MRI evidence of olfactory system alterations in patients with COVID-19 and neurological symptoms

Journal of Neurology https://doi.org/10.1007/s00415-023-11561-0 ORIGINAL COMMUNICATION MRI evidence of olfactory system alterations in patients with COVID‑19 and neurological symptoms Serena Capelli1 · Anna Caroli1 · Antonino Barletta2 · Alberto Arrigoni1 · Angela Napolitano2 · Giulio Pezzetti2 · Luca Giovanni Longhi3 · Rosalia Zangari4 · Ferdinando Luca Lorini5 · Maria Sessa6 Andrea Remuzzi7 · Simonetta Gerevini2 · Received: 9 November 2022 / Revised: 29 December 2022 / Accepted: 9 January 2023 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2023 Abstract Background and objective Despite 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. Methods 196 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. Results COVID-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. * Simonetta Gerevini 1 Bioengineering Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica, BG, Italy 2 Department of Neuroradiology, ASST Papa Giovanni XXIII, Piazza OMS 1, 24127 Bergamo, Italy 3 Neurosurgical Intensive Care Unit, Department of Anesthesia and Critical Care Medicine, ASST Papa Giovanni XXIII, Bergamo, Italy 4 FROM Research Foundation, ASST Papa Giovanni XXIII, Bergamo, Italy 5 Department of Emergency and Critical Care Area, ASST Papa Giovanni XXIII, Bergamo, Italy 6 Department of Neurology, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy 7 Department of Management, Information and Production Engineering, University of Bergamo, Dalmine, BG, Italy 13 Vol.:(0123456789) Journal of Neurology Graphical abstract Keywords MRI · COVID-19 · Olfactory bulbs · Olfactory system · Olfactory dysfunction Introduction Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), causing the coronavirus disease 2019 (COVID-19), initiated a worldwide pandemic that, as of February 2022, has resulted in more than 430 billion confirmed cases and about 5.9 million deaths worldwide [1]. The most common manifestations of COVID-19 are pulmonary in nature, but a number of neurological complications, including smell and taste disorders, cranial nerve deficits, polyneuropathies, cerebrovascular disorders, encephalopathies and inflammatory central nervous system (CNS) syndromes, headache, and seizures, have been increasingly reported [2]. COVID-19 neurological complications are expected to be associated with the suspected neuroinvasive potential of human coronaviruses (CoVs) [3, 4]. A large body of evidence has demonstrated that the total loss or a reduced sense of smell (anosmia and hyposmia, respectively) are the most common neurological complications of COVID-19 [4, 5], especially occurring in otherwise asymptomatic subjects and in early phases of the disease [6]. In spite of the high incidence of olfactory dysfunction (OD) in COVID-19 [7], its underlying mechanism has not been fully elucidated, yet. Nasal and oropharyngeal cavities are considered the possible gateways for many viral pathogens, including SARS-CoV-2. However, unlike other post viral olfactory dysfunctions, COVID-19-related anosmia and hyposmia are not correlated with nasal obstruction or rhinitis, suggesting that they may be rather associated with the neurotropism of the virus. The widespread 13 angiotensin-converting enzyme 2 (ACE2) expression in the brain and in the olfactory bulbs makes them a potential target of COVID-19 and supports the hypothesis of neuroinvasion through the olfactory system [4]. The olfactory system, mediating the sense of smell, is phylogenetically one of the most primitive sensory systems. Olfaction is conveyed by the first cranial nerve (CN I), which originates in the olfactory neuroepithelium, located in the posterosuperior portion of each nasal cavity (olfactory cleft). The epithelium includes the somas of the bipolar olfactory neurons, which are both receptors and neurons of the first order of the olfactory pathway. These represent the origin of the olfactory nerve fibers, and they have the unique ability to regenerate thanks to the stem cells located in the epithelium. The dendrites of the olfactory neurons directly project to the surface of the epithelium, so as to bind to the odorant molecules that reach the nasal cavity. This exposure of the dendrites to the external environment is well-known to be exploited by many viruses, including the Coronaviruses, as a gateway to the central nervous system by retrograde axonal transport [8, 9]. The axons of the first order olfactory nerves group together in the form of small nerve bundles (fila olfactoria) and pass through the small foramina of the cribriform plate of the ethmoid bone, entering the olfactory bulbs through their ventral surface. The olfactory bulb (OB) is a bilateral, elliptical, ventrodorsally-oriented extension of the telencephalon. It represents the primary center of the olfactory system, serving as a relay station for the impulses coming from the epithelium and bound for the olfactory cortex. The Journal of Neurology olfactory tract (OT) is a thin, myelinated nervous projection that, from the OB, runs posteriorly ending in perforate substance [8]. Brain MR imaging is a useful and consolidated method for evaluating olfactory dysfunction (OD) [10, 11]. 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 [12–18]. Only a (...truncated)