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.

Spontaneous Intracerebral Hemorrhage (ICH) associated with pregnancy and SARS-CoV-2 infection: a case report.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is predominately known as a respiratory disease associated with pneumonia, acute respiratory distress syndrome and multiorgan failure. However, extra-pulmonary complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are increasingly being recognized. In this regard, some studies implied the hemostatic and vascular involvements in patients with SARS-CoV-2 infection. CASE PRESENTATION: We describe a case of spontaneous Intracerebral Hemorrhage (ICH) in a pregnant patient with COVID-19 and history of cesarean section a week before the occurrence of ICH. The patient underwent emergent craniotomy with acceptable outcome. Hemorrhagic events, including ICH, may happen during COVID-19 infection with several possible mechanisms. CONCLUSION: COVID-19 patients, especially high-risk groups, are at a risk of intracranial hemorrhage. Therefore, close follow-up must be maintained and hemorrhagic events must be kept in mind in these cases.

Intracerebral Hemorrhage in COVID-19 Patients with Pulmonary Failure: A Propensity Score-Matched Registry Study.

BACKGROUND: Hypercoagulability in Coronavirus Disease 2019 (COVID-19) causes deep vein thrombosis and pulmonary embolism necessitating systemic anticoagulation. Case reports of intracerebral hemorrhages in ventilated COVID-19 patients warrant precaution. It is unclear, however, if COVID-19 patients with acute respiratory distress syndrome (ARDS) with or without veno-venous extracorporeal membrane oxygenation therapy (VV-ECMO) have more intracerebral hemorrhages (ICH) compared to other ARDS patients. METHODS: We conducted a retrospective observational single-center study enrolling all patients with ARDS from 01/2018 to 05/2020. PCR-positive SARS-CoV-2 patients with ARDS were allocated to the COVID-19 group. Propensity score matching was performed for age, VV-ECMO, and bleeding risk. RESULTS: A total of 163 patients with moderate or severe ARDS were identified, 47 (28.8%) in the COVID-19 group, and 116 (71.2%) in the non-COVID-19 group. In 63/163 cases (38.7%), VV-ECMO therapy was required. The ICU survival was 52.8%. COVID-19 patients were older, more often male, and exhibited a lower SOFA score, but the groups showed similar rates of VV-ECMO therapy. Treatments with antiplatelet agents (p = 0.043) and therapeutic anticoagulation (p = 0.028) were significantly more frequent in the COVID-19 patients. ICH was detected in 22 patients (13.5%) with no statistical difference between the groups (11.2 vs. 19.1% without and with SARS-CoV-2, respectively, p = 0.21). Propensity score matching confirmed similar rates of ICH in both groups (12.8 vs. 19.1% without and with SARS-CoV-2, respectively, p = 0.57), thus leveling out possible confounders. CONCLUSIONS: Intracerebral hemorrhage was detected in every tenth patient with ARDS. Despite statistically higher rates of antiplatelet therapy and therapeutic anticoagulation in COVID-19 patients, we found a similar rate of ICH in patients with ARDS due to COVID-19 compared to other causes of ARDS.

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.

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.

Intracerebral endotheliitis and microbleeds are neuropathological features of COVID-19.

Coronavirus disease 19 (COVID-19) is a rapidly evolving pandemic caused by the coronavirus Sars-CoV-2. Clinically manifest central nervous system symptoms have been described in COVID-19 patients and could be the consequence of commonly associated vascular pathology, but the detailed neuropathological sequelae remain largely unknown. A total of six cases, all positive for Sars-CoV-2, showed evidence of cerebral petechial hemorrhages and microthrombi at autopsy. Two out of six patients showed an elevated risk for disseminated intravascular coagulopathy according to current criteria and were excluded from further analysis. In the remaining four patients, the hemorrhages were most prominent at the grey and white matter junction of the neocortex, but were also found in the brainstem, deep grey matter structures and cerebellum. Two patients showed vascular intramural inflammatory infiltrates, consistent with Sars-CoV-2-associated endotheliitis, which was associated by elevated levels of the Sars-CoV-2 receptor ACE2 in the brain vasculature. Distribution and morphology of patchy brain microbleeds was clearly distinct from hypertension-related hemorrhage, critical illness-associated microbleeds and cerebral amyloid angiopathy, which was ruled out by immunohistochemistry. Cerebral microhemorrhages in COVID-19 patients could be a consequence of Sars- CoV-2-induced endotheliitis and more general vasculopathic changes and may correlate with an increased risk of vascular encephalopathy.

