Neuropathology of Pediatric SARS-CoV-2 Infection in the Forensic Setting: Novel Application of Ex Vivo Imaging in Analysis of Brain Microvasculature

Abstract

Two years into the COVID-19 pandemic, there are few published accounts of postmortem SARS-CoV-2 pathology in children. We report 8 such cases (4 infants aged 7–36 weeks, 4 children aged 5–15 years). Four underwent ex vivo magnetic resonance neuroimaging, to assist in identification of subtle lesions related to vascular compromise. All infants were found unresponsive (3 in unsafe sleeping conditions); all but 1 had recent rhinitis and/or influenza-like illness (ILI) in the family; 1 had history of sickle cell disease. Ex vivo neuroimaging in 1 case revealed white matter (WM) signal hyperintensity and diffuse exaggeration of perivascular spaces, corresponding microscopically to WM mineralization. Neurohistology in the remaining 3 infants variably encompassed WM gliosis and mineralization; brainstem gliosis; perivascular vacuolization; perivascular lymphocytes and brainstem microglia. One had ectopic hippocampal neurons (with pathogenic variant in DEPDC5). Among the children, 3 had underlying conditions (e.g., obesity, metabolic disease, autism) and all presented with ILI. Three had laboratory testing suggesting multisystem inflammatory syndrome (MIS-C). Two were hospitalized for critical care including mechanical ventilation and extracorporeal membrane oxygenation (ECMO); one (co-infected with adenovirus) developed right carotid stroke ipsilateral to the ECMO cannula and the other required surgery for an ingested foreign body. Autopsy findings included: acute lung injury in 3 (1 with microthrombi); and one each with diabetic ketoacidosis and cardiac hypertrophy; coronary and cerebral arteritis and aortitis, resembling Kawasaki disease; and neuronal storage and enlarged fatty liver. All 4 children had subtle meningoencephalitis, focally involving the brainstem. On ex vivo neuroimaging, 1 had focal pontine susceptibility with corresponding perivascular inflammation/expanded perivascular spaces on histopathology. Results suggest SARS-CoV-2 in infants may present as sudden unexpected infant death, while in older children, signs and symptoms point to severe disease. Underlying conditions may predispose to fatal outcomes. As in adults, the neuropathologic changes may be subtle, with vascular changes such as perivascular vacuolization and gliosis alongside sparse perivascular lymphocytes. Detection of subtle vascular pathology is enhanced by ex vivo neuroimaging. Additional analysis of the peripheral/autonomic nervous system and investigation of co-infection in children with COVID-19 is necessary to understand risk for cardiovascular collapse/sudden death.

Medico-legal analysis of cases of children who died suddenly due to pneumonia undiagnosed in their lifetime

“…Each time, case files were made available for analysis with the permission of the prosecutor's office upon a written request of the investigator. Apart from the results of post-mortem examinations in each case, the available medical records (health się, że złotym standardem w tego typu przypadkach powinno być wykonanie: pośmiertnych badań obrazowych (przynajmniej RTG), badań histopatologicznych, neuropatologicznych, mikrobiologicznych oraz genetycznych [4][5][6][7]. Niestety w polskich realiach dostęp do części z tych badań jest istotnie ograniczony, w zależności od możliwości konkretnego ośrodka medyczno-sądowego.…”

“…It is emphasized that the gold standard in this type of cases should be conducting post-mortem imaging (at Arch Med Sadowej Kryminol 2022; vol. 72 (4): 165-182 least X-rays), histopathological, neuropathological, microbiological and genetic tests [4][5][6][7]. Unfortunately, in the Polish reality, access to some of these tests is significantly limited, depending on the capabilities of a particular medico-legal center.…”

What Can We Still Learn from Brain Autopsies in COVID-19?

“…Published neuroradiographic-histopathologic case series include a 13-person and 7-person series in adults, 8,58 and an 8-person series in children and infants. 40 Among adults, the majority of whom were hospitalized and critically ill, areas of punctate hyperintensities on MRI corresponded to endothelial cell basal lamina thinning and fibrinogen leakage on histopathological examination. This finding was more commonly observed in the infratentorial (midbrain, pons, medulla, cerebellum) than in cortical (cerebral cortex, olfactory bulb) or subcortical (basal ganglia, splenium) regions.…”

“…3). 40 The majority of published reports in this age group are from children with at least one significant preexisting condition, hospitalized in critical condition, such as pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2, who suffered hypoxic-ischemic injury, and/or had severe coinfections. The predominant neuropathological findings were vascular congestion, reactive microgliosis with occasional microglial nodules, and neuronal ischemia.…”

“…39 Four infants who died at home unexpectedly and were incidentally found to have COVID-19 exhibited minimal neuropathological changes, including white matter mineralization, reactive gliosis, and perivascular vacuolization and inflammation. 40 Perivascular lymphocytes have also been observed in cases of sudden unexplained infant death without SARS-CoV-2 infection, making it challenging to attribute the observed histological findings to COVID-19 in these specific cases. Based on a limited number of published reports, the neuropathological changes of acute COVID-19 in infants and children are variable and nonspecific, without evidence of direct viral infection of brain parenchyma.…”