The outbreak of coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), has become a significant and urgent threat to the global health. This review provided strong support for CNS infection with SARS‐CoV‐2 and shed light on neurological mechanism underlying the lethality of SARS‐CoV‐2 infection. Among the published data, only 1.28% COVID‐19 patients who underwent cerebrospinal fluid (CSF) tests were positive to SARS‐CoV‐2 in CSF. However, this does not mean the absence of CNS infection in most COVID‐19 patients, because postmortem studies revealed that some patients with CNS infection showed negative results in CSF tests for SARS‐CoV‐2. Among 20 neuropathological studies reported so far, SARS‐CoV‐2 was detected in the brain of 58 cases in 9 studies, and three studies have provided sufficient details on the CNS infection in COVID‐19 patients. Almost all in vitro and in vivo experiments support the neuroinvasive potential of SARS‐CoV‐2. In infected animals, SARS‐CoV‐2 was found within neurons in different brain areas with a wide spectrum of neuropathology, consistent with the reported clinical symptoms in COVID‐19 patients. Several lines of evidence indicate that SARS‐CoV‐2 used hematopoietic route to enter the CNS. But more evidence supports the trans‐neuronal hypothesis. SARS‐CoV‐2 has been found to invade the brain via the olfactory, gustatory and trigeminal pathways, especially at the early stage of infection. Severe COVID‐19 patients with neurological deficits are at a higher risk of mortality, and only the infected animals showing neurological symptoms became dead, suggesting that neurological involvement may be one cause of death. This article is protected by copyright. All rights reserved.

To provide instructive clues for clinical practice and further research of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we analyzed the existing literature on viral neuroinvasion of SARS-CoV-2 in coronavirus disease 2019 (COVID-19) patients. To date, SARS-CoV-2 has been detected in the cerebrospinal fluid (CSF) or brain parenchyma in quite a few patients, which provide undeniable evidence for the neuroinvasive potential of this novel coronavirus. In contrast with the cerebrum and cerebellum, the detection rate of SARS-CoV-2 was higher in the olfactory system and the brainstem, both of which also showed severe microgliosis and lymphocytic infiltrations. As compared with the number of patients who underwent viral testing in the central nervous system (CNS), the number of patients showing positive results seems very small. However, it seems too early to conclude that the neuroinvasion of SARS-CoV-2 is rare in COVID-19 patients because the detection methods or sampling procedures in some studies may not be suitable or sufficient to reveal the CNS infection induced by neurotropic viruses. Moreover, the primary symptoms and/or causes of death were distinctly different among examined patients, which probably caused more conspicuous pathological changes than those due to the direct infection that usually localized to specific brain areas.Unfortunately, most autopsy studies did not provide sufficient details about neurological symptoms or suspected diagnoses of the examined patients, and the documentation of neuropathological changes was often incomplete. Given the complex pathophysiology of COVID-19 and the characteristics of neurotropic viruses, it is understandable that any study of the CNS infection may inevitably have limitations.

The peculiar features of coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), are challenging the current biological knowledge. Early in Feb, 2020, we suggested that SARS-CoV-2 may possess neuroinvasive potential similar to that of many other coronaviruses. Since then, a variety of neurological manifestations have been associated with SARS-CoV-2 infection, which was supported in some patients with neuroimaging and/or cerebrospinal fluid tests. To date, at least 27 autopsy studies on the brains of COVID-19 patients can be retrieved through PubMed/MEDLINE, among which neuropathological alterations were observed in the brainstem in 78 of 134 examined patients, and SARS-CoV-2 nucleic acid and viral proteins were detected in the brainstem in 16/49 (32.7%) and 18/71 (25.3%) cases, respectively. To shed some light on the peculiar respiratory manifestations of COVID-19 patients, this review assessed the existing evidence about the neurogenic mechanism underlying the respiratory failure induced by SARS-CoV-2 infection. Acknowledging the neurological involvement has important guiding significance for the prevention, treatment, and prognosis of SARS-CoV-2 infection.

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