Weighted Gene Co-Expression Network Analysis to Identify Potential Biological Processes and Key Genes in COVID-19-Related Stroke.

The purpose of this research was to explore the underlying biological processes causing coronavirus disease 2019- (COVID-19-) related stroke. The Gene Expression Omnibus (GEO) database was utilized to obtain four COVID-19 datasets and two stroke datasets. Thereafter, we identified key modules via weighted gene co-expression network analysis, following which COVID-19- and stroke-related crucial modules were crossed to identify the common genes of COVID-19-related stroke. The common genes were intersected with the stroke-related hub genes screened via Cytoscape software to discover the critical genes associated with COVID-19-related stroke. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis for common genes associated with COVID-19-related stroke, and the Reactome database was used to annotate and visualize the pathways involved in the key genes. Two COVID-19-related crucial modules and one stroke-related crucial module were identified. Subsequently, the top five genes were screened as hub genes after visualizing the genes of stroke-related critical module using Cytoscape. By intersecting the COVID-19- and stroke-related crucial modules, 28 common genes for COVID-19-related stroke were identified. ITGA2B and ITGB3 have been further identified as crucial genes of COVID-19-related stroke. Functional enrichment analysis indicated that both ITGA2B and ITGB3 were involved in integrin signaling and the response to elevated platelet cytosolic Ca2+, thus regulating platelet activation, extracellular matrix- (ECM-) receptor interaction, the PI3K-Akt signaling pathway, and hematopoietic cell lineage. Therefore, platelet activation, ECM-receptor interaction, PI3K-Akt signaling pathway, and hematopoietic cell lineage may represent the potential biological processes associated with COVID-19-related stroke, and ITGA2B and ITGB3 may be potential intervention targets for COVID-19-related stroke.

Neurological Sequelae of COVID-19.

BACKGROUND: Though primarily a pulmonary disease, Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus can generate devastating disease states that affect multiple organ systems including the central nervous system (CNS). The various neurological disorders associated with COVID-19 range in severity from mild symptoms such as headache, or myalgias to more severe symptoms such as stroke, psychosis, and anosmia. While some of the COVID-19 associated neurological complications are mild and reversible, a significant number of patients suffer from stroke. Studies have shown that COVID-19 infection triggers a wave of inflammatory cytokines that induce endothelial cell dysfunction and generate coagulopathy that increases the risk of stroke or thromboses. Inflammation of the endothelium following infection may also destabilize atherosclerotic plaque and induce thrombotic stroke. Although uncommon, there have also been reports of hemorrhagic stroke associated with COVID-19. The proposed mechanisms include a blood pressure increase caused by infection leading to a reduction in angiotensin converting enzyme-2 (ACE-2) levels that results in an imbalance of the renin-angiotensin system ultimately manifesting inflammation and vasoconstriction. Coagulopathy, as demonstrated by elevated prothrombin time (PT), has also been posited as a factor contributing to hemorrhagics stroke in patients with COVID-19. Other neurological conditions associated with COVID-19 include encephalopathy, anosmia, encephalitis, psychosis, brain fog, headache, depression, and anxiety. Though there are several hypotheses reported in the literature, a unifying pathophysiological mechanism of many of these disorders remains unclear. Pulmonary dysfunction leading to poor oxygenation of the brain may explain encephalopathy and other disorders in COVID-19 patients. Alternatively, a direct invasion of the CNS by the virus or breach of the blood-brain barrier by the systemic cytokines released during infection may be responsible for these conditions. Notwithstanding, the relationship between the inflammatory cytokine levels and conditions such as depression and anxiety is contradictory and perhaps the social isolation during the pandemic may in part be a contributing factor to some of the reported CNS disorders. OBJECTIVE: In this article, we review the current literature pertaining to some of the most significant and common neurological disorders such as ischemic and hemorrhagic stroke, encephalopathy, encephalitis, brain fog, Long COVID, headache, Guillain-Barre syndrome, depression, anxiety, and sleep disorders in the setting of COVID-19. We summarize some of the most relevant literature to provide a better understanding of the mechanistic details regarding these disorders in order to help physicians monitor and treat patients for significant COVID-19 associated neurologic impairments. METHODS: A literature review was carried out by the authors using PubMed with the search terms "COVID-19" and "Neurology", "Neurological Manifestations", "Neuropsychiatric Manifestations", "Stroke", "Encephalopathy", "Headache", "Guillain-Barre syndrome", "Depression", "Anxiety", "Encephalitis", "Seizure", "Spasm", and "ICUAW". Another search was carried out for "Long-COVID" and "Post-Acute COVID-19" and "Neurological Manifestations" or "Neuropsychiatric Manifestations". Articles such as case reports, case series, and cohort studies were included as references. No language restrictions were enforced. In the case of anxiety and depression, attempts were made to focus mainly on articles describing these conditions in infected patients. RESULTS: A total of 112 articles were reviewed. The incidence, clinical outcomes, and pathophysiology of selected neurological disorders are discussed below. Given the recent advent of this disease, the incidence of certain neurologic sequelae was not always available. Putative mechanisms for each condition in the setting of COVID-19 are outlined.

