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Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MassachusettsDepartment of Ophthalmology, Harvard Medical School, Boston, Massachusetts
Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MassachusettsDepartment of Ophthalmology, Harvard Medical School, Boston, Massachusetts
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was originally identified as an outbreak in Wuhan, China, toward the end of 2019 and quickly became a global pandemic, with a large death toll. Originally identified as a respiratory disease, similar to previously discovered SARS and Middle East respiratory syndrome (MERS), concern has since been raised about the effects of SARS-CoV-2 infection on the vasculature. This viral-vascular involvement is of particular concern with regards to the small vessels present in the brain, with mounting evidence demonstrating that SARS-CoV-2 is capable of crossing the blood-brain barrier. Severe symptoms, termed coronavirus disease 2019 (COVID-19), often result in neurologic complications, regardless of patient age. These neurologic complications range from mild to severe across all demographics; however, the long-term repercussions of neurologic involvement on patient health are still unknown.
Currently, there are approximately 140 million confirmed infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide, and about 3,000,000 deaths associated with SARS-CoV-2 infection (Johns Hopkins University & Medicine, Coronavirus Resource Center, https://coronavirus.jhu.edu, last accessed April 17, 2021) manifesting as severe coronavirus disease 2019, or coronavirus disease 2019 (COVID-19). Approximately 15% of individuals affected by COVID-19 develop severe disease, and 6% are critically ill, resulting in respiratory failure and/or multiple organ dysfunction or failure.
Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.
Genomic characterization indicates that bats and rodents are the likely gene sources of α- and β-coronaviruses (CoVs), whereas γ- and δ-CoVs likely arise from avian sources.
Ocular tropism of coronavirus (CoVs): a comparison of the interaction between the animal-to-human transmitted coronaviruses (SARS-CoV-1, SARS-CoV-2, MERS-CoV, CoV-229E, NL63, OC43, HKU1) and the eye.
To date, seven human coronaviruses have been identified with the ability to cause respiratory, enteric, hepatic, and neurologic diseases in different animal species, including cattle and cats. These viruses are responsible for about 5% to 10% of acute respiratory infections, including the common cold.
Ocular tropism of coronavirus (CoVs): a comparison of the interaction between the animal-to-human transmitted coronaviruses (SARS-CoV-1, SARS-CoV-2, MERS-CoV, CoV-229E, NL63, OC43, HKU1) and the eye.
SARS-CoV-2 is a member of the β- coronaviruses and is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) with high sequence homology.
These coronaviruses appear to infect the respiratory and gastrointestinal tract, with patients presenting symptoms of fever, cough, and shortness of breath, whereas less common symptoms include diarrhea, vomiting, and nausea.
Because of the multiorgan involvement of COVID-19, it has been hypothesized that COVID-19 is a vascular disease that primarily affects endothelial cells.
This direct injury and release of inflammatory and apoptosis inducing mediators leads to localized microvascular inflammation, which triggers endothelial activation, leading to vasodilation and prothrombotic conditions, which cause increased patient mortality.
Viral infections of the brain are less common than those of other organs as they involve penetration of the blood-brain barrier (BBB). Several viruses, including polio and West Nile virus, are able to cause neurologic complications, but the reasons why they occur in <1 in 100 patients are not understood.
The route of entry of the virus into the brain, such as in the blood supply, or by direct infection of vascular endothelial cells, plays a role in the number and type of neurologic symptoms presented by the patient.
Although the route of entry of the virus may still be unknown, recent publications have highlighted neurologic manifestations that have been observed in 42% of COVID-19 patients at disease onset, 63% during hospitalization, and 82% at some time during the course of the disease.
In addition, a significant link was seen between magnetic resonance imaging abnormalities and persistent neurologic deficits, which continued 3 months after disease onset in 55% of patients.
This review explores the role of the vasculature, specifically within the context of the neurologic manifestations of COVID-19. Herein, the neurologic manifestations reported with SARS-CoV-2 infection are reviewed. The evidence that suggests blood vessels are involved in SARS-CoV-2 infection is surveyed. Finally, the multiple pathologic processes (thromboembolic, inflammatory, and secondary processes) within blood vessels that may contribute to the neurologic manifestations of COVID-19 infection are considered.
