Endothelial Dysfunction in the Brain: Setting the Stage for Stroke and Other Cerebrovascular Complications of COVID-19.

The Coronavirus disease 2019 (COVID)-19 pandemic has already affected millions worldwide, with a current mortality rate of 2.2%. While it is well-established that severe acute respiratory syndrome-coronavirus-2 causes upper and lower respiratory tract infections, a number of neurological sequelae have now been reported in a large proportion of cases. Additionally, the disease causes arterial and venous thromboses including pulmonary embolism, myocardial infarction, and a significant number of cerebrovascular complications. The increasing incidence of large vessel ischemic strokes as well as intracranial hemorrhages, frequently in younger individuals, and associated with increased morbidity and mortality, has raised questions as to why the brain is a major target of the disease. COVID-19 is characterized by hypercoagulability with alterations in hemostatic markers including high D-dimer levels, which are a prognosticator of poor outcome. Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19.

Acute Viral Illnesses and Ischemic Stroke: Pathophysiological Considerations in the Era of the COVID-19 Pandemic.

The severe acute respiratory syndrome coronavirus 2 or coronavirus disease 2019 (COVID-19) pandemic has raised concerns about the correlation with this viral illness and increased risk of stroke. Although it is too early in the pandemic to know the strength of the association between COVID-19 and stroke, it is an opportune time to review the relationship between acute viral illnesses and stroke. Here, we summarize pathophysiological principles and available literature to guide understanding of how viruses may contribute to ischemic stroke. After a review of inflammatory mechanisms, we summarize relevant pathophysiological principles of vasculopathy, hypercoagulability, and hemodynamic instability. We will end by discussing mechanisms by which several well-known viruses may cause stroke in an effort to inform our understanding of the relationship between COVID-19 and stroke.

Cross-Talk Between Key Players in Patients with COVID-19 and Ischemic Stroke: A Review on Neurobiological Insight of the Pandemic.

The global pandemic of novel coronavirus disease 2019 (COVID-19) has taken the entire human race by surprise and led to an unprecedented number of mortalities worldwide so far. Current clinical studies have interpreted that angiotensin-converting enzyme 2 (ACE2) is the host receptor for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). In addition, ACE2 is the major component of the renin-angiotensin system. ACE2 deteriorates angiotensin II, a peptide that is responsible for the promotion of stroke. The downregulation of ACE2 further activates an immunological cascade. Thus, researchers need to explore and examine the possible links between COVID-19 and ischemic stroke (IS). Human ACE2 expression level and pattern in various tissues might be decisive for the vulnerability, symptoms, and treatment outcomes of the SARS-CoV-2 infection. The swift increase in the knowledge of SARS-CoV-2 has given creditable evidence that SARS-CoV-2 infected patients also encounter neurological deficits. As the SARS-CoV-2 binds to ACE2, it will hamper the activity of ACE2 in providing neuroprotection, especially in the case of stroke patients. Due to the downregulation of ACE2, the inflammatory response is activated in the ischemic penumbra. The COVID-19 pandemic has affected people with various pre-existing diseases, including IS, in such a way that these patients need special care and attention for their survival. Several clinical trials are currently ongoing worldwide as well as many other projects are in different stages of conceptualization and planning to facilitate the effective management of stroke patients with COVID-19 infection.

Stroke Code Presentations, Interventions, and Outcomes Before and During the COVID-19 Pandemic.

BACKGROUND: Anecdotal reports suggest fewer patients with stroke symptoms are presenting to hospitals during the coronavirus disease 2019 (COVID-19) pandemic. We quantify trends in stroke code calls and treatments at 3 Connecticut hospitals during the local emergence of COVID-19 and examine patient characteristics and stroke process measures at a Comprehensive Stroke Center (CSC) before and during the pandemic. METHODS: Stroke code activity was analyzed from January 1 to April 28, 2020, and corresponding dates in 2019. Piecewise linear regression and spline models identified when stroke codes in 2020 began to decline and when they fell below 2019 levels. Patient-level data were analyzed in February versus March and April 2020 at the CSC to identify differences in patient characteristics during the pandemic. RESULTS: A total of 822 stroke codes were activated at 3 hospitals from January 1 to April 28, 2020. The number of stroke codes/wk decreased by 12.8/wk from February 18 to March 16 (P=0.0360) with nadir of 39.6% of expected stroke codes called from March 10 to 16 (30% decrease in total stroke codes during the pandemic weeks in 2020 versus 2019). There was no commensurate increase in within-network telestroke utilization. Compared with before the pandemic (n=167), pandemic-epoch stroke code patients at the CSC (n=211) were more likely to have histories of hypertension, dyslipidemia, coronary artery disease, and substance abuse; no or public health insurance; lower median household income; and to live in the CSC city (P<0.05). There was no difference in age, sex, race/ethnicity, stroke severity, time to presentation, door-to-needle/door-to-reperfusion times, or discharge modified Rankin Scale. CONCLUSIONS: Hospital presentation for stroke-like symptoms decreased during the COVID-19 pandemic, without differences in stroke severity or early outcomes. Individuals living outside of the CSC city were less likely to present for stroke codes at the CSC during the pandemic. Public health initiatives to increase awareness of presenting for non-COVID-19 medical emergencies such as stroke during the pandemic are critical.

