A case-based systematic review on the SARS-COVID-2-associated cerebrovascular diseases and the possible virus routes of entry.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sparked a global pandemic that continues to affect various facets of human existence. Many sources reported virus-induced acute cerebrovascular disorders. Systematically, this paper reviews the case studies of COVID-19-related acute cerebrovascular diseases such as ischaemic stroke, intracerebral hemorrhage, and cerebral sinus thrombosis. We also spoke about how SARS-CoV-2 can infect the brain and trigger the aforementioned disorders. We stated that SARS-CoV-2 neuroinvasion and BBB dysfunction could cause the observed disorders; however, further research is required to specify the mechanisms and pathogenesis of the virus.

Cytokine storm induced by SARS-CoV-2 infection: The spectrum of its neurological manifestations.

The new coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can trigger a hyperinflammatory state characterized by elevated cytokine levels known as hypercytokinemia or cytokine storm, observed most often in severe patients. Though COVID-19 is known to be a primarily respiratory disease, neurological complications affecting both the central and peripheral nervous systems have also been reported. This review discusses potential routes of SARS-CoV-2 neuroinvasion and pathogenesis, summarizes reported neurological sequelae of COVID-19, and examines how aberrant cytokine levels may precipitate these complications. Clarification of the pathogenic mechanisms of SARS-CoV-2 is needed to encourage prompt diagnosis and optimized care. In particular, identifying the presence of cytokine storm in patients with neurological COVID-19 manifestations will facilitate avenues for treatment. Future investigations into aberrant cytokine levels in COVID-19 patients with neurological symptoms as well as the efficacy of cytokine storm-targeting treatments will be critical in elucidating the pathogenic mechanisms and effective treatments of COVID-19.

Assessment of cerebrovascular disease with computed tomography in COVID-19 patients: correlation of a novel specific visual score with increased mortality risk.

PURPOSE: Cerebrovascular disease (CVD) is considered a major risk factor for fatal outcome in COVID-19. We aimed to evaluate the possible association between computed tomography (CT) signs of chronic CVD and mortality in infected patients. MATERIALS AND METHODS: We performed a double-blind retrospective evaluation of the cerebral CT scans of 83 COVID-19 patients looking for CT signs of chronic CVD. We developed a rapid visual score, named CVD-CT, which summarized the possible presence of parietal calcifications and dolichosis, with or without ectasia, of intracranial arteries, areas of chronic infarction and leukoaraiosis. Statistical analysis was carried out with weighted Cohen's K test for inter-reader agreement and logistic regression to evaluate the association of in-hospital mortality with CVD-CT, chest X-ray (CXR) severity score (Radiographic Assessment of Lung Edema-RALE) for radiological assessment of pulmonary disease, sex and age. RESULTS: CVD-CT (odds ratio 1.6, 95% C.I. 1.2-2.1, p = 0.001) was associated with increased risk of mortality. RALE showed an almost significant association (odds ratio 1.05, 95% C.I. 1-1.1, p 0.06), whereas age and sex did not. CONCLUSION: CVD-CT is associated with risk of mortality in COVID-19 patients. The presence of CT signs of chronic CVD may be correlated to a condition of fragility of the circulatory system, which constitutes a key risk factor for death in infected patients.

Neurological Complications of COVID-19: Underlying Mechanisms and Management.

COVID-19 is a severe respiratory disease caused by the newly identified human coronavirus (HCoV) Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The virus was discovered in December 2019, and in March 2020, the disease was declared a global pandemic by the World Health Organization (WHO) due to a high number of cases. Although SARS-CoV-2 primarily affects the respiratory system, several studies have reported neurological complications in COVID-19 patients. Headache, dizziness, loss of taste and smell, encephalitis, encephalopathy, and cerebrovascular diseases are the most common neurological complications that are associated with COVID-19. In addition, seizures, neuromuscular junctions' disorders, and Guillain-Barré syndrome were reported as complications of COVID-19, as well as neurodegenerative and demyelinating disorders. However, the management of these conditions remains a challenge. In this review, we discuss the prevalence, pathogenesis, and mechanisms of these neurological sequelae that are secondary to SARS-CoV-2 infection. We aim to update neurologists and healthcare workers on the possible neurological complications associated with COVID-19 and the management of these disease conditions.

Update on cerebrovascular manifestations of COVID-19.

