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Cells
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Neurological Symptoms and COVID-19 Pandemic
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Neurological Symptoms and COVID-19 Pandemic

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 (10 October 2023) | Viewed by 45363

Special Issue Editors

Dr. Nicola Montemurro

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Guest Editor
Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy
Interests: brain; medicine; glioblastoma; spine; hydrocephalus; brain tumor; surgery; diabetes; trauma; vascular
Special Issues, Collections and Topics in MDPI journals
Dr. Luca Ricciardi

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Guest Editor
Department of Neuroscience, Mental Health and Sense Organs (NESMOS), Sant’Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy
Interests: spine surgery; spinal surgery; spinal cord injury; microneurosurgery; neuroanatomy; brain injury; traumatic brain injury; glioma; spine
Special Issues, Collections and Topics in MDPI journals
Dr. Alba Scerrati

E-Mail Website
Guest Editor
Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy
Interests: functional neurosurgery; cerebrovascular disease; neuro-oncology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The current COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to spread across the world. Patients typically present with fever, shortness of breath and cough, but some patients develop neurological sequelae, such as headache and neuroinflammatory or cerebrovascular disease, and these conditions are more frequent in patients with severe COVID-19. Effective vaccines against SARS-CoV-2 have been rapidly developed and are being administered with the aim of preventing COVID-19, stopping viral circulation and terminating the pandemic.

COVID-19 induces an inflammatory response and, in severe cases, a cytokine storm that can damage the CNS. The ability of COVID-19 to produce a cytokine storm and inflammation might be at the center of the pathogenicity of the virus; however, little is known about this virus. This Special Issue will contribute significantly to the development of anti-COVID-19 strategies by collecting and publishing innovative concepts, suggestions and research data for the identification and validation of specific drug targets and cell-mediated immunity.

In addition, patients with COVID-19 infection are at increased risk for thrombotic events as various anticoagulation regimens are now being considered for these patients, and different types of vaccines are not free from side effects and intracranial complications. Endothelial dysfunction, activation of the renin–angiotensin–aldosterone system (RAAS) with the release of procoagulant plasminogen activator inhibitor (PAI-1) and hyperimmune responses with activated platelets seem to be significant contributors to thrombogenesis in COVID-19.

We welcome original papers, systematic reviews, and reviews on this interesting and current topic that lay emphasis on neuroinflammation, specific drug targets, hyperimmune responses and clinical neurological symptoms.

We look forward to your contributions.

Dr. Nicola Montemurro
Dr. Luca Ricciardi
Dr. Alba Scerrati
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • SARS-Cov-2
  • COVID-19
  • stroke
  • intracranial hemorrhage
  • neuroinflammatory
  • drug targets
  • hyperimmune response
  • vaccines
  • side effects

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Published Papers (9 papers)

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Research

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13 pages, 2341 KiB  
Article
Effect of Ultra-Micronized Palmitoylethanolamide and Luteolin on Olfaction and Memory in Patients with Long COVID: Results of a Longitudinal Study
by Pietro De Luca, Angelo Camaioni, Pasquale Marra, Giovanni Salzano, Giovanni Carriere, Luca Ricciardi, Resi Pucci, Nicola Montemurro, Michael J. Brenner and Arianna Di Stadio
Cells 2022, 11(16), 2552; https://doi.org/10.3390/cells11162552 - 17 Aug 2022
Cited by 42 | Viewed by 4446
Abstract
In this study, we investigated whether treatment with palmitoylethanolamide and luteolin (PEA-LUT) leads to improvement in the quantitative or qualitative measures of olfactory dysfunction or relief from mental clouding in patients affected by long COVID. Patients with long COVID olfactory dysfunction were allocated [...] Read more.
In this study, we investigated whether treatment with palmitoylethanolamide and luteolin (PEA-LUT) leads to improvement in the quantitative or qualitative measures of olfactory dysfunction or relief from mental clouding in patients affected by long COVID. Patients with long COVID olfactory dysfunction were allocated to different groups based on the presence (“previously treated”) or absence (“naïve”) of prior exposure to olfactory training. Patients were then randomized to receive PEA-LUT alone or in combination with olfactory training. Olfactory function and memory were assessed at monthly intervals using self-report measures and quantitative thresholds. A total of 69 patients (43 women, 26 men) with an age average of 40.6 + 10.5 were recruited. PEA-LUT therapy was associated with a significant improvement in validated odor identification scores at the baseline versus each subsequent month; assessment at 3 months showed an average improvement of 10.7 + 2.6, CI 95%: 6–14 (p < 0.0001). The overall prevalence of parosmia was 79.7% (55 patients), with a significant improvement from the baseline to 3 months (p < 0.0001), namely in 31 patients from the Naïve 1 group (72%), 15 from the Naïve 2 group (93.7%), and 9 from the remaining group (90%). Overall, mental clouding was detected in 37.7% (26 subjects) of the cases, with a reduction in severity from the baseline to three months (p = 0.02), namely in 15 patients from the Naïve 1 group (34.8%), 7 from the Naïve 2 group (43.7%), and 4 from the remaining group (40%). Conclusions. In patients with long COVID and chronic olfactory loss, a regimen including oral PEA-LUT and olfactory training ameliorated olfactory dysfunction and memory. Further investigations are necessary to discern biomarkers, mechanisms, and long-term outcomes. Full article
(This article belongs to the Special Issue Neurological Symptoms and COVID-19 Pandemic)
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Review

