key: cord-0963714-a0t38or8 authors: Fabbri, Viscardo P.; Foschini, Maria P.; Lazzarotto, Tiziana; Gabrielli, Liliana; Cenacchi, Giovanna; Gallo, Carmine; Aspide, Raffaele; Frascaroli, Guido; Cortelli, Pietro; Riefolo, Mattia; Giannini, Caterina; D’Errico, Antonietta title: Brain ischemic injury in CoViD19 infected patients: a series of 10 post‐mortem cases date: 2020-10-01 journal: Brain Pathol DOI: 10.1111/bpa.12901 sha: e3b7d047f59d79582aec5e7af09f82db3753ce3a doc_id: 963714 cord_uid: a0t38or8 The coronavirus disease 2019 (COVID‐19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). COVID‐19 symptoms are not limited to the respiratory tract, but complications have been described involving other organs including brain. At present, data on SARS‐CoV‐2 neuropathological features are limited [4, 5, 8, 10] and most frequently focused on cases presenting neurological symptoms. This article is protected by copyright. All rights reserved SARS-CoV-2 RNA was present in the olfactory nerve and brain tissue of one (of 10 tested) patients (case 1). In this patient olfactory bulb neurons, olfactory tract and brain tissue did not show any specific histological change suggestive of direct viral damage (Fig. 1A) . The SARS-CoV-2-RNA positive case presented several comorbidities, had the shortest disease course (death occurred 6 days only after the symptoms onset) and showed viral involvement of kidney, liver and heart in addition to brain and lungs, thus suggesting haematogenous spread. On macroscopic examination, all cases presented an oedematous brain surface with widened gyri, flattened surface, narrowed sulci and meningeal congestion. Brain weight ranged from 1300 to 1870 g. (mean 1560 g.). In two cases bilateral uncal herniation was identified (cases 5, 6) . Areas of cerebral infarction were present in three cases (cases 1, 2, 3). Meninges were grossly congested: purulent accumulation on the leptomeningeal vault was observed in case 8 whereas focal subarachnoid haemorrhage was identified in case 9. On histology, all cases presented intraparenchymal intravascular microthrombi ( Fig. 1B) with focal microscopic (usually 1-2 mm in size) cortical or deep-seated (located in the basal ganglia and through the brainstem) recent infarcts (Fig. 1C) . Small blood vessels ectasia, perivascular oedema, perivascular micro-haemorrhages and scattered hemosiderin-laden macrophages were also noticed ( Fig. 1D, 1E ). Necrotic blood vessels or perivascular inflammation were not identified. Immunohistochemical analysis (CD20, CD3, CD4, CD8, CD68) did not highlight lymphocytic or macrophage accumulation. Only case 4 showed a mild perivascular T-lymphocytic infiltration CD3+ No microglial nodules or evidence of neuronophagia were present. Intravascular microthrombi and multiple infarcts are in keeping with the hypercoagulable state of SARS-CoV-2 infected patients [1] leading to large and small vessels thrombosis. Our data, together with previously published data, indicate that most likely the same pathogenetic events may occur in CNS SARS-CoV-2 related injuries. This article is protected by copyright. All rights reserved Ischemic red neurons were present through the hippocampal CA1 region, the para-hippocampal region (case 10) and the cerebellar Purkinje cells, consistent with global ischemic injury. Also the brainstem showed, in addition to microthrombi and ischemic damage, reactive gliosis and microglial activation most likely due to preterminal hypoxic-ischemic injury. These data, consistent with those of Jensen et al [4] , Kantonen et al [5] and Solomon et al [8] , suggest that the hypoxic-ischemic general condition, related to the respiratory failure, may indeed be worsened by the consequent brainstem damage appearing as a final event [6] . Bacterial superinfection was histologically suspected in two cases (cases 8, 9): leptomeningeal thrombi composed of dense fibrin with neutrophils were detected ( Fig. Fig. 1H, 1I ). In these patients Pseudomonas aeruginosa, Candida albicans, Staphylococcus capitis, Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus (MRSA) were respectively isolated in bronchoalveolar lavage fluid and from blood cultures. Infective meningoencephalitis has been well-documented as a complication during SARS-CoV-2 infection [7] . In the remaining cases leptomeningeal vascular congestions was seen. The leptomeningeal vascular alterations detected in the present cases, are consistent with the findings described by Helms et al. who detected, on Magnetic Resonance Imaging, leptomeningeal spaces enhancement in 8/13 patients and bilateral frontal hypoperfusion in 11 patients [3] . Furthermore, in Helms et al series, three asymptomatic patients presented small acute or subacute-ischemic strokes [3] . The present study has some limitations, including the small sample size and the absence of premortem specific neurologic symptoms. In addition, autopsies were not consecutive, but performed on cases that experienced an unexpectedly fatal course. Therefore, data shown here may not reflect the pathologic involvement of all SARS-CoV-2 infected patients. Nevertheless, in spite of these limitations, this study supports the hypothesis formulated by Romoli et al [9] that SARS-CoV-2 related brain injury maybe the consequence of several pathogenetic mechanisms in addition to direct viral damage. Furthermore, brain lesions were present even in absence of specific neurological symptoms. Therefore, it is possible that brain involvement is an underestimated feature in SARS-CoV-2 infected patients. This article is protected by copyright. All rights reserved The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. All the authors contributed to the design and implementation of the research in their own field (pathology, microbiology, neurology, intensive care), to the analysis of the results and to the writing of the manuscript. This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved All the data supporting the findings of this study (histologic specimens, clinical data) are available from the corresponding author on request. All the data that have been cited in this paper are openly available in PubMed® at https://pubmed.ncbi.nlm.nih.gov/. This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19 Pathological post-mortem findings in lungs infected with SARS COV-2 Neurologic Features in Severe SARS-CoV-2 Infection Neuropathological Findings in Two Patients with Fatal COVID-19 Neuropathologic features of four autopsied COVID-19 patients Brainstem involvement and respiratory failure in COVID-19 A first case of meningitis/encephalitis associated with SARS-Coronavirus-2