Microvascular injury and hypoxic damage: emerging neuropathological signatures in COVID-19

Jaunmuktane, Zane; Mahadeva, Ula; Gréen, Anna; Sekhawat, Vivek; Barrett, Nicholas; Childs, Lucy; Shankar-Hari, Manu; Thom, Maria; Jäger, Hans Rolf; Brandner, Sebastian

doi:10.1007/s00401-020-02190-2

Cited by 92 publications

(133 citation statements)

References 11 publications

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“…Our findings do not eliminate the possibility of direct nervous system invasion of SARS-CoV-2, however, given our large sample size it is likely that such a complication is rare. The possibility of endothelial or microvascular viral invasion 28,29 has been hypothesized to account for some of the unusual strokes and intracerebral hemorrhages reported in the context of SARS-CoV-2…”

Section: A C C E P T E Dmentioning

confidence: 99%

A Prospective Study of Neurologic Disorders in Hospitalized Patients With COVID-19 in New York City

Frontera

Sabadia²,

Lalchan³

et al. 2021

Neurology

264

316

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Objective:To determine the prevalence and associated mortality of well-defined neurologic diagnoses among COVID-19 patients, we prospectively followed hospitalized SARS-Cov-2 positive patients and recorded new neurologic disorders and hospital outcomes.Methods:We conducted a prospective, multi-center, observational study of consecutive hospitalized adults in the NYC metropolitan area with laboratory-confirmed SARS-CoV-2 infection. The prevalence of new neurologic disorders (as diagnosed by a neurologist) was recorded and in-hospital mortality and discharge disposition were compared between COVID-19 patients with and without neurologic disorders.Results:Of 4,491 COVID-19 patients hospitalized during the study timeframe, 606 (13.5%) developed a new neurologic disorder in a median of 2 days from COVID-19 symptom onset. The most common diagnoses were: toxic/metabolic encephalopathy (6.8%), seizure (1.6%), stroke (1.9%), and hypoxic/ischemic injury (1.4%). No patient had meningitis/encephalitis, or myelopathy/myelitis referable to SARS-CoV-2 infection and 18/18 CSF specimens were RT-PCR negative for SARS-CoV-2. Patients with neurologic disorders were more often older, male, white, hypertensive, diabetic, intubated, and had higher sequential organ failure assessment (SOFA) scores (all P<0.05). After adjusting for age, sex, SOFA-scores, intubation, past history, medical complications, medications and comfort-care-status, COVID-19 patients with neurologic disorders had increased risk of in-hospital mortality (Hazard Ratio[HR] 1.38, 95% CI 1.17-1.62, P<0.001) and decreased likelihood of discharge home (HR 0.72, 95% CI 0.63-0.85, P<0.001).Conclusions:Neurologic disorders were detected in 13.5% of COVID-19 patients and were associated with increased risk of in-hospital mortality and decreased likelihood of discharge home. Many observed neurologic disorders may be sequelae of severe systemic illness.

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Section: A C C E P T E Dmentioning

confidence: 99%

A Prospective Study of Neurologic Disorders in Hospitalized Patients With COVID-19 in New York City

Frontera

Sabadia²,

Lalchan³

et al. 2021

Neurology

264

316

View full text Add to dashboard Cite

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“…In COVID-19 patients, magnetic resonance imaging detected lesions that are compatible with a microvascular pathology [17][18][19][20][21] . Autopsy studies have con rmed this interpretation 17,[22][23][24] . However, the mechanisms that lead to small vessel disease in COVID-19 are still unclear.…”

Section: Introductionmentioning

confidence: 84%

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

Wenzel¹,

Lampe²,

Mueler-Fielitz³

et al. 2020

Preprint

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Several lines of evidence suggest that neurological symptoms in COVID-19 patients are partially due to damage to small vessels. However, the potential mechanisms are unclear. Here, we show that brain endothelial cells express SARS-CoV-2 receptors. The main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of NF-κB signaling. By ablating NEMO, Mpro induces the death of human brain endothelial cells and a microvascular pathology in mice that is similar to what we find in the brain of COVID-19 patients. Importantly, the inhibition of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Our data suggest RIPK as a therapeutic target to treat the neuropathology of COVID-19.

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“…In fact, SWI hypointensities in the corpus callosum and in the cortical/iuxtacortical regions of COVID-19 patients with neurological impairment have been reported [7], but their pathological correlate is not univocal, as they could represent microbleeds or microthrombi. In one pathology study, microhemorrages were detected on brain tissue at the location of SWI hypointensities [8]. Though a coagulopathic disorder has been reported in COVID-19 patients, diffuse, mostly peripherally distributed brain microbleeds can also be the expression of critical illness in ICU patients [9].…”

Section: Discussionmentioning

confidence: 99%

Brain microvascular occlusive disorder in COVID-19: a case report

et al. 2020

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We describe the case of a COVID-19 patient with severely impaired consciousness after sedation hold, showing magnetic resonance imaging (MRI) findings of (i) acute bilateral supratentorial ischemic lesions involving the fronto-parietal white matter and the corpus callosum and (ii) multiple diffuse susceptibility weighted imaging (SWI) hypointense foci, infra and supratentorial, predominantly bithalamic, suggestive of microhemorrhage or alternatively microthrombi. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA was detected in the cerebrospinal fluid. Our findings suggest the occurrence of vascular damage, predominantly involving microvessels. The underlying mechanisms, which include direct and indirect penetration of the virus to the central nervous system and systemic cardiorespiratory complications, are yet to be elucidated, and a direct correlation with SARS-CoV-2 infection remains uncertain.

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Microvascular injury and hypoxic damage: emerging neuropathological signatures in COVID-19

Cited by 92 publications

References 11 publications

A Prospective Study of Neurologic Disorders in Hospitalized Patients With COVID-19 in New York City

A Prospective Study of Neurologic Disorders in Hospitalized Patients With COVID-19 in New York City

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

Brain microvascular occlusive disorder in COVID-19: a case report

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