Prevalence of acute neurological complications and pathological neuroimaging findings in critically ill COVID-19 patients with and without VV-ECMO treatment.

Acute brain injuries such as intracerebral hemorrhage (ICH) and ischemic stroke have been reported in critically ill COVID-19 patients as well as in patients treated with veno-venous (VV)-ECMO independently of their COVID-19 status. The purpose of this study was to compare critically ill COVID-19 patients with and without VV-ECMO treatment with regard to acute neurological symptoms, pathological neuroimaging findings (PNIF) and long-term deficits. The single center study was conducted in critically ill COVID-19 patients between February 1, 2020 and June 30, 2021. Demographic, clinical and laboratory parameters were extracted from the hospital's databases. Retrospective imaging modalities included head computed tomography (CT) and magnetic resonance imaging (MRI). Follow-up MRI and neurological examinations were performed on survivors > 6 months after the primary occurrence. Of the 440 patients, 67 patients received VV-ECMO treatment (15%). Sixty-four patients (24 with VV-ECMO) developed acute neurological symptoms (pathological levels of arousal/brain stem function/motor responses) during their ICU stay and underwent neuroimaging with brain CT as the primary modality. Critically ill COVID-19 patients who received VV-ECMO treatment had a significantly lower survival during their hospital stay compared to those without (p < 0.001). Among patients treated with VV-ECMO, 10% showed acute PNIF in one of the imaging modalities during their ICU stay (vs. 4% of patients in the overall COVID-19 ICU cohort). Furthermore, 9% showed primary or secondary ICH of any severity (vs. 3% overall), 6% exhibited severe ICH (vs. 1% overall) and 1.5% were found to have non-hemorrhagic cerebral infarctions (vs. < 1% overall). There was a weak, positive correlation between patients treated with VV-ECMO and the development of acute neurological symptoms. However, the association between the VV-ECMO treatment and acute PNIF was negligible. Two survivors (one with VV-ECMO-treatment/one without) showed innumerable microhemorrhages, predominantly involving the juxtacortical white matter. None of the survivors exhibited diffuse leukoencephalopathy. Every seventh COVID-19 patient developed acute neurological symptoms during their ICU stay, but only every twenty-fifth patient had PNIF which were mostly ICH. VV-ECMO was found to be a weak risk factor for neurological complications (resulting in a higher imaging rate), but not for PNIF. Although logistically complex, repeated neuroimaging should, thus, be considered in all critically ill COVID-19 patients since ICH may have an impact on the treatment decisions and outcomes.

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.

Imaging features and ultraearly hematoma growth in intracerebral hemorrhage associated with COVID-19.

PURPOSE: Intracerebral hemorrhage (ICH) is an uncommon but deadly event in patients with COVID-19 and its imaging features remain poorly characterized. We aimed to describe the clinical and imaging features of COVID-19-associated ICH. METHODS: Multicenter, retrospective, case-control analysis comparing ICH in COVID-19 patients (COV19 +) versus controls without COVID-19 (COV19 -). Clinical presentation, laboratory markers, and severity of COVID-19 disease were recorded. Non-contrast computed tomography (NCCT) markers (intrahematoma hypodensity, heterogeneous density, blend sign, irregular shape fluid level), ICH location, and hematoma volume (ABC/2 method) were analyzed. The outcome of interest was ultraearly hematoma growth (uHG) (defined as NCCT baseline ICH volume/onset-to-imaging time), whose predictors were explored with multivariable linear regression. RESULTS: A total of 33 COV19 + patients and 321 COV19 - controls with ICH were included. Demographic characteristics and vascular risk factors were similar in the two groups. Multifocal ICH and NCCT markers were significantly more common in the COV19 + population. uHG was significantly higher among COV19 + patients (median 6.2 mL/h vs 3.1 mL/h, p = 0.027), and this finding remained significant after adjustment for confounding factors (systolic blood pressure, antiplatelet and anticoagulant therapy), in linear regression (B(SE) = 0.31 (0.11), p = 0.005). This association remained consistent also after the exclusion of patients under anticoagulant treatment (B(SE) = 0.29 (0.13), p = 0.026). CONCLUSIONS: ICH in COV19 + patients has distinct NCCT imaging features and a higher speed of bleeding. This association is not mediated by antithrombotic therapy and deserves further research to characterize the underlying biological mechanisms.

Fatal cerebral haemorrhage after COVID-19 vaccine. / Fatal hjerneblødning etter covid-19-vaksine.

