Importance Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear. Objective To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19. Setting, Design, and Participants Case series of patients (age Exposures Severe acute respiratory syndrome coronavirus 2. Main Outcomes and Measures Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge. Results Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barre syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19–related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died. Conclusions and Relevance In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown.

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Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8798975

Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis

SARS-CoV-2 has been reported to show a capacity for invading the brains of humans and model animals. However, it remains unclear whether and how SARS-CoV-2 crosses the blood-brain barrier (BBB). Herein, SARS-CoV-2 RNA was occasionally detected in the vascular wall and perivascular space, as well as in brain microvascular endothelial cells (BMECs) in the infected K18-hACE2 transgenic mice. Moreover, the permeability of the infected vessel was increased. Furthermore, disintegrity of BBB was discovered in the infected hamsters by administration of Evans blue. Interestingly, the expression of claudin5, ZO-1, occludin and the ultrastructure of tight junctions (TJs) showed unchanged, whereas, the basement membrane was disrupted in the infected animals. Using an in vitro BBB model that comprises primary BMECs with astrocytes, SARS-CoV-2 was found to infect and cross through the BMECs. Consistent with in vivo experiments, the expression of MMP9 was increased and collagen IV was decreased while the markers for TJs were not altered in the SARS-CoV-2-infected BMECs. Besides, inflammatory responses including vasculitis, glial activation, and upregulated inflammatory factors occurred after SARS-CoV-2 infection. Overall, our results provide evidence supporting that SARS-CoV-2 can cross the BBB in a transcellular pathway accompanied with basement membrane disrupted without obvious alteration of TJs.

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SARS-CoV-2 crosses the blood-brain barrier accompanied with basement membrane disruption without tight junctions alteration.

SARS-CoV-2, which causes the Coronavirus Disease 2019 (COVID-19) pandemic, has a brain neurotropism through binding to the receptor angiotensin-converting enzyme 2 expressed by neurones and glial cells, including astrocytes and microglia. Systemic infection which accompanies severe cases of COVID-19 also triggers substantial increase in circulating levels of chemokines and interleukins that compromise the blood-brain barrier, enter the brain parenchyma and affect its defensive systems, astrocytes and microglia. Brain areas devoid of a blood-brain barrier such as the circumventricular organs are particularly vulnerable to circulating inflammatory mediators. The performance of astrocytes and microglia, as well as of immune cells required for brain health, is considered critical in defining the neurological damage and neurological outcome of COVID-19. In this review, we discuss the neurotropism of SARS-CoV-2, the implication of neuroinflammation, adaptive and innate immunity, autoimmunity, as well as astrocytic and microglial immune and homeostatic functions in the neurological and psychiatric aspects of COVID-19. The consequences of SARS-CoV-2 infection during ageing, in the presence of systemic comorbidities, and for the exposed pregnant mother and foetus are also covered.

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Neuropathobiology of COVID-19: The Role for Glia

Introduction The increasing evidence of SARS-CoV-2 impact on the central nervous system (CNS) raises key questions on its impact for risk of later life cognitive decline, Alzheimer's disease (AD), and other dementia. Methods The Alzheimer's Association and representatives from more than 30 countries-with technical guidance from the World Health Organization-have formed an international consortium to study the short-and long-term consequences of SARS-CoV-2 on the CNS-including the underlying biology that may contribute to AD and other dementias. This consortium will link teams from around the world covering more than 22 million COVID-19 cases to enroll two groups of individuals including people with disease, to be evaluated for follow-up evaluations at 6, 9, and 18 months, and people who are already enrolled in existing international research studies to add additional measures and markers of their underlying biology. Conclusions The increasing evidence and understanding of SARS-CoV-2's impact on the CNS raises key questions on the impact for risk of later life cognitive decline, AD, and other dementia. This program of studies aims to better understand the long-term consequences that may impact the brain, cognition, and functioning-including the underlying biology that may contribute to AD and other dementias.

https://alz-journals.onlinelibrary.wiley.com/doi/pdf/10.1002/alz.12255

The chronic neuropsychiatric sequelae of COVID-19: The need for a prospective study of viral impact on brain functioning.

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier.

Tissue engineering of the blood-brain barrier (BBB) in vitro has been rapidly expanding to address the challenges of mimicking the native structure and function of the BBB. Most of these models utilize 2D conventional microfluidic techniques. However, 3D microvascular models offer the potential to more closely recapitulate the cytoarchitecture and multicellular arrangement of in vivo microvasculature, and also can recreate branching and network topologies of the vascular bed. In this perspective, we discuss current 3D brain microvessel modeling techniques including templating, printing, and self-assembling capillary networks. Furthermore, we address the use of biological matrices and fluid dynamics. Finally, key challenges are identified along with future directions that will improve development of next generation of brain microvasculature models.

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The Use of Tissue Engineering to Fabricate Perfusable 3D Brain Microvessels in vitro

Treatment of HIV-infected patients with antiretroviral therapy (ART) has effectively suppressed viral replication; however, the central nervous system is still a major target and reservoir of the virus leading to the possible development of HIV-associated neurocognitive disorders (HAND). Furthermore, a hallmark feature of HAND is the disruption of the blood–brain barrier that leads to loss of tight junction protein (TJP) complexes. Extracellular vesicles (EVs), released by every cell type in the body, occur in greater quantities in response to cellular activation or injury. We have found that inflammatory insults activate brain endothelial cells (EC) and induce the release of EVs containing TJPs such as Occludin. We thus hypothesized that HIV infection and unresolved neuroinflammation will result in the release of brain-EC derived EVs. Herein, our results show elevated levels of brain-EC EVs in a humanized mouse model of HIV infection. Furthermore, while ART reduced brain-EC EVs, it was unable to completely resolve increased vesicles detectable in the blood. In addition to inflammatory insults, HIV-1 viral proteins (Tat and gp120) increased the release of Occludin + vesicles from human brain microvasculature ECs. This increase in vesicle release could be prevented by knock-down of the small GTPase ARF6. ARF6 has been shown to regulate EV biogenesis in other cell types, and we provide further evidence for the involvement of ARF6 in brain EC derived EVs. Overall, this study offers insight into the process of brain vascular remodeling (via EVs) in the setting of neuroinflammation and thus provides possibilities for biomarker monitoring and targeting of ARF6.

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Correction to: Extracellular Microvesicles Released From Brain Endothelial Cells are Detected in Animal Models Of HIV‑1 Signifying Unresolved Inflammation.

Jonathan F. Hale

Papers

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier.

The Use of Tissue Engineering to Fabricate Perfusable 3D Brain Microvessels in vitro

Correction to: Extracellular Microvesicles Released From Brain Endothelial Cells are Detected in Animal Models Of HIV‑1 Signifying Unresolved Inflammation.