neuroimaging community. We believe that this tool is an improvement for the macroscopical labeling of activated area compared to labeling assessed using the Talairach atlas brain in which deformations are well known. However, this tool does not alleviate the need for more sophisticated labeling strategies based on anatomical or cytoarchitectonic probabilistic maps.
To investigate the consequences of olfactory loss and explore specific questions related to the effect of duration of olfactory loss, degree of olfactory sensitivity, and cause of the olfactory loss.
A total of 278 consecutive patients with hyposmia or anosmia were examined.
Causes of olfactory loss were categorized as follows: trauma (17%), upper respiratory tract infection (URI) (39%), sinonasal disease (21%), congenital anosmia (3%), idiopathic causes (18%), or other causes (3%). Our data suggest that (1) recovery rate was higher in URI olfactory loss than in olfactory loss from other causes; (2) likelihood of recovery seemed to decrease with increased duration of olfactory loss; and (3) the elderly are more prone to URI olfactory loss than younger patients. Regarding changes in quality of life (QoL), we found that (1) in most patients olfactory loss caused food-related problems; (2) loss in QoL did not change with duration of olfactory loss; (3) younger patients had more complaints than older ones, and women had more complaints than men; (4) complaint scores were higher in hyposmic patients than in anosmic patients; and (5) self-rated depression did not relate to measured olfactory function.
Among many complaints of olfactory loss, the predominant ones were food related. This loss in QoL seemed to be of greater importance in younger than in older people, and women seem to be affected more strongly than men.
It has been shown that olfactory epithelium can be safely biopsied from the living, intact human being. Observations of the ultrastructure of this epithelium shows changes that can then be correlated with the etiology and degree of olfactory loss, allowing a greater understanding of both normal transduction and of the pathology of dysfunction. Examples of the common forms of olfactory dysfunction are presented and discussed. Additionally, the technique will allow additional immuno-histochemical and molecular study of the tissue, will increase the understanding of both normal and pathological function and should translate to new therapeutic regimens.
The perception of odorant molecules provides the essential information that allows animals to explore their surrounding. We describe here how the external world of scents may sculpt the activity of the first central relay of the olfactory system, i.e., the olfactory bulb. This structure is one of the few brain areas to continuously replace one of its neuronal populations: the local GABAergic interneurons. How the newly generated neurons integrate into a pre-existing neural network and how basic olfactory functions are maintained when a large percentage of neurons are subjected to continuous renewal, are important questions that have recently received new insights. Furthermore, we shall see how the adult neurogenesis is specifically subjected to experience-dependent modulation. In particular, we shall describe the sensitivity of the bulbar neurogenesis to the activity level of sensory inputs from the olfactory epithelium and, in turn, how this neurogenesis may adjust the neural network functioning to optimize odor information processing. Finally, we shall discuss the behavioral consequences of the bulbar neurogenesis and how it may be appropriate for the sense of smell. By maintaining a constitutive turnover of bulbar interneurons subjected to modulation by environmental cues, we propose that adult ongoing neurogenesis in the olfactory bulb is associated with improved olfactory memory. These recent findings not only provide new fuel for the molecular and cellular bases of sensory perception but should also shed light onto cellular bases of learning and memory.
In the nose, the capacity to detect and react to volatile chemicals is mediated by two separate but interrelated sensory pathways, the olfactory and trigeminal systems. Because most chemosensory stimulants, at sufficient concentration, produce both olfactory and trigeminal sensations (i.e., stinging, burning or pungent), it is relevant to seek how these anatomically distinct systems could interact. This study was designed to evaluate by psychophysical measurements the modifications of the olfactory sensitivity of 20 subjects to phenyl ethyl alcohol (PEA) and butanol (BUT), after trigeminal stimulation with allyl isothiocyanate (AIC). Thresholds obtained in two separate sessions, one with and the other without previous trigeminal stimulation, were compared using a two-alternative forced-choice procedure, with a classical ascending concentrations method. The results showed that, whatever the odorant (PEA or BUT), AIC trigeminal activation produced a decrease in the olfactory thresholds, corresponding to an increase in olfactory sensitivity. These data confirm that in physiological conditions the trigeminal system modulates the activity of olfactory receptor cells but do not exclude the possibility of a central modulation of olfactory information by trigeminal stimuli. These findings are discussed in terms of methodological and physiological conditions.
A viral upper respiratory infection is one of the most commonly identified causes of olfactory loss, accounting for 20% to 30% of patients in most series. Given the ubiquitous nature of upper respiratory infections, it is not clear what predisposes some patients to develop this complication. Studies have demonstrated degenerative changes within the olfactory epithelium, the severity of which seems to correlate with the severity of olfactory loss. Although no available therapy has proved effective, long-term follow-up data have found that approximately two thirds of these patients eventually experience a significant improvement in their olfactory function.