Intracranial hemorrhage in COVID-19 patients during extracorporeal membrane oxygenation for acute respiratory failure: a nationwide register study report.

BACKGROUND: In severe cases, SARS-CoV-2 infection leads to acute respiratory distress syndrome (ARDS), often treated by extracorporeal membrane oxygenation (ECMO). During ECMO therapy, anticoagulation is crucial to prevent device-associated thrombosis and device failure, however, it is associated with bleeding complications. In COVID-19, additional pathologies, such as endotheliitis, may further increase the risk of bleeding complications. To assess the frequency of bleeding events, we analyzed data from the German COVID-19 autopsy registry (DeRegCOVID). METHODS: The electronic registry uses a web-based electronic case report form. In November 2021, the registry included N = 1129 confirmed COVID-19 autopsy cases, with data on 63 ECMO autopsy cases and 1066 non-ECMO autopsy cases, contributed from 29 German sites. FINDINGS: The registry data showed that ECMO was used in younger male patients and bleeding events occurred much more frequently in ECMO cases compared to non-ECMO cases (56% and 9%, respectively). Similarly, intracranial bleeding (ICB) was documented in 21% of ECMO cases and 3% of non-ECMO cases and was classified as the immediate or underlying cause of death in 78% of ECMO cases and 37% of non-ECMO cases. In ECMO cases, the three most common immediate causes of death were multi-organ failure, ARDS and ICB, and in non-ECMO cases ARDS, multi-organ failure and pulmonary bacterial ± fungal superinfection, ordered by descending frequency. INTERPRETATION: Our study suggests the potential value of autopsies and a joint interdisciplinary multicenter (national) approach in addressing fatal complications in COVID-19.

Tectal Hemorrhage in the Setting of COVID-19 Infection.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has emerging evidence of a relationship to intracranial hemorrhage. The hemorrhages described to date often affect patients on anticoagulation, of advanced age, of nonwhite race, and requiring mechanical ventilation. Unusual or rare hemorrhage patterns have not as yet been described in the literature as being associated with COVID-19. CASE REPORT: A 36-year-old Hispanic male with no significant past medical history presented with isolated tectal intraparenchymal hemorrhage with intraventricular hemorrhage in the setting of no identifiable risk factors other than COVID-19. His management required temporizing with external ventricular drainage and subsequent endoscopic third ventriculostomy for ongoing obstruction of the cerebral aqueduct following the hemorrhage. He was discharged and did clinically well. To our knowledge, this is the first report of an intraparenchymal hematoma of the brain isolated to the midbrain tectum with only COVID-19 as a risk factor. CONCLUSION: COVID-19 may predispose patients to rare types of intraparenchymal hematomas which remain amenable to standard management algorithms.

Posterior Reversible Encephalopathy Syndrome and brain haemorrhage as COVID-19 complication: a review of the available literature.

BACKGROUND: SARS-CoV-2 infection has been associated with various neurological manifestations. Since patients affected by SARS-CoV-2 infection present coagulation and immune system dysregulation, ischemic or haemorragic stroke is not uncommon, irrespective of respiratory distress. However, the occurrence of focal neurological deficits together with other symptoms like headache, cortical blindness, seizure and altered mental status should prompt the diagnosis of Posterior Reversible Encephalopathy Syndrome (PRES). Antithrombotic treatment, the alteration of endothelial function, and coagulopathy due to COVID-19 and PRES leading to the breakdown of blood-brain barrier may then contribute to the occurrence of a brain haemorrhage. METHODS: We describe the case of a COVID-19 patient who developed bilateral occipital lobe haemorrhages suggestive of haemorrhagic PRES. We then reviewed the available literature about haemorrhagic evolution of PRES in COVID-19. RESULTS: We describe the clinical and radiological features of five COVID-19 patients who developed haemorrhagic PRES. CONCLUSIONS: Coagulopathy and endothelial dysfunction resulting from the massive release of cytokines during the host immune response may be key factors in the pathogenesis of COVID-19-related PRES. Antithrombotic therapy and the leakage of the blood-brain barrier can subsequently increase the risk of haemorrhagic transformation of the lesioned brain tissue. A prompt diagnosis of PRES is mandatory, since the timely interruption/reversal of antithrombotic therapy may be a key determinant for a good prognosis.

SARS-CoV-2 and Stroke Characteristics: A Report From the Multinational COVID-19 Stroke Study Group.

[Figure: see text].