Coronavirus Disease 2019 Complicated by Multiple Simultaneous Intracerebral Hemorrhages.

The relationship between coronavirus disease 2019 (COVID-19) and intracerebral hemorrhage remains unclear. We herein report a case of severe COVID-19 pneumonia complicated by multiple simultaneous intracerebral hemorrhages (MSICH). The patient died eight days after the episode of MSICH. No apparent coagulopathy was observed; however, extracorporeal membrane oxygenation and anticoagulation might have caused the occurrence of MSICH. Laboratory findings showed hypercoagulability, suggesting that thrombotic etiologies, such as sinus thrombosis or cerebral infarction, might also have caused MSICH. MSICH can occur as a fatal complication of COVID-19, and this should be considered when providing treatment.

SARS-CoV-2-Associated Acute Hemorrhagic, Necrotizing Encephalitis (AHNE) Presenting with Cognitive Impairment in a 44-Year-Old Woman without Comorbidities: A Case Report.

BACKGROUND Acute hemorrhagic necrotizing encephalitis (AHNE) is a rare manifestation of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. AHNE usually involves the subcortical white matter but not the cortical grey matter. This study describes the disruptive effects of AHNE associated with SARS-CoV-2 on cognitive function in a previously healthy and sound middle-aged woman resulting from alterations in cortical areas involved in the cognitive network. CASE REPORT A 44-year-old previously healthy woman with a history of inter-state travel developed a flu-like illness, followed by acute, steadily progressive cognitive impairment. She was admitted in a comatose state after a first tonic-clonic seizure. Blood tests were non-informative. Cerebral magnetic resonance imaging (MRI) was indicative of AHNE. Cerebrospinal fluid analysis showed mild lymphocytosis with normal protein and normal glucose but an elevated IgG index. After testing positive for SARS-CoV-2, she was administered steroids. Treatment was ineffective, and the patient died. CONCLUSIONS SARS-CoV-2 is a potential central nervous system (CNS) pathogen, which may manifest as AHNE. These patients may present with generalized tonic-clonic seizures and frontal dysexecutive syndrome, with cognitive impairment being the presenting feature of neuro-coronavirus disease-2019 (COVID-19). The patient described in this report is unique for acute-onset and isolated cognitive impairments due to SARS-CoV-2 infection in the absence of clinical or radiological respiratory manifestations. These findings may help in the early detection and diagnosis of neuro-COVID-19, especially among clinicians and neurologists working in areas of endemic SARS-CoV-2 infection.

Intracranial hemorrhage in critically ill patients hospitalized for COVID-19.

In this study, we report three cases of spontaneous intracranial hemorrhage in patients who were initially hospitalized at our tertiary care center in Washington, DC with symptoms of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was diagnosed in all three patients, who were critically ill, requiring intubation and ventilatory support. During their protracted hospitalizations, subsequent imaging disclosed intracranial hemorrhages, including intracerebral and subarachnoid hemorrhages, in the context of anticoagulation and coagulopathy. We believe this is related to the tropism of SARS-CoV-2 to the endothelial lining of the cerebral vasculature via their angiotensin-converting enzyme (ACE) II receptors. Given our findings, we advocate heightened vigilance for intracerebral hemorrhage events, and scanning when practicable, in COVID-19 patients which have prolonged ventilatory support and depressed neurologic examinations.

