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Understanding the Neuropathogenesis of SARS-CoV-2: A Review – Neurology
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category-neuropathogenesis tag-central-nervous-system tag-covid-19 tag-encephalitis tag-guillain-barre-syndrome tag-long-term-sequelae tag-neurological-manifestations tag-neuropathogenesis tag-peripheral-nervous-system tag-sars-cov-2 tag-stroke" itemtype="https://schema.org/CreativeWork" itemscope> <div class="inside-article"> <div class="featured-image page-header-image-single "> <img width="1200" height="628" src="https://neurocare.blog/archive/wp-content/uploads/2024/10/banner-16-min-scaled-e1729079660834.jpg" class="attachment-full size-full" alt="" itemprop="image" decoding="async" fetchpriority="high" /> </div> <header class="entry-header"> <h1 class="entry-title" itemprop="headline">Understanding the Neuropathogenesis of SARS-CoV-2: A Review</h1> <div class="entry-meta"> <span class="posted-on"><time class="entry-date published" datetime="2024-10-16T17:24:29+05:30" itemprop="datePublished">October 16, 2024</time></span> <span class="byline">by <span class="author vcard" itemprop="author" itemtype="https://schema.org/Person" itemscope><a class="url fn n" href="https://neurocare.blog/archive/author/neurocare/" title="View all posts by neurocare" rel="author" itemprop="url"><span class="author-name" itemprop="name">neurocare</span></a></span></span> </div> </header> <div class="entry-content" itemprop="text"> <h3><b>Introduction</b></h3> <p><span style="font-weight: 400;">The novel severe acute respiratory syndrome coronavirus 2, known as SARS-CoV-2, causing COVID-19 infection, gave the world an unprecedented health blow, and in this regard, a lot of scientific inquiries on the biology of the disease were undertaken. In fact, though most of the focus has been upon respiratory issues, considerable neurological involvement is well supported by increasingly growing data. Neurotropism and the capability of SARS-CoV-2 to enter the CNS have raised an alert for its potential long-term neurological consequence. This article reviews the current understanding of neuropathogenesis caused by the novel coronavirus SARS-CoV-2, with a special focus on neurological symptoms, mechanisms of neuroinvasion, and potential long-term consequences.</span></p> <h3><b>Mechanisms of neuroinvasion</b></h3> <p><span style="font-weight: 400;">Its entry to the brain is thought to be via several routes. One hypothesis is that the virus enters the brain through the olfactory nerve, bypassing the blood-brain barrier. A high number of anosmias or loss of smell in COVID-19 patients supports this theory. Another possible route of dissemination is hematogenous: through infection of the virus in the blood-brain barrier endothelial cells, leading to increased permeability and allowing access of the virus into the central nervous system. The virus may also use the vagus nerve or other peripheral nerves to enter the brainstem and other parts of the central nervous system.</span></p> <p><span style="font-weight: 400;">Once inside, these infections spread by hijacking the transport system, moving along axons inside neurons. Several infections also carry out cell-to-cell spread that avoids immune surveillance and extracellular space. Elucidation of these routes is essential in developing therapeutic strategies to prevent or reduce the outcomes of neuroinvasive diseases.</span></p> <p><span style="font-weight: 400;">Because these ACE2 receptors are expressed in a general manner by several parts of the brain, including both neurons and glial cells, their neuropathogenesis might depend on the capability of SARS-CoV-2 to bind with these ACE2 receptors. One of the most likely mechanisms for neurotoxicity is a direct viral attack mediated by the spike viral protein through the ACE2 receptors. Moreover, severe manifestations of COVID-19 feature a hyperinflammatory status, also known as a “cytokine storm,” which leads to further CNS involvement because of an increase in the pervasive inflammation and oxidative stress, causing a further lesion of neural structures. Such knowledge is essential to treat neurological symptoms in COVID-19 patients and gives a chance for targeted therapy that may protect the nervous system from the long-term consequences of SARS-CoV-2 infection.