Composition, Function, and Weaknesses of the Blood-Brain Barrier
The structure and mode of replication of coronaviruses are related, and the relatedness of human CoVs to the neurotropic animal coronaviruses is predictive of the ability of SARS-CoV-2 to invade the central nervous system (CNS), suggesting some tropism for neural tissue.
The ACE2 receptor is ubiquitous across several organ systems, including the lungs, heart, and kidney, but the expression of ACE2 in the brain is significantly lower than that of other organs.
However, in an in vitro model of the human BBB, the function of the BBB is negatively affected by the SARS-CoV-2 spike protein, and brain endothelial cells showed a distinct proinflammatory response when exposed to the spike protein.
Therefore, the virus must likely overcome the BBB, which plays a critical role in CNS homeostasis, and provides a fundamental level of protection from microorganisms and viruses.
Specifically, the interaction between endothelial cells and pericytes within a common basal lamina via peg-and-socket junctions, as well as the direct encasing of retinal capillaries by astrocytic end feet and microglia, form the neurovascular unit.
Furthermore, the endothelial cells in particular, within the CNS, form a tight barrier via continuous tight junctions, lack of fenestration, and low pinocytic activity, drastically limiting the transport of molecules between the vascular system and the CNS.
Although experimental evidence regarding SARS-CoV-2 neuroinvasiveness is still lacking, there is evidence obtained through post-mortem studies that indicate that the virus has reached the brain microvasculature, cerebrospinal fluid (CSF), as well as the neurons.
This may in part be due to the fact that not all blood vessels within the CNS are composed of the cellular constituents of the neurovascular unit, and the integrity of the BBB varies throughout some portions of the CNS, such as the choroid plexus or the circumventricular organs, allowing for secretion of CSF and other neurosecretory functions.
Neuronal retrograde dissemination as well as hematogenous dissemination are potential pathways for SARS-CoV-2 to enter the CNS. Neuronal retrograde dissemination uses a protein called dynein to move viruses along the axon in the retrograde direction, from synapse to soma.
This process may involve direct infection of cerebral vascular endothelial cells due to leukocyte tethering, which allows immediate passage across the BBB into the CNS.
In addition to leukocyte activation and the trafficking of infected leukocytes through the blood-brain, the blood-CSF barrier may also be utilized as a hematogenous dissemination route, whereby infected hematopoietic cells are used as Trojan horses to transport virus into the CNS via the blood supply.
A systemic viral infection can also lead to inflammation-induced breakdown of the BBB, allowing viruses to slip through literal cracks between endothelial cells and into the CNS.
Although the activation, inflammation, and immune response of endothelial cells may be enough to compromise the BBB alone, the actions of the matrix metalloproteinase family of proteins may play a role in BBB integrity loss. Matrix metalloproteinase proteins are specifically relevant to BBB integrity, and up-regulation of SARS-CoV-2 spike protein has been shown to significantly up-regulate many of these key proteins.
The heterogeneity of barrier function within the CNS may additionally explain some of the variability of neurologic manifestations of COVID-19.
Neurologic Manifestations of SARS-CoV-2 Infection
Patients with severe respiratory disease are reported to have multiple neurologic manifestations. In a case study of 509 consecutive patients admitted with confirmed COVID-19 in Chicago, IL, a significantly higher risk of neurologic complications was seen in patients with severe symptoms of COVID-19.
The neuro-invasiveness of SARS-CoV has been established previously, and because of the similarities between the two coronaviruses, a similar risk of neuro-invasiveness may be extrapolated to SARS-CoV-2.
The coronavirus family, including SARS-CoV-2, has been associated with seizures, status epilepticus, encephalitis, acute disseminated encephalomyelitis, Guillan-Barre syndrome, leukoencephalopathy, and critical illness neuromyopathy.
Although coronaviruses, including SARS-CoV-2, have been isolated from brain tissue in autopsy specimens, the presence of neutralizing antibodies in patient serum and cerebrospinal fluid has also been detected.
Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study.
The likely early symptoms of COVID-19 include a fever and headache, with approximately 11% of emergency departments presenting patients experiencing headache.
Patients have reported headaches as pulsating, stabbing, or pressing, which normally indicates different headache types, such as migraine or tension. In the context of COVID-19, headache is likely to occur in conjunction with gastrointestinal symptoms.