Cerebral Microhemorrhage and Purpuric Rash in COVID-19: The Case for a Secondary Microangiopathy.

INTRODUCTION: Since the emergence of Coronavirus Disease 19 (COVID-19) pandemic, multiple neurologic complications in infected patients have been reported. Despite these reports, the mechanism of COVID-19 nervous system injury is not well understood. We report the case of a COVID-19 patient with diffuse microhemorrhages on brain MRI, positive anticardiolipin antibodies, and purpuric rash with biopsy showing a thrombotic vasculopathy, all features suggestive of secondary microangiopathy. CASE REPORT: A 69-year-old male with history of hypertension, chronic kidney disease, and hypothyroidism presented with one week of dyspnea, cough, diarrhea, and fevers. Chest x-ray demonstrated bibasilar consolidations and nasopharyngeal reverse transcriptase polymerase chain reaction confirmed SARS-CoV-2 infection. He had subsequent respiratory decline requiring intubation the day after admission. He developed a truncal morbilliform rash and diffuse purpura, a biopsy of which showed small dermal blood vessels with intraluminal microthrombi consistent with thrombotic vasculopathy. He was found to have elevated aCL IgM and IgG and equivocal lupus anticoagulant study. Brain MRI obtained for persistent encephalopathy showed innumerable areas of susceptibility weighted imaging changes throughout the bilateral juxtacortical white matter, corpus callosum, basal ganglia, and brainstem, as well as multiple small areas of FLAIR hyperintensities, consistent with microhemorrhage DISCUSSION: While there have been several reported cases of neurologic manifestations of COVID-19, the pathophysiology may not be related to neurotropism of the virus itself. The new development of antiphospholipid antibodies and thrombotic vasculopathy in dermal blood vessels in this patient suggest a secondary microangiopathy potentially related to a virally-induced inflammatory state.

Pathophysiology of SARS-CoV-2 infection in patients with intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is associated with old age and underlying conditions such as hypertension and diabetes. ICH patients are vulnerable to SARS-CoV-2 infection and develop serious complications as a result of infection. The pathophysiology of ICH patients with SARS-CoV-2 infection includes viral invasion, dysfunction of the ACE2-Ang (1-7)-MasR and ACE-Ang II-AT1R axes, overactive immune response, cytokine storm, and excessive oxidative stress. These patients have high morbidity and mortality due to hyaline membrane formation, respiratory failure, neurologic deficits, and multiple organ failure.

Potential mechanisms of hemorrhagic stroke in elderly COVID-19 patients.

The novel severe acute respiratory syndrome coronavirus 2 is the causative agent of coronavirus disease 2019, a new human infectious disease. While fever, cough, and respiratory distress are typical first symptoms, a fraction of those affected present instead with neurological symptoms suggestive of central nervous system compromise. This review summarizes the potential contribution of coronavirus disease 2019 to hemorrhagic stroke in the elderly and proposes possible mechanisms. Reports show that the most affected patients have underlying chronic diseases such as hypertension and diabetes, which are two key risk factors for hemorrhagic stroke. Angiotensin-converting enzyme 2 is the main host cell surface receptor interacting with the severe acute respiratory syndrome coronavirus 2 spike glycoprotein to allow viral entry and infection. We speculate that ensuing downregulation of angiotensin-converting enzyme 2 expression may compound the risk conferred by pre-existing comorbidities and critically influence the pathogenesis of hemorrhagic stroke by elevating blood pressure and impairing cerebrovascular endothelial function. Additionally, both age- and/or disease-related immune dysfunction and enhanced catecholamine release secondary to anxiety and stress may also aggravate central nervous system symptoms of severe acute respiratory syndrome coronavirus 2 infection. Thus, assessment of systemic inflammatory biomarkers and tight control of hemodynamic parameters upon admission are crucial to minimize mortality and morbidity in coronavirus disease 2019 patients with central nervous system symptoms suggestive of incipient stroke.