</span></p> <h3><b>Neurological manifestations</b></h3> <p><span style="font-weight: 400;">Neurological manifestations of COVID-19 range from minor symptoms such as headache and dizziness to severe diseases such as encephalitis, stroke, and Guillain-Barre syndrome. Symptoms could be divided into three major categories: musculoskeletal issues, peripheral nervous system manifestations, and central nervous system complications.</span></p> <p></div></div> <div style="background: #f7f7f7;border: 1px solid rgba(0, 0, 0, 0.07);"> <div style="padding: 30px;"><div class="Adblock-main"> <div class="Adblock-head"> <h2>Yearwise Publication Trend on <b>“<a href="https://neurocare.blog/publication-trends/index/neuropathogenesis" target="_blank" title="neuropathogenesis - yearwise publication trends">neuropathogenesis</a>”</b></h2> </div> </div><div class="results-container"><div class="chart-block" style="padding:15px;"> <div class="left"> <div id="results" class="results"></div> </div> <div class="right"> <div class="chart-container"><canvas id="publicationChart"></canvas></div> </div> <div class="keywordsdiv"> <div style="text-align:center;"><b>Find publication trends on relevant topics</b> </div> <span class="gp-icon icon-tags"><svg viewBox="0 0 512 512" aria-hidden="true" xmlns="http://www.w3.org/2000/svg" width="1em" height="1em"><path d="M20 39.5c-8.836 0-16 7.163-16 16v176c0 4.243 1.686 8.313 4.687 11.314l224 224c6.248 6.248 16.378 6.248 22.626 0l176-176c6.244-6.244 6.25-16.364.013-22.615l-223.5-224A15.999 15.999 0 00196.5 39.5H20zm56 96c0-13.255 10.745-24 24-24s24 10.745 24 24-10.745 24-24 24-24-10.745-24-24z"></path><path d="M259.515 43.015c4.686-4.687 12.284-4.687 16.97 0l228 228c4.686 4.686 4.686 12.284 0 16.97l-180 180c-4.686 4.687-12.284 4.687-16.97 0-4.686-4.686-4.686-12.284 0-16.97L479.029 279.5 259.515 59.985c-4.686-4.686-4.686-12.284 0-16.97z"></path></svg></span> <span id="keyword-stats"></span> </div> </div></div></div><div class="inside-article"><style> table { margin: 0 0 1.5em; 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if (!statistics || Object.keys(statistics).length === 0) { resultsContainer.innerHTML = '<p>No data found.</p>'; return; } var tableHTML = `<div class='pub-scroll'> <table class='tablediv' border='1' cellspacing='0' cellpadding='0'> <tr> <th>Year</th> <th>Publication Count</th> </tr>`; Object.entries(statistics).sort(([yearA], [yearB]) => yearB - yearA).forEach(([year, count]) => { const displayCount = count === 0 ? 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It is one of the potential speculated mechanisms responsible for the increased stroke risk in these cohorts of patients due to the combination of endothelial dysfunction and the hypercoagulable state it can cause.</span></p> <p><b>Acute disseminated encephalomyelitis (ADEM),</b><span style="font-weight: 400;"> an immune-mediated illness that almost invariably follows a preceding infectious phase, has also been noted in patients with COVID-19; it presents as demyelination and multifocal neurological deficits.</span></p> <h4><b>Peripheral nervous system complications</b></h4> <p><b>Guillain-Barre Syndrome</b><span style="font-weight: 400;">: This is a very rare but possibly fatal disease that has been reported in COVID-19 patients. An immune attack on peripheral nerves results in paralysis and muscle weakness in the GBS.</span></p> <p><b>Cranial nerve palsy:</b><span style="font-weight: 400;"> COVID-19 is considered to be associated with cranial neuropathy, which causes loss of hearing, facial paralysis, and a reduction in taste.</span></p> <h4><b>Symptoms related to the musculoskeletal system</b></h4> <p><b>Muscle aches and rhabdomyolysis: </b><span style="font-weight: 400;">The most common complications among COVID-19 sufferers are muscle aches and weakness; some of them are also suffering from rhabdomyolysis, a severe breakdown of muscle tissue that may cause renal injury.</span></p> <p><b>Guillain-Barre syndrome:</b><span style="font-weight: 400;"> This is a less common but more dangerous disease that has also been reported in COVID-19 patients. GBS is an immune attack by the human body against peripheral nerves leading to paralysis and muscle weakness.