BACKGROUND: New vaccines against COVID-19 are being rolled out globally. AstraZeneca's vaccine ChAdOx1 nCoV-19 was not known to cause vaccine-induced immune thrombotic thrombocytopenia (VITT) at the time of this case. CASE PRESENTATION: The patient was a previously healthy woman in her thirties with headaches that developed one week after vaccination with ChAdOx1 nCoV-19. Three days later, her condition deteriorated rapidly, and she presented to the emergency department with slurred speech, uncoordinated movements and reduced consciousness. Symptoms progressed to left-sided hemiparesis and her level of consciousness deteriorated. Computed tomography (CT) of the head showed a large right-sided haemorrhage and incipient herniation. She was found to have severe thrombocytopenia 37 x 109/l, (ref 145 - 390 x 109/l). In spite of efforts to reduce intracranial pressure, the patient died the following day. Post mortem examination revealed antibodies to PF4, and fresh small thrombi were found in the transverse sinus, frontal lobe and pulmonary artery. INTERPRETATION: Severe thrombocytopenia and antibodies to PF4 make a diagnosis of vaccine-induced immune thrombotic thrombocytopenia (VITT) likely.

COVID-19-related diffuse leukoencephalopathy with microbleeds and persistent coma: a case report with good clinical outcome.

A 60-year-old patient presented with respiratory distress, after recently being tested COVID-19 positive and was mechanically ventilated for 15 days. After cessation of sedation, he remained in deep comatose state, without any reaction on pain stimuli (Glasgow Coma Score 3). MRI of the brain showed diffuse leukoencephalopathy and multiple (>50) microbleeds. Diffuse COVID-19-associated leukoencephalopathy with microhaemorrhages is associated with a poor prognosis. However, 3 months later, our patient showed a remarkable recovery and was able to walk independently. This case report shows COVID-related leukoencephalopathy and intracerebral microbleeds, even with persistent comatose state, may have a favourable clinical outcome and prolonged treatment should be considered in individual cases.

Intracerebral hemorrhage in COVID-19: A narrative review.

Coronavirus Disease 19 (COVID-19) pandemic affects the worldwide healthcare system and our understanding of this disease grows rapidly. Although COVID-19 is a mainly respiratory disease, neurological manifestations are not uncommon. The aim of this review is to report on the etiology, clinical profile, location, and outcome of patients with intracerebral hemorrhage (ICH) and COVID-19. This review includes 36 studies examining ICH in the clinical presentation of COVID-19. Overall, 217 cases with intracranial hemorrhage, of which 188 ICHs, were reported. Generally, a low incidence of both primary and secondary ICH was found in 8 studies [106 (0.25%) out of 43,137 hospitalized patients with COVID-19]. Available data showed a median age of 58 years (range: 52-68) and male sex 64%, regarding 36 and 102 patients respectively. Furthermore, 75% of the patients were on prior anticoagulation treatment, 52% had a history of arterial hypertension, and 61% were admitted in intensive care unit. Location of ICH in deep structures/basal ganglia was ascertained in only 7 cases making arterial hypertension an improbable etiopathogenetic mechanism. Mortality was calculated at 52.7%. Disease related pathophysiologic mechanisms support the hypothesis that SARS-CoV2 can cause ICH, however typical ICH risk factors such as anticoagulation treatment, or admission to ICU should also be considered as probable causes. Physicians should strongly suspect the possibility of ICH in individuals with severe COVID-19 admitted to ICU and treated with anticoagulants. It is not clear whether ICH is related directly to COVID-19 or reflects expected comorbidity and/or complications observed in severely ill patients.

Early postmortem brain MRI findings in COVID-19 non-survivors.

OBJECTIVES: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is considered to have potential neuroinvasiveness that might lead to acute brain disorders or contribute to respiratory distress in patients with coronavirus disease 2019 (COVID-19). This study investigates the occurrence of structural brain abnormalities in non-survivors of COVID-19 in a virtopsy framework. METHODS: In this prospective, monocentric, case series study, consecutive patients who fulfilled the following inclusion criteria benefited from an early postmortem structural brain MRI: death <24 hours, SARS-CoV-2 detection on nasopharyngeal swab specimen, chest CT scan suggestive of COVID-19, absence of known focal brain lesion, and MRI compatibility. RESULTS: Among the 62 patients who died of COVID-19 from March 31, 2020, to April 24, 2020, at our institution, 19 decedents fulfilled the inclusion criteria. Parenchymal brain abnormalities were observed in 4 decedents: subcortical microbleeds and macrobleeds (2 decedents), cortico-subcortical edematous changes evocative of posterior reversible encephalopathy syndrome (PRES; 1 decedent), and nonspecific deep white matter changes (1 decedent). Asymmetric olfactory bulbs were found in 4 other decedents without downstream olfactory tract abnormalities. No brainstem MRI signal abnormality was observed. CONCLUSIONS: Postmortem brain MRI demonstrates hemorrhagic and PRES-related brain lesions in non-survivors of COVID-19. SARS-CoV-2-related olfactory impairment seems to be limited to olfactory bulbs. Brainstem MRI findings do not support a brain-related contribution to respiratory distress in COVID-19.

