Neurologic manifestations of COVID-19 in critically ill patients: results of the prospective multicenter registry PANDEMIC.

BACKGROUND: Neurologic manifestations are increasingly reported in patients with coronavirus disease 2019 (COVID-19). Yet, data on prevalence, predictors and relevance for outcome of neurological manifestations in patients requiring intensive care are scarce. We aimed to characterize prevalence, risk factors and impact on outcome of neurologic manifestations in critically ill COVID-19 patients. METHODS: In the prospective, multicenter, observational registry study PANDEMIC (Pooled Analysis of Neurologic DisordErs Manifesting in Intensive care of COVID-19), we enrolled COVID-19 patients with neurologic manifestations admitted to 19 German intensive care units (ICU) between April 2020 and September 2021. We performed descriptive and explorative statistical analyses. Multivariable models were used to investigate factors associated with disorder categories and their underlying diagnoses as well as to identify predictors of outcome. RESULTS: Of the 392 patients included in the analysis, 70.7% (277/392) were male and the mean age was 65.3 (SD ± 3.1) years. During the study period, a total of 2681 patients with COVID-19 were treated at the ICUs of 15 participating centers. New neurologic disorders were identified in 350 patients, reported by these centers, suggesting a prevalence of COVID-19-associated neurologic disorders of 12.7% among COVID-19 ICU patients. Encephalopathy (46.2%; 181/392), cerebrovascular (41.0%; 161/392) and neuromuscular disorders (20.4%; 80/392) were the most frequent categories identified. Out of 35 cerebrospinal fluid analyses with reverse transcriptase PCR for SARS-COV-2, only 3 were positive. In-hospital mortality was 36.0% (140/389), and functional outcome (mRS 3 to 5) of surviving patients was poor at hospital discharge in 70.9% (161/227). Intracerebral hemorrhage (OR 6.2, 95% CI 2.5-14.9, p < 0.001) and acute ischemic stroke (OR 3.9, 95% CI 1.9-8.2, p < 0.001) were the strongest predictors of poor outcome among the included patients. CONCLUSIONS: Based on this well-characterized COVID-19 ICU cohort, that comprised 12.7% of all severe ill COVID-19 patients, neurologic manifestations increase mortality and morbidity. Since no reliable evidence of direct viral affection of the nervous system by COVID-19 could be found, these neurologic manifestations may for a great part be indirect para- or postinfectious sequelae of the infection or severe critical illness. Neurologic ICU complications should be actively searched for and treated.

COVID-19 and Risk of Acute Ischemic Stroke Among Medicare Beneficiaries Aged 65 Years or Older: Self-Controlled Case Series Study.

BACKGROUND AND OBJECTIVES: Findings of association between coronavirus disease 2019 (COVID-19) and stroke remain inconsistent, ranging from significant association to absence of association to less than expected ischemic stroke among hospitalized patients with COVID-19. The current study examined the association between COVID-19 and risk of acute ischemic stroke (AIS). METHODS: We included 37,379 Medicare fee-for-service (FFS) beneficiaries aged ≥65 years diagnosed with COVID-19 from April 1, 2020, through February 28, 2021, and AIS hospitalization from January 1, 2019, through February 28, 2021. We used a self-controlled case series design to examine the association between COVID-19 and AIS and estimated the incidence rate ratios (IRRs) by comparing incidence of AIS in risk periods (0-3, 4-7, 8-14, 15-28 days after diagnosis of COVID-19) vs control periods. RESULTS: Among 37,379 Medicare FFS beneficiaries with COVID-19 and AIS, the median age at diagnosis of COVID-19 was 80.4 (interquartile range 73.5-87.1) years and 56.7% were women. When AIS at day of exposure (day = 0) was included in the risk periods, IRRs at 0-3, 4-7, 8-14, and 15-28 days following COVID-19 diagnosis were 10.3 (95% confidence interval 9.86-10.8), 1.61 (1.44-1.80), 1.44 (1.32-1.57), and 1.09 (1.02-1.18); when AIS at day 0 was excluded in the risk periods, the corresponding IRRs were 1.77 (1.57-2.01) (day 1-3), 1.60 (1.43-1.79), 1.43 (1.31-1.56), and 1.09 (1.01-1.17), respectively. The association appeared to be stronger among younger beneficiaries and among beneficiaries without prior history of stroke but largely consistent across sex and race/ethnicities. DISCUSSION: Risk of AIS among Medicare FFS beneficiaries was 10 times (day 0 cases in the risk period) as high during the first 3 days after diagnosis of COVID-19 as during the control period and the risk associated with COVID-19 appeared to be stronger among those aged 65-74 years and those without prior history of stroke. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with increased risk of AIS in the first 3 days after diagnosis in Medicare FFS beneficiaries ≥65 years of age.

