Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review
Open accessAbstract
Importance: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, causing human coronavirus disease 2019 (COVID-19), which has now spread into a worldwide pandemic. The pulmonary manifestations of COVID-19 have been well described in the literature. Two similar human coronaviruses that cause Middle East respiratory syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS-CoV-1) are known to cause disease in the central and peripheral nervous systems. Emerging evidence suggests COVID-19 has neurologic consequences as well. Observations: This review serves to summarize available information regarding coronaviruses in the nervous system, identify the potential tissue targets and routes of entry of SARS-CoV-2 into the central nervous system, and describe the range of clinical neurological complications that have been reported thus far in COVID-19 and their potential pathogenesis. Viral neuroinvasion may be achieved by several routes, including transsynaptic transfer across infected neurons, entry via the olfactory nerve, infection of vascular endothelium, or leukocyte migration across the blood-brain barrier. The most common neurologic complaints in COVID-19 are anosmia, ageusia, and headache, but other diseases, such as stroke, impairment of consciousness, seizure, and encephalopathy, have also been reported. Conclusions and Relevance: Recognition and understanding of the range of neurological disorders associated with COVID-19 may lead to improved clinical outcomes and better treatment algorithms. Further neuropathological studies will be crucial to understanding the pathogenesis of the disease in the central nervous system, and longitudinal neurologic and cognitive assessment of individuals after recovery from COVID-19 will be crucial to understand the natural history of COVID-19 in the central nervous system and monitor for any long-term neurologic sequelae.
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Both pro-inflammatory factors and viruses can cross the blood-brain barrier and enter the central nervous system, initiating a neuroinflammatory process.
“both pro-inflammatory factors and viruses can cross the blood–brain barrier (BBB) and enter the central nervous system (CNS), initiating a neuroinflammatory process [10].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [10]
Since SARS-CoV can infect immune cells, it is likely that SARS-CoV-2 also uses the Trojan horse route toward the CNS.
“This mechanism is observed for HIV, and since SARS-CoV can infect immune cells, it is likely that SARS-CoV-2 also uses this route toward the CNS [10].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [10]
Viral infection affects BBB integrity by mechanisms including phosphorylation of tight junction proteins, disruption of the basal lamina or of the actin cytoskeleton, or by invading BBB-epithelial cells and furthermore astrocytes.
“Viral infection also affects BBB integrity by different mechanisms, including phosphorylation of tight junction proteins, disruption of the basal lamina or of the actin cytoskeleton, or by invading BBB-epithelial cells and furthermore astrocytes [10, 31].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [10]
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“SARS-CoV-2 infections differ pathophysiologically from other RTIs, often involving intense systemic inflammation, endothelial dysfunction, and neurological sequelae [20,21].”
- Authors
- Zubair, A. S., McAlpine, L. S., Gardin, T., Farhadian, S., Kuruvilla, D. E., & Spudich, S.
- Affiliations
- Yale University (US)
- Corresponding author
- Spudich, Serena
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2020-08-01
- Volume
- 77
- Issue
- 8
- Pages
- 1018
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC7484225
- OpenAlex
- W3029172496
- Cited by
- 923
- References
- 104
- Citations by year
- 2026: 24 · 2025: 34 · 2024: 62 · 2023: 130 · 2022: 204 · 2021: 313 · 2020: 154
- FWCI
- 22.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR001863)
- National Institute of Mental Health (K23MH118999)
- National Institute of Allergy and Infectious Diseases (R01AI157488)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
- Health Sciences › Medicine › Infectious Diseases › Infectious Encephalopathies and Encephalitis
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- COVID-19 pandemic, SARS-CoV-2, neurological symptoms, neuroinvasion, olfactory nerve, blood-brain barrier, anosmia, ageusia, stroke, encephalopathy, seizures, impaired consciousness, MERS-CoV, SARS-CoV-1
- MeSH terms
- Betacoronavirus, COVID-19, SARS-CoV-2, Animals, Humans, Nervous System Diseases, Pneumonia, Viral, Coronavirus Infections, Severe Acute Respiratory Syndrome, Pandemics
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