The novel member of coronaviruses family, severe acute respiratory coronavirus-2 (SARS-CoV-2), with high structural homology to SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS) has spread rapidly with about 20 million cases infection and over 700,000 deaths. SARS-CoV-2 has been emerged as a worldwide disaster due to non-specific few respiratory and gastrointestinal manifestations at the onset of disease as well as long incubation period. Surprisingly, not only respiratory failure but also the underlying coagulation disorder and neurovascular involvement worsen the clinical outcome of infected patients. In this review article, we describe the probable mechanisms of SARS-CoV-2 infection and stroke occurrence. We will also discuss the cerebrovascular events following SARS-CoV-2 infection, the recommended therapies, and future prospects to better manage these patients in coronavirus disease 2019 (COVID-19) outbreak.

The neurological manifestations of COVID-19: a review article.

RESULTS: Various neurological manifestations have been reported in the literature associated with COVID-19, which in the current study are classified into Central Nervous System (CNS) related manifestations including headache, dizziness, impaired consciousness, acute cerebrovascular disease, epilepsy, and Peripheral Nervous System (PNS) related manifestations such as hyposmia/anosmia, hypogeusia/ageusia, muscle pain, and Guillain-Barre syndrome. CONCLUSION: During the current context of COVID-19 pandemic, physicians should be aware of wide spectrum of neurological COVID-19 sign and symptoms for early diagnosis and isolation of patients. In this regard, COVID-19 has been associated with many neurological manifestations such as confusion, anosmia, and ageusia. Also, various evidences support the possible CNS roles in the COVID-19 pathophysiology. In this regard, further investigation of CNS involvement of SARS-COV-2 is suggested.

[COVID-19: neurological manifestations : What we know so far]. / COVID-19: neurologische Manifestationen : Was wir bisher wissen.

Shortly after the beginning of the global COVID-19 pandemic there was also an increasing number of reports of neurological complications in infected patients. Many case reports and case series described associated diseases of the central and peripheral nervous systems and cerebrovascular complications. This review article provides a short overview of the currently confusing picture of recent findings.

Impact of cerebrovascular and cardiovascular diseases on mortality and severity of COVID-19-systematic review, meta-analysis, and meta-regression.

BACKGROUND: We conducted a systematic review and meta-analysis to evaluate the latest evidence on the association between cerebrovascular, and cardiovascular diseases and poor outcome in patients with Coronavirus Disease 2019 (COVID-19) pneumonia. METHODS: A comprehensive systematic literature search was performed using PubMed, SCOPUS, EuropePMC, and Cochrane Central Database. The outcome of interest was composite poor outcome that comprised of mortality and severe COVID-19. RESULTS: A total of 4448 patients were obtained from 16 studies. Cerebrovascular disease was associated with an increased composite poor outcome (RR 2.04 [1.43,2.91], p<0.001; I2: 77%). Subgroup analysis revealed that cerebrovascular disease was associated with mortality (RR 2.38 [1.92,2.96], p<0.001; I2: 0%) and showed borderline significance for severe COVID-19 (RR 1.88 [1.00,3.51], p = 0.05; I2: 87%). Cardiovascular disease was associated with increased composite poor outcome (RR 2.23 [1.71,2.91], p<0.001; I2: 60%), mortality (RR 2.25 [1.53,3.29], p<0.001; I2: 33%) and severe COVID-19 (RR 2.25 [1.51,3.36], p<0.001; I2: 76%). Meta-regression demonstrate that the association was not influenced by gender, age, hypertension, diabetes, and respiratory comorbidities. Furthermore, the association between cerebrovascular disease and poor outcome was not affected by cardiovascular diseases and vice versa. CONCLUSION: Cerebrovascular and cardiovascular diseases were associated with an increased risk for poor outcome in patients with COVID-19.

Cerebrovascular manifestations of herpes simplex virus infection of the central nervous system: a systematic review.