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.

Acute Large Vessel Ischemic Stroke in Patients With COVID-19-Related Multisystem Inflammatory Syndrome.

BACKGROUND: Acute ischemic stroke (AIS) is rare in children, and diagnosis is often delayed. Neurological involvement may occur in multisystem inflammatory syndrome in children (MIS-C), but very few cases of AIS in patients with MIS-C have been reported. PATIENT DESCRIPTIONS: We two patients with AIS presenting with large vessel occlusive disease in previously healthy adolescents recently exposed to SARS-CoV-2 infection. RESULTS: Both patients were subsequently diagnosed with and treated for MIS-C. Here, we discuss the course of their treatments and clinical responses. CONCLUSION: Early recognition and diagnosis of AIS with large vessel occlusion in children with MIS-C is critical to make available all treatment options to improve clinical outcomes.

Leveraging Genetic Data to Elucidate the Relationship Between COVID-19 and Ischemic Stroke.

Background The relationship between COVID-19 and ischemic stroke is poorly understood due to potential unmeasured confounding and reverse causation. We aimed to leverage genetic data to triangulate reported associations. Methods and Results Analyses primarily focused on critical COVID-19, defined as hospitalization with COVID-19 requiring respiratory support or resulting in death. Cross-trait linkage disequilibrium score regression was used to estimate genetic correlations of critical COVID-19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both COVID-19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C-reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical COVID-19 was associated with increased risk of any cardiovascular outcome for which genetic correlation was identified. There was evidence of genetic correlation between critical COVID-19 and ischemic stroke (rg=0.29, false discovery rate [FDR]=0.012), body mass index (rg=0.21, FDR=0.00002), and C-reactive protein (rg=0.20, FDR=0.00035), but no other trait investigated. In Mendelian randomization, liability to critical COVID-19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical COVID-19 liability 1.03, 95% CI 1.00-1.06, P-value=0.03). Similar estimates were obtained for ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking, and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical COVID-19. Conclusions These data support that liability to critical COVID-19 is associated with an increased risk of ischemic stroke. The host response predisposing to severe COVID-19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors.

Case Report: Dengue Hemorrhagic Fever with Ischemic Stroke.

Several neurological manifestations are recognized in dengue infection, but stroke is a rare complication. We report a case of ischemic stroke in a patient with dengue hemorrhagic fever. A 52-year-old previously healthy male presented with a history of fever for 2 days, and left-sided weakness and numbness of sudden onset. MRI scanning showed a right-sided thalamic lacunar infarct. Diagnosis of dengue fever was made based on leuco-thrombocytopenia, positive dengue nonstructural protein-1 (NS-1) antigen, and positive dengue IgM antibodies. Severity of limb weakness correlated with the critical phase of dengue hemorrhagic fever (DHF). He was discharged home with good recovery from neurological symptoms and disability. Strokes are rare in dengue, and are mainly hemorrhagic strokes related to thrombocytopenia. Ischemic stroke is even rarer. More evidence is needed for confirmation of dengue as a pathogenic mechanism of ischemic stroke.

