Abstract and Introduction
Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74 years (38–97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity.
Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20–30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem.
We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions.
The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.
Neurological manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are increasingly recognized and include seizures,[2,3] cerebrovascular accidents,[4–8] encephalopathy, isolated cases of acute necrotizing haemorrhagic encephalopathy and Guillain-Barré syndrome. Many of the neurological conditions seen in the context of SARS-CoV-2 infection are associated with systemic effects, including multi-organ damage, hypercoagulability and a proinflammatory state.[11–14] Whether SARS-CoV-2 directly infects the brain remains controversial. Related β-coronaviruses such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) show neuro-invasive potential,[1,15–17] and clinicians have reported cases of meningoencephalitis in coronavirus disease 2019 (COVID-19) patients, without neuropathological confirmation.[3,16,18–23] Further characterization of the neuropathological and molecular findings in COVID-19 brains is needed to understand the pathophysiological mechanisms underlying the neurological conditions seen in the context of COVID-19.
A few autopsy studies have reported the neuropathological findings of patients with SARS-CoV-2 infections (Supplementary Table 1), including hypoxic changes, vascular lesions, demyelinating pathology resembling acute disseminated encephalomyelitis, reactive astrocytosis and microgliosis and cerebral haemorrhage or haemorrhagic suffusion. Viral RNA has been detected at low levels by quantitative reverse transcriptase-PCR (qRT-PCR) in some cases,[27–29] but evidence directly linking virus to the COVID-associated neuropathology is controversial. We present the neuropathological findings of 41 consecutive patients with histories of confirmed SARS-CoV-2 infection, investigating the clinical and pathological characteristics.
Brain. 2021;144(9):2696-2708. © 2021 Oxford University Press