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24 pages, 3281 KiB  
Review
COVID-19 and Alzheimer’s Disease Share Common Neurological and Ophthalmological Manifestations: A Bidirectional Risk in the Post-Pandemic Future
by Giuseppina Amadoro, Valentina Latina, Egidio Stigliano and Alessandra Micera
Cells 2023, 12(22), 2601; https://doi.org/10.3390/cells12222601 - 10 Nov 2023
Cited by 8 | Viewed by 2773
Abstract
A growing body of evidence indicates that a neuropathological cross-talk takes place between the coronavirus disease 2019 (COVID-19) -the pandemic severe pneumonia that has had a tremendous impact on the global economy and health since three years after its outbreak in December 2019- [...] Read more.
A growing body of evidence indicates that a neuropathological cross-talk takes place between the coronavirus disease 2019 (COVID-19) -the pandemic severe pneumonia that has had a tremendous impact on the global economy and health since three years after its outbreak in December 2019- and Alzheimer’s Disease (AD), the leading cause of dementia among human beings, reaching 139 million by the year 2050. Even though COVID-19 is a primary respiratory disease, its causative agent, the so-called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), is also endowed with high neuro-invasive potential (Neurocovid). The neurological complications of COVID-19, resulting from the direct viral entry into the Central Nervous System (CNS) and/or indirect systemic inflammation and dysregulated activation of immune response, encompass memory decline and anosmia which are typically associated with AD symptomatology. In addition, patients diagnosed with AD are more vulnerable to SARS-CoV-2 infection and are inclined to more severe clinical outcomes. In the present review, we better elucidate the intimate connection between COVID-19 and AD by summarizing the involved risk factors/targets and the underlying biological mechanisms shared by these two disorders with a particular focus on the Angiotensin-Converting Enzyme 2 (ACE2) receptor, APOlipoprotein E (APOE), aging, neuroinflammation and cellular pathways associated with the Amyloid Precursor Protein (APP)/Amyloid beta (Aβ) and tau neuropathologies. Finally, the involvement of ophthalmological manifestations, including vitreo-retinal abnormalities and visual deficits, in both COVID-19 and AD are also discussed. Understanding the common physiopathological aspects linking COVID-19 and AD will pave the way to novel management and diagnostic/therapeutic approaches to cope with them in the post-pandemic future. Full article
(This article belongs to the Special Issue Neurological Symptoms and COVID-19 Pandemic)
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16 pages, 364 KiB  
Review
Cardiovascular, Pulmonary, and Neuropsychiatric Short- and Long-Term Complications of COVID-19
by Małgorzata Kobusiak-Prokopowicz, Katarzyna Fułek, Michał Fułek, Konrad Kaaz, Andrzej Mysiak, Donata Kurpas, Jan Aleksander Beszłej, Anna Brzecka and Jerzy Leszek
Cells 2022, 11(23), 3882; https://doi.org/10.3390/cells11233882 - 1 Dec 2022
Cited by 10 | Viewed by 3295
Abstract
Beginning with the various strategies of the SARS-CoV-2 virus to invade our bodies and manifest infection, and ending with the recent long COVID, we are witnessing the evolving course of the disease in addition to the pandemic. Given the partially controlled course of [...] Read more.
Beginning with the various strategies of the SARS-CoV-2 virus to invade our bodies and manifest infection, and ending with the recent long COVID, we are witnessing the evolving course of the disease in addition to the pandemic. Given the partially controlled course of the COVID-19 pandemic, the greatest challenge currently lies in managing the short- and long-term complications of COVID-19. We have assembled current knowledge of the broad spectrum of cardiovascular, pulmonary, and neuropsychiatric sequelae following SARS-CoV-2 infection to understand how these clinical manifestations collectively lead to a severe form of the disease. The ultimate goal would be to better understand these complications and find ways to prevent clinical deterioration. Full article
(This article belongs to the Special Issue Neurological Symptoms and COVID-19 Pandemic)
20 pages, 1221 KiB  
Review
The Adverse Outcome Pathway Framework Applied to Neurological Symptoms of COVID-19
by Helena T. Hogberg, Ann Lam, Elan Ohayon, Muhammad Ali Shahbaz, Laure-Alix Clerbaux, Anna Bal-Price, Sandra Coecke, Rachel Concha, Francesca De Bernardi, Eizleayne Edrosa, Alan J. Hargreaves, Katja M. Kanninen, Amalia Munoz, Francesca Pistollato, Surat Saravanan, Natàlia Garcia-Reyero, Clemens Wittwehr and Magdalini Sachana
Cells 2022, 11(21), 3411; https://doi.org/10.3390/cells11213411 - 28 Oct 2022
Cited by 9 | Viewed by 4697
Abstract
Several reports have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to also be neurotropic. However, the mechanisms by which SARS-CoV-2 induces neurologic injury, including neurological and/or psychological symptoms, remain unclear. In this review, the available knowledge on [...] Read more.