Cerebral hemorrhage during the active phase of SARS-CoV-2 infection in a patient with amyloid angiopathy: case report. / Hemorragia cerebral durante fase ativa de infecção por SARS-CoV-2 em paciente com angiopatia amiloide: relato de caso.

The neurological changes associated with COVID-19 have been frequently described, especially in cases of greater severity, and are related to multifactorial causes, such as endothelial dysfunction, inflammatory mediator release (cytokine storm), endothelial dysfunction and hypoxemia. We report the case of a female patient, 88 years old, with cerebral hemorrhage associated with amyloid angiopathy in the context of SARS-CoV-2 infection.

As alterações neurológicas associadas à COVID-19 têm sido frequentemente descritas, principalmente nos casos de maior severidade, e estão relacionadas a causas multifatoriais, como a disfunção endotelial, a liberação de mediadores inflamatórios (cytokine storm), a disfunção endotelial e a hipoxemia. Relatamos o caso de uma paciente do sexo feminino, 88 anos, com quadro de hemorragia cerebral associada à angiopatia amiloide, no contexto de infecção por SARS-CoV-2.

Cerebrovascular disease in patients with COVID-19: neuroimaging, histological and clinical description.

Since the appearance of the first case of coronavirus disease 2019 (COVID-19) a pandemic has emerged affecting millions of individuals worldwide. Although the main clinical manifestations are respiratory, an increase in neurological conditions, specifically acute cerebrovascular disease, has been detected. We present cerebrovascular disease case incidence in hospitalized patients with SARS-CoV-2 infection. Patients were confirmed by microbiological/serological testing, or on chest CT semiology. Available data on co-morbidity, laboratory parameters, treatment administered, neuroimaging, neuropathological studies and clinical evolution during hospitalization, measured by the modified Rankin scale, were analysed. A bivariate study was also designed to identify differences between ischaemic and haemorrhagic subtypes. A statistical model of binary logistic regression and sensitivity analysis was designed to study the influence of independent variables over prognosis. In our centre, there were 1683 admissions of patients with COVID-19 over 50 days, of which 23 (1.4%) developed cerebrovascular disease. Within this group of patients, cerebral and chest CT scans were performed in all cases, and MRI in six (26.1%). Histological samples were obtained in 6/23 cases (two brain biopsies, and four arterial thrombi). Seventeen patients were classified as cerebral ischaemia (73.9%, with two arterial dissections), five as intracerebral haemorrhage (21.7%), and one leukoencephalopathy of posterior reversible encephalopathy type. Haemorrhagic patients had higher ferritin levels at the time of stroke (1554.3 versus 519.2, P = 0.004). Ischaemic strokes were unexpectedly frequent in the vertebrobasilar territory (6/17, 35.3%). In the haemorrhagic group, a characteristic radiological pattern was identified showing subarachnoid haemorrhage, parieto-occipital leukoencephalopathy, microbleeds and single or multiple focal haematomas. Brain biopsies performed showed signs of thrombotic microangiopathy and endothelial injury, with no evidence of vasculitis or necrotizing encephalitis. The functional prognosis during the hospital period was unfavourable in 73.9% (17/23 modified Rankin scale 4-6), and age was the main predictive variable (odds ratio = 1.5; 95% confidence interval 1.012-2.225; P = 0.043). Our series shows cerebrovascular disease incidence of 1.4% in patients with COVID-19 with high morbidity and mortality. We describe pathological and radiological data consistent with thrombotic microangiopathy caused by endotheliopathy with a haemorrhagic predisposition.

Large and Small Cerebral Vessel Involvement in Severe COVID-19: Detailed Clinical Workup of a Case Series.

