Insights into Molecular and Cellular Mechanisms of NeuroCOVID

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (20 December 2023) | Viewed by 41301

Special Issue Editors


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Guest Editor
Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Via E. Ramarini, Monterotondo Scalo, 32 - 00015 Rome, Italy
Interests: NeuroCOVID-19; SARS-CoV-2; post-COVID-19 syndrome; microRNA; RNA-induced silencing complex (RISC); RNA-binding protein; neurodegenerative disease; Alzheimer’s disease; small non-coding RNA; RNA metabolism; cellular and molecular neurobiology; translational biomedicine
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Guest Editor
Department of Sense Organs, University Sapienza of Rome, Policlinico Umberto I, Viale del Policlinico, 155 Rome, Italy
Interests: otolaryngology; speech and language pathology; audiology; head and neck surgery; hearing disorders; ENT; rhinology; sleep disorders and sleep medicine; sinusitis; anosmia; neuroCOVID; post-COVID-19
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), Department of Sense Organs, University Sapienza of Rome, Viale del Policlinico, 155 Rome, Italy
Interests: gut-brain axis; pediatric rare disease; neurophins: BDNF; NGF; anitoxidant and antiinflammatory natural compounds: probiotics and Polyphenols
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Post-COVID-19 syndrome (PCS), or long-haul COVID, is defined by the persistence or recurrence of symptoms after initial SARS-CoV-2 infection. This condition continues for more than 12 weeks and cannot be attributed to other clinical situations. PCS patients are affected by neurological, cardiac, and respiratory symptoms like dyspnea, fatigue, loss of olfactory and taste function with anosmia and dysgeusia, neurocognitive symptoms defined as “brain fog”, sleep disturbance, weakness, and chronic pain reducing physical and mental quality of life. In particular, the brain involvement, and more generally the central and peripheral nervous systems, as potential target organs of SARS-CoV-2 that can be affected during and after infection has been defined as neuroCOVID. Numerous studies have documented neurological and neuropsychological complications, and the effects of COVID-19 on the nervous system are becoming better defined. Now, it is evident that these disorders can also affect young people (30–50 years of age) who 1) had never previously experienced these symptoms, 2) had developed even very mild forms of COVID, or 3) had not experienced breathing problems. The aim of this Special Issue entitled “Insights into Molecular and Cellular Mechanisms of NeuroCOVID” is to explore integrated models of translational biomedical research starting from long-lasting post-infective neurobiological modifications, exploring common molecular and cellular determinants of the neurosensorial and neurological clinical manifestation of this neuroCOVID wave. Original research and review articles from this Special Issue will provide recent molecular and cellular neurobiological findings as well as translational biomedicine studies that highlight working hypotheses, route(s) for SARS-CoV-2 entry to the CNS, relative consequences, post-infective neuropathology, potential relationships with neurodegenerative diseases, and therapy. Researchers and clinicians are allied in unraveling the molecular and cellular pathogenetic mechanisms and the clinical development of this unexpected SARS-CoV-2 infectious evolution, mapping the geography of neuroCOVID.

Dr. Christian Barbato
Prof. Dr. Antonio Minni
Dr. Carla Petrella
Guest Editors

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Keywords

  • SARS-CoV-2
  • neuroCOVID
  • post-COVID-19 syndrome
  • neurodegenerative disease
  • brain fog
  • anosmia
  • dysgeusia
  • neurocognitive disease
  • neurosensorial
  • Alzheimer’s disease
  • Parkinson’s disease
  • non-coding RNA
  • neurotherapy

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Published Papers (9 papers)

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Editorial

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3 pages, 167 KiB  
Editorial
Insights into Molecular and Cellular Mechanisms of NeuroCOVID
by Christian Barbato, Carla Petrella and Antonio Minni
Cells 2024, 13(21), 1790; https://doi.org/10.3390/cells13211790 - 29 Oct 2024
Viewed by 262
Abstract
Post-COVID-19 syndrome (PCS) is defined by the persistence or recurrence of symptoms after an initial acute SARS-CoV-2 infection [...] Full article
(This article belongs to the Special Issue Insights into Molecular and Cellular Mechanisms of NeuroCOVID)