Acute ischaemic stroke associated with SARS-CoV-2 infection in North America.

BACKGROUND: To analyse the clinical characteristics of COVID-19 with acute ischaemic stroke (AIS) and identify factors predicting functional outcome. METHODS: Multicentre retrospective cohort study of COVID-19 patients with AIS who presented to 30 stroke centres in the USA and Canada between 14 March and 30 August 2020. The primary endpoint was poor functional outcome, defined as a modified Rankin Scale (mRS) of 5 or 6 at discharge. Secondary endpoints include favourable outcome (mRS ≤2) and mortality at discharge, ordinal mRS (shift analysis), symptomatic intracranial haemorrhage (sICH) and occurrence of in-hospital complications. RESULTS: A total of 216 COVID-19 patients with AIS were included. 68.1% (147/216) were older than 60 years, while 31.9% (69/216) were younger. Median [IQR] National Institutes of Health Stroke Scale (NIHSS) at presentation was 12.5 (15.8), and 44.2% (87/197) presented with large vessel occlusion (LVO). Approximately 51.3% (98/191) of the patients had poor outcomes with an observed mortality rate of 39.1% (81/207). Age >60 years (aOR: 5.11, 95% CI 2.08 to 12.56, p<0.001), diabetes mellitus (aOR: 2.66, 95% CI 1.16 to 6.09, p=0.021), higher NIHSS at admission (aOR: 1.08, 95% CI 1.02 to 1.14, p=0.006), LVO (aOR: 2.45, 95% CI 1.04 to 5.78, p=0.042), and higher NLR level (aOR: 1.06, 95% CI 1.01 to 1.11, p=0.028) were significantly associated with poor functional outcome. CONCLUSION: There is relationship between COVID-19-associated AIS and severe disability or death. We identified several factors which predict worse outcomes, and these outcomes were more frequent compared to global averages. We found that elevated neutrophil-to-lymphocyte ratio, rather than D-Dimer, predicted both morbidity and mortality.

Quadrantanopia as the only symptom of post-COVID stroke in the occipital pole: Case report.

RATIONALE: This is a case report describing delayed complications of COVID-19 pneumonia, which evolved into the vascular-ischemic complications leading to quadrantanopia and MRI findings consistent with recent ischemic event in the occipital pole of the brain. PATIENT CONCERNS: We report a case of a 46-year-old woman with quadrantanopia due to stroke confirmed with brain MRI, secondary to COVID-19 infection with chronically elevated D-dimers and treated with anticoagulation/antithrombotic modalities. Quadrantanopia was the only symptom recognized by the patient of a stroke localized in the occipital pole of the brain. DIAGNOSIS: The patient was diagnosed with quadrantanopia due to stroke confirmed with brain MRI, secondary to COVID-19 infection. INTERVENTION: Patient underwent ophthalmological examination and MRI. OUTCOMES: A thrombotic or ischemic risks in the chronic recovery from COVID-19 should be considered in patients with elevated D-dimers. LESSONS: An MRI should be considered as a long term follow up for post-COVID-19 patients reporting ophthalmic or neurologic complains.

