Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review

Abstract

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.

Figure 1.. Angiotensin-Converting Enzyme 2 (ACE2) Expression in the Brain

Emerging data suggest that ACE2 receptors are expressed in multiple regions of the human and mouse brain, including the motor cortex, posterior cingulate cortex, ventricles, substantia nigra, olfactory bulb, middle temporal gyrus, ventrolateral medulla, nucleus of tractus solitarius, and dorsal motor nucleus of the vagus nerve (A) and on several key cell types that make up the central nervous system, including neurons, microglia, astrocytes, and oligodendrocytes (B).^– C, ACE2 receptors on a medullary neuron binding to the SPIKE protein on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Figure 2.. Transsynaptic Viral Spread

A, Coronavirus (CoV) has been shown to spread via the transcribrial route from the olfactory epithelium along the olfactory nerve to the olfactory bulb within the central nervous system. B, CoV has been shown to spread retrograde via transsynaptic transfer using an endocytosis or exocytosis mechanism and a fast axonal transport (FAT) mechanism of vesicle transport to move virus along microtubules back to neuronal cell bodies.

Figure 3.. Mechanisms of Spread Across the Blood-Brain Barrier

A, Infected vascular endothelial cells have been shown to spread severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to glial cells in the central nervous system. B, Known as the Trojan horse mechanism, infected leukocytes can cross the blood-brain barrier to infect the central nervous system. CoV indicates coronavirus.