These dual symptoms of gastrointestinal tract involvement with headache are linked to the gut-brain axis, which is affected by significant cytokine release, common in COVID-19 patients,
including tumor necrosis factor-α, ILs, and calcitonin gene-related peptide, a neuropeptide significantly linked to trigeminovascular activation, which leads to headache.
Further neurologic complications and cerebrovascular events include cerebrovascular accident, Guillian-Barre syndrome, acute transverse myelitis, and, although difficult to detect, acute encephalitis.
Coronaviruses have been detected in both the cerebrum and cerebrospinal fluid of individuals with seizures, encephalitis, and encephalomyelitis. The first case of encephalitis associated with SARS-CoV-2 infection was reported in May 2020 in a 24-year-old man,
The higher risk of neurologic complications in patients with severe symptoms is caused primarily by a higher frequency of encephalopathy, especially in older patients.
Patients diagnosed with encephalitis have demonstrated signs of immune-mediated small-vessel damage, leading to altered integrity of the blood-brain barrier and brain edema.
Secondary CNS vasculitis is a rare condition characterized by inflammation of the blood vessels in the brain or spine caused by viral infection, leading to varied symptoms, including confusion and significant forgetfulness.
Because of its rarity, few patients diagnosed with COVID-19 have exhibited symptoms and been included in case studies as confirmed vasculitis patients. The condition often presents as multiple ischemic small-vessel lesions and hyperdense blood areas, with scans showing injury to the intracranial microvasculature.
The pattern seen on the scans is characteristic of disease processes that progress from endoluminal, vessel wall (vasculitis), or perivascular (leukoencephalopathy) cellular proliferation.
Of the few case studies available, patients were treated with steroids and immunoglobulin (Ig), as well as IL inhibitors, with varied outcomes for the patients.
Cerebrovascular accident (alias stroke) is associated with COVID-19 diagnosis, across all age ranges, but is especially concerning in younger patients (aged <50 years) without the expected risk factors.
Hypercoagulopathy, resulting from viral effects on systemic and CNS coagulation pathways, has been a growing concern, and anticoagulant administration is associated with decreased mortality in COVID-19 patients. In a case study of 32 critically ill patients, 8 had severe CNS involvement. Three patients were imaged with vessel wall sequence magnetic resonance imaging and showed contrast enhancement, suggesting large-vessel pathologies with an inflammatory component; however CSF samples were negative for SARS-CoV-2.
There have since been reports that PCR analysis of the CSF may be not reliable for the diagnosis because SARS-CoV-2 dissemination in the brain can be transient and its CSF titer may be extremely low.
Across the published articles available by mid-2020, it was calculated that between 0.2% and 1% of those infected with COVID-19 develop ischemic strokes.
This compares with annual rates of roughly 0.1% of the population in the United Kingdom and 0.2% of the population in the United States. Both the presentation and outcome are generally worse in stroke associated with a COVID-19 diagnosis compared with other strokes.
Patients whose symptoms include severe pneumonia and multiorgan failure are more likely to additionally develop stroke, and the outcome for these patients is poor.
Reported cerebrovascular events are predominantly found in older patients; however, acute mental state alterations, although represented in all age groups, are considered to be disproportionately found in younger patients.
Additional, long-term studies are required, but there is also speculation that COVID-19 infection may have long-term negative implications on the incidence of Alzheimer disease within the population.
Disrupted cardiorespiratory function causes metabolic dysfunction that may increase risk for future Alzheimer disease and related dementia, whereas the extreme inflammatory response to the infection causes the release of ILs and tumor necrosis factor-α.
These data on the impact of the CNS insult to patients support the fact that the neurologic complications from SARS-CoV-2 infection may have longer-lasting consequences, and in fact be more debilitating, than the initial respiratory symptoms of the disease.
As COVID-19 mainly presents as a respiratory disease, it is not surprising that post-mortem studies in patients with COVID-19 identified diffuse alveolar damage in patients with severe disease, indicating pulmonary epithelial cell involvement.
West Nile virus infection modulates human brain microvascular endothelial cells tight junction proteins and cell adhesion molecules: transmigration across the in vitro blood-brain barrier.