Several reports have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to also be neurotropic. However, the mechanisms by which SARS-CoV-2 induces neurologic injury, including neurological and/or psychological symptoms, remain unclear. In this review, the available knowledge on the neurobiological mechanisms underlying COVID-19 was organized using the AOP framework. Four AOPs leading to neurological adverse outcomes (AO), anosmia, encephalitis, stroke, and seizure, were developed. Biological key events (KEs) identified to induce these AOs included binding to ACE2, blood–brain barrier (BBB) disruption, hypoxia, neuroinflammation, and oxidative stress. The modularity of AOPs allows the construction of AOP networks to visualize core pathways and recognize neuroinflammation and BBB disruption as shared mechanisms. Furthermore, the impact on the neurological AOPs of COVID-19 by modulating and multiscale factors such as age, psychological stress, nutrition, poverty, and food insecurity was discussed. Organizing the existing knowledge along an AOP framework can represent a valuable tool to understand disease mechanisms and identify data gaps and potentially contribute to treatment, and prevention. This AOP-aligned approach also facilitates synergy between experts from different backgrounds, while the fast-evolving and disruptive nature of COVID-19 emphasizes the need for interdisciplinarity and cross-community research. Full article
(This article belongs to the Special Issue Neurological Symptoms and COVID-19 Pandemic)
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25 pages, 9774 KiB  
Review
Medicinal Herbs in the Relief of Neurological, Cardiovascular, and Respiratory Symptoms after COVID-19 Infection A Literature Review
by Joanna Nawrot, Justyna Gornowicz-Porowska, Jaromir Budzianowski, Gerard Nowak, Grzegorz Schroeder and Joanna Kurczewska
Cells 2022, 11(12), 1897; https://doi.org/10.3390/cells11121897 - 11 Jun 2022
Cited by 20 | Viewed by 9838
Abstract
COVID-19 infection causes complications, even in people who have had a mild course of the disease. The most dangerous seem to be neurological ailments: anxiety, depression, mixed anxiety–depressive (MAD) syndromes, and irreversible dementia. These conditions can negatively affect the respiratory system, circulatory system, [...] Read more.
COVID-19 infection causes complications, even in people who have had a mild course of the disease. The most dangerous seem to be neurological ailments: anxiety, depression, mixed anxiety–depressive (MAD) syndromes, and irreversible dementia. These conditions can negatively affect the respiratory system, circulatory system, and heart functioning. We believe that phytotherapy can be helpful in all of these conditions. Clinical trials confirm this possibility. The work presents plant materials (Valeriana officinalis, Melissa officinalis, Passiflora incarnata, Piper methysticum, Humulus lupulus, Ballota nigra, Hypericum perforatum, Rhodiola rosea, Lavandula officinalis, Paullinia cupana, Ginkgo biloba, Murraya koenigii, Crataegus monogyna and oxyacantha, Hedera helix, Polygala senega, Pelargonium sidoides, Lichen islandicus, Plantago lanceolata) and their dominant compounds (valeranon, valtrate, apigenin, citronellal, isovitexin, isoorientin, methysticin, humulone, farnesene, acteoside, hypericin, hyperforin, biapigenin, rosavidin, salidroside, linalool acetate, linalool, caffeine, ginkgolide, bilobalide, mihanimbine, epicatechin, hederacoside C,α-hederine, presegenin, umckalin, 6,7,8-trixydroxybenzopyranone disulfate, fumaroprotocetric acid, protolichesteric acid, aucubin, acteoside) responsible for their activity. It also shows the possibility of reducing post-COVID-19 neurological, respiratory, and cardiovascular complications, which can affect the functioning of the nervous system. Full article
(This article belongs to the Special Issue Neurological Symptoms and COVID-19 Pandemic)
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20 pages, 1075 KiB  
Review
SARS-CoV-2 Attacks in the Brain: Focus on the Sialome
by Przemyslaw Wielgat, Karolina Narejko and Halina Car
Cells 2022, 11(9), 1458; https://doi.org/10.3390/cells11091458 - 26 Apr 2022
Cited by 5 | Viewed by 3751
Abstract
The epidemiological observations suggest that respiratory and gastrointestinal symptoms caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) are accompanied by short- and long-term neurological manifestations. There is increasing evidence that the neuroinvasive potential of SARS-CoV-2 is closely related to its capacity to interact [...] Read more.
The epidemiological observations suggest that respiratory and gastrointestinal symptoms caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) are accompanied by short- and long-term neurological manifestations. There is increasing evidence that the neuroinvasive potential of SARS-CoV-2 is closely related to its capacity to interact with cell membrane sialome. Given the wide expression of sialylated compounds of cell membranes in the brain, the interplay between cell membrane sialoglycans and the virus is crucial for its attachment and cell entry, transport, neuronal damage and brain immunity. Here, we focus on the significance of the brain sialome in the progress of coronavirus disease 2019 (COVID-19) and SARS-CoV-2-induced neuropathology. Full article
(This article belongs to the Special Issue Neurological Symptoms and COVID-19 Pandemic)
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Other