Supra and infratentorial massive strokes in previously healthy young patients with SARS-CoV-2. The role of neurosurgery / Ictus masivos supra e infratentoriales en pacientes jóvenes previamente sanos con SARS-CoV-2. El rol de la neurocirugía

The coronavirus disease 2019 (COVID-19) has amazed by its distinct forms of presentation and severity. COVID-19 patients can develop large-scale ischemic strokes in previously healthy patients without risk factors, especially in patients who develop an acute respiratory distress syndrome (SARS-CoV-2). We hypothesize that ischemic events are usually the result of the combined process of a pro-inflammatory and pro-coagulant state plus vascular endothelial dysfunction probably potentiated by hypoxia, hemodynamic instability, and immobilization, as reported in other cases. To the best of our knowledge, we report the first case of partial obstruction of a vertebral artery in a patient with COVID-19. Decompressive surgery remains a life-saving maneuver in these patients (as in other non-COVID-19 strokes) and requires further investigation (AU)

La enfermedad por coronavirus 2019 (COVID-19) ha sorprendido por sus distintas formas de presentación y gravedad. Los pacientes con COVID-19 pueden desarrollar accidentes cerebrovasculares isquémicos a gran escala, incluso aquellos previamente sanos, sin factores de riesgo, y especialmente los que desarrollan un síndrome de dificultad respiratoria aguda (SARS-CoV-2). Presumimos que los eventos isquémicos son generalmente el resultado del proceso combinado de un estado proinflamatorio y procoagulante, más una posible disfunción endotelial vascular, probablemente potenciada por hipoxia, inestabilidad hemodinámica e inmovilización, como se ha reportado en otros casos. Hasta nuestro conocimiento reportamos el primer caso de una obstrucción parcial de una arteria vertebral en un paciente con COVID-19. La cirugía descompresiva sigue siendo una maniobra que salva vidas (como en otros accidentes cerebrovasculares que no están relacionados con la COVID-19) y requiere más investigación (AU)

Long-term effects of coronavirus disease 2019 on the cardiovascular system, CV COVID registry: A structured summary of a study protocol.

BACKGROUND: Patients presenting with the coronavirus-2019 disease (COVID-19) may have a high risk of cardiovascular adverse events, including death from cardiovascular causes. The long-term cardiovascular outcomes of these patients are entirely unknown. We aim to perform a registry of patients who have undergone a diagnostic nasopharyngeal swab for SARS-CoV-2 and to determine their long-term cardiovascular outcomes. STUDY AND DESIGN: This is a multicenter, observational, retrospective registry to be conducted at 17 centers in Spain and Italy (ClinicalTrials.gov number: NCT04359927). Consecutive patients older than 18 years, who underwent a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV2 in the participating institutions, will be included since March 2020, to August 2020. Patients will be classified into two groups, according to the results of the RT-PCR: COVID-19 positive or negative. The primary outcome will be cardiovascular mortality at 1 year. The secondary outcomes will be acute myocardial infarction, stroke, heart failure hospitalization, pulmonary embolism, and serious cardiac arrhythmias, at 1 year. Outcomes will be compared between the two groups. Events will be adjudicated by an independent clinical event committee. CONCLUSION: The results of this registry will contribute to a better understanding of the long-term cardiovascular implications of the COVID19.

A Review of Neurological Involvement in Patients with SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of the recent pandemic of coronavirus disease 19 (COVID-19). As the infection spreads, there is increasing evidence of neurological and psychiatric involvement in COVID-19. Headache, impaired consciousness, and olfactory and gustatory dysfunctions are common neurological manifestations described in the literature. Studies demonstrating more specific and more severe neurological involvement such as cerebrovascular insults, encephalitis and Guillain-Barre syndrome are also emerging. Respiratory failure, a significant condition that leads to mortality in COVID-19, is hypothesized to be partly due to brainstem impairment. Notably, some of these neurological complications seem to persist long after infection. This review aims to provide an update on what is currently known about neurological involvement in patients with COVID-19 due to SARS-CoV-2 infection. In this review, we demonstrate invasion routes of SARS-CoV-2, provide evidence to support the neurotropism hypothesis of the virus, and investigate the pathological mechanisms that underlie neurological complications associated with SARS-CoV-2.