West Nile virus infection modulates human brain microvascular endothelial cells tight junction proteins and cell adhesion molecules: transmigration across the in vitro blood-brain barrier.
Like many other viruses, the mechanisms underlying cerebral endothelial susceptibility and individual patient neurologic responses to SARS-CoV-2 are unknown.
Figure 1Comparison of normal blood vessels versus potential disease states of blood vessels in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients. The figure was generated with Biorender.com (BioRender, Toronto, ON, Canada).
Endothelial cells in a healthy environment are able to prevent coagulation, inhibit inflammation, and control blood flow and the passage of proteins from blood into tissues by modulation of vascular permeability.
Evidence based on COVID-19 risk factors, which include old age, obesity, hypertension, and diabetes mellitus, indicates a link between endothelial cells and COVID-19, as all of the above are characterized by pre-existing vascular dysfunction.
As endothelial cells play a crucial role in maintaining hemostasis and vessel wall integrity, localized dysfunction of pulmonary microvascular cells is likely to be a key component in the thromboinflammatory processes that result in COVID-19 vasculopathy.
Evidence from autopsies indicates direct viral tissue injury and localized cytokine release induce microvascular inflammation, which triggers endothelial activation.
The lungs of COVID-19 autopsy patients have features of severe endothelial injury associated with intracellular SARS-CoV-2 virus and disrupted endothelial cell membranes.
Comorbidities of severe COVID-19, which are linked to vascular endothelial damage, such as atherosclerosis, cause significant damage to the endothelial glycocalyx, whereas SARS-CoV-2 can induce cytokine release, also leading to systemic degradation of the vascular endothelial glycocalyx.
Microthrombosis of the small-vessel myocardial vasculature is a relatively common finding in COVID-19 patients and may persist even after viral clearance.
Further evidence of vascular cell involvement in coagulopathy, most obviously seen in thrombi formation in the lungs and in ischemic strokes, is also visible in the blood vessels of the skin. Rashes, described as livedoid and purpuric, are visible manifestations of a suspected underlying pulmonary thrombotic state in COVID-19 patients.
These rashes have been noted to occur in patients already receiving therapeutic dose anticoagulation therapies to stave off suspected pulmonary embolism.
especially as punch biopsies indicated pauci-inflammatory thrombogenic vasculopathy involving capillaries, venules, and/or arterioles in conjunction with significantly elevated D-dimer levels. In these cases, patients were not believed to be experiencing alternate conditions resulting in thrombi formation, including disseminated intravascular coagulation (DIC), because of their normal levels of fibrinogen.
Disruption of the endothelial cells is not an end point in itself, but rather a component of a thromboinflammatory feedback loop within small vessels, wherein disruption, cytokine release, and coagulation cascade activation lead to a comparably hypoxic environment that exacerbates the aforementioned factors.
Although, in the lungs, thrombotic complications are likely to relate, at least in part, to endothelial inflammation and injury, its in the cerebrovascular system is currently limited.
Mechanisms of Vascular Damage in SARS-CoV-2 Infection
Cytokine release syndrome, also described as cytokine storm, is of serious concern in COVID-19 patients as it has been linked to increased patient mortality.
This leads to the release of proinflammatory cytokines, such as tumor necrosis factor-α and IL-6 and IL-1β, as well as chemokines, including vascular endothelial growth factor, monocyte chemoattractant protein-1, and CXCL10.
For example, IL-6 expression is significantly higher in fatal outcomes compared with survivors and is also used an indicator of the need for mechanical ventilation.
The activated phenotype of endothelial cells, which is induced by inflammatory cytokines and chemokines, promotes adhesions and infiltration of neutrophils, which produce large amounts of histotoxic mediators, including neutrophil extracellular traps, which leads to endothelial cell injury.
These activated endothelial cells initiate coagulation by expressing fibrinogen, among others, leading to platelet binding, fibrin production, and thrombus formation.
The microvascular inflammation caused by release of inflammatory and apoptosis-inducing mediators, followed by endothelial activation, leads to increased patient mortality.
However, the question remains as to whether the pathobiology and neuroinfectiveness of SARS-CoV-2 mean that damage occurs from direct effects of the virus on the CNS tissue, or whether damage occurs as a secondary insult, triggered by hypoxia, immune response cytokine release, or clotting cascades.