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17 pages, 2352 KiB  
Hypothesis
Mechanistic Understanding of the Olfactory Neuroepithelium Involvement Leading to Short-Term Anosmia in COVID-19 Using the Adverse Outcome Pathway Framework
by Muhammad Ali Shahbaz, Francesca De Bernardi, Arto Alatalo, Magdalini Sachana, Laure-Alix Clerbaux, Amalia Muñoz, Surat Parvatam, Brigitte Landesmann, Katja M. Kanninen and Sandra Coecke
Cells 2022, 11(19), 3027; https://doi.org/10.3390/cells11193027 - 27 Sep 2022
Cited by 15 | Viewed by 4584
Abstract
Loss of the sense of smell (anosmia) has been included as a COVID-19 symptom by the World Health Organization. The majority of patients recover the sense of smell within a few weeks postinfection (short-term anosmia), while others report persistent anosmia. Several studies have [...] Read more.
Loss of the sense of smell (anosmia) has been included as a COVID-19 symptom by the World Health Organization. The majority of patients recover the sense of smell within a few weeks postinfection (short-term anosmia), while others report persistent anosmia. Several studies have investigated the mechanisms leading to anosmia in COVID-19; however, the evidence is scattered, and the mechanisms remain poorly understood. Based on a comprehensive review of the literature, we aim here to evaluate the current knowledge and uncertainties regarding the mechanisms leading to short-term anosmia following SARS-CoV-2 infection. We applied an adverse outcome pathway (AOP) framework, well established in toxicology, to propose a sequence of measurable key events (KEs) leading to short-term anosmia in COVID-19. Those KEs are (1) SARS-CoV-2 Spike proteins binding to ACE-2 expressed by the sustentacular (SUS) cells in the olfactory epithelium (OE); (2) viral entry into SUS cells; (3) viral replication in the SUS cells; (4) SUS cell death; (5) damage to the olfactory sensory neurons and the olfactory epithelium (OE). This AOP-aligned approach allows for the identification of gaps where more research should be conducted and where therapeutic intervention could act. Finally, this AOP gives a frame to explain several disease features and can be linked to specific factors that lead to interindividual differences in response to SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue Neurological Symptoms and COVID-19 Pandemic)
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38 pages, 2010 KiB  
Systematic Review
Encephalitis in Patients with COVID-19: A Systematic Evidence-Based Analysis
by Md Asiful Islam, Cinzia Cavestro, Sayeda Sadia Alam, Shoumik Kundu, Mohammad Amjad Kamal and Faruque Reza
Cells 2022, 11(16), 2575; https://doi.org/10.3390/cells11162575 - 18 Aug 2022
Cited by 38 | Viewed by 6397
Abstract
Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly infects the respiratory system, several investigations have shown the involvement of the central nervous system (CNS) along the course of the illness, with encephalitis being one of the symptoms. The objective of this systematic [...] Read more.
Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly infects the respiratory system, several investigations have shown the involvement of the central nervous system (CNS) along the course of the illness, with encephalitis being one of the symptoms. The objective of this systematic review was to evaluate the characteristics (clinical, neuro-radiological aspects, and laboratory features) and outcomes of encephalitis in COVID-19 patients. PubMed, Scopus, and Google Scholar databases were searched from 1 December 2019 until 21 July 2022 to identify case reports and case series published on COVID-19 associated with encephalitis. The quality of the included studies was assessed by the Joanna Briggs Institute critical appraisal checklists. This systematic review included 79 studies, including 91 COVID-19 patients (52.7% male) experiencing encephalitis, where 85.6% were adults (49.3 ± 20.2 years), and 14.4% were children (11.2 ± 7.6 years). RT-PCR was used to confirm 92.2% of the COVID-19 patients. Encephalitis-related symptoms were present in 78.0% of COVID-19 patients at the time of diagnosis. In these encephalitis patients, seizure (29.5%), confusion (23.2%), headache (20.5%), disorientation (15.2%), and altered mental status (11.6%) were the most frequently reported neurologic manifestations. Looking at the MRI, EEG, and CSF findings, 77.6%, 75.5%, and 64.1% of the patients represented abnormal results. SARS-CoV-2-associated or -mediated encephalitis were the most common type observed (59.3%), followed by autoimmune encephalitis (18.7%). Among the included patients, 66.7% were discharged (37.8% improved and 28.9% fully recovered), whereas 20.0% of the reported COVID-19-positive encephalitis patients died. Based on the quality assessment, 87.4% of the studies were of high quality. Although in COVID-19, encephalitis is not a typical phenomenon, SARS-CoV-2 seems like a neuropathogen affecting the brain even when there are no signs of respiratory illness, causing a high rate of disability and fatality. Full article
(This article belongs to the Special Issue Neurological Symptoms and COVID-19 Pandemic)
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5 pages, 1466 KiB  
Case Report
Vogt-Koyanagi-Harada Disease Exacerbation Associated with COVID-19 Vaccine
by Begoña De Domingo, Miguel López, Maria Lopez-Valladares, Esperanza Ortegon-Aguilar, Bernardo Sopeña-Perez-Argüelles and Francisco Gonzalez
Cells 2022, 11(6), 1012; https://doi.org/10.3390/cells11061012 - 16 Mar 2022
Cited by 14 | Viewed by 3980
Abstract
We describe a case of Vogt-Koyanagi-Harada (VKH) disease exacerbation after COVID-19 vaccination. A 46-year-old woman presented with a bilateral granulomatous uveitis 2 days after the first dose of COVID-19 mRNA vaccine (Comirnaty, Pfizer-BioNTech), and was diagnosed with a complete Vogt-Koyanagi-Harada (VKH) disease 4 [...] Read more.
We describe a case of Vogt-Koyanagi-Harada (VKH) disease exacerbation after COVID-19 vaccination. A 46-year-old woman presented with a bilateral granulomatous uveitis 2 days after the first dose of COVID-19 mRNA vaccine (Comirnaty, Pfizer-BioNTech), and was diagnosed with a complete Vogt-Koyanagi-Harada (VKH) disease 4 days after receiving the second dose of the vaccine. Three weeks before the first dose, she had been consulted for blurred vision and mild headaches. The case resolved with high dose intravenous corticosteroids, followed by oral prednisone. The close temporal relationship between the COVID-19 vaccine doses and the worsening of VKH symptoms strongly suggests COVID-19 vaccination as the trigger of its exacerbation. Full article
(This article belongs to the Special Issue Neurological Symptoms and COVID-19 Pandemic)
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