What can cerebrospinal fluid testing and brain autopsies tell us about viral neuroinvasion of SARS-CoV-2

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.