Research

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17 pages, 3150 KiB  
Article
Biomarkers of Neurological Damage: From Acute Stage to Post-Acute Sequelae of COVID-19
by Maria Antonella Zingaropoli, Patrizia Pasculli, Christian Barbato, Carla Petrella, Marco Fiore, Federica Dominelli, Tiziana Latronico, Federica Ciccone, Michele Antonacci, Grazia Maria Liuzzi, Giuseppina Talarico, Giuseppe Bruno, Gioacchino Galardo, Francesco Pugliese, Miriam Lichtner, Claudio Maria Mastroianni, Antonio Minni and Maria Rosa Ciardi
Cells 2023, 12(18), 2270; https://doi.org/10.3390/cells12182270 - 13 Sep 2023
Cited by 3 | Viewed by 1455
Abstract
Background: Neurological symptoms (NS) in COVID-19 are related to both acute stage and long-COVID. We explored levels of brain injury biomarkers (NfL and GFAP) and myeloid activation marker (sCD163) and their implications on the CNS. Materials and Methods: In hospitalized COVID-19 patients [...] Read more.
Background: Neurological symptoms (NS) in COVID-19 are related to both acute stage and long-COVID. We explored levels of brain injury biomarkers (NfL and GFAP) and myeloid activation marker (sCD163) and their implications on the CNS. Materials and Methods: In hospitalized COVID-19 patients plasma samples were collected at two time points: on hospital admission (baseline) and three months after hospital discharge (Tpost). Patients were stratified according to COVID-19 severity based on acute respiratory distress syndrome (ARDS) onset (severe and non-severe groups). A further stratification according to the presence of NS (with and without groups) at baseline (requiring a puncture lumbar for diagnostic purposes) and according to NS self-referred at Tpost was performed. Finally, cerebrospinal fluid (CSF) samples were collected from patients with NS present at baseline. Results: We enrolled 144 COVID-19 patients (62 female/82 male; median age [interquartile range, IQR]): 64 [55–77]) and 53 heathy donors (HD, 30 female/23 male; median age [IQR]: 64 [59–69]). At baseline, higher plasma levels of NfL, GFAP and sCD163 in COVID-19 patients compared to HD were observed (p < 0.0001, p < 0.0001 and p < 0.0001, respectively), especially in those with severe COVID-19 (p < 0.0001, p < 0.0001 and p < 0.0001, respectively). Patients with NS showed higher plasma levels of NfL, GFAP and sCD163 compared to those without (p = 0.0023, p < 0.0001 and 0.0370, respectively). At baseline, in COVID-19 patients with NS, positive correlations between CSF levels of sCD163 and CSF levels of NfL (ρ = 0.7536, p = 0.0017) and GFAP were observed (ρ = 0.7036, p = 0.0045). At Tpost, the longitudinal evaluation performed on 77 COVID-19 patients showed a significant reduction in plasma levels of NfL, GFAP and sCD163 compared to baseline (p < 0.0001, p < 0.0001 and p = 0.0413, respectively). Finally, at Tpost, in the severe group, higher plasma levels of sCD163 in patients with NS compared to those without were reported (p < 0.0001). Conclusions: High plasma levels of NfL, GFAP and sCD163 could be due to a proinflammatory systemic and brain response involving microglial activation and subsequent CNS damage. Our data highlight the association between myeloid activation and CNS perturbations. Full article
(This article belongs to the Special Issue Insights into Molecular and Cellular Mechanisms of NeuroCOVID)
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16 pages, 715 KiB  
Article
COVID-19 Affects Serum Brain-Derived Neurotrophic Factor and Neurofilament Light Chain in Aged Men: Implications for Morbidity and Mortality
by Carla Petrella, Maria Antonella Zingaropoli, Flavio Maria Ceci, Patrizia Pasculli, Tiziana Latronico, Grazia Maria Liuzzi, Maria Rosa Ciardi, Antonio Angeloni, Evaristo Ettorre, Michela Menghi, Christian Barbato, Giampiero Ferraguti, Antonio Minni and Marco Fiore