Neurologic and neuroimaging findings in patients with COVID-19: A retrospective multicenter study.

OBJECTIVE: To describe neuroimaging findings and to report the epidemiologic and clinical characteristics of patients with coronavirus disease 2019 (COVID-19) with neurologic manifestations. METHODS: In this retrospective multicenter study (11 hospitals), we included 64 patients with confirmed COVID-19 with neurologic manifestations who underwent a brain MRI. RESULTS: The cohort included 43 men (67%) and 21 women (33%); their median age was 66 (range 20-92) years. Thirty-six (56%) brain MRIs were considered abnormal, possibly related to severe acute respiratory syndrome coronavirus. Ischemic strokes (27%), leptomeningeal enhancement (17%), and encephalitis (13%) were the most frequent neuroimaging findings. Confusion (53%) was the most common neurologic manifestation, followed by impaired consciousness (39%), presence of clinical signs of corticospinal tract involvement (31%), agitation (31%), and headache (16%). The profile of patients experiencing ischemic stroke was different from that of other patients with abnormal brain imaging: the former less frequently had acute respiratory distress syndrome (p = 0.006) and more frequently had corticospinal tract signs (p = 0.02). Patients with encephalitis were younger (p = 0.007), whereas agitation was more frequent for patients with leptomeningeal enhancement (p = 0.009). CONCLUSIONS: Patients with COVID-19 may develop a wide range of neurologic symptoms, which can be associated with severe and fatal complications such as ischemic stroke or encephalitis. In terms of meningoencephalitis involvement, even if a direct effect of the virus cannot be excluded, the pathophysiology seems to involve an immune or inflammatory process given the presence of signs of inflammation in both CSF and neuroimaging but the lack of virus in CSF. CLINICALTRIALSGOV IDENTIFIER: NCT04368390.

Spectrum of Neurological Manifestations in Covid-19: A Review.

COVID-19, in most patients, presents with mild flu-like illness. Elderly patients with comorbidities, like hypertension, diabetes, or lung and cardiac disease, are more likely to have severe disease and deaths. Neurological complications are frequently reported in severely or critically ill patients with comorbidities. In COVID-19, both central and peripheral nervous systems can be affected. The SARS-CoV-2 virus causes the disease COVID-19 and has the potential to invade the brain. The SARS-CoV-2 virus enters the brain either via a hematogenous route or olfactory system. Angiotensin-converting enzyme two receptors, present on endothelial cells of cerebral vessels, are a possible viral entry point. The most severe neurological manifestations, altered sensorium (agitation, delirium, and coma), are because of hypoxic and metabolic abnormalities. Characteristic cytokine storm incites severe metabolic changes and multiple organ failure. Profound coagulopathies may manifest with ischemic or hemorrhagic stroke. Rarely, SARS-CoV-2 virus encephalitis or pictures like acute disseminated encephalomyelitis or acute necrotizing encephalopathy have been reported. Nonspecific headache is a commonly experienced neurological symptom. A new type of headache "personal protection equipment-related headache" has been described. Complete or partial anosmia and ageusia are common peripheral nervous system manifestations. Recently, many cases of Guillain-Barré syndrome in COVID-19 patients have been observed, and a postinfectious immune-mediated inflammatory process was held responsible for this. Guillain-Barré syndrome does respond to intravenous immunoglobulin. Myalgia/fatigue is also common, and elevated creatine kinase levels indicate muscle injury. Most of the reports about neurological complications are currently from China. COVID-19 pandemic is spreading to other parts of the world; the spectrum of neurological complications is likely to widen further.

COVID-19: A Global Threat to the Nervous System.

In less than 6 months, the severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) has spread worldwide infecting nearly 6 million people and killing over 350,000. Initially thought to be restricted to the respiratory system, we now understand that coronavirus disease 2019 (COVID-19) also involves multiple other organs, including the central and peripheral nervous system. The number of recognized neurologic manifestations of SARS-CoV-2 infection is rapidly accumulating. These may result from a variety of mechanisms, including virus-induced hyperinflammatory and hypercoagulable states, direct virus infection of the central nervous system (CNS), and postinfectious immune mediated processes. Example of COVID-19 CNS disease include encephalopathy, encephalitis, acute disseminated encephalomyelitis, meningitis, ischemic and hemorrhagic stroke, venous sinus thrombosis, and endothelialitis. In the peripheral nervous system, COVID-19 is associated with dysfunction of smell and taste, muscle injury, the Guillain-Barre syndrome, and its variants. Due to its worldwide distribution and multifactorial pathogenic mechanisms, COVID-19 poses a global threat to the entire nervous system. Although our understanding of SARS-CoV-2 neuropathogenesis is still incomplete and our knowledge is evolving rapidly, we hope that this review will provide a useful framework and help neurologists in understanding the many neurologic facets of COVID-19. ANN NEUROL 2020;88:1-11 ANN NEUROL 2020;88:1-11.