Neuropathological findings from COVID‐19 patients with neurological symptoms argue against a direct brain invasion of SARS‐CoV‐2: A critical systematic review

Abstract

Background and purpose Neuropathological studies can elucidate the mechanisms of nervous system damage associated with SARS‐CoV‐2 infection. Despite literature on this topic is rapidly expanding, correlations between neurological symptoms and brain pathology findings in COVID‐19 patients remain largely unknown. Methods We performed a systematic literature review on neuropathological studies in COVID‐19, including 438 patients from 45 articles published by April 22, 2021. We retrieved quantitative data regarding demographic, clinical, and neuropathological findings. We carried out a Wilcoxon rank sum test or χ2 test to compare patients' subgroups based on different clinical and brain pathology features. Results Neuropathological findings in COVID‐19 patients were microgliosis (52.5%), astrogliosis (45.6%), inflammatory infiltrates (44.0%), hypoxic‐ischemic lesions (40.8%), edema (25.3%), and hemorrhagic lesions (20.5%). SARS‐CoV‐2 RNA and proteins were identified in brain specimens of 41.9% and 28.3% of subjects, respectively. Detailed clinical information was available from 245 patients (55.9%), and among them, 96 subjects (39.2%) had presented with neurological symptoms in association with typical COVID‐19 manifestations. We found that: (i) the detection rate of SARS‐CoV‐2 RNA and proteins in brain specimens did not differ between patients with versus those without neurological symptoms; (ii) brain edema, hypoxic‐ischemic lesions, and inflammatory infiltrates were more frequent in subjects with neurological impairment; (iii) neurological symptoms were more common among older individuals. Conclusions Our systematic revision of clinical correlates in COVID‐19 highlights the pathogenic relevance of brain inflammatory reaction and hypoxic‐ischemic damage rather than neuronal viral load. This analysis indicates that a more focused study design is needed, especially in the perspective of potential therapeutic trials.

The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2

“…In humans, activated microglia were found in the olfactory bulb, midbrain (specifically, in the substantia nigra), hindbrain, dorsal motor nucleus of the vagus nerve, and the pre-Bötzinger complex in the medulla [70]. Furthermore, multifocal microgliosis and astrogliosis were reported in older patients [71], although it could not be ruled out that these were associated with host factors [72]. Perivascular and parenchymal infiltrations of CD8 + cytotoxic T cells and macrophages have been reported postmortem in patients with COVID-19 and in intranasally inoculated mice at 6 days post inoculation [61,71,73].…”

COVID-19 induces neuroinflammation and loss of hippocampal neurogenesis

“…Moreover, an alarmingly high fraction of patients, perhaps as high as 33%, continue to suffer neuropsychiatric symptoms post-hospital discharge, including a dysexecutive syndrome consisting of inattention, disorientation, and poor movement coordination 2,3,[9][10][11][12][13] . Postmortem human neuropathological ndings in COVID-19 include hypoxic damage, microglial activation, astrogliosis, leukocytic in ltration and microhemorrhages [14][15][16] , suggesting that, at least in some cases, the CNS undergoes neuropathological sequelae associated with hypoxia and neuroin ammation. This is supported by neuroimaging studies in post-acute COVID-19 patients, showing disruption of fractional anisotropy and diffusivity, suggesting micro-structural and functional alterations of the hippocampus 17 , a brain region critical for memory formation, and part of a conserved subcortical network involved in anxiety and stress responses.…”

Multinational characterization of neurological phenotypes in patients hospitalized with COVID-19

“…Second, encephalitis and myelitis have variable manifestations 12 and were likely under-reported due to difficulties of performing diagnostic studies ( e.g., magnetic resonance imaging, lumbar puncture) especially during the early phase of pandemic. Neuropathological examinations have not uncovered evidence of direct viral infection of the central nervous system (CNS) 33 , though more studies are needed to confirm whether the mechanisms underlying encephalitis (with or without myelitis) are direct CNS invasion by SARS-CoV-2, acute systemic inflammation with secondary CNS involvement, and/or post-infectious immune-mediated effect on the CNS 2 , 34 , 35 .…”