Cells 2023, 12(4), 655; https://doi.org/10.3390/cells12040655 - 17 Feb 2023
Cited by 13 | Viewed by 2169
Abstract
Background and Methods: Severe COVID-19 is known to induce neurological damage (NeuroCOVID), mostly in aged individuals, by affecting brain-derived neurotrophic factor (BDNF), matrix metalloproteinases (MMP) 2 and 9 and the neurofilament light chain (NFL) pathways. Thus, the aim of this pilot study was [...] Read more.
Background and Methods: Severe COVID-19 is known to induce neurological damage (NeuroCOVID), mostly in aged individuals, by affecting brain-derived neurotrophic factor (BDNF), matrix metalloproteinases (MMP) 2 and 9 and the neurofilament light chain (NFL) pathways. Thus, the aim of this pilot study was to investigate BDNF, MMP-2, MMP-9, and NFL in the serum of aged men affected by COVID-19 at the beginning of the hospitalization period and characterized by different outcomes, i.e., attending a hospital ward or an intensive care unit (ICU) or with a fatal outcome. As a control group, we used a novelty of the study, unexposed age-matched men. We also correlated these findings with the routine blood parameters of the recruited individuals. Results: We found in COVID-19 individuals with severe or lethal outcomes disrupted serum BDNF, NFL, and MMP-2 presence and gross changes in ALT, GGT, LDH, IL-6, ferritin, and CRP. We also confirmed and extended previous data, using ROC analyses, showing that the ratio MMPs (2 and 9) versus BDNF and NFL might be a useful tool to predict a fatal COVID-19 outcome. Conclusions: Serum BDNF and NFL and/or their ratios with MMP-2 and MMP-9 could represent early predictors of NeuroCOVID in aged men. Full article
(This article belongs to the Special Issue Insights into Molecular and Cellular Mechanisms of NeuroCOVID)
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19 pages, 5242 KiB  
Article
SARS-CoV-2 Pattern Provides a New Scoring System and Predicts the Prognosis and Immune Therapeutic Response in Glioma
by Fan Jiang, Deng-Feng Lu, Zheng Zhan, Gui-Qiang Yuan, Guang-Jie Liu, Jing-Yu Gu, Xiao-Ou Sun and Zhong Wang
Cells 2022, 11(24), 3997; https://doi.org/10.3390/cells11243997 - 10 Dec 2022
Cited by 4 | Viewed by 1849
Abstract
Objective: Glioma is the most common primary malignancy of the adult central nervous system (CNS), with a poor prognosis and no effective prognostic signature. Since late 2019, the world has been affected by the rapid spread of SARS-CoV-2 infection. Research on SARS-CoV-2 is [...] Read more.
Objective: Glioma is the most common primary malignancy of the adult central nervous system (CNS), with a poor prognosis and no effective prognostic signature. Since late 2019, the world has been affected by the rapid spread of SARS-CoV-2 infection. Research on SARS-CoV-2 is flourishing; however, its potential mechanistic association with glioma has rarely been reported. The aim of this study was to investigate the potential correlation of SARS-CoV-2-related genes with the occurrence, progression, prognosis, and immunotherapy of gliomas. Methods: SARS-CoV-2-related genes were obtained from the human protein atlas (HPA), while transcriptional data and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Glioma samples were collected from surgeries with the knowledge of patients. Differentially expressed genes were then identified and screened, and seven SARS-CoV-2 related genes were generated by LASSO regression analysis and uni/multi-variate COX analysis. A prognostic SARS-CoV-2-related gene signature (SCRGS) was then constructed based on these seven genes and validated in the TCGA validation cohort and CGGA cohort. Next, a nomogram was established by combining critical clinicopathological data. The correlation between SCRGS and glioma related biological processes was clarified by Gene set enrichment analysis (GSEA). In addition, immune infiltration and immune score, as well