Massive Ischemic Strokes in a Young Patient With Severe Coronavirus Disease 2019 Pneumonia.

Stroke is an identified sequela of severe coronavirus disease 2019 (COVID-19) infection. While the pathophysiology remains poorly understood, endothelial dysfunction and intravascular thrombosis secondary to sepsis-induced hypercoagulability likely increase the risk of stroke. This report describes the rare case of an otherwise healthy 42-year-old male who developed large bilateral ischemic infarcts during admission for severe hypoxemic respiratory failure secondary to COVID pneumonia. This report adds to scarce literature describing massive cerebrovascular injury in COVID patients and emphasizes the importance of increased clinical suspicion for stroke in patients who exhibit acute change in mental status or motor function, as well as rapid clinical deterioration.

Concomitant acute limb ischemia and multiple acute ischemic strokes complicating COVID-19: a case report.

Since the spread of the coronavirus disease 2019 (COVID-19) pandemic, cardiovascular complications are interestingly increasing, particularly thrombotic events, especially in those requiring intensive care. Venous thromboembolism is well known to occur in patients infected by the SARS-CoV-2, but only a few arterial thromboembolism cases have been previously reported. Herein, we report the case of a COVID-19 complicated by a concomitant acute right limb ischemia and multiple acute ischemic strokes. This rare case emphasizes the hypercoagulable state described in COVID-19 patients and the need for anticoagulation therapy to prevent these severe complications.

[A case of cerebral embolism with Coronavirus disease 2019].

A 63-year-old man, who had persistent fever for a month, was admitted to the hospital with sudden left arm palsy with a National Institutes of Health Stroke Scale score of 3. Consequently, brain MRI showed hyperintensity of the bilateral occipital, right parietal, and right frontal lobes on diffusion-weighted imaging. Moreover, FLAIR presented hyperintensity of the left occipital lobe. Magnetic resonance angiography detected the deficit of the blood-flow signal of the horizontal segment of the middle cerebral artery. He was diagnosed with acute ischemic stroke. In addition, chest CT showed ground-glass opacities, and test to detect SARS-CoV-2 was positive. Cerebral embolism was suspected. However, the source was unknown. His ischemic stroke was possibly associated with coagulation abnormality caused by coronavirus disease 2019.

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.

Ischemic Cerebellar Stroke in a 4-Year-Old Boy After Chickenpox: An Atypical Vascular Involvement.

Cerebrovascular events in pediatric population are very rare. Up to 30% may result from varicella zoster (VZV) arteriopathy, usually as a delayed complication of varicella primary infection. The most typical pattern includes involvement of anterior brain circulation arteries, probably by VZV migration from the trigeminal ganglia. Strokes related with VZV usually have a good prognosis, but risk of recurrence is greater when compared to other stroke etiologies in this age group. We report the case of a 4-year-old boy, immunocompetent, who presented a basilar artery stenosis and a cerebellar stroke, an extremely rare presentation of VZV arteriopathy. The investigation workup and treatment are detailed, as the clinical and imaging follow-up after one year.

The Role of Anticoagulation in Post-COVID-19 Concomitant Stroke, Myocardial Infarction, and Left Ventricular Thrombus: A Case Report.