A Comparison of Thrombosis and Hemorrhage Rates in Patients With Severe Respiratory Failure Due to Coronavirus Disease 2019 and Influenza Requiring Extracorporeal Membrane Oxygenation.

OBJECTIVES: Extracorporeal membrane oxygenation is a lifesaving therapy for patients with severe acute respiratory distress syndrome refractory to conventional mechanical ventilation. It is frequently complicated by both thrombosis and hemorrhage. A markedly prothrombotic state associated with high rates of venous thromboembolism has been described in patients with severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019) infection. These rates have currently not been described during extracorporeal membrane oxygenation in comparison to other viral pneumonias. DESIGN: Retrospective observational study. SETTING: Single high-volume tertiary critical care department at a university hospital. PATIENTS: Patients 16 years old or greater receiving venovenous extracorporeal membrane oxygenation between March 1, 2020, and May 31, 2020, with coronavirus disease 2019 were compared with a cohort of patients with influenza pneumonia between June 1, 2012, and May 31, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The rates of venous thromboembolism and hemorrhage were compared in patients with coronavirus disease 2019 against a historic population of patients with influenza pneumonia who required extracorporeal membrane oxygenation. There were 51 patients who received extracorporeal membrane oxygenation due to coronavirus disease 2019 and 80 patients with influenza. At cannulation for extracorporeal membrane oxygenation, 37% of patients with coronavirus disease 2019 compared with 8% of patients with influenza had filling defects on CT pulmonary angiography (p = 0.0001). Catheter-associated deep vein thrombosis shown on ultrasound Doppler after decannulation was present in 53% with coronavirus disease 2019 versus 25% with influenza (p = 0.01). The rates of intracranial hemorrhage at the time of cannulation were 16% with coronavirus disease 2019 and 14% with influenza (p = 0.8). Elevated d-dimer levels were seen in both conditions and were significantly higher in those with pulmonary thromboembolism than those without in coronavirus disease 2019 (p = 0.02). Fibrinogen and C-reactive protein levels were significantly higher in those with coronavirus disease 2019 than influenza (p < 0.01). CONCLUSIONS: Significant rates of pulmonary thromboembolism and of catheter-associated deep vein thrombosis were seen in both viral infections but were greater in those requiring the use of extracorporeal membrane oxygenation in coronavirus disease 2019 than for influenza.

COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital.

Many patients with SARS-CoV-2 infection develop neurological signs and symptoms; although, to date, little evidence exists that primary infection of the brain is a significant contributing factor. We present the clinical, neuropathological and molecular findings of 41 consecutive patients with SARS-CoV-2 infections who died and underwent autopsy in our medical centre. The mean age was 74 years (38-97 years), 27 patients (66%) were male and 34 (83%) were of Hispanic/Latinx ethnicity. Twenty-four patients (59%) were admitted to the intensive care unit. Hospital-associated complications were common, including eight patients (20%) with deep vein thrombosis/pulmonary embolism, seven (17%) with acute kidney injury requiring dialysis and 10 (24%) with positive blood cultures during admission. Eight (20%) patients died within 24 h of hospital admission, while 11 (27%) died more than 4 weeks after hospital admission. Neuropathological examination of 20-30 areas from each brain revealed hypoxic/ischaemic changes in all brains, both global and focal; large and small infarcts, many of which appeared haemorrhagic; and microglial activation with microglial nodules accompanied by neuronophagia, most prominently in the brainstem. We observed sparse T lymphocyte accumulation in either perivascular regions or in the brain parenchyma. Many brains contained atherosclerosis of large arteries and arteriolosclerosis, although none showed evidence of vasculitis. Eighteen patients (44%) exhibited pathologies of neurodegenerative diseases, which was not unexpected given the age range of our patients. We examined multiple fresh frozen and fixed tissues from 28 brains for the presence of viral RNA and protein, using quantitative reverse-transcriptase PCR, RNAscope® and immunocytochemistry with primers, probes and antibodies directed against the spike and nucleocapsid regions. The PCR analysis revealed low to very low, but detectable, viral RNA levels in the majority of brains, although they were far lower than those in the nasal epithelia. RNAscope® and immunocytochemistry failed to detect viral RNA or protein in brains. Our findings indicate that the levels of detectable virus in coronavirus disease 2019 brains are very low and do not correlate with the histopathological alterations. These findings suggest that microglial activation, microglial nodules and neuronophagia, observed in the majority of brains, do not result from direct viral infection of brain parenchyma, but more likely from systemic inflammation, perhaps with synergistic contribution from hypoxia/ischaemia. Further studies are needed to define whether these pathologies, if present in patients who survive coronavirus disease 2019, might contribute to chronic neurological problems.