BACKGROUND AND PURPOSE: Case series indicating cerebrovascular disorders in coronavirus disease 2019 (COVID-19) have been published. Comprehensive workups, including clinical characteristics, laboratory, electroencephalography, neuroimaging, and cerebrospinal fluid findings, are needed to understand the mechanisms. METHODS: We evaluated 32 consecutive critically ill patients with COVID-19 treated at a tertiary care center from March 9 to April 3, 2020, for concomitant severe central nervous system involvement. Patients identified underwent computed tomography, magnetic resonance imaging, electroencephalography, cerebrospinal fluid analysis, and autopsy in case of death. RESULTS: Of 32 critically ill patients with COVID-19, 8 (25%) had severe central nervous system involvement. Two presented with lacunar ischemic stroke in the early phase and 6 with prolonged impaired consciousness after termination of analgosedation. In all but one with delayed wake-up, neuroimaging or autopsy showed multiple cerebral microbleeds, in 3 with additional subarachnoid hemorrhage and in 2 with additional small ischemic lesions. In 3 patients, intracranial vessel wall sequence magnetic resonance imaging was performed for the first time to our knowledge. All showed contrast enhancement of vessel walls in large cerebral arteries, suggesting vascular wall pathologies with an inflammatory component. Reverse transcription-polymerase chain reactions for SARS-CoV-2 in cerebrospinal fluid were all negative. No intrathecal SARS-CoV-2-specific IgG synthesis was detectable. CONCLUSIONS: Different mechanisms of cerebrovascular disorders might be involved in COVID-19. Acute ischemic stroke might occur early. In a later phase, microinfarctions and vessel wall contrast enhancement occur, indicating small and large cerebral vessels involvement. Central nervous system disorders associated with COVID-19 may lead to long-term disabilities. Mechanisms should be urgently investigated to develop neuroprotective strategies.

Superficial Cerebral Venous Thrombosis and Intracerebral Hematoma in a 48-Year-Old Man with SARS-CoV-2 Infection: A Case Report.

BACKGROUND Pandemic coronavirus disease 2019 (COVID-19) originated in Wuhan, China, and is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Severe respiratory symptoms are a hallmark of the disease, which may also include complications related to a hypercoagulable state and central nervous system involvement. These complications can occur during either the acute or the recovery phase. The cerebral involvement typically manifests as intracranial hypertension, intracerebral hemorrhage, diffuse encephalopathy, or cerebral venous thrombosis. The hemorrhagic form of cerebral venous thrombosis can be a diagnostic challenge and is treated by anticoagulation therapy, despite the existence of an intracerebral hemorrhage. This report describes a case of superficial cerebral venous thrombosis and intracerebral hematoma in a 48-year-old man weeks after recovering from the acute phase of SARSCoV-2 infection. CASE REPORT A 48-year-old man with a past medical history of SARS-CoV-2 infection confirmed by SARS-CoV-2 reverse-transcription polymerase chain reaction presented with left upper-limb numbness, weakness, and impaired positional sensorium. After initial stabilization, noncontrast computerized tomography and magnetic resonance imaging confirmed an intracerebral hemorrhage with underlying cerebral venous thrombosis. The patient was successfully treated with enoxaparin anticoagulation therapy, and symptoms improved over the following 12 days. CONCLUSIONS Central nervous system venous thrombosis is an atypical presentation of the hypercoagulable state primarily seen in younger patients, and it can occur in a delayed fashion after recovery from mild forms of COVID-19.

COVID-19-related diffuse posthypoxic leukoencephalopathy and microbleeds masquerades as acute necrotizing encephalopathy.

BACKGROUND: The complications of coronavirus disease 2019 (COVID-19), the clinical entity caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are not limited to the respiratory system. Leukoencephalopathy with microbleeds is increasingly seen in patients with COVID-19. New information is needed to delineate better the clinical implications of this infectious disease. CASE REPORT: A 46-year-old man with confirmed SARS-CoV-2 infection was admitted to the intensive care unit (ICU) with severe COVID-19. After transfer to the general wards, the patient was noted drowsy, disorientated, with slow thinking and speech. A brain MRI showed bilateral symmetrical hyperintense lesions in the deep and subcortical whiter matter, involving the splenium of the corpus callosum, as well as multiple microhemorrhages implicating the splenium and subcortical white matter. No contrast-enhanced lesions were observed in brain CT or MRI. CSF analysis showed no abnormalities, including a negative rtRT-PCR for SARS-CoV-2. An outpatient follow-up visit showed near-complete clinical recovery and resolution of the hyperintense lesions on MRI, without microbleeds change. CONCLUSION: We present the case of a survivor of severe COVID-19 who presented diffuse posthypoxic leukoencephalopathy, and microbleeds masquerading as acute necrotizing encephalopathy. We postulate that this kind of cerebral vasogenic edema with microbleeds could be the consequence of hypoxia, inflammation, the prothrombotic state and medical interventions such as mechanical ventilation and anticoagulation.