BACKGROUND Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily affects the lungs but can involve any organ. The medical community is struggling to cope with the critical illness associated with the disease. On top of that, patients who have recovered from COVID-19 have presented with complications such as thrombotic episodes in various organs both during and after being infected with SARS-CoV-2. A COVID-19-associated prothrombotic state has been mentioned in multiple recent research articles. The role of anticoagulants is debatable, because even after receiving them prophylactically, many patients have experienced thrombotic episodes. The situation, therefore, represents a challenge to the medical community. CASE REPORT We report on a COVID-19-associated prothrombotic state in a 65-year-old man with no history of comorbid illness. Initially, he presented with right-sided weakness and was found to have had an acute ischemic stroke. Urgent imaging after the stroke revealed changes on electrocardiography that were remarkable for left bundle branch block. The patient's elevated cardiac enzyme levels correlated with a silent acute myocardial infarction (MI). His echocardiogram revealed a left ventricular (LV) thrombus. He was managed with a multidisciplinary approach involving Neurology, Cardiology, and Medicine. CONCLUSIONS COVID-19-associated prothrombotic episodes involving arterial and venous systems have been reported in the literature. But concomitant stroke, acute MI, and LV thrombus rarely have been documented. The role of prophylactic or therapeutic anticoagulation is still unclear because even when patients are on these drugs, they continue to develop thrombotic episodes. Indeed, further studies are required to develop a standard management plan for what can be a fatal situation.

Ischaemic stroke as an initial presentation in patients with COVID-19: evaluation of a case series in an emergency in Brazil.

The disease caused by the new coronavirus, initially described in China in December 2019, became known as coronavirus disease 2019 and quickly spread to countries on all continents, becoming a pandemic with an important global impact. Despite being a virus that typically affects the respiratory tract, some studies have already described neurological manifestations associated with this infection, including acute ischaemic vascular insult. We report a case series including 30 patients, who presented with neurological symptoms during admission to our service, being diagnosed with ischaemic stroke and, concomitantly, coronavirus disease 2019. In the subgroup of patients analysed, a state of hypercoagulability and pro thrombosis was observed through laboratory tests, probably related to the cytokine storm syndrome associated with infection by this virus. With that, we discussed the possibility of this finding being an aggravating factor in the occurrence of stroke in these patients.

Viral protein R polymorphisms in the pathogenesis of HIV-associated acute ischaemic stroke: a case-control study.

HIV-1 viral proteins have been implicated in endothelial dysfunction, which is a major determinant of ischaemic stroke risk in HIV-infected individuals. Polymorphisms in HIV-1 viral protein R (Vpr) may alter its potential to promote endothelial dysfunction, by modifying its effects on viral replication, reactivation of latent cells, upregulation of pro-inflammatory cytokines and infection of macrophages. We analysed Vpr polymorphisms and their association with acute ischaemic stroke by comparing Vpr signature amino acids between 54 HIV-infected individuals with acute ischaemic stroke, and 80 age-matched HIV-infected non-stroke controls. Isoleucine at position 22 and serine at position 41 were associated with ischaemic stroke in HIV. Individuals with stroke had lower CD4 counts and CD4 nadirs than controls. These polymorphisms are unique to individuals with stroke compared to South African subtype C and the control group consensus sequences. Signature Vpr polymorphisms are associated with acute ischaemic stroke in HIV. These may increase stroke risk by promoting endothelial dysfunction and susceptibility to opportunistic infections. Therapeutic targeting of HIV-1 viral proteins may present an additional mechanism of decreasing stroke risk in HIV-infected individuals.

Sex Differences in Extrahepatic Outcomes After Antiviral Treatment for Hepatitis C.