Clinical characteristics and admission patterns of stroke patients during the COVID 19 pandemic: A single center retrospective, observational study from the Abu Dhabi, United Arab Emirates.

OBJECTIVE: To compare ischemic and hemorrhagic stroke patients with COVID-19 to non-COVID-19 controls, and to describe changes in stroke admission patterns during the pandemic. METHODS: This is a single center, retrospective, observational study. All consecutive patients admitted with primary diagnosis of ischemic/ hemorrhagic stroke between March1st -May10th 2020 were included and compared with the same time period in 2019. RESULTS: There was a 41.9% increase in stroke admissions in 2020 (148 vs 210,P = .001). When comparing all ischemic strokes, higher rate of large vessel occlusion (LVO) (18.3% vs 33.8%,P = .008) and significant delay in initiation of mechanical thrombectomy after hospital arrival (67.75 vs 104.30 minutes,P = .001) was observed in 2020. When comparing all hemorrhagic strokes, there were no differences between the two years. Among 591 COVID-19 admissions, 31 (5.24%) patients with stroke including 19 with ischemic (3.21%) and 12 with hemorrhagic stroke (2.03%) were identified. Patients with COVID-19 and ischemic stroke were significantly younger (58.74 vs 48.11 years,P = .002), predominantly male (68.18% vs 94.74%,P = .016), had lesser vascular risk factors, had more severe clinical presentation (NIHSS 7.01 vs 17.05,P < .001), and higher rate of LVO (23.6% vs. 63.1%,P = .006). There was no difference in the rate of endovascular thrombectomy, but time to groin puncture was significantly longer in COVID-19 patients (83.41 vs 129.50 minutes,P = .003). For hemorrhagic stroke, COVID-19 patients did not differ from non-COVID-19 patients. CONCLUSIONS: Stroke continues to occur during this pandemic and stroke pathways have been affected by the pandemic. Stroke occurs in approximately 5% of patients with COVID-19. COVID-19 associated ischemic stroke occurs in predominantly male patients who are younger, with fewer vascular risk factors, can be more severe, and have higher rates of LVO. Despite an increase in LVO during the pandemic, treatment with mechanical thrombectomy has not increased. COVID-19 associated hemorrhagic stroke does not differ from non-COVID-19 hemorrhagic stroke patients.

Changes in Characteristics, Treatment and Outcome in Patients with Hemorrhagic Stroke During COVID-19.

BACKGROUND AND PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has had a comprehensive impact on healthcare services worldwide. We sought to determine whether COVID-19 affected the treatment and prognosis of hemorrhagic stroke in a regional medical center in mainland China. METHODS: Patients with hemorrhagic stroke admitted in the Neurosurgery Department of West China Hospital from January 24, 2020, to March 25, 2020 (COVID-19 period), and from January 24, 2019, to March 25, 2019 (pre-COVID-19 period), were identified. Clinical characteristics, hospital arrival to neurosurgery department arrival time (door-to-department time), reporting rate of pneumonia and 3-month mRS (outcome) were compared. RESULTS: A total of 224 patients in the pre-COVID-19 period were compared with 126 patients in the COVID-19 period. Milder stroke severity was observed in the COVID-19 period (NIHSS 6 [2-20] vs. 3 [2-15], p = 0.005). The median door-to-department time in the COVID-19 period was approximately 50 minutes longer than that in the pre-COVID-19 period (96.5 [70.3-193.3] vs. 144.5 [93.8-504.5], p = 0.000). A higher rate of pneumonia complications was reported in the COVID-19 period (40.6% vs. 60.7%, p = 0.000). In patients with moderate hemorrhagic stroke, the percentage of good outcomes (mRS < 3) in the pre-COVID-19 period was much higher than that in the COVID-19 period (53.1% vs. 26.3%, p = 0.047). CONCLUSIONS: COVID-19 may have several impacts on the treatment of hemorrhagic stroke and may influence the clinical outcomes of specific patients. Improvements in the treatment process for patients with moderate stroke may help to improve the overall outcome of hemorrhagic stroke during COVID-19.