Bottlenecks in the Acute Stroke Care System during the COVID-19 Pandemic in Catalonia.

INTRODUCTION: The COVID-19 pandemic resulted in significant healthcare reorganizations, potentially striking standard medical care. We investigated the impact of the COVID-19 pandemic on acute stroke care quality and clinical outcomes to detect healthcare system's bottlenecks from a territorial point of view. METHODS: Crossed-data analysis between a prospective nation-based mandatory registry of acute stroke, Emergency Medical System (EMS) records, and daily incidence of COVID-19 in Catalonia (Spain). We included all stroke code activations during the pandemic (March 15-May 2, 2020) and an immediate prepandemic period (January 26-March 14, 2020). Primary outcomes were stroke code activations and reperfusion therapies in both periods. Secondary outcomes included clinical characteristics, workflow metrics, differences across types of stroke centers, correlation analysis between weekly EMS alerts, COVID-19 cases, and workflow metrics, and impact on mortality and clinical outcome at 90 days. RESULTS: Stroke code activations decreased by 22% and reperfusion therapies dropped by 29% during the pandemic period, with no differences in age, stroke severity, or large vessel occlusion. Calls to EMS were handled 42 min later, and time from onset to hospital arrival increased by 53 min, with significant correlations between weekly COVID-19 cases and more EMS calls (rho = 0.81), less stroke code activations (rho = -0.37), and longer prehospital delays (rho = 0.25). Telestroke centers were afflicted with higher reductions in stroke code activations, reperfusion treatments, referrals to endovascular centers, and increased delays to thrombolytics. The independent odds of death increased (OR 1.6 [1.05-2.4], p 0.03) and good functional outcome decreased (mRS ≤2 at 90 days: OR 0.6 [0.4-0.9], p 0.015) during the pandemic period. CONCLUSION: During the COVID-19 pandemic, Catalonia's stroke system's weakest points were the delay to EMS alert and a decline of stroke code activations, reperfusion treatments, and interhospital transfers, mostly at local centers. Patients suffering an acute stroke during the pandemic period had higher odds of poor functional outcome and death. The complete stroke care system's analysis is crucial to allocate resources appropriately.

Management of Stroke During COVID-19 Pandemic: The Challenges in Nepal.

The COVID-19 pandemic has significantly affected health care delivery globally. COVID-19 is associated with varied neurological manifestations including acute ischemic stroke. In densely populated South Asian nations like Nepal that have suboptimal baseline health care systems, we foresee unique challenges during this pandemic to ensure effective stroke management as well as the safety of health care workers involved in the management of stroke patients. Keywords: COVID-19; health care workers; safety; stroke management.

Post-infectious inflammatory syndrome associated with SARS-CoV-2 in a paediatric patient with Down syndrome.

Neurological complications of SARS-CoV-2 continue to be recognised. In children, neurological phenomenon has been reported generally in the acute infectious period. It is possible that SARS-CoV-2 could trigger an immune-mediated post-infectious phenomenon. Here, we present a unique case of post-infectious marantic cardiac lesion causing cerebrovascular accident in a patient with Down syndrome.

The emerging association between COVID-19 and acute stroke.

Prior to COVID-19, only two human-tropic coronaviruses resulted in epidemics and cerebrovascular disease was rarely reported. Evidence now suggests that 1-6% of hospitalized COVID-19 patients develop stroke. According to some reports, stroke risk is more than sevenfold greater in patients with COVID-19 than influenza. Concerningly, outcomes of COVID-19-related stroke are often worse than in stroke patients without COVID-19 from the same cohorts. In this review, we highlight the emerging association between COVID-19 and stroke and discuss putative pathogenetic mechanisms. Etiology of stroke in COVID-19 patients is likely multifactorial, related to coagulopathy, inflammation, platelet activation, and alterations to the vascular endothelium. Significant work remains to be done to better understand the pathogenesis of COVID-19-related stroke and for designing optimal primary and secondary prevention strategies.

Missed cerebrovascular events during prolonged sedation for COVID-19 pneumonia.