</span></p> <p><b>Neurological manifestations:</b><span style="font-weight: 400;"> Cranial nerve palsy There is involvement of cranial nerves due to the COVID-19 infection, which can eventually lead to hearing loss, facial paralysis, and loss of taste.</span></p> <p><b>Symptoms of musculoskeletal systems:</b></p> <p><b>Myalgia and Rhabdomyolysis: </b><span style="font-weight: 400;">One of the common symptoms of COVID-19 includes muscle ache and weakness. In severe cases, they may show rhabdomyolysis—a disastrous breakdown of muscles that might lead to renal injury.</span></p> <p></div></div> <div style="background: #f7f7f7;border: 1px solid rgba(0, 0, 0, 0.07);"> <div style="padding: 30px;"><div class="Adblock-main"> <div class="Adblock-head"> <h2>Recent Publications on <b>“<a href="https://neurocare.blog/recent-publications/index/neuropathogenesis" target="_blank" rel="noopener" title="neuropathogenesis - yearwise publication list">neuropathogenesis</a>”</b></h2> </div> </div> <div class="pb-main"><div class="article-scroll"><div id="results_recent" class="results"></div></div><div class="keywordsdiv" style="margin: 0px 15px;margin-top:20px;"> <div style="text-align:center;"><b>Find publications on relevant topics</b> </div> <span class="gp-icon icon-tags"><svg viewBox="0 0 512 512" aria-hidden="true" xmlns="http://www.w3.org/2000/svg" width="1em" height="1em"><path d="M20 39.5c-8.836 0-16 7.163-16 16v176c0 4.243 1.686 8.313 4.687 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"'"); str = str.replace(/\\'/g, "'"); str = str.replace(/\\'/g, "'"); return str; } function displayResults_recent(papers) { var resultsContainer = document.getElementById('results_recent'); if (!papers || papers.length === 0) { resultsContainer.innerHTML = '<p>No recent publications found.</p>'; return; } papers.forEach(paper => { var publicationBlock = document.createElement('div'); publicationBlock.className = 'publication-block'; var title_de = decodeString(paper.title); var publicationHTML = ` <div style="margin-bottom: 10px;line-height: 24px;"><a href="${paper.url}" target="_blank" title="${title_de}">${title_de}</a></div> <p><strong>Issue Release:</strong> ${paper.publishedDate}</p> `; publicationBlock.innerHTML = publicationHTML; resultsContainer.appendChild(publicationBlock); }); } function displayKeywordPapers(keywords) { var resultsContainer = document.getElementById('keyword-papers'); resultsContainer.innerHTML = ''; if (!keywords || keywords.length === 0) { resultsContainer.innerHTML = '<p>No data found.</p>'; return; } var keywordHTML = ''; keywords.forEach((key, index) => { let key_replace = key.replace(/ /g, '-'); key_replace = key_replace.toLowerCase(); keywordHTML += `<a href="https://neurocare.blog/recent-publications/index/${key_replace}" target="_blank" title="${key} - publication list">${key}</a>`; if (index < keywords.length - 1) { keywordHTML += ', '; } }); resultsContainer.innerHTML = keywordHTML; } // Call the function with the PHP data var recent_papers = [ { "title": "Limited HIV-associated neuropathologies and lack of immune activation in sub-saharan African individuals with late-stage subtype C HIV-1 infection.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38943022", "publishedDate": "2024" }, { "title": "Non-Coding RNAs in HIV Infection, NeuroHIV, and Related Comorbidities.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38891030", "publishedDate": "2024" }, { "title": "Hyperactivation of MEK1 in cortical glutamatergic neurons results in projection axon deficits and aberrant motor learning.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38826084", "publishedDate": "2024" }, { "title": "SARS-CoV-2-Related Olfactory Dysfunction: Autopsy Findings, Histopathology, and Evaluation of Viral RNA and ACE2 Expression in Olfactory Bulbs.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38672185", "publishedDate": "2024" }, { "title": "NLRP3-dependent pyroptosis exacerbates Coxsackievirus A16 and Coxsackievirus A10-induced inflammatory response and viral replication in SH-SY5Y cells.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38705479", "publishedDate": "2024" }, { "title": "Chikungunya virus infection in human microglial C20 cells induces mitochondria-mediated apoptosis.