SARS-Cov-2 infection and neuropathological findings: a report of 18 cases and review of the literature

Abstract

Introduction COVID-19-infected patients harbour neurological symptoms such as stroke and anosmia, leading to the hypothesis that there is direct invasion of the central nervous system (CNS) by SARS-CoV-2. Several studies have reported the neuropathological examination of brain samples from patients who died from COVID-19. However, there is still sparse evidence of virus replication in the human brain, suggesting that neurologic symptoms could be related to mechanisms other than CNS infection by the virus. Our objective was to provide an extensive review of the literature on the neuropathological findings of postmortem brain samples from patients who died from COVID-19 and to report our own experience with 18 postmortem brain samples. Material and methods We used microscopic examination, immunohistochemistry (using two different antibodies) and PCR-based techniques to describe the neuropathological findings and the presence of SARS-CoV-2 virus in postmortem brain samples. For comparison, similar techniques (IHC and PCR) were applied to the lung tissue samples for each patient from our cohort. The systematic literature review was conducted from the beginning of the pandemic in 2019 until June 1st, 2022. Results In our cohort, the most common neuropathological findings were perivascular haemosiderin-laden macrophages and hypoxic-ischaemic changes in neurons, which were found in all cases (n = 18). Only one brain tissue sample harboured SARS-CoV-2 viral spike and nucleocapsid protein expression, while all brain cases harboured SARS-CoV-2 RNA positivity by PCR. A colocalization immunohistochemistry study revealed that SARS-CoV-2 antigens could be located in brain perivascular macrophages. The literature review highlighted that the most frequent neuropathological findings were ischaemic and haemorrhagic lesions, including hypoxic/ischaemic alterations. However, few studies have confirmed the presence of SARS-CoV-2 antigens in brain tissue samples. Conclusion This study highlighted the lack of specific neuropathological alterations in COVID-19-infected patients. There is still no evidence of neurotropism for SARS-CoV-2 in our cohort or in the literature.

Neuropathological findings in Down syndrome, Alzheimer’s disease and control patients with and without SARS-COV-2: preliminary findings

“…The presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleoprotein regions, found low but detectable viral RNA levels in brain tissue but were unable to detect immunohistochemical evidence of viral particles [ 75 ]. On the other hand, another autopsy study provided evidence for peri-vascular hemosiderin-laden macrophages and hypoxic-ischemic changes in neurons [ 52 ], which we also observed (data not shown). Although immunostaining for SARS-CoV-2 viral spike and nucleoprotein was seen in a single brain, PCR revealed SARS-CoV-2 RNA in all brains [ 52 ].…”

“…On the other hand, another autopsy study provided evidence for peri-vascular hemosiderin-laden macrophages and hypoxic-ischemic changes in neurons [ 52 ], which we also observed (data not shown). Although immunostaining for SARS-CoV-2 viral spike and nucleoprotein was seen in a single brain, PCR revealed SARS-CoV-2 RNA in all brains [ 52 ]. In another autopsy study, confocal imaging of sections stained for fluorescence, RNAscope, and immunohistochemistry demonstrated extracellular SARS-CoV-2 virions but failed to show viral particles in the brain parenchyma or olfactory bulb [ 50 ].…”

Neuropathology in COVID-19 autopsies is defined by microglial activation and lesions of the white matter with emphasis in cerebellar and brain stem areas

“…Meinhardt et al ( 3 ) reported SARS-CoV-2 RNA in the olfactory bulb ( 3 ). Lebrun et al reported SARS-CoV-2 RNA positivity in the brain by PCR in all ( n = 18) analyzed cases, while only one patient harbored SARS-CoV-2 viral proteins in the brain tissue ( 30 ). Solomon et al ( 11 ) achieved mixed results and argued that samples might have been contaminated by blood ( 11 ).…”

Microglia at the blood brain barrier in health and disease

“…A recent example of this is infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the etiological agent of coronavirus disease 2019 (COVID-19). Although SARS-CoV-2 was originally hypothesized to induce neurological symptoms, such as loss of smell and taste and altered consciousness, through direct infection of the brain, multiple case reports demonstrate little to no virus within the CNS compartment, including among patients that died due to severe disease ( Schurink et al, 2020 ; Fullard et al, 2021 ; Thakur et al, 2021 ; Lebrun et al, 2023 ; Song et al, 2023 ). Virus has been reported in brain endothelium or olfactory epithelium/mucosa in infected human subjects and non-human primates (NHPs), however, this does not extend to cells residing within the brain parenchyma ( Meinhardt et al, 2021 ; Thakur et al, 2021 ; Rutkai et al, 2022 ).…”