Cerebrovascular complications among critically ill patients with COVID-19 have yet to be fully characterized. In this retrospective case series from a single academic tertiary care referral center in New York City, we present 12 patients with ischemic or hemorrhagic strokes that were found on imaging after a period of prolonged sedation in the setting of COVID-19 pneumonia. This series demonstrates a pattern of cerebrovascular events clinically masked by deep sedation required for management of COVID-19 related acute respiratory distress syndrome (ARDS). Of the 12 patients included, 10 had ischemic stroke, 4 of which had hemorrhagic conversion, and 2 had primary intracerebral hemorrhage. Ten patients were on therapeutic anticoagulation prior to discovery of their stroke, and the remainder received intermediate dose anticoagulation (in a range between prophylactic and therapeutic levels). Additional studies are needed to further characterize the counterbalancing risks of ischemic and hemorrhagic stroke, as well as the optimal management of this patient population.

Neurological Manifestation of SARS-CoV-2 Induced Inflammation and Possible Therapeutic Strategies Against COVID-19.

There are regular reports of extrapulmonary infections and manifestations related to the ongoing COVID-19 pandemic. Coronaviruses are potentially neurotropic, which renders neuronal tissue vulnerable to infection, especially in elderly individuals or in those with neuro-comorbid conditions. Complaints of ageusia, anosmia, myalgia, and headache; reports of diseases such as stroke, encephalopathy, seizure, and encephalitis; and loss of consciousness in patients with COVID-19 confirm the neuropathophysiological aspect of this disease. The brain is linked to pulmonary organs, physiologically through blood circulation, and functionally through the nervous system. The interdependence of these vital organs may further aggravate the pathophysiological aspects of COVID-19. The induction of a cytokine storm in systemic circulation can trigger a neuroinflammatory cascade, which can subsequently compromise the blood-brain barrier and activate microglia- and astrocyte-borne Toll-like receptors, thereby leading to neuronal tissue damage. Hence, a holistic approach should be adopted by healthcare professionals while treating COVID-19 patients with a history of neurodegenerative disorders, neuropsychological complications, or any other neuro-compromised conditions. Imperatively, vaccines are being developed at top priority to contain the spread of the severe acute respiratory syndrome coronavirus 2, and different vaccines are at different stages of development globally. This review discusses the concerns regarding the neuronal complications of COVID-19 and the possible mechanisms of amelioration.

CNS implications of COVID-19: a comprehensive review.

COVID-19 was first reported in December 2019 in the Wuhan city of China, and since then it has spread worldwide taking a heavy toll on human life and economy. COVID-19 infection is commonly associated with symptoms like coughing, fever, and shortness of breath, besides, the reports of muscle pain, anosmia, hyposmia, and loss of taste are becoming evident. Recent reports suggest the pathogenic invasion of the SARS-CoV-2 into the CNS, that could thereby result in devastating long term complications, primarily because some of these complications may go unnoticed for a long time. Evidence suggest that the virus could enter the CNS through angiotensin-converting enzyme-2 (ACE-2) receptor, neuronal transport, haematogenous route, and nasal route via olfactory bulb, cribriform plate, and propagates through trans-synaptic signalling, and shows retrograde movement into the CNS along nerve fiber. COVID-19 induces CNS inflammation and neurological degenerative damage through a diverse mechanism which includes ACE-2 receptor damage, cytokine-associated injury or cytokine storm syndrome, secondary hypoxia, demyelination, blood-brain barrier disruption, neurodegeneration, and neuroinflammation. Viral invasion into the CNS has been reported to show association with complications like Parkinsonism, Alzheimer's disorder, meningitis, encephalopathy, anosmia, hyposmia, anxiety, depression, psychiatric symptoms, seizures, stroke, etc. This review provides a detailed discussion of the CNS pathogenesis of COVID-19. Authors conclude that the COVID-19 cannot just be considered as a disorder of the pulmonary or peripheral system, rather it has a significant CNS involvement. Therefore, CNS aspects of the COVID-19 should be monitored very closely to prevent long term CNS complications, even after the patient has recovered from COVID-19.

Acute confusional state as a prognostic sign of COVID-19 large-vessel occlusion (LVO).