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38716191", "publishedDate": "2024" }, { "title": "Sex-Biased Associations of Circulating Ferroptosis Inhibitors with Reduced Lipid Peroxidation and Better Neurocognitive Performance in People with HIV.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/39334701", "publishedDate": "2024" }, { "title": "Neurosymptomatic HIV-1 CSF escape is associated with replication in CNS T cells and inflammation.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/39352388", "publishedDate": "2024" }, { "title": "White matter microstructural changes in post-traumatic headache: A diffusion tensor imaging (DTI) study.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/39211879", "publishedDate": "2024" }, { "title": "Central Nervous System Disorders of Marine Mammals: Models for Human Disease?", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/39204284", "publishedDate": "2024" }, { "title": "Exposure to urban particulate matter alters responses of olfactory mucosal cells to SARS-CoV-2 infection.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38341073", "publishedDate": "2024" }, { "title": "A pilot investigation of the association between HIV-1 Vpr amino acid sequence diversity and the tryptophan-kynurenine pathway as a potential mechanism for neurocognitive impairment.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38395987", "publishedDate": "2024" }, { "title": "Involvement of Autophagic Machinery in Neuropathogenesis: Targeting and Relevant Methods of Detection.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38441722", "publishedDate": "2024" }, { "title": "Exploratory Analysis of MicroRNA Alterations in a Neurodevelopmental Mouse Model for Autism Spectrum Disorder and Schizophrenia.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38474035", "publishedDate": "2024" }, { "title": "Macrophage migration inhibitor factor (MIF): Potential role in cognitive impairment disorders.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38548489", "publishedDate": "2024" }, { "title": "SARS-CoV and SARS-CoV-2 display limited neuronal infection and lack the ability to transmit within synaptically connected axons in stem cell-derived human neurons.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38172412", "publishedDate": "2024" }, { "title": "SARS-CoV-2-associated T-cell infiltration in the central nervous system.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38304555", "publishedDate": "2024" }, { "title": "Assessment of the relationship between the dopaminergic pathway and severe acute respiratory syndrome coronavirus 2 infection, with related neuropathological features, and potential therapeutic approaches in COVID-19 infection.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38282395", "publishedDate": "2024" }, { "title": "Zika Virus Neuropathogenesis-Research and Understanding.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/39057782", "publishedDate": "2024" }, { "title": "Neuropathogenesis of SARS-CoV-2 in human neuronal, microglial and glial cells.", "url": "https:\/\/pubmed.ncbi.nlm.nih.gov\/38976047", "publishedDate": "2024" } ]; var keywordsArray = ["SARS-CoV-2","COVID-19","neuropathogenesis","neurological manifestations","central nervous system","peripheral nervous system","encephalitis","stroke","Guillain-Barr\u00e9 syndrome","long-term sequelae"]; displayResults_recent(recent_papers); displayKeywordPapers(keywordsArray); // function stripslashes(str) { // if (typeof str === 'string') { // return str.replace(/\/g, ''); // } // } </script></p> <h3><b>Long-term neurological sequelae</b></h3> <p><span style="font-weight: 400;">Long-term</span><span style="font-weight: 400;"> neurological effects of COVID-19 are still being studied, yet judging from the results so far, it is now becoming apparent that in some chronic patients there might be some long-standing problems. Such “long haulers” may come up. with a variety of other problems, though, including anxiety, sadness, and chronic fatigue, and cognitive dysfunction described as “brain fog.” The mechanisms of such prolonged deficiency are not clear and may include not only direct viral effects on the neurological system but also immunological reactions, long-lasting inflammation, </span><span style="font-weight: 400;">or direct viral effects on the nervous system.