BACKGROUND: Intracerebral hemorrhage and ischemic stroke are increasingly recognized complications of central nervous system (CNS) infection by herpes simplex virus (HSV). AIM OF THE STUDY: To analyze clinical, imaging, and laboratory findings and outcomes of cerebrovascular manifestations of HSV infection. METHODS: Systematic literature review from January 2000 to July 2018. RESULTS: We identified 38 patients (median age 45 years, range 1-73) comprising 27 cases of intracerebral hemorrhage, 10 of ischemic stroke, and 1 with cerebral venous sinus thrombosis. Intracerebral hemorrhage was predominantly (89%) a complication of HSV encephalitis located in the temporal lobe. Hematoma was present on the first brain imaging in 32%, and hematoma evacuation was performed in 30% of these cases. Infarction was frequently multifocal, and at times preceded by hemorrhage (20%). Both a stroke-like presentation and presence of HSV encephalitis in a typical location were rare (25% and 10%, respectively). There was evidence of cerebral vasculitis in 63%, which was exclusively located in large-sized vessels. Overall mortality was 21% for hemorrhage and 0% for infarction. HSV-1 was a major cause of hemorrhagic complications, whereas HSV-2 was the most prevalent agent in the ischemic manifestations. CONCLUSION: We found a distinct pathogenesis, cause, and outcome for HSV-related cerebral hemorrhage and infarction. Vessel disruption within a temporal lobe lesion caused by HSV-1 is the presumed mechanism for hemorrhage, which may potentially have a fatal outcome. Brain ischemia is mostly related to multifocal cerebral large vessel vasculitis associated with HSV-2, where the outcome is more favorable.

Cerebrovascular events after herpes zoster infection: a risk that should be not underestimated.

The occurrence of a cerebrovascular event after a herpes zoster (HZ) infection represents a nightmare in clinical practice, especially in those patients with concomitant cardiovascular comorbidities/risk factors and disease related per se to a higher risk of zoster infection. Moreover, the absence of a consensus opinion regarding a specific and adequate prevention of cerebrovascular events in these patients further complicates the treatment. Accumulating evidences demonstrated that HZ and HZ ophtalmicus (HZO) increase the risk of cerebrovascular events in the short-and long-term periods. Moreover, patient's ages < 40 years old, despite having fewer traditional cardiovascular comorbidities, demonstrated a higher risk of cerebrovascular events after both HZ and HZO infection. Further prospective studies are needed to analyse the role of antiviral treatments and vaccination in these subjects to clarify if they could be able to reduce the risk of stroke after a zoster infection. In the meanwhile, physicians must be aware of a higher risk of cerebrovascular events, especially in younger patients, with few cardiovascular risk factors, after an HZ infection.

Targeted RNA Sequencing of VZV-Infected Brain Vascular Adventitial Fibroblasts Indicates That Amyloid May Be Involved in VZV Vasculopathy.

BACKGROUND AND OBJECTIVES: Compared with stroke controls, patients with varicella zoster virus (VZV) vasculopathy have increased amyloid in CSF, along with increased amylin (islet amyloid polypeptide [IAPP]) and anti-VZV antibodies. Thus, we examined the gene expression profiles of VZV-infected primary human brain vascular adventitial fibroblasts (HBVAFs), one of the initial arterial cells infected in VZV vasculopathy, to determine whether they are a potential source of amyloid that can disrupt vasculature and potentiate inflammation. METHODS: Mock- and VZV-infected quiescent HBVAFs were harvested at 3 days postinfection. Targeted RNA sequencing of the whole-human transcriptome (BioSpyder Technologies, TempO-Seq) was conducted followed by gene set enrichment and pathway analysis. Selected pathways unique to VZV-infected cells were confirmed by enzyme-linked immunoassays, migration assays, and immunofluorescence analysis (IFA) that included antibodies against amylin and amyloid-beta, as well as amyloid staining by Thioflavin-T. RESULTS: Compared with mock, VZV-infected HBVAFs had significantly enriched gene expression pathways involved in vascular remodeling and vascular diseases; confirmatory studies showed secretion of matrix metalloproteinase-3 and -10, as well increased migration of infected cells and uninfected cells when exposed to conditioned media from VZV-infected cells. In addition, significantly enriched pathways involved in amyloid-associated diseases (diabetes mellitus, amyloidosis, and Alzheimer disease), tauopathy, and progressive neurologic disorder were identified; predicted upstream regulators included amyloid precursor protein, apolipoprotein E, microtubule-associated protein tau, presenilin 1, and IAPP. Confirmatory IFA showed that VZV-infected HBVAFs contained amyloidogenic peptides (amyloid-beta and amylin) and intracellular amyloid. DISCUSSION: Gene expression profiles and pathway enrichment analysis of VZV-infected HBVAFs, as well as phenotypic studies, reveal features of pathologic vascular remodeling (e.g., increased cell migration and changes in the extracellular matrix) that can contribute to cerebrovascular disease. Furthermore, the discovery of amyloid-associated transcriptional pathways and intracellular amyloid deposition in HBVAFs raise the possibility that VZV vasculopathy is an amyloid disease. Amyloid deposition may contribute to cell death and loss of vascular wall integrity, as well as potentiate chronic inflammation in VZV vasculopathy, with disease severity and recurrence determined by the host's ability to clear virus infection and amyloid deposition and by the coexistence of other amyloid-associated diseases (i.e., Alzheimer disease and diabetes mellitus).

