Neurological Aspects of SARS-CoV-2 Infection: Mechanisms and Manifestations

Abstract

The human infection of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a public health emergency of international concern that has caused more than 16.8 million new cases and 662,000 deaths as of July 30, 2020. Although coronavirus disease 2019 (COVID-19), which is associated with this virus, mainly affects the lungs, recent evidence from clinical and pathological studies indicates that this pathogen has a broad infective ability to spread to extrapulmonary tissues, causing multiorgan failure in severely ill patients. In this regard, there is increasing preoccupation with the neuroinvasive potential of SARS-CoV-2 due to the observation of neurological manifestations in COVID-19 patients. This concern is also supported by the neurotropism previously documented in other human coronaviruses, including the 2002-2003 SARS-CoV-1 outbreak. Hence, in the current review article, we aimed to summarize the spectrum of neurological findings associated with COVID-19, which include signs of peripheral neuropathy, myopathy, olfactory dysfunction, meningoencephalitis, Guillain-Barré syndrome, and neuropsychiatric disorders. Furthermore, we analyze the mechanisms underlying such neurological sequela and discuss possible therapeutics for patients with neurological findings associated with COVID-19. Finally, we describe the host-and pathogen-specific factors that determine the tissue tropism of SARS-CoV-2 and possible routes employed by the virus to invade the nervous system from a pathophysiological and molecular perspective. In this manner, the current manuscript contributes to increasing the current understanding of the neurological aspects of COVID-19 and the impact of the current pandemic on the neurology field.

Neuropathologic findings of patients with COVID-19: a systematic review

“…The pathological features of COVID-19 greatly resemble those seen on SARS and Middle East respiratory syndrome (MERS) coronavirus infection [ 25 ]. Therefore, previous observations regarding routes of viral entry and propagation made on the aforementioned coronaviruses can be hypothesized here as well [ 54 ].…”

“…Recent reports indicate that ACE2 is also expressed in neurons, astrocytes, and oligodendrocytes, as well as in the substantia nigra, ventricles, middle temporal gyrus, posterior cingulate cortex, and olfactory bulb [ 53 ]. Additionally, it has been determined that tissue patterns of expression of transmembrane serine protease (TMPRSS2 and TMPRSS4), and cathepsin L is another decisive factor that determines the tropism of the virus [ 54 ]. TMPRSS4 can be demonstrated in the cerebral cortex, hippocampus, caudate, thyroid gland, adrenal gland, nasopharynx, bronchi, lung, stomach, duodenum, colon, rectum, gallbladder, pancreas, and genitourinary tract [ 54 ].…”

“…Additionally, it has been determined that tissue patterns of expression of transmembrane serine protease (TMPRSS2 and TMPRSS4), and cathepsin L is another decisive factor that determines the tropism of the virus [ 54 ]. TMPRSS4 can be demonstrated in the cerebral cortex, hippocampus, caudate, thyroid gland, adrenal gland, nasopharynx, bronchi, lung, stomach, duodenum, colon, rectum, gallbladder, pancreas, and genitourinary tract [ 54 ].

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“…Retrograde viral dissemination, on the other hand, is a process wherein a virus infects neurons in the periphery uses the transport machinery within those cells to gain access to the CNS [ 53 ]. In this sense, the virus could penetrate the CNS through the neuroepithelium of the olfactory mucosa to reach the olfactory bulb, gain access to the mitral cells and the olfactory nerve, and then spread to adjacent areas of the brain such as the hippocampus and other brain structures [ 53 , 54 ]. This route was demonstrated in mice with intracranially inoculated SARS-CoV-1 and was supported by anosmia as one of the early symptoms in COVID-19 infection [ 3 , 5 , 54 ].…”

Pain during and after COVID-19 in Germany and worldwide: a narrative review of current knowledge

“… 18 , 87 , 91 Although the exact mechanisms are not known thus far, routes of entry to the CNS might include breaching of the blood–brain barrier, the olfactory bulb, or the vagus nerve, whereas direct nerve or muscle injury might be one reason for the observed neuropathy or myopathy. 31 …”