COVID-19 is well known for its respiratory symptoms, but severe presentations can alter haemostasis, causing acute end-organ damage with poor outcomes. Among its various neurological presentations, cerebrovascular events often present as small-vessel strokes. Although uncommon, in predisposed individuals, large-vessel occlusions (LVOs) can occur as a possible consequence of direct viral action (viral burden or antigenic structure) or virus-induced cytokine storm. Subtle presentations and complicated stroke care pathways continue to exist, delaying timely care. We present a unique case of COVID-19 LVO manifesting as an acute confusional state in an elderly man in April 2020. CT angiography revealed 'de novo' occlusions of the left internal carotid artery and proximal right vertebral artery, effectively blocking anterior and posterior circulations. Delirium can lead to inaccurate stroke scale assessments and prolong initiation of COVID-19 stroke care pathways. Future studies are needed to look into the temporal relationship between confusion and neurological manifestations.

Decline and Recurrence of Stroke Consultations during the COVID-19 Pandemic Lockdown Parallels Population Activity Levels.

BACKGROUND: The COVID-19 pandemic lockdown (CPL) lead to a significant decrease in emergency admissions worldwide. We performed a timely analysis of ischemic stroke (IS) and related consultations using the telestroke TEMPiS "working diagnosis" database prior (PL), within (WL), and after easing (EL) of CPL. METHODS: Twelve hospitals were selected and data analyzed regarding IS (including intravenous thrombolysis [intravenous recombinant tissue plasminogen; IV rtPA] and endovascular thrombectomy [EVT]) and related events from February 1 to June 15 during 2017-2020. In addition, we aimed to correlate events to various mobile phone mobility data. RESULTS: Following the significant reduction of IS, IV rtPA, and EVT cases during WL compared to PL in 2020 longitudinally (p values <0.048), we observed increasing numbers of consultations, IS, recommendations for EVT, and IV rtPA with the network in EL over WL not reaching PL levels yet. Absolute numbers of all consultations paralleled best to mobility data of public transportation over walking and driving mobility. CONCLUSIONS: While the decrease in emergency admissions including stroke during CPL can only be in part attributed by patients not seeking medical attention, stroke awareness in the pandemic, and direct COVID-19 triggered stroke remains of high importance. The number of consultations in TEMPiS during the lockdown parallels best with mobility of public transportation. As a consequence, exposure to common viruses, well-known triggers for acute cerebrovascular events and other diseases, are reduced and may add to the decline in stroke consultations. Further studies comparing national responses toward the course of the COVID-19 pandemic and stroke incidences are needed.

Potential mechanisms of cerebrovascular diseases in COVID-19 patients.

Since the outbreak of coronavirus disease 2019 (COVID-19) in 2019, it is gaining worldwide attention at the moment. Apart from respiratory manifestations, neurological dysfunction in COVID-19 patients, especially the occurrence of cerebrovascular diseases (CVD), has been intensively investigated. In this review, the effects of COVID-19 infection on CVD were summarized as follows: (I) angiotensin-converting enzyme 2 (ACE2) may be involved in the attack on vascular endothelial cells by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), leading to endothelial damage and increased subintimal inflammation, which are followed by hemorrhage or thrombosis; (II) SARS-CoV-2 could alter the expression/activity of ACE2, consequently resulting in the disruption of renin-angiotensin system which is associated with the occurrence and progression of atherosclerosis; (III) upregulation of neutrophil extracellular traps has been detected in COVID-19 patients, which is closely associated with immunothrombosis; (IV) the inflammatory cascade induced by SARS-CoV-2 often leads to hypercoagulability and promotes the formation and progress of atherosclerosis; (V) antiphospholipid antibodies are also detected in plasma of some severe cases, which aggravate the thrombosis through the formation of immune complexes; (VI) hyperglycemia in COVID-19 patients may trigger CVD by increasing oxidative stress and blood viscosity; (VII) the COVID-19 outbreak is a global emergency and causes psychological stress, which could be a potential risk factor of CVD as coagulation, and fibrinolysis may be affected. In this review, we aimed to further our understanding of CVD-associated COVID-19 infection, which could improve the therapeutic outcomes of patients. Personalized treatments should be offered to COVID-19 patients at greater risk for stroke in future clinical practice.