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

Abstract

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.

Viral mapping in COVID-19 deceased in the Augsburg autopsy series of the first wave: A multiorgan and multimethodological approach

“…The rate of positivity, regardless of the method, was calculated to be 52%. The rate of viral detection in the cerebrospinal fluids of 468 patients was 6.4% [8]. We also analyzed CSF in 15 cases, and all of them were negative by RT-qPCR, which matches with the results of Serrano (9 analyzed CSF, all negative) [49].…”

“…The discussion of whether there is a direct brain involvement of the virus or not is open, but our data support the hypothesis of no direct involvement. This is also supported by a systematic review of Li [8].…”

“…Serrano et al showed a frequency of viral detection in 20% of cases [49]. Analyzing the results of 28 autopsy studies, Li et al reported a mean frequency RNA-based virus detection of 33% in 93 cases [8]. The rate of positivity, regardless of the method, was calculated to be 52%.…”

“…Therefore, the aim was to analyze the macroscopic, microscopic changes and the spread of the virus in the deceased patients for the first step and to generate tissue and liquid samples for further investigations in terms of mechanisms of the disease. After overcoming initial restrictions regarding performing autopsies in cases of COVID-19, especially in Europe, several pathologists and forensic scientists of different departments started structured activities in this direction [5][6][7][8]. The main finding from autopsies is diffuse alveolar damage (DAD) [9,10].…”

Infectious disease-associated encephalopathies

“…Viral neurotropism may involve binding of SARS-CoV-2 to ACE2 at peripheral nerve terminals, followed by retrograde trans-synaptic passage into the CNS [ 159 ]. Other mechanisms include leukocyte migration across the BBB or binding to endothelial cells, allowing the virus to cross the BBB via the microcirculation [ 157 ].…”