as immune checkpoint expression and immune escape, were further analyzed to assess the role of SCRGS in glioma-associated immune landscape and the responsiveness of immunotherapy. Finally, the reliability of SCRGS was verified by quantitative real-time polymerase chain reaction (qRT-PCR) on glioma samples. Results: The prognostic SCRGS contained seven genes, REEP6, CEP112, LARP4B, CWC27, GOLGA2, ATP6AP1, and ERO1B. Patients were divided into high- and low-risk groups according to the median SARS-CoV-2 Index. Overall survival was significantly worse in the high-risk group than in the low-risk group. COX analysis and receiver operating characteristic (ROC) curves demonstrated excellent predictive power for SCRGS for glioma prognosis. In addition, GSEA, immune infiltration, and immune scores indicated that SCRGS could potentially predict the tumor microenvironment, immune infiltration, and immune response in glioma patients. Conclusions: The SCRGS established here can effectively predict the prognosis of glioma patients and provide a potential direction for immunotherapy. Full article
(This article belongs to the Special Issue Insights into Molecular and Cellular Mechanisms of NeuroCOVID)
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18 pages, 2465 KiB  
Article
Neuro-Axonal Damage and Alteration of Blood–Brain Barrier Integrity in COVID-19 Patients
by Maria Antonella Zingaropoli, Marco Iannetta, Lorenzo Piermatteo, Patrizia Pasculli, Tiziana Latronico, Laura Mazzuti, Laura Campogiani, Leonardo Duca, Giampiero Ferraguti, Manuela De Michele, Gioacchino Galardo, Francesco Pugliese, Guido Antonelli, Massimo Andreoni, Loredana Sarmati, Miriam Lichtner, Ombretta Turriziani, Francesca Ceccherini-Silberstein, Grazia Maria Liuzzi, Claudio Maria Mastroianni and Maria Rosa Ciardiadd Show full author list remove Hide full author list
Cells 2022, 11(16), 2480; https://doi.org/10.3390/cells11162480 - 10 Aug 2022
Cited by 17 | Viewed by 3887
Abstract
Neurofilament light chain (NfL) is a specific biomarker of neuro-axonal damage. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in blood–brain barrier (BBB) integrity. We explored neuro-axonal damage, alteration of BBB integrity and SARS-CoV-2 RNA presence in COVID-19 patients with severe neurological symptoms (neuro-COVID) [...] Read more.
Neurofilament light chain (NfL) is a specific biomarker of neuro-axonal damage. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in blood–brain barrier (BBB) integrity. We explored neuro-axonal damage, alteration of BBB integrity and SARS-CoV-2 RNA presence in COVID-19 patients with severe neurological symptoms (neuro-COVID) as well as neuro-axonal damage in COVID-19 patients without severe neurological symptoms according to disease severity and after recovery, comparing the obtained findings with healthy donors (HD). Overall, COVID-19 patients (n = 55) showed higher plasma NfL levels compared to HD (n = 31) (p < 0.0001), especially those who developed ARDS (n = 28) (p = 0.0005). After recovery, plasma NfL levels were still higher in ARDS patients compared to HD (p = 0.0037). In neuro-COVID patients (n = 12), higher CSF and plasma NfL, and CSF MMP-2 levels in ARDS than non-ARDS group were observed (p = 0.0357, p = 0.0346 and p = 0.0303, respectively). SARS-CoV-2 RNA was detected in four CSF and two plasma samples. SARS-CoV-2 RNA detection was not associated to increased CSF NfL and MMP levels. During COVID-19, ARDS could be associated to CNS damage and alteration of BBB integrity in the absence of SARS-CoV-2 RNA detection in CSF or blood. CNS damage was still detectable after discharge in blood of COVID-19 patients who developed ARDS during hospitalization. Full article
(This article belongs to the Special Issue Insights into Molecular and Cellular Mechanisms of NeuroCOVID)
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Review