Reversible Cerebral Vasoconstriction Syndrome and Multisystem Inflammatory Syndrome in Children With COVID-19.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) involves multiple organs and shows increased inflammatory markers. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, several studies have reported the association between severe COVID-19 and MIS-C. Reversible cerebral vasoconstriction syndrome (RCVS) presents with thunderclap headaches and multifocal reversible vasoconstriction on imaging. RCVS is very rare in children. This article reports two cases of pediatric COVID-19 with severe MIS-C and clinical and imaging features indicative of RCVS. METHODS: Clinical, laboratory, and imaging data of the patients were reviewed. The diagnosis of RCVS was confirmed based on clinical symptomatology and brain magnetic resonance imaging findings. RESULTS: Two pediatric patients with clinical findings compatible with severe MIS-C and hemodynamic compromise presented to the hospital. During their hospitalization course, they developed thunderclap headaches and neurological deficits. Both were receiving vasoactive agents, intravenous immunoglobulin, and immunosuppressants. Imaging studies showed marked multifocal cerebral vasoconstriction in both cases and infarcts in one. The course and management of the patients will be presented. After controlling inflammation and elimination of triggers, both patients were ultimately symptom free upon discharge. Cerebral vasoconstriction had completely resolved on follow-up imaging. CONCLUSIONS: Although a variety of symptoms including headaches may be seen in pediatric COVID-19 patients with MIS-C, RCVS should be considered as a differential diagnosis in cases of thunderclap headache accompanied by neurological signs in these patients. Imaging findings and follow-up are also key in establishing the diagnosis.

[Metabolic and cardiovascular effects of combined antiretroviral therapy in patients with HIV infection. Systematic review of literature]. / Effetti metabolici e cardiovascolari della terapia antiretrovirale combinata in pazienti con infezione da HIV. Rassegna sistematica della letteratura.

In HIV infected patients an increased incidence of cardiac events has been reported since the introduction of highly active antiretroviral therapy (HAART). Antiretroviral drugs' regimens are, in fact, associated with several metabolic side effects, such as dyslipidemia, impaired glucose metabolism and abnormal body fat distribution, that increase cardiovascular risk of HIV subjects. In addition, HIV infection itself, the chronic inflammatory status and the frequent presence in this population of traditional risk factors contribute to an higher incidence of cardio and cerebrovascular events. In last years several studies showed the occurrence of carotid vascular impairment in patients treated with protease inhibitors (PI). Similarly the DAD Study reported an increase of 26% of the risk of myocardial infarction in patients on HAART and that this risk was independently associated with longer exposure to PI, after multivariate adjustments. A correct evaluation of the metabolic status before starting HAART and an adequate control of drugs-related metabolic abnormalities may reduce the incidence of cardiac events and still improve HIV patients prognosis. This review will focus on the metabolic effects of antiretroviral drugs and on the contribution of combination antiretroviral therapy on cardiovascular risk.

The impact of the COVID-19 pandemic on cerebrovascular disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a systemic disease that affects nearly all organ systems through infection and subsequent dysregulation of the vascular endothelium. One of the most striking phenomena has been a coronavirus disease 2019 (COVID-19)-associated coagulopathy. Given these findings, questions naturally emerged about the prothrombotic impact of COVID-19 on cerebrovascular disease and whether ischemic stroke is a clinical feature specific to COVID-19 pathophysiology. Early reports from China and several sites in the northeastern United States seemed to confirm these suspicions. Since these initial reports, many cohort studies worldwide observed decreased rates of stroke since the start of the pandemic, raising concerns for a broader impact of the pandemic on stroke treatment. In this review, we provide a comprehensive assessment of how the pandemic has affected stroke presentation, epidemiology, treatment, and outcomes to better understand the impact of COVID-19 on cerebrovascular disease. Much evidence suggests that this decline in stroke admissions stems from the global response to the virus, which has made it more difficult for patients to get to the hospital once symptoms start. However, there does not appear to be a demonstrable impact on quality metrics once patients arrive at the hospital. Despite initial concerns, there is insufficient evidence to ascribe a causal relationship specific to the pathogenicity of SARS-CoV-2 on the cerebral vasculature. Nevertheless, when patients infected with SARS-CoV-2 present with stroke, their presentation is likely to be more severe, and they have a markedly higher rate of in-hospital mortality than patients with either acute ischemic stroke or COVID-19 alone.