INTRODUCTION: Despite recognized differences in the rates of cardiovascular and renal disease between men and women in the general population, studies of the downstream effects of antiviral treatment for hepatitis C (HCV) have not investigated differences in outcomes based on sex. We analyzed sex differences in risk of acute coronary syndrome (ACS), end-stage renal disease (ESRD), and ischemic stroke by treatment and response in a large US-based multisite cohort of HCV patients. METHODS: Observation started at the HCV diagnosis date (untreated) or last antiviral treatment start (treated). Treatment selection bias was addressed using an inverse probability-weighting approach. We estimated the effect of treatment on the cumulative incidence of outcomes using the Fine-Gray method (subdistribution hazard ratios [sHR] and 95% confidence intervals [95% CI]). Death was a competing risk. RESULTS: Roughly 40% of 15,295 HCV patients were women. After controlling for other risk factors, sustained virological response (SVR) (interferon-based [IFN] or direct-acting antiviral [DAA]) significantly reduced risk of all outcomes, particularly among female patients. Female patients who achieved SVR after IFN-based treatment had significantly lower risk of ACS compared with male patients with SVR from either treatment type (sHR 0.45 [95% CI 0.35-0.59] vs 0.81 [95% CI 0.69-0.96, for DAA SVR] and sHR 0.72 [95% 0.62, 0.85, for IFN SVR]). Successful treatment seemed to be most protective against ESRD; female patients who achieved SVR were at 66%-68% lower risk than untreated patients (sHR 0.32 [95% CI 0.17-0.60 for DAA SVR] and 0.34 [95% CI 0.20-0.58 for IFN SVR]), whereas men were at 38%-42% lower risk (sHR 0.62 [95% CI 0.46-0.85 for DAA SVR] and 0.58 [95% CI 0.43-0.76 for IFN SVR]). IFN treatment failure significantly increased risk of all outcomes by 50%-100% among female patients. Compared with no treatment, female patients who experienced IFN treatment failure were at 63% increased risk of ACS (sHR 1.63 [95% CI 1.35-1.96]), almost twice the risk of ESRD (sHR 1.95 [95% CI 1.43-2.66]) and 51% increased risk of stroke (sHR 1.49 [95%CI 1.11-2.00]). DISCUSSION: SVR reduced the risk of extrahepatic complications, particularly in females. The significantly increased risk associated with IFN TF in women-a subset who represented roughly 10% of that group-underscores the importance of prioritizing these patients for DAA treatment irrespective of the fibrosis stage.

Stroke etiologies in patients with COVID-19: the SVIN COVID-19 multinational registry.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) is associated with a small but clinically significant risk of stroke, the cause of which is frequently cryptogenic. In a large multinational cohort of consecutive COVID-19 patients with stroke, we evaluated clinical predictors of cryptogenic stroke, short-term functional outcomes and in-hospital mortality among patients according to stroke etiology. METHODS: We explored clinical characteristics and short-term outcomes of consecutively evaluated patients 18 years of age or older with acute ischemic stroke (AIS) and laboratory-confirmed COVID-19 from 31 hospitals in 4 countries (3/1/20-6/16/20). RESULTS: Of the 14.483 laboratory-confirmed patients with COVID-19, 156 (1.1%) were diagnosed with AIS. Sixty-one (39.4%) were female, 84 (67.2%) white, and 88 (61.5%) were between 60 and 79 years of age. The most frequently reported etiology of AIS was cryptogenic (55/129, 42.6%), which was associated with significantly higher white blood cell count, c-reactive protein, and D-dimer levels than non-cryptogenic AIS patients (p

Ischemic stroke and purpuric dermatitis as COVID-19-related complications in a peritoneal dialysis patient.

Patients on dialysis may have an elevated risk of severe coronavirus disease 2019 (COVID-19) and its complications due to their high prevalence of comorbidities. Here we describe the case of an 80-year-old male undergoing peritoneal dialysis with a moderate SARS-CoV-2 infection who developed a purpuric dermatitis and ischemic stroke after successful recovery from his bilateral pneumonia. Erythemato-papular lesions affecting trunk and lower limbs appeared 17 days after the onset of SARS-CoV-2 symptoms. These kind of lesions are an infrequent cutaneous manifestation of COVID-19. The pathology revealed a moderate purpuric dermatitis affecting superficial dermis and corticoesteroids were prescribed achieving complete resolution. Arterial thrombosis affecting cerebellar vermis emerged 30 days after the onset of COVID-19 symptoms. It occurred 5 days after withdrawal of antithrombotic prophylaxis that the patient received from his admission until 2 weeks after discharge. He completely recovered from his paresis and continued on his regular antiaggregation therapy. This is the first case report published of a patient with PD with such COVID-19-related complications. More experience is needed to determine the appropriate length of antithrombotic prophylaxis especially in high-risk individuals.