Autopsied patients have SARS-CoV-2–infected frontal lobe microvascular endothelial cells and tissue damage, characterized by cell lysis and dysfunction, as well as evidence of localized cytokine release,
Interestingly, although ACE2 receptor is required for SARS-CoV-2 to bind and gain access to the cell, this binding reduces ACE2 enzyme activity, activating the kallikrein-bradykinin pathway, and increasing vascular permeability.
This increased permeability leads to the release of inflammatory cytokines such as ILs and tumor necrosis factor-α, whose downstream mediators promote fluid retention, leading to increased vascular leakage.
Likely cofactors remain a mystery, however, in our understanding of the association of SARS-CoV-2 infection with cerebrovascular events.
Although considered a mild symptom, headache caused by SARS-CoV-2 infection is attributed to a possible pathophysiological mechanism involving the peripheral trigeminal nerve endings. This occurs either by direct viral activation or through vasculopathy caused by increased circulating proinflammatory cytokines and hypoxia.
With regard to the rare neurologic symptoms, including encephalitis and vasculitis, immune-mediated small-vessel damage, leading to altered integrity of the blood-brain barrier, followed by brain edema, is the proposed mechanism.
In patients with vasculitis, this immune-mediated small-vessel damage leads to ischemic lesions, as well as hyperdense blood areas, due to intracranial microvasculature injury.
Immune-related COVID-19 pathology in pediatric populations was recently described in the United States and in Europe. These children developed a Kawasaki-like syndrome, believed to be associated with COVID-19.
Hypotheses as to the mechanism of action for both ischemic and hemorrhagic stroke onset include disseminated intravascular coagulation (alias consumption coagulopathy)
This transition is indicative of serious malfunctions in both the clotting cascade, possibly due to disseminated intravascular coagulation, as well as lack of integrity of the vessel walls caused by endothelial damage.
This immune-driven endothelial damage is likely a large contributor to the increased risk of ischemic and hemorrhagic stroke seen in COVID-19 patients.
In addition, hypercoagulability and vasculitis due to intracranial cytokine storm, leading to macrothrombi and microthrombi formation in the vessels, are also proposed as mechanisms.
The large number of studies relating to COVID-19 (an early January 2021 PubMed search returned >85,000 COVID-19 hits) indicate the urgency in the scientific community to determine the factors causing increased patient mortality. Although improving patient survival rates is of the utmost importance, the impact of the endothelium-linked CNS insult to COVID-19 patients cannot be overstated. Research articles discussing long COVID and post–COVID-19 neurological syndrome have been recently published.
As the pandemic is still ongoing, it is too early to describe the future clinical needs of these patients. However, current evidence indicates that the long-term neurologic complications from SARS-CoV-2 infection may be more debilitating than the initial respiratory symptoms of the disease.
We thank Michel Plantevin and Andrew Firger for supporting publication. H.A.B.W. thanks the Consular Information Unit and the Nonimmigrant Visa Unit at the US Embassy in London, UK, for assistance in obtaining a National Interest Exemption Waiver to allow her return to the United States during the COVID-19 pandemic to work on this project. L.A.K. thanks Dr. Nahyoung Grace Lee for support.
References
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McGoogan J.M.
Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention.
Ocular tropism of coronavirus (CoVs): a comparison of the interaction between the animal-to-human transmitted coronaviruses (SARS-CoV-1, SARS-CoV-2, MERS-CoV, CoV-229E, NL63, OC43, HKU1) and the eye.
Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study.
West Nile virus infection modulates human brain microvascular endothelial cells tight junction proteins and cell adhesion molecules: transmigration across the in vitro blood-brain barrier.
Small Blood Vessel Disease in the Brain Theme Issue
Supported by Michel Plantevin and the National Eye Institute of the NIH award R01EY027739 (L.A.K.).
H.A.B.W. and L.A.K. contributed equally to this work.
Disclosures: L.A.K. is listed as an inventor in a patent application for the treatment of pulmonary fibrosis and coronavirus disease 2019.
This article is part of a review series on small blood vessel disease in the brain, addressing current knowledge, new mechanisms, biomarkers, and therapeutic approaches.
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