Can we predict the severe course of COVID-19 - a systematic review and meta-analysis of indicators of clinical outcome?

BACKGROUND: COVID-19 has been reported in over 40million people globally with variable clinical outcomes. In this systematic review and meta-analysis, we assessed demographic, laboratory and clinical indicators as predictors for severe courses of COVID-19. METHODS: This systematic review was registered at PROSPERO under CRD42020177154. We systematically searched multiple databases (PubMed, Web of Science Core Collection, MedRvix and bioRvix) for publications from December 2019 to May 31st 2020. Random-effects meta-analyses were used to calculate pooled odds ratios and differences of medians between (1) patients admitted to ICU versus non-ICU patients and (2) patients who died versus those who survived. We adapted an existing Cochrane risk-of-bias assessment tool for outcome studies. RESULTS: Of 6,702 unique citations, we included 88 articles with 69,762 patients. There was concern for bias across all articles included. Age was strongly associated with mortality with a difference of medians (DoM) of 13.15 years (95% confidence interval (CI) 11.37 to 14.94) between those who died and those who survived. We found a clinically relevant difference between non-survivors and survivors for C-reactive protein (CRP; DoM 69.10 mg/L, CI 50.43 to 87.77), lactate dehydrogenase (LDH; DoM 189.49 U/L, CI 155.00 to 223.98), cardiac troponin I (cTnI; DoM 21.88 pg/mL, CI 9.78 to 33.99) and D-Dimer (DoM 1.29mg/L, CI 0.9 to 1.69). Furthermore, cerebrovascular disease was the co-morbidity most strongly associated with mortality (Odds Ratio 3.45, CI 2.42 to 4.91) and ICU admission (Odds Ratio 5.88, CI 2.35 to 14.73). DISCUSSION: This comprehensive meta-analysis found age, cerebrovascular disease, CRP, LDH and cTnI to be the most important risk-factors that predict severe COVID-19 outcomes and will inform clinical scores to support early decision-making.

Cerebrovascular comorbidity, high blood levels of C-reactive protein and D-dimer are associated with disease outcomes in COVID-19 patients.

The emerging coronavirus disease (COVID-19) swept the world, affecting more than 200 countries and territories. As of August 22, 2020, the pandemic infected more than 23,329,752 including 807,054 patients who have died. Although the main clinical features of the pandemic disease are respiratory, cerebrovascular comorbidities emerged as one of the leading causes of death associated with COVID-19. Different case reports have indicated that C-reactive protein (CRP) and D-dimer (pro-inflammatory biomarkers) were elevated in COVID-19 patients, which can significantly increase the risk of ischemic stroke. Available data on cerebrovascular complications in COVID-19 patients were collected and a meta-analysis was designed and carried out to evaluate the risk of severity and mortality associated with high levels of CRP and D-dimer levels in COVID-19 patients. In addition, we aimed to describe the overall event rate of pre-existing cerebrovascular disease in COVID-19 patients. In our analysis, 5,614 cases have been studied, out of these patients 164 cases have developed cerebrovascular comorbities. Cerebrovascular comorbidity increased the risk of disease severity (odd ratio = 4.4; 95% CI: 1.48 to 12.84) and mortality (odd ratio = 7.0; 95% CI: 2.56 to 18.99). Statistical analyses showed that CRP and D-dimer serum levels were elevated by six-folds in the severe cases of COVID-19 patients. This significant increase in these two proteins levels can serve as a vital indicator for COVID-19 patients who are at increased risk of severe COVID-19 cerebrovascular complications, such as stroke.

[Vaccinoprophylaxis of chronic somatic diseases exacerbations in groups of risk].

Modem version of I. Mechnikov's hypothesis on association of somatic diseases with infectious agents is presented. List of bacteria and viruses associated with various types of cardiomyopathies, atherosclerosis, gastritis, gastric and duodenal ulcerative disease, type 1 diabetes mellitus. Literature data showing that influenza vaccination reduces number of fatal myocardial infarctions and strokes during winter seasons as well as number of hospitalizations due to exacerbations of chronic cardiovascular and cerebrovascular diseases are summarized. Data on probability of coincidence of influenza vaccination and sudden death in elderly persons are reviewed.