</span></p> <h3><b>Pathophysiological insights from related coronaviruses</b></h3> <p><span style="font-weight: 400;">Such SARS-CoV-2 neuropathogenesis mechanisms were further elucidated by studies contrasting them with other coronaviruses, in particular with MERS-CoV and SARS-CoV-1, which shared similar neuroinvasive properties. MERS-CoV and SARS-CoV-1 have been demonstrated to cause peripheral neuropathies and encephalitis. This special spike characteristic of the SARS-CoV-2 may have neuropathogenic pathways equal or comparable by structure and action but may carry further neuroinvasive features.</span></p> <h3><b>Conclusion</b></h3> <p><span style="font-weight: 400;">The virus SARS-CoV-2 has proved to have the potential for severe impacts on the nervous system and may lead to further wide variations of neurological symptoms and issues. Understanding neuroinvasion processes and subsequent pathophysiology becomes very important to manage such issues and reduce long-term consequences. It will require further study to better elucidate the full neuropathogenic potential of SARS-CoV-2 and to provide specific treatment strategies aimed at halting and treating neurological injury in COVID-19.</span></p> <p></p> <h3><b>References</b></h3> <ol> <li>Gao, X., Chen, W., Guo, L., Zhang, T.Z. and Zhao, H.Q., 2020. <a href="https://europepmc.org/article/med/33378810">Asymptomatic infection of COVID-19 and its challenge to epidemic prevention and control.</a> <i>Zhonghua liu Xing Bing xue za zhi= Zhonghua Liuxingbingxue Zazhi</i>, <i>41</i>(12), pp.1985-1988.</li> <li>Zambreanu, L., Lightbody, S., Bhandari, M., Hoskote, C., Kandil, H., Houlihan, C.F. and Lunn, M.P., 2020. <a href="https://jnnp.bmj.com/content/91/11/1229.abstract">A case of limbic encephalitis associated with asymptomatic COVID-19 infection. </a><i>Journal of Neurology, Neurosurgery & Psychiatry</i>, <i>91</i>(11), pp.1229-1230.</li> <li>Khoo, A., McLoughlin, B., Cheema, S., Weil, R.S., Lambert, C., Manji, H., Zandi, M.S. and Morrow, J.M., 2020. <a href="https://jnnp.bmj.com/content/91/9/1013.abstract">Postinfectious brainstem encephalitis associated with SARS-CoV-2.</a> <i>Journal of Neurology, Neurosurgery & Psychiatry</i>, <i>91</i>(9), pp.1013-1014.</li> <li>Abdel-Mannan, O., Eyre, M., Löbel, U., Bamford, A., Eltze, C., Hameed, B., Hemingway, C. and Hacohen, Y., 2020. <a href="https://jamanetwork.com/journals/jamaneurology/fullarticle/2767979">Neurologic and radiographic findings associated with COVID-19 infection in children.</a> <i>JAMA neurology</i>, <i>77</i>(11), pp.1440-1445.</li> <li>Riollano‐Cruz, M., Akkoyun, E., Briceno‐Brito, E., Kowalsky, S., Reed, J., Posada, R., Sordillo, E.M., Tosi, M., Trachtman, R. and Paniz‐Mondolfi, A., 2021. <a href="https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.26224">Multisystem inflammatory syndrome in children related to COVID‐19: A New York City experience. </a><i>Journal of Medical Virology</i>, <i>93</i>(1), pp.424-433.</li> <li>Rivas-García, S., Bernal, J. and Bachiller-Corral, J., 2020. <a href="https://academic.oup.com/rheumatology/article/59/8/2174/5862543">Rhabdomyolysis as the main manifestation of coronavirus disease 2019.</a> <i>Rheumatology</i>, <i>59</i>(8), pp.2174-2176.</li> <li>Wilson, A.J., Troy‐Barnes, E., Subhan, M., Clark, F., Gupta, R., Fielding, A.K., Kottaridis, P., Mansour, M.R., O’Nions, J., Payne, E. and Chavda, N., 2020. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362128/">Successful remission induction therapy with gilteritinib in a patient with de novo FLT3‐mutated acute myeloid leukaemia and severe COVID‐19.</a> <i>British Journal of Haematology</i>, <i>190</i>(4), p.e189.</li> </ol> <p></div></div> <div style="background: #f7f7f7;border: 1px solid rgba(0, 0, 0, 0.07);"> <div style="padding: 30px;"><div class="Adblock-main"> <div class="Adblock-head"> <h2>Top Experts on “<b style="color:#000;font-size:22px;">neuropathogenesis</b>“</h2> </div> </div><div class="author-main"><div id="results_author"></div><div style="text-align: center;"><a class="register-button" href="https://neurocare.blog/expert-search" target="_blank" rel="noopener">Find experts on any field</a></div></div><div class="inside-article" style="background: none;border: none;box-shadow: none;margin-top: -70px;"> <style> .author-block { padding: 15px; 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