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24 pages, 2454 KiB  
Review
Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics
by Albert Leng, Manuj Shah, Syed Ameen Ahmad, Lavienraj Premraj, Karin Wildi, Gianluigi Li Bassi, Carlos A. Pardo, Alex Choi and Sung-Min Cho
Cells 2023, 12(5), 816; https://doi.org/10.3390/cells12050816 - 6 Mar 2023
Cited by 77 | Viewed by 13329
Abstract
The development of long-term symptoms of coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed “long COVID” or post-acute sequela of COVID-19 (PASC), can implicate persistent neurological complications in up to one third of patients and present as fatigue, “brain [...] Read more.
The development of long-term symptoms of coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed “long COVID” or post-acute sequela of COVID-19 (PASC), can implicate persistent neurological complications in up to one third of patients and present as fatigue, “brain fog”, headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, and peripheral neuropathy. Pathogenic mechanisms of these symptoms of long COVID remain largely unclear; however, several hypotheses implicate both nervous system and systemic pathogenic mechanisms such as SARS-CoV2 viral persistence and neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, and endotheliopathy. Outside of the CNS, SARS-CoV-2 can invade the support and stem cells of the olfactory epithelium leading to persistent alterations to olfactory function. SARS-CoV-2 infection may induce abnormalities in innate and adaptive immunity including monocyte expansion, T-cell exhaustion, and prolonged cytokine release, which may cause neuroinflammatory responses and microglia activation, white matter abnormalities, and microvascular changes. Additionally, microvascular clot formation can occlude capillaries and endotheliopathy, due to SARS-CoV-2 protease activity and complement activation, can contribute to hypoxic neuronal injury and blood–brain barrier dysfunction, respectively. Current therapeutics target pathological mechanisms by employing antivirals, decreasing inflammation, and promoting olfactory epithelium regeneration. Thus, from laboratory evidence and clinical trials in the literature, we sought to synthesize the pathophysiological pathways underlying neurological symptoms of long COVID and potential therapeutics. Full article
(This article belongs to the Special Issue Insights into Molecular and Cellular Mechanisms of NeuroCOVID)
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24 pages, 1181 KiB  
Review
Role of SARS-CoV-2 Spike-Protein-Induced Activation of Microglia and Mast Cells in the Pathogenesis of Neuro-COVID
by Theoharis C. Theoharides and Duraisamy Kempuraj
Cells 2023, 12(5), 688; https://doi.org/10.3390/cells12050688 - 22 Feb 2023
Cited by 36 | Viewed by 7754
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). About 45% of COVID-19 patients experience several symptoms a few months after the initial infection and develop post-acute sequelae of SARS-CoV-2 (PASC), referred to as “Long-COVID,” characterized by persistent physical and [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). About 45% of COVID-19 patients experience several symptoms a few months after the initial infection and develop post-acute sequelae of SARS-CoV-2 (PASC), referred to as “Long-COVID,” characterized by persistent physical and mental fatigue. However, the exact pathogenetic mechanisms affecting the brain are still not well-understood. There is increasing evidence of neurovascular inflammation in the brain. However, the precise role of the neuroinflammatory response that contributes to the disease severity of COVID-19 and long COVID pathogenesis is not clearly understood. Here, we review the reports that the SARS-CoV-2 spike protein can cause blood–brain barrier (BBB) dysfunction and damage neurons either directly, or via activation of brain mast cells and microglia and the release of various neuroinflammatory molecules. Moreover, we provide recent evidence that the novel flavanol eriodictyol is particularly suited for development as an effective treatment alone or together with oleuropein and sulforaphane (ViralProtek®), all of which have potent anti-viral and anti-inflammatory actions. Full article
(This article belongs to the Special Issue Insights into Molecular and Cellular Mechanisms of NeuroCOVID)
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Other

