key: cord-0058138-uapthpri
authors: Aronica, Eleonora; Gerevini, Simonetta
title: The Neuropathology Spectrum in Deceased Patients with COVID-19
date: 2021-03-18
journal: Neuroimaging of Covid-19
DOI: 10.1007/978-3-030-67521-9_9
sha: ae0dd9d083327e08610b02e1accaae27cbbafd96
doc_id: 58138
cord_uid: uapthpri

There is increasing evidence of neurological and psychiatric manifestations in patients with COVID-19 [1, 2]. Recent postmortem studies reported a large spectrum of neuropathological features that support the neuro-invasive potential of SARS-CoV-2 [3–5]. Given the complex pathophysiology of COVID-19 associated neurological manifestation, the pathological changes observed at postmortem examination often reflect the combination of both direct and indirect cytopathic effects mediated by the virus, as well as of nonspecific complications of severe disease in the deceased patients with COVID-19 (i.e. critical illness-related encephalopathy [6]; and/or pre-existing medical conditions). Thus, all these factors need to be considered when interpreting neuropathological findings [3, 7]. Hypoxia-ischemia, observed in the majority of critically ill cases of Covid-19, does not account for all relevant neuropathological observations provided by postmortem neuropathological studies in single cases or small patient cohorts [8–14]. However, among these studies the extent and significance of neuroinflammatory changes associated with SARS-CoV-2 infection are still matter of discussion, with often contradictory conclusions. In particular, it remains unclear to what extent the reported microglia activation and occasionally the presence of sparse lymphocytic infiltrates (T lymphocytes) represents COVID-19-specific findings [6, 7].

There is an increasing evidence of neurological and psychiatric manifestations in patients with COVID-19 [1, 2] . Recent postmortem studies reported a large spectrum of neuropathological features that support the neuro-invasive potential of SARS-CoV-2 [3] [4] [5] . Given the complex pathophysiology of COVID-19 associated neurological manifestation, the pathological changes observed at postmortem examination often reflect the combination of both direct and indirect cytopathic effects mediated by the virus, as well as of nonspecific complications of severe disease in the deceased patients with COVID-19 (i.e. critical illness-related encephalopathy [6] ; and/or pre-existing medical conditions). Thus, all these factors need to be considered when interpreting neuropathological findings [3, 7] . Hypoxiaischemia, observed in the majority of critically ill cases of Covid-19, does not account for all relevant neuropathological observations provided by postmortem neuropathological studies in single cases or small patient cohorts [8] [9] [10] [11] [12] [13] [14] . However, among these studies the extent and significance of neuroinflammatory changes associated with SARS-CoV-2 infection are still matter of discussion, with often contradictory conclusions. In particular, it remains unclear to what extent the reported microglia activation and occasionally the presence of sparse lymphocytic infiltrates (T lymphocytes) represents COVID-19-specific findings [6, 7] .

In an autopsy cohort study performed in the Netherlands, detailed neuropathological examination was performed in 8 of 21 patients with full body autopsies and showed but only sparse T lymphocytes in parenchyma, but massive activation of microglia with microglial nodules, especially in the olfactory bulbs and brainstem ( [15] ; Fig. 9 .1d-n). Given the regional heterogeneity and phenotypes of human microglia [16] , whether microglia activated belongs to a specific subtype certainly deserves further attention, particularly in relation to the pattern of regional vulnerability observed in the context of a COVID-19 infection. Additionally, there is also evidence of increased blood-brain barrier (BBB) permeability (e.g. albumin extravasation, and its uptake in astrocytes; Fig. 9 .1m). Understanding the association of neurological conditions in patients with SARS-CoV-2 infection with BBB dysfunction, particularly dissecting the underlying direct or indirect mechanisms, is worthy of future investigation [17] . Another recent study provides a detailed description of the neuropathological changes related to COVID-19 in a cohort of 43 patients who died with COVID-19 in Germany [18] . Matschke and colleagues focused on the inflammatory changes and detection of SARS-CoV-2. They confirmed the occurrence of generally mild neuropathological changes, with however pronounced activation of the neuroinflammatory response, with prominent involvement of the brainstem. This is in line with previous observations, supporting the activation of the adaptive and, particularly, of the innate immune response [18] . This study does not provide evidence for CNS damage directly caused by SARS-CoV-2. Accordingly, the presence of SARS-CoV-2 did not seem to be associated with the severity of the observed neuroinflammatory changes [18] .

An ongoing task for neuropathology experts is to contribute to dissect the complex pathophysiology of COVID-19 associated neurological manifestation, in particular to understand the role of a direct SARS-CoV-2 brain infection versus the sequels of an over activation of the systemic immune response, as well as the relationship between hypoxemia, diffuse cerebral micro-bleeds and coma in COVID-19 patients. In this effort it would also be important to evaluate also deceased patients with COVID-19 without significant neurological manifestations (as appropriate control cohorts). It is also essential to create a multidisciplinary team with close collaboration between neuropathology and neuroradiology. In particular postmortem MRI applied to clinically well-defined COVID-19 cases could contribute to better define the MRI signatures of neuropathological lesions in COVID-19 associated neurological and psychiatric manifestations.

Neurological associations of COVID-19

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic

Invited review: the spectrum of neuropathology in COVID-19

Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms

COVID-19: what if the brain had a role in causing the deaths?

Correlates of critical illnessrelated encephalopathy predominate postmortem COVID-19 neuropathology

Catch me if you can: SARS-CoV-2 detection in brains of deceased patients with COVID-19

Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology

Early evidence of pronounced brain involvement in fatal COVID-19 outcomes

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Neuronophagia and microglial nodules in a SARS-CoV-2 patient with cerebellar hemorrhage

Neuropathologic features of four autopsied COVID-19 patients

The spectrum of pathological findings in coronavirus disease (COVID-19) and the pathogenesis of SARS-CoV-2

Postmortem neuropathology in Covid-19

Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study

Human microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometry

Neurological complications associated with the blood-brain barrier damage induced by the inflammatory response during SARS-CoV-2 infection

Neuropathology of patients with COVID-19 in Germany: a post-mortem case series