Neuronophagia and microglial nodules in a SARS-CoV-2 patient with cerebellar hemorrhage.

We document the neuropathologic findings of a 73-year old man who died from acute cerebellar hemorrhage in the context of relatively mild SARS-CoV2 infection. The patient developed sudden onset of headache, nausea, and vomiting, immediately followed by loss of consciousness on the day of admission. Emergency medical services found him severely hypoxemic at home, and the patient suffered a cardiac arrest during transport to the emergency department. The emergency team achieved return of spontaneous circulation after over 17 min of resuscitation. A chest radiograph revealed hazy bilateral opacities; and real-time-PCR for SARS-CoV-2 on the nasopharyngeal swab was positive. Computed tomography of the head showed a large right cerebellar hemorrhage, with tonsillar herniation and intraventricular hemorrhage. One day after presentation, he was transitioned to comfort care and died shortly after palliative extubation. Autopsy performed 3 h after death showed cerebellar hemorrhage and acute infarcts in the dorsal pons and medulla. Remarkably, there were microglial nodules and neuronophagia bilaterally in the inferior olives and multifocally in the cerebellar dentate nuclei. This constellation of findings has not been reported thus far in the context of SARS-CoV-2 infection.

Cerebrovascular Complications of COVID-19.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) evolved quickly into a global pandemic with myriad systemic complications, including stroke. We report the largest case series to date of cerebrovascular complications of COVID-19 and compare with stroke patients without infection. METHODS: Retrospective case series of COVID-19 patients with imaging-confirmed stroke, treated at 11 hospitals in New York, between March 14 and April 26, 2020. Demographic, clinical, laboratory, imaging, and outcome data were collected, and cases were compared with date-matched controls without COVID-19 from 1 year prior. RESULTS: Eighty-six COVID-19-positive stroke cases were identified (mean age, 67.4 years; 44.2% women). Ischemic stroke (83.7%) and nonfocal neurological presentations (67.4%) predominated, commonly involving multivascular distributions (45.8%) with associated hemorrhage (20.8%). Compared with controls (n=499), COVID-19 was associated with in-hospital stroke onset (47.7% versus 5.0%; P<0.001), mortality (29.1% versus 9.0%; P<0.001), and Black/multiracial race (58.1% versus 36.9%; P=0.001). COVID-19 was the strongest independent risk factor for in-hospital stroke (odds ratio, 20.9 [95% CI, 10.4-42.2]; P<0.001), whereas COVID-19, older age, and intracranial hemorrhage independently predicted mortality. CONCLUSIONS: COVID-19 is an independent risk factor for stroke in hospitalized patients and mortality, and stroke presentations are frequently atypical.

Acute Cerebrovascular Events in Hospitalized COVID-19 Patients.

BACKGROUND AND PURPOSE: Initial reports suggest a significant risk of thrombotic events, including stroke, in patients hospitalized with coronavirus disease 2019 (COVID-19). However, there is little systematic data on stroke incidence and mechanisms, particularly in racially diverse populations in the United States. METHODS: We performed a retrospective, observational study of stroke incidence and mechanisms in all patients with COVID-19 hospitalized from March 15 to May 3, 2020, at 3 Philadelphia hospitals. RESULTS: We identified 844 hospitalized patients with COVID-19 (mean age 59 years, 52% female, 68% Black); 20 (2.4%) had confirmed ischemic stroke; and 8 (0.9%) had intracranial hemorrhage. Of the ischemic stroke patients, mean age was 64 years, with only one patient (5%) under age 50, and 80% were Black. Conventional vascular risk factors were common, with 95% of patients having a history of hypertension and 60% a history of diabetes mellitus. Median time from onset of COVID symptoms to stroke diagnosis was 21 days. Stroke mechanism was cardioembolism in 40%, small vessel disease in 5%, other determined mechanism in 20%, and cryptogenic in 35%. Of the 11 patients with complete vascular imaging, 3 (27%) had large vessel occlusion. Newly positive antiphospholipid antibodies were present in >75% of tested patients. Of the patients with intracranial hemorrhage, 5/8 (63%) were lobar intraparenchymal hemorrhages, and 3/8 (38%) were subarachnoid hemorrhage; 4/8 (50%) were on extracorporeal membrane oxygenation. CONCLUSIONS: We found a low risk of acute cerebrovascular events in patients hospitalized with COVID-19. Most patients with ischemic stroke had conventional vascular risk factors, and traditional stroke mechanisms were common.