25 pages, 4259 KiB  
Systematic Review
Prevalence of Olfactory Dysfunction with the Omicron Variant of SARS-CoV-2: A Systematic Review and Meta-Analysis
by Christopher S. von Bartheld and Lingchen Wang
Cells 2023, 12(3), 430; https://doi.org/10.3390/cells12030430 - 28 Jan 2023
Cited by 35 | Viewed by 5547
Abstract
The omicron variant is thought to cause less olfactory dysfunction than previous variants of SARS-CoV-2, but the reported prevalence differs greatly between populations and studies. Our systematic review and meta-analysis provide information regarding regional differences in prevalence as well as an estimate of [...] Read more.
The omicron variant is thought to cause less olfactory dysfunction than previous variants of SARS-CoV-2, but the reported prevalence differs greatly between populations and studies. Our systematic review and meta-analysis provide information regarding regional differences in prevalence as well as an estimate of the global prevalence of olfactory dysfunction based on 62 studies reporting information on 626,035 patients infected with the omicron variant. Our estimate of the omicron-induced prevalence of olfactory dysfunction in populations of European ancestry is 11.7%, while it is significantly lower in all other populations, ranging between 1.9% and 4.9%. When ethnic differences and population sizes are considered, the global prevalence of omicron-induced olfactory dysfunction in adults is estimated to be 3.7%. Omicron’s effect on olfaction is twofold to tenfold lower than that of the alpha or delta variants according to previous meta-analyses and our analysis of studies that directly compared the prevalence of olfactory dysfunction between omicron and previous variants. The profile of the prevalence differences between ethnicities mirrors the results of a recent genome-wide association study that connected a gene locus encoding an odorant-metabolizing enzyme, UDP glycosyltransferase, to the extent of COVID-19-related loss of smell. Our analysis is consistent with the hypothesis that this enzyme contributes to the observed population differences. Full article
(This article belongs to the Special Issue Insights into Molecular and Cellular Mechanisms of NeuroCOVID)
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21 pages, 1822 KiB  
Systematic Review
Clinical Implications of COVID-19 Presence in CSF: Systematic Review of Case Reports
by Ibrahim Elmakaty, Khaled Ferih, Omar Karen, Amr Ouda, Ahmed Elsabagh, Ahmed Amarah and Mohammed Imad Malki
Cells 2022, 11(20), 3212; https://doi.org/10.3390/cells11203212 - 13 Oct 2022
Cited by 7 | Viewed by 3735
Abstract
This systematic review focused on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients that had detected SARS-CoV-2 virus in cerebrospinal fluid (CSF). A systematic literature search was carried out in PubMed, Embase, Scopus, Web of Science, Medrxiv, and Biorxiv databases from inception to [...] Read more.
This systematic review focused on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients that had detected SARS-CoV-2 virus in cerebrospinal fluid (CSF). A systematic literature search was carried out in PubMed, Embase, Scopus, Web of Science, Medrxiv, and Biorxiv databases from inception to 19 December 2021. Case reports or case series involving patients with proved SARS-CoV-2 presence in CSF by polymerize chain reaction were included. Our search strategy produced 23 articles documenting a total of 23 patients with positive SARS-CoV-2 in the CSF. Fever (55%) was the most common symptom, followed by headaches (41%), cough (32%), and vomiting/nausea (32%). The majority of the cases included was encephalitis (57%), 8 of which were confirmed by magnetic resonance imaging. The second most prevalent presentation was meningitis. The cerebral spinal fluid analysis found disparities in protein levels and normal glucose levels in most cases. This study demonstrates that SARS-CoV-2 can enter the nervous system via various routes and cause CNS infection symptoms. SARS-CoV-2 has been shown to infect the CNS even when no respiratory symptoms are present and nasopharyngeal swabs are negative. As a result, SARS-CoV-2 should be considered as a possible cause of CNS infection and tested for in the CSF. Full article
(This article belongs to the Special Issue Insights into Molecular and Cellular Mechanisms of NeuroCOVID)
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