Fatal intracranial haemorrhage in a hypertensive patient with atrial fibrillation and coronavirus disease 2019.

We present a case of a fatal cerebral haemorrhage in an 82-year-old male patient with coronavirus disease 2019 (COVID-19), who was taking prophylactic oral anticoagulation because of atrial fibrillation (rivaroxaban 20 mg q.d. for two years). On admission, the patient was deeply comatose, mechanically ventilated, with tachycardia up to 150 bpm, high blood pressure >210/120 mmHg and a body temperature >39°C. A computed tomography scan of the head showed a large intracerebral haemorrhage located in the deep structures of the right hemisphere, with a mass effect and bleeding to the ventricles. Rivaroxaban was discontinued at admission. The patient tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but he did not have typical symptoms of pneumonia. In the following days, the patient's neurological condition did not improve, and a fever of up to 40°C and abnormal coagulation parameters remained resistant to pharmacotherapy. The patient developed multi-system organ failure and died on day 8. Here, we review the recent literature and discuss the possible association of SARS-CoV-2-mediated endothelial injury and cardiovascular disorders with cerebrovascular complications. We postulate that anti-inflammatory treatment in COVID-19 and the stabilisation of endothelium functions can be particularly important in patients with pre-existing cardiovascular conditions.

Critical illness-associated cerebral microbleeds for patients with severe COVID-19: etiologic hypotheses.

BACKGROUND AND PURPOSE: During the COVID-19 outbreak, the presence of extensive white matter microhemorrhages was detected by brain MRIs. The goal of this study was to investigate the origin of this atypical hemorrhagic complication. METHODS: Between March 17 and May 18, 2020, 80 patients with severe COVID-19 infections were admitted for acute respiratory distress syndrome to intensive care units at the University Hospitals of Strasbourg for whom a brain MRI for neurologic manifestations was performed. 19 patients (24%) with diffuse microhemorrhages were compared to 18 control patients with COVID-19 and normal brain MRI. RESULTS: The first hypothesis was hypoxemia. The latter seemed very likely since respiratory failure was longer and more pronounced in patients with microhemorrhages (prolonged endotracheal intubation (p = 0.0002), higher FiO2 (p = 0.03), increased use of extracorporeal membrane oxygenation (p = 0.04)). A relevant hypothesis, the role of microangiopathy, was also considered, since patients with microhemorrhages presented a higher increase of the D-Dimers (p = 0.01) and a tendency to more frequent thrombotic events (p = 0.12). Another hypothesis tested was the role of kidney failure, which was more severe in the group with diffuse microhemorrhages (higher creatinine level [median of 293 µmol/L versus 112 µmol/L, p = 0.04] and more dialysis were introduced in this group during ICU stay [12 versus 5 patients, p = 0.04]). CONCLUSIONS: Blood-brain barrier dysfunction secondary to hypoxemia and high concentration of uremic toxins seems to be the main mechanism leading to critical illness-associated cerebral microbleeds, and this complication remains to be frequently described in severe COVID-19 patients.

Cerebral microhaemorrhage in COVID-19: a critical illness related phenomenon?

BACKGROUND: Cerebral microhaemorrhages are increasingly being recognised as a complication of COVID-19. This observational retrospective study aims to further investigate the potential pathophysiology through assessing the pattern of microhaemorrhage and clinical characteristics of patients with COVID-19 and microhaemorrhage. By comparing with similar patterns of microhaemorrhage in other non-COVID-19 disease, this study aims to propose possible common pathogenic mechanisms. METHODS: A retrospective observational case series was performed identifying all patients with COVID-19 complicated by cerebral microhaemorrhage on MRI. The distribution and number of microhaemorrhages were recorded using the microbleed anatomical scale, and patients' baseline characteristics and salient test results were also recorded. RESULTS: Cerebral microhaemorrhages were noted to have a predilection for the corpus callosum, the juxtacortical white matter and brainstem. All patients had a preceding period of critical illness with respiratory failure and severe hypoxia necessitating intubation and mechanical ventilation. DISCUSSION: This study demonstrates a pattern of cerebral microhaemorrhage that is similar to the pattern reported in patients with non-COVID-19 related critical illness and other causes of severe hypoxia. This raises questions regarding whether microhaemorrhage occurs from endothelial dysfunction due the direct effect of SARS-CoV-2 infection